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Ortel, Thomas Lee

Overview:

My research program investigates the molecular mechanisms whereby various congenital and acquired abnormalities result in ‘dysfunctional’ hemostasis (i.e., hemorrhage or thrombosis) to better understand the molecular mechanisms and interactions that are necessary for normal hemostasis. We are particularly interested in the mechanisms whereby antibodies and other inhibitors can interfere with normal hemostatic mechanisms. Several projects extensively overlap and focus on the assembly and function of procoagulant (e.g., factor X-ase and prothrombinase) and anticoagulant (e.g., activated protein C complex) phospholipid membrane-dependent complexes.

We utilize a variety of approaches in these studies. Monoclonal antibodies, single-chain variable domain fragments, polyclonal antibodies prepared from patients with factor VIII inhibitors, and site-specific mutagenesis have all been used to characterize structure-function relationships in coagulation factor VIII. Our laboratory has also extensively characterized anti-factor V antibodies, investigating autoantibodies as well as xenogenic antibodies developing after exposure to topical bovine thrombin preparations which contain trace amounts of contaminating bovine factor V. We have also characterized how antiphospholipid antibodies interfere with the activated protein C complex, a lipid-dependent natural anticoagulant complex that proteolytically inactivates factor Va and factor VIIIa.

Our current studies are focusing on two antibody-mediated thrombotic syndromes, heparin-induced thrombocytopenia and antiphospholipid antibody syndrome. First, we are initiating a large clinical trial investigating the incidence of clinically-significant heparin-induced thrombocytopenia in patients who develop anti-heparin/platelet factor 4 antibodies following cardiac bypass procedures. While these antibodies are commonly seen following cardiac bypass, the true incidence of thromboembolic complications related to these prothrombotic antibodies remains unknown. We are also collaborating with investigators in the Center for Human Genetics on a large, multi-center study exploring the genetics of familial antiphospholipid antibody syndrome. In addition, we have used a genomic strategy to investigate patients with antiphospholipid antibody syndrome and have identified a gene expression profile that appears to be unique to patients with this syndrome in contrast to patients with venous thromboembolism who do not have these autoantibodies.

We also participate in a variety of collaborative research efforts, both with individual investigators as well as participating in multi-center clinical research studies. For example, we are one of seventeen centers participating in the NIH-supported Transfusion Medicine/Hemostasis Network, and we are currently conducting a trial through this network to define the optimal dose of platelets for patients needing platelet transfusions for hypoproliferative thrombocytopenia. We are also part of a multi-center registry of patients with thrombotic thrombocytopenic purpura, and we are one of eight centers in the Hemostasis and Thrombosis Center pilot program sponsored by the Centers for Disease Control and Prevention. Participation in these registries and networks provides us with access to the patient populations that we study in the research laboratory.

Positions:

Chief, Division of Hematology in the Department of Medicine

Medicine, Hematology
School of Medicine

Professor of Medicine

Medicine, Hematology
School of Medicine

Professor of Pathology

Pathology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 1983

Ph.D. — Indiana University at Bloomington

M.D. 1985

M.D. — Indiana University at Indianapolis

Medical Resident, Medicine

Duke University

Fellow In Hematology Oncology, Medicineq

Duke University

News:

Grants:

Postdoctoral training in genomic medicine research

Administered By
Duke Center for Applied Genomics and Precision Medicine
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
June 14, 2017
End Date
May 31, 2022

Transfusion Medicine and Hematology

Administered By
Medicine, Hematology
AwardedBy
National Institutes of Health
Role
Preceptor
Start Date
July 01, 1975
End Date
June 30, 2021

A Whole Blood Collection from subjects clinicially diagnosed with PNH

Administered By
Medicine, Hematology
AwardedBy
Discovery Life Sciences, Inc.
Role
Principal Investigator
Start Date
February 01, 2015
End Date
January 31, 2020

A Phase I/II Open-Label Safety and Dose-Finding Study of Adeno- Associated Virus (AAV) rh10-Mediated Gene Transfer of Human Factor IX in Adults With Moderate/Severe to Severe Hemophilia B

Administered By
Medicine, Hematology
AwardedBy
Dimension Therapeutics, Inc.
Role
Principal Investigator
Start Date
October 10, 2016
End Date
October 09, 2018

Defining the role of therapeutic plasma exchange in heparin induced thrombocytopenia

Administered By
Medicine, Hematology
AwardedBy
Hemophilia & Thrombosis Research Society
Role
Co-Mentor
Start Date
October 01, 2017
End Date
September 30, 2018

U.S. External Site Protocol for Evaluation of Precision Performances of STA-THROMBIN ON STA-SATELLITE

Administered By
Medicine, Hematology
AwardedBy
Diagnostica Stago
Role
Principal Investigator
Start Date
July 21, 2017
End Date
July 31, 2018

External Evaluation of Assay Applications on The Sysmex CS2500 and CS-5100 Analyzer (Wave C)

Administered By
Medicine, Hematology
AwardedBy
Siemens Healthcare Diagnostics
Role
Principal Investigator
Start Date
August 08, 2016
End Date
May 31, 2018

Development Of Prognostic Platelet RNA Biomarkers To Tailor Antiplatelet Therapy

Administered By
Duke Center for Applied Genomics and Precision Medicine
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
July 05, 2013
End Date
May 31, 2018

Duke-UNC Clinical Hematology and Transfusion Research Career Development Program

Administered By
Medicine, Hematology
AwardedBy
National Institutes of Health
Role
Associate Program Director
Start Date
September 28, 2006
End Date
April 30, 2018

An integrated and diverse genomic medicine program for undiagnosed diseases

Administered By
Pediatrics, Medical Genetics
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
July 01, 2014
End Date
March 31, 2018

Improving Pain in Sickle Cell Patients With Targeted Antithrombotic Therapy

Administered By
Medicine, Hematology
AwardedBy
National Institutes of Health
Role
Co-Mentor
Start Date
December 01, 2014
End Date
November 30, 2017

Training Program in Inflammatory and Immunological Diseases

Administered By
Medicine, Rheumatology and Immunology
AwardedBy
National Institutes of Health
Role
Preceptor
Start Date
September 30, 1980
End Date
August 31, 2017

STA - Coag Control ABN PLUS Precision Study

Administered By
Medicine, Hematology
AwardedBy
Stago
Role
Principal Investigator
Start Date
July 21, 2017
End Date
August 20, 2017

Evaluation of an Automated Information Extraction Tool for Identification of Venous Thromboembolism in Electronic Health Records (EHRs)

Administered By
Medicine, Hematology
AwardedBy
Association of American Medical Colleges
Role
Principal Investigator
Start Date
August 15, 2016
End Date
August 14, 2017

Population-based Surveillance And Ourcomes of Venous Thromboembolism

Administered By
Medicine, Hematology
AwardedBy
Centers for Disease Control and Prevention
Role
Principal Investigator
Start Date
October 01, 2015
End Date
August 14, 2017

Anticoagulation Withdrawal in Antiphospholipid Syndrome

Administered By
Medicine, Hematology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
August 05, 2014
End Date
June 30, 2017

BRIDGE CCC

Administered By
Duke Clinical Research Institute
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
June 25, 2008
End Date
March 31, 2017

Siemens CS-2100i and CS-5100 New Generation Analyzers

Administered By
Medicine, Hematology
AwardedBy
Siemens Healthcare Diagnostics
Role
Principal Investigator
Start Date
June 08, 2015
End Date
January 31, 2017

Precision Performance of STA® -COAG CONTROL (N + ABN) PLUS ON STA -SATELLITE®

Administered By
Medicine, Hematology
AwardedBy
Stago
Role
Principal Investigator
Start Date
July 11, 2016
End Date
December 10, 2016

ALXN1007

Administered By
Medicine, Hematology
AwardedBy
Alexion Pharmaceuticals, Inc.
Role
Principal Investigator
Start Date
July 01, 2014
End Date
November 28, 2016

Field Study to evaluate the activity of a site specific of B-Domain Deleted (BDD) pegylated recombinant FVIII protein (BAY 94-9027) in plasma samples measured with both chromogenic and one stage assa

Administered By
Medicine, Hematology
AwardedBy
Bayer Healthcare Pharmaceuticals Inc
Role
Principal Investigator
Start Date
November 02, 2015
End Date
November 01, 2016

Public Health Surveillance of Bleeding

Administered By
Medicine, Hematology
AwardedBy
Centers for Disease Control and Prevention
Role
Co Investigator
Start Date
September 30, 2011
End Date
September 29, 2016

Adherence to Venous Thromboembolism Prophylaxis Guidelines in Hospitalized Elders

Administered By
Center for the Study of Aging and Human Development
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
September 01, 2014
End Date
August 31, 2016

Promoting the Health of Individuals with Clotting Disorders

Administered By
Medicine, Hematology
AwardedBy
Centers for Disease Control and Prevention
Role
Principal Investigator
Start Date
September 01, 2013
End Date
September 29, 2015

Population-based Surveillance And Outcomes of Venous Thromboembolism

Administered By
Medicine, Hematology
AwardedBy
Centers for Disease Control and Prevention
Role
Principal Investigator
Start Date
April 01, 2012
End Date
March 31, 2015

12091912 INR Project

Administered By
Medicine, Hematology
AwardedBy
DSRV Inc
Role
Principal Investigator
Start Date
January 19, 2013
End Date
November 18, 2014

Transfusion Medicine/Hemostasis Core Clinical Center

Administered By
Medicine, Hematology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 01, 2007
End Date
August 31, 2014

Clinical Significance of protamine/heparin antibodies after CPB

Administered By
Medicine, Hematology
AwardedBy
National Institutes of Health
Role
Consultant
Start Date
August 01, 2011
End Date
May 31, 2014

Responses of Myocardial Ischemia to Sertraline Treatment

Administered By
Psychiatry & Behavioral Sciences, Behavioral Medicine
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
September 01, 2006
End Date
June 30, 2013

Thrombosis and Hemostasis Centers Research and Prevention Network

Administered By
Medicine, Hematology
AwardedBy
Centers for Disease Control and Prevention
Role
Principal Investigator
Start Date
September 30, 2002
End Date
June 30, 2013

Phase I Clinical Trial Describing the Pharmacogenomics of Aspirin

Administered By
Duke Center for Applied Genomics and Precision Medicine
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
September 30, 2009
End Date
August 31, 2012

Molecular Biology Of Human Coagulation Factor V

Administered By
Medicine, Hematology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
January 01, 1991
End Date
March 31, 2012

Rare Thrombotic Diseases Clinical Research Network

Administered By
Medicine, Hematology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
March 01, 2004
End Date
December 31, 2010

Lung Injury Protection by Coagulation Blockade

Administered By
Medicine, Pulmonary, Allergy, and Critical Care Medicine
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
September 15, 2005
End Date
June 30, 2010

Pharmacologic Prevention of Arteriovenous Graft Thrombosis

Administered By
Neurosurgery, Neuro-Oncology
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
February 05, 2007
End Date
June 30, 2009

Biomarker Studies for Novel Anti-Cancer Agents

Administered By
Medicine, Medical Oncology
AwardedBy
National Institutes of Health
Role
Consultant
Start Date
May 28, 2003
End Date
February 29, 2008

Hormone replacement therapy and ischemic stroke severity

Administered By
Neurology, Stroke and Vascular Neurology
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
September 30, 2001
End Date
July 31, 2007

Integrated Program for Persons with Hemostatic Disorders

Administered By
Medicine, Medical Oncology
AwardedBy
Centers for Disease Control
Role
Principal Investigator
Start Date
September 30, 2001
End Date
June 30, 2007

Mentored Clinical Research Scholar Program

Administered By
Medicine, Infectious Diseases
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
September 30, 2002
End Date
September 29, 2006

Does NO mediate clinical anti-VEGF vascular effects

Administered By
Medicine, Medical Oncology
AwardedBy
National Institutes of Health
Role
Consultant
Start Date
September 26, 2003
End Date
August 31, 2006

Genetic Analysis of Hereditary Macrothrombocytopenias

Administered By
Medicine, Medical Oncology
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
February 15, 2001
End Date
November 30, 2004

Pathophysiology of Antiphospholipid Antibody Syndromes

Administered By
Medicine, Hematology
AwardedBy
Department of Health and Human Services
Role
Principal Investigator
Start Date
April 01, 1999
End Date
March 31, 2004
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Awards:

Pew Scholars in the Biomedical Sciences. Pew Charitable Trusts, The.

Type
National
Awarded By
Pew Charitable Trusts, The
Date
January 01, 1995

Publications:

Clinical outcomes in a cohort of patients with heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) is a thrombotic disorder usually prompting treatment with non-heparin anticoagulants. The benefits and risks of such treatments have not been fully assessed.We analyzed data for 442 patients having a positive heparin-platelet factor 4 antibody test and recent heparin exposure. The primary outcome was a composite endpoint (death, limb amputation/gangrene, or new thrombosis). Secondary outcomes included bleeding and the effect of anticoagulation.Seventy-one patients (16%) had HIT with thrombosis (HIT-T); 284 (64%) had HIT without thrombosis (isolated HIT); 87 (20%) did not have HIT. An intermediate or high "4T" score was found in 85%, 58%, and 8% of the three respective groups. Non-heparin anticoagulation was begun in 80%, 56%, and 45%. The composite endpoint occurred in 48%, 36%, and 17% (P = .01) of which 61%, 38%, and 40% were receiving non-heparin anticoagulation. Compared with the no HIT group, the composite endpoint was significantly more likely in HIT-T [HR 2.48 (1.35-4.55), P = .003)] and marginally more likely in isolated HIT [HR 1.66 (0.96-2.85), P = .071]. Importantly, risk increased (HR 1.77, P = .02) after platelet transfusion. Major bleeding occurred in 48%, 36%, and 16% of the three groups (P = .005). Non-heparin anticoagulation was not associated with a reduction in composite endpoint events in either HIT group.HIT patients have high risks of death, limb amputation/gangrene, thrombosis, and bleeding. Non-heparin anticoagulant treatment may not benefit all patients and should be considered only after careful assessment of the relative risks of thrombosis and bleeding in individual patients.

Authors
Kuter, DJ; Konkle, BA; Hamza, TH; Uhl, L; Assmann, SF; Kiss, JE; Kaufman, RM; Key, NS; Sachais, BS; Hess, JR; Ness, P; McCrae, KR; Leissinger, C; Strauss, RG; McFarland, JG; Neufeld, E; Bussel, JB; Ortel, TL
MLA Citation
Kuter, DJ, Konkle, BA, Hamza, TH, Uhl, L, Assmann, SF, Kiss, JE, Kaufman, RM, Key, NS, Sachais, BS, Hess, JR, Ness, P, McCrae, KR, Leissinger, C, Strauss, RG, McFarland, JG, Neufeld, E, Bussel, JB, and Ortel, TL. "Clinical outcomes in a cohort of patients with heparin-induced thrombocytopenia." American journal of hematology 92.8 (August 2017): 730-738.
PMID
28388835
Source
epmc
Published In
American Journal of Hematology
Volume
92
Issue
8
Publish Date
2017
Start Page
730
End Page
738
DOI
10.1002/ajh.24759

Comparison of Fatal or Irreversible Events With Extended-Duration Betrixaban Versus Standard Dose Enoxaparin in Acutely Ill Medical Patients: An APEX Trial Substudy.

Extended-duration betrixaban showed a significant reduction in venous thromboembolism in the APEX trial (Acute Medically Ill VTE Prevention With Extended Duration Betrixaban Study). Given the variable clinical impact of different efficacy and safety events, one approach to assess net clinical outcomes is to include only those events that are either fatal or cause irreversible harm.This was a post hoc analysis of the APEX trial-a multicenter, double-blind, randomized controlled trial comparing extended-duration betrixaban versus standard-of-care enoxaparin. A composite of all fatal or irreversible safety (fatal bleeding or intracranial hemorrhage) and efficacy events (cardiopulmonary death, myocardial infarction, pulmonary embolism, and ischemic stroke) was evaluated in a time-to-first event analysis. In patients with positive D-dimer results, betrixaban reduced fatal or irreversible events at 35 to 42 days (4.80% versus 3.54%; hazard ratio, 0.73; absolute risk reduction, 1.26%; number needed to treat, 79 [P=0.033]) and at study end at 77 days (6.27% versus 4.36%; hazard ratio, 0.70; absolute risk reduction, 1.91%; number needed to treat, 52 [P=0.005]) versus enoxaparin. In all patients, betrixaban reduced fatal or irreversible events at 35 to 42 days (4.08% versus 2.90%; hazard ratio, 0.71; absolute risk reduction, 1.18%; number needed to treat, 86 [P=0.006]) and 77 days (5.17% versus 3.64%; hazard ratio, 0.70; absolute risk reduction, 1.53%; number needed to treat, 65 [P=0.002]).Among hospitalized medically ill patients, extended-duration betrixaban demonstrated an ≈30% reduction in fatal or irreversible ischemic or bleeding events compared with standard-duration enoxaparin. A total of 65 patients would require treatment with betrixaban to prevent 1 fatal or irreversible event versus enoxaparin.URL: http://www.ClinicalTrials.gov. Unique identifier: NCT01583218.

Authors
Gibson, CM; Korjian, S; Chi, G; Daaboul, Y; Jain, P; Arbetter, D; Goldhaber, SZ; Hull, R; Hernandez, AF; Lopes, RD; Gold, A; Cohen, AT; Harrington, RA; APEX Investigators,
MLA Citation
Gibson, CM, Korjian, S, Chi, G, Daaboul, Y, Jain, P, Arbetter, D, Goldhaber, SZ, Hull, R, Hernandez, AF, Lopes, RD, Gold, A, Cohen, AT, Harrington, RA, and APEX Investigators, . "Comparison of Fatal or Irreversible Events With Extended-Duration Betrixaban Versus Standard Dose Enoxaparin in Acutely Ill Medical Patients: An APEX Trial Substudy." Journal of the American Heart Association 6.7 (July 11, 2017).
PMID
28698258
Source
epmc
Published In
Journal of the American Heart Association
Volume
6
Issue
7
Publish Date
2017
DOI
10.1161/jaha.117.006015

Heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) is an immune complication of heparin therapy caused by antibodies to complexes of platelet factor 4 (PF4) and heparin. Pathogenic antibodies to PF4/heparin bind and activate cellular FcγRIIA on platelets and monocytes to propagate a hypercoagulable state culminating in life-threatening thrombosis. It is now recognized that anti-PF4/heparin antibodies develop commonly after heparin exposure, but only a subset of sensitized patients progress to life-threatening complications of thrombocytopenia and thrombosis. Recent scientific developments have clarified mechanisms underlying PF4/heparin immunogenicity, disease susceptibility, and clinical manifestations of disease. Insights from clinical and laboratory findings have also been recently harnessed for disease prevention. This review will summarize our current understanding of HIT by reviewing pathogenesis, essential clinical and laboratory features, and management.

Authors
Arepally, GM
MLA Citation
Arepally, GM. "Heparin-induced thrombocytopenia." Blood 129.21 (May 2017): 2864-2872. (Review)
PMID
28416511
Source
epmc
Published In
Blood
Volume
129
Issue
21
Publish Date
2017
Start Page
2864
End Page
2872
DOI
10.1182/blood-2016-11-709873

Mental stress-induced left ventricular dysfunction and adverse outcome in ischemic heart disease patients.

Aims Mental stress-induced myocardial ischemia (MSIMI) occurs in up to 70% of patients with clinically stable ischemic heart disease and is associated with increased risk of adverse prognosis. We aimed to examine the prognostic value of indices of MSIMI and exercise stress-induced myocardial ischemia (ESIMI) in a population of ischemic heart disease patients that was not confined by having a recent positive physical stress test. Methods and results The Responses of Mental Stress Induced Myocardial Ischemia to Escitalopram Treatment (REMIT) study enrolled 310 subjects who underwent mental and exercise stress testing and were followed annually for a median of four years. Study endpoints included time to first and total rate of major adverse cardiovascular events, defined as all-cause mortality and hospitalizations for cardiovascular causes. Cox and negative binomial regression adjusting for age, sex, resting left ventricular ejection fraction, and heart failure status were used to examine associations of indices of MSIMI and ESIMI with study endpoints. The continuous variable of mental stress-induced left ventricular ejection fraction change was significantly associated with both endpoints (all p values < 0.05). For every reduction of 5% in left ventricular ejection fraction induced by mental stress, patients had a 5% increase in the probability of a major adverse cardiovascular event at the median follow-up time and a 20% increase in the number of major adverse cardiovascular events endured over the follow-up period of six years. Indices of ESIMI did not predict endpoints ( ps > 0.05). Conclusion In patients with stable ischemic heart disease, mental, but not exercise, stress-induced left ventricular ejection fraction change significantly predicts risk of future adverse cardiovascular events.

Authors
Sun, JL; Boyle, SH; Samad, Z; Babyak, MA; Wilson, JL; Kuhn, C; Becker, RC; Ortel, TL; Williams, RB; Rogers, JG; O'Connor, CM; Velazquez, EJ; Jiang, W
MLA Citation
Sun, JL, Boyle, SH, Samad, Z, Babyak, MA, Wilson, JL, Kuhn, C, Becker, RC, Ortel, TL, Williams, RB, Rogers, JG, O'Connor, CM, Velazquez, EJ, and Jiang, W. "Mental stress-induced left ventricular dysfunction and adverse outcome in ischemic heart disease patients." European journal of preventive cardiology 24.6 (April 2017): 591-599.
PMID
28067532
Source
epmc
Published In
European Journal of Preventive Cardiology
Volume
24
Issue
6
Publish Date
2017
Start Page
591
End Page
599
DOI
10.1177/2047487316686435

Validating the HERDOO2 rule to guide treatment duration for women with unprovoked venous thrombosis: multinational prospective cohort management study.

Objective To prospectively validate the HERDOO2 rule (Hyperpigmentation, Edema, or Redness in either leg; D-dimer level ≥250 μg/L; Obesity with body mass index ≥30; or Older age, ≥65 years), which states that women with none or one of the criteria can safely discontinue anticoagulants after short term treatment.Design Prospective cohort management study.Setting 44 secondary or tertiary care centres in seven countries.Participants Of 3155 consecutive eligible participants with a first unprovoked venous thromboembolism (VTE, proximal leg deep vein thrombosis or pulmonary embolism) who completed 5-12 months of short term anticoagulant treatment, 370 declined to participate, leaving 2785 enrolled participants. 2.3% were lost to follow-up.Interventions Women with none or one of the HERDOO2 criteria were classified as at low risk of recurrent VTE and discontinued anticoagulants (intervention arm), whereas anticoagulant management for high risk women (≥2 HERDOO2 criteria) and men was left to the discretion of the clinicians and patients (observation arm).Main outcome measure Recurrent symptomatic VTE (independently and blindly adjudicated) over one year of follow-up.Results Of 1213 women, 631 (51.3%) were classified as low risk and 591 discontinued oral anticoagulant treatment. In the primary analysis, 17 low risk women who discontinued anticoagulants developed recurrent VTE during 564 patient years of follow-up (3.0% per patient year, 95% confidence interval 1.8% to 4.8%). In 323 high risk women and men who discontinued anticoagulants, 25 had VTE during 309 patient years of follow-up (8.1%, 5.2% to 11.9%), whereas in 1802 high risk women and men who continued anticoagulants 28 had recurrent VTE during 1758 patient years of follow-up (1.6%, 1.1% to 2.3%).Conclusions Women with a first unprovoked VTE event and none or one of the HERDOO2 criteria have a low risk of recurrent VTE and can safely discontinue anticoagulants after completing short term treatment.Trial registration clinicaltrials.gov NCT00967304.

Authors
Rodger, MA; Le Gal, G; Anderson, DR; Schmidt, J; Pernod, G; Kahn, SR; Righini, M; Mismetti, P; Kearon, C; Meyer, G; Elias, A; Ramsay, T; Ortel, TL; Huisman, MV; Kovacs, MJ; REVERSE II Study Investigators,
MLA Citation
Rodger, MA, Le Gal, G, Anderson, DR, Schmidt, J, Pernod, G, Kahn, SR, Righini, M, Mismetti, P, Kearon, C, Meyer, G, Elias, A, Ramsay, T, Ortel, TL, Huisman, MV, Kovacs, MJ, and REVERSE II Study Investigators, . "Validating the HERDOO2 rule to guide treatment duration for women with unprovoked venous thrombosis: multinational prospective cohort management study." BMJ (Clinical research ed.) 356 (March 17, 2017): j1065-.
PMID
28314711
Source
epmc
Published In
BMJ (Clinical research ed.)
Volume
356
Publish Date
2017
Start Page
j1065
DOI
10.1136/bmj.j1065

Dalteparin thromboprophylaxis in cancer patients at high risk for venous thromboembolism: A randomized trial.

Ambulatory cancer patients at high-risk for venous thromboembolism (VTE) can be identified using a validated risk score (Khorana score). We evaluated the benefit of outpatient thromboprophylaxis with dalteparin in high-risk patients in a multicenter randomized study.Cancer patients with Khorana score≥3 starting a new systemic regimen were screened for VTE and if negative randomized to dalteparin 5000units daily or observation for 12weeks. Subjects were screened with lower extremity ultrasounds every 4weeks on study and with chest CT at 12weeks. The primary efficacy endpoint was all VTE over 12weeks and primary safety endpoint was clinically relevant bleeding events over 13weeks. The study was terminated early due to low accrual.Of 117 enrolled patients, 10 (8.5%) had VTE on baseline screening and were not randomized. Of 98 randomized patients, VTE occurred in 12% (N=6/50) of patients on dalteparin and 21% (N=10/48) on observation (hazard ratio, HR 0.69, 95% CI 0.23-1.89). Major bleeding was similar (N=1) in each arm but clinically relevant bleeding was higher in dalteparin arm (N=7 versus 1 on observation) (HR=7.0, 95% CI 1.2-131.6). There was no difference in overall survival.Thromboprophylaxis is associated with a non-significantly reduced risk of VTE and significantly increased risk of clinically relevant bleeding in this underpowered study. The Khorana score successfully identifies patients with high incidence of VTE both at baseline and during treatment. Future studies should continue to focus on risk-adapted approaches to reduce the burden of VTE in cancer.clinicaltrials.gov identifier: NCT00876915.

Authors
Khorana, AA; Francis, CW; Kuderer, NM; Carrier, M; Ortel, TL; Wun, T; Rubens, D; Hobbs, S; Iyer, R; Peterson, D; Baran, A; Kaproth-Joslin, K; Lyman, GH
MLA Citation
Khorana, AA, Francis, CW, Kuderer, NM, Carrier, M, Ortel, TL, Wun, T, Rubens, D, Hobbs, S, Iyer, R, Peterson, D, Baran, A, Kaproth-Joslin, K, and Lyman, GH. "Dalteparin thromboprophylaxis in cancer patients at high risk for venous thromboembolism: A randomized trial." March 2017.
PMID
28139259
Source
epmc
Published In
Thrombosis Research
Volume
151
Publish Date
2017
Start Page
89
End Page
95
DOI
10.1016/j.thromres.2017.01.009

Associations between positive emotional well-being and stress-induced myocardial ischemia: Well-being scores predict exercise-induced ischemia.

Depressive symptoms have been associated with myocardial ischemia induced by mental (MSIMI) and exercise (ESIMI) stress in clinically stable ischemic heart disease (IHD) patients, but the association between positive emotions and inducible ischemia is less well characterized. The objective of this study was to examine the associations between ratings of well-being and stress-induced ischemia.Subjects were adult patients with documented IHD underwent mental and exercise stress testing for the Responses of Myocardial Ischemia to Escitalopram Treatment (REMIT) trial. The General Well-Being Schedule (GWBS), with higher scores reflecting greater subjective well-being, and the Center for Epidemiologic Studies Depression Scale (CES-D) were obtained from the REMIT participants. Echocardiography was used to measure ischemic responses to mental stress and Bruce protocol treadmill exercise testing. Data were analyzed using logistic regression adjusting for age, sex, resting left-ventricular ejection fraction (LVEF), and resting wall motion score index, as well as health-related behaviors.GWBS scores were obtained for 210 individuals, with MSIMI present in 92 (43.8%) and ESIMI present in 64 (30.5%). There was a significant inverse correlation between GWBS-PE (Positive Emotion subscale) scores and probability of ESIMI (OR=0.55 (95%CI 0.36-0.83), p=0.005). This association persisted after additional control for CESD subscales measuring negative and positive emotions and for variables reflecting health-related behaviors. A similar inverse correlation between GWBS-PE and MSIMI was observed, but did not reach statistical significance (OR=0.81 (95%CI 0.54-1.20), p=0.28).This is, to our knowledge, the first study demonstrating that greater levels of self-reported positive emotions are associated with a lower likelihood of ESIMI among patients with known IHD. Our results highlight the important interface functions of the central nervous and cardiovascular systems and underscore areas for future investigation.

Authors
Feigal, JP; Boyle, SH; Samad, Z; Velazquez, EJ; Wilson, JL; Becker, RC; Williams, RB; Kuhn, CM; Ortel, TL; Rogers, JG; O'Connor, CM; Jiang, W
MLA Citation
Feigal, JP, Boyle, SH, Samad, Z, Velazquez, EJ, Wilson, JL, Becker, RC, Williams, RB, Kuhn, CM, Ortel, TL, Rogers, JG, O'Connor, CM, and Jiang, W. "Associations between positive emotional well-being and stress-induced myocardial ischemia: Well-being scores predict exercise-induced ischemia." Journal of psychosomatic research 93 (February 2017): 14-18.
PMID
28107887
Source
epmc
Published In
Journal of Psychosomatic Research
Volume
93
Publish Date
2017
Start Page
14
End Page
18
DOI
10.1016/j.jpsychores.2016.11.012

2017 ACC Expert Consensus Decision Pathway for Periprocedural Management of Anticoagulation in Patients With Nonvalvular Atrial Fibrillation: A Report of the American College of Cardiology Clinical Expert Consensus Document Task Force.

Authors
Doherty, JU; Gluckman, TJ; Hucker, WJ; Januzzi, JL; Ortel, TL; Saxonhouse, SJ; Spinler, SA
MLA Citation
Doherty, JU, Gluckman, TJ, Hucker, WJ, Januzzi, JL, Ortel, TL, Saxonhouse, SJ, and Spinler, SA. "2017 ACC Expert Consensus Decision Pathway for Periprocedural Management of Anticoagulation in Patients With Nonvalvular Atrial Fibrillation: A Report of the American College of Cardiology Clinical Expert Consensus Document Task Force." Journal of the American College of Cardiology 69.7 (February 2017): 871-898.
PMID
28081965
Source
epmc
Published In
JACC - Journal of the American College of Cardiology
Volume
69
Issue
7
Publish Date
2017
Start Page
871
End Page
898
DOI
10.1016/j.jacc.2016.11.024

The association of anti-platelet factor 4/heparin antibodies with early and delayed thromboembolism after cardiac surgery.

Essentials We evaluated antibody status, thromboembolism and survival after cardiac surgery. Positive antibody tests are common - over 50% are seropositive at 30 days. Seropositivity did not increase thromboembolism or impair survival after cardiac surgery. Results show heparin induced thrombocytopenia antibody screening after surgery is not warranted.Background Heparin-induced thrombocytopenia (HIT) is a prothrombotic response to heparin therapy with platelet-activating, anti-platelet factor 4 (PF4)/heparin antibodies leading to thrombocytopenia associated with thromboembolism. Objective We tested the hypothesis that anti-PF4/heparin antibodies are associated with thromboembolism after cardiac surgery. Methods This multicenter, prospective cohort study collected laboratory and clinical data up to 30 days after surgery and longer-term clinical follow-up data. The primary outcome variable combined new arterial or venous thromboembolic complications (TECs) with all-cause death until 90 days after surgery. Laboratory analyses included platelet counts and anti-PF4/heparin antibody titers (GTI ELISA), with a confirmatory excess heparin step and serotonin release assay. Chi-square testing was used to test the relationship between our outcome and HIT antibody seropositivity. Results Initially, 1021 patients were enrolled between August 2006 and May 2009, and follow-up was completed in December 2014. Seropositivity defined by OD > 0.4 was common, being almost 20% preoperatively, > 30% by discharge, and > 60% by day 30. Death (1.7% within 30 days) or TECs (69 in total) were more likely if the partient was seronegative (OD < 0.4), but positivity defined by OD > 1.0 or including an excess heparin confirmatory step resulted in equal incidence of death or TECs, whether the patient was seronegative or seropositive. Incorporating the serotonin release assay for platelet-activating antibodies did not alter these findings. Conclusions Seropositivity for anti-PF4/heparin antibodies does not increase the risk of death or thromboembolism after cardiac surgery. Screening is not indicated, and seropositivity should only be interpreted in the context of clinical evidence for HIT.Duke IRB Protocol #00010736.

Authors
Welsby, IJ; Krakow, EF; Heit, JA; Williams, EC; Arepally, GM; Bar-Yosef, S; Kong, DF; Martinelli, S; Dhakal, I; Liu, WW; Krischer, J; Ortel, TL
MLA Citation
Welsby, IJ, Krakow, EF, Heit, JA, Williams, EC, Arepally, GM, Bar-Yosef, S, Kong, DF, Martinelli, S, Dhakal, I, Liu, WW, Krischer, J, and Ortel, TL. "The association of anti-platelet factor 4/heparin antibodies with early and delayed thromboembolism after cardiac surgery." Journal of thrombosis and haemostasis : JTH 15.1 (January 2017): 57-65.
PMID
27714919
Source
epmc
Published In
Journal of Thrombosis and Haemostasis
Volume
15
Issue
1
Publish Date
2017
Start Page
57
End Page
65
DOI
10.1111/jth.13533

A rare cutaneous manifestation of hemorrhagic bullae to low-molecular-weight heparin and fondaparinux: report of two cases.

Authors
Komforti, MK; Bressler, ES; Selim, MA; Bressler, GS; Ortel, TL
MLA Citation
Komforti, MK, Bressler, ES, Selim, MA, Bressler, GS, and Ortel, TL. "A rare cutaneous manifestation of hemorrhagic bullae to low-molecular-weight heparin and fondaparinux: report of two cases." Journal of cutaneous pathology 44.1 (January 2017): 104-106. (Letter)
PMID
27766660
Source
epmc
Published In
Journal of Cutaneous Pathology
Volume
44
Issue
1
Publish Date
2017
Start Page
104
End Page
106
DOI
10.1111/cup.12821

Effect of intravenous lidocaine on the transcerebral inflammatory response during cardiac surgery: a randomized-controlled trial.

Postoperative cognitive dysfunction (POCD) occurs frequently after cardiac surgery. The pathophysiology of POCD remains elusive, but previous work showed that intravenous lidocaine may be protective against POCD, possibly by modulating cerebral inflammation. We hypothesized that intravenous lidocaine would attenuate the cerebral inflammatory response to cardiopulmonary bypass (CPB) by reducing the transcerebral activation gradients of platelets, leukocytes, and/or platelet-leukocyte conjugates.We studied 202 patients undergoing cardiac surgery with CPB in this prospective randomized double-blinded placebo-controlled trial. Subjects were randomized to receive either intravenous lidocaine (bolus + 48-hr infusion) or placebo (identical infusion volume and duration). Paired jugular venous and radial arterial blood samples were drawn at several time points and analyzed by fluorescence-activated cell sorting to identify activated platelets and platelet-leukocyte conjugates. Transcerebral activation gradients were calculated by subtracting arterial values from venous values and were compared between groups using repeated measures regression models with covariate adjustment for age, sex, surgery type, and CPB duration.Beginning after aortic cross-clamp release and peaking ten minutes after the termination of CPB, the mean (SD) transcerebral activation gradient of platelet-monocyte conjugates decreased in lidocaine-treated vs placebo-treated patients [-1.84 (11.47) mean linear fluorescence intensity (MLFI) vs 1.46 (13.88) MLFI, respectively; mean difference, -4.08 MLFI; 95% confidence interval, -7.86 to -0.29; P = 0.03). No difference was seen at any time point for activated platelets or for platelet-neutrophil conjugates.While lidocaine did not affect the systemic or transcerebral activation of platelets or leukocytes, we did observe a reduction in the transcerebral activation of platelet-monocyte conjugates after aortic cross-clamp release. This may be a manifestation of reduced cerebral inflammation during cardiopulmonary bypass in response to treatment with lidocaine. This trial was registered at ClinicalTrials.gov (NCT00938964).

Authors
Klinger, RY; Cooter, M; Berger, M; Podgoreanu, MV; Stafford-Smith, M; Ortel, TL; Welsby, IJ; Levy, JH; Rinder, HM; Newman, MF; Mathew, JP; Neurologic Outcomes Research Group (NORG) of The Duke Heart Center,
MLA Citation
Klinger, RY, Cooter, M, Berger, M, Podgoreanu, MV, Stafford-Smith, M, Ortel, TL, Welsby, IJ, Levy, JH, Rinder, HM, Newman, MF, Mathew, JP, and Neurologic Outcomes Research Group (NORG) of The Duke Heart Center, . "Effect of intravenous lidocaine on the transcerebral inflammatory response during cardiac surgery: a randomized-controlled trial." Canadian journal of anaesthesia = Journal canadien d'anesthesie 63.11 (November 2016): 1223-1232.
PMID
27470233
Source
epmc
Published In
Canadian Journal of Anesthesia / Journal canadien d'anesthésie
Volume
63
Issue
11
Publish Date
2016
Start Page
1223
End Page
1232
DOI
10.1007/s12630-016-0704-0

Systems Pharmacogenomics Finds RUNX1 Is an Aspirin-Responsive Transcription Factor Linked to Cardiovascular Disease and Colon Cancer.

Aspirin prevents cardiovascular disease and colon cancer; however aspirin's inhibition of platelet COX-1 only partially explains its diverse effects. We previously identified an aspirin response signature (ARS) in blood consisting of 62 co-expressed transcripts that correlated with aspirin's effects on platelets and myocardial infarction (MI). Here we report that 60% of ARS transcripts are regulated by RUNX1 - a hematopoietic transcription factor - and 48% of ARS gene promoters contain a RUNX1 binding site. Megakaryocytic cells exposed to aspirin and its metabolite (salicylic acid, a weak COX-1 inhibitor) showed up regulation in the RUNX1 P1 isoform and MYL9, which is transcriptionally regulated by RUNX1. In human subjects, RUNX1 P1 expression in blood and RUNX1-regulated platelet proteins, including MYL9, were aspirin-responsive and associated with platelet function. In cardiovascular disease patients RUNX1 P1 expression was associated with death or MI. RUNX1 acts as a tumor suppressor gene in gastrointestinal malignancies. We show that RUNX1 P1 expression is associated with colon cancer free survival suggesting a role for RUNX1 in aspirin's protective effect in colon cancer. Our studies reveal an effect of aspirin on RUNX1 and gene expression that may additionally explain aspirin's effects in cardiovascular disease and cancer.

Authors
Voora, D; Rao, AK; Jalagadugula, GS; Myers, R; Harris, E; Ortel, TL; Ginsburg, GS
MLA Citation
Voora, D, Rao, AK, Jalagadugula, GS, Myers, R, Harris, E, Ortel, TL, and Ginsburg, GS. "Systems Pharmacogenomics Finds RUNX1 Is an Aspirin-Responsive Transcription Factor Linked to Cardiovascular Disease and Colon Cancer." EBioMedicine 11 (September 2016): 157-164.
PMID
27566955
Source
epmc
Published In
EBioMedicine
Volume
11
Publish Date
2016
Start Page
157
End Page
164
DOI
10.1016/j.ebiom.2016.08.021

Inter-observer reliability of the HERDOO2 clinical decision rule.

Authors
Gauthier, K; Le Gal, G; Shivakumar, S; Anderson, D; Chagnon, I; Solymoss, S; Ortel, T; Yeo, E; Kearon, C; Rodger, M
MLA Citation
Gauthier, K, Le Gal, G, Shivakumar, S, Anderson, D, Chagnon, I, Solymoss, S, Ortel, T, Yeo, E, Kearon, C, and Rodger, M. "Inter-observer reliability of the HERDOO2 clinical decision rule." Thrombosis research 141 (May 2016): 136-138. (Letter)
PMID
27031923
Source
epmc
Published In
Thrombosis Research
Volume
141
Publish Date
2016
Start Page
136
End Page
138
DOI
10.1016/j.thromres.2016.03.015

Effectiveness of Intermittent Pneumatic Compression Devices for Venous Thromboembolism Prophylaxis in High-Risk Surgical Patients: A Systematic Review.

Thromboprophylaxis regimens include pharmacologic and mechanical options such as intermittent pneumatic compression devices (IPCDs). There are a wide variety of IPCDs available, but it is uncertain if they vary in effectiveness or ease of use. This is a systematic review of the comparative effectiveness of IPCDs for selected outcomes (mortality, venous thromboembolism [VTE], symptomatic or asymptomatic deep vein thrombosis, major bleeding, ease of use, and adherence) in postoperative surgical patients.We searched MEDLINE (via PubMed), Embase, CINAHL, and Cochrane CENTRAL from January 1, 1995, to October 30, 2014, for randomized controlled trials, as well as relevant observational studies on ease of use and adherence.We identified 14 eligible randomized controlled trials (2633 subjects) and 3 eligible observational studies (1724 subjects); most were conducted in joint arthroplasty patients. Intermittent pneumatic compression devices were comparable to anticoagulation for major clinical outcomes (VTE: risk ratio, 1.39; 95% confidence interval, 0.73-2.64). Limited data suggest that concurrent use of anticoagulation with IPCD may lower VTE risk compared with anticoagulation alone, and that IPCD compared with anticoagulation may lower major bleeding risk. Subgroup analyses did not show significant differences by device location, mode of inflation, or risk of bias elements. There were no consistent associations between IPCDs and ease of use or adherence.Intermittent pneumatic compression devices are appropriate for VTE thromboprophylaxis when used in accordance with current clinical guidelines. The current evidence base to guide selection of a specific device or type of device is limited.

Authors
Pavon, JM; Adam, SS; Razouki, ZA; McDuffie, JR; Lachiewicz, PF; Kosinski, AS; Beadles, CA; Ortel, TL; Nagi, A; Williams, JW
MLA Citation
Pavon, JM, Adam, SS, Razouki, ZA, McDuffie, JR, Lachiewicz, PF, Kosinski, AS, Beadles, CA, Ortel, TL, Nagi, A, and Williams, JW. "Effectiveness of Intermittent Pneumatic Compression Devices for Venous Thromboembolism Prophylaxis in High-Risk Surgical Patients: A Systematic Review." The Journal of arthroplasty 31.2 (February 2016): 524-532. (Review)
PMID
26525487
Source
epmc
Published In
Journal of Arthroplasty
Volume
31
Issue
2
Publish Date
2016
Start Page
524
End Page
532
DOI
10.1016/j.arth.2015.09.043

Medical compression stockings in the treatment of acute leg pain after proximal deep vein thrombosis: A randomized trial

Authors
Kahn, SR; Shapiro, S; Ducruet, T; Wells, PS; Rodger, MA; Kovacs, MJ; Anderson, D; Tagalakis, V; Morrison, DR; Solymoss, S; Miron, MJ; Yeo, E; Smith, R; Schulman, S; Kassis, J; Kearon, C; Chagnon, I; Wong, T; Deniers, C; Hanmiah, R; Kaatz, S; Selby, R; Rathbun, S; Desmarais, S; Opatrny, L; Ortel, TL; Galanaud, JP; Ginsberg, JS
MLA Citation
Kahn, SR, Shapiro, S, Ducruet, T, Wells, PS, Rodger, MA, Kovacs, MJ, Anderson, D, Tagalakis, V, Morrison, DR, Solymoss, S, Miron, MJ, Yeo, E, Smith, R, Schulman, S, Kassis, J, Kearon, C, Chagnon, I, Wong, T, Deniers, C, Hanmiah, R, Kaatz, S, Selby, R, Rathbun, S, Desmarais, S, Opatrny, L, Ortel, TL, Galanaud, JP, and Ginsberg, JS. "Medical compression stockings in the treatment of acute leg pain after proximal deep vein thrombosis: A randomized trial." Vasomed 28.1 (January 1, 2016): 46-.
Source
scopus
Published In
Vasomed
Volume
28
Issue
1
Publish Date
2016
Start Page
46

Bridging Anticoagulation in Patients with Atrial Fibrillation.

Authors
Douketis, JD; Hasselblad, V; Ortel, TL
MLA Citation
Douketis, JD, Hasselblad, V, and Ortel, TL. "Bridging Anticoagulation in Patients with Atrial Fibrillation." The New England journal of medicine 374.1 (January 2016): 93-94. (Letter)
PMID
26736004
Source
epmc
Published In
The New England journal of medicine
Volume
374
Issue
1
Publish Date
2016
Start Page
93
End Page
94
DOI
10.1056/nejmc1513255

Association between inflammation biomarkers, anatomic extent of deep venous thrombosis, and venous symptoms after deep venous thrombosis

Authors
Rabinovich, A; Cohen, JM; Cushman, M; Kahn, SR; Anderson, DR; Chagnon, I; Demers, C; Desmarais, S; Ginsberg, JS; Hanmiah, R; Kaatz, S; Kassis, J; Kearon, C; Kovacs, MJ; Lazo-Langner, A; Miron, M-J; Opatrny, L; Ortel, TL; Rathbun, S; Rodger, MA; Schulman, S; Selby, R; Smith, R; Solymoss, S; Tagalakis, V; Wells, PS; Wong, T; Yeo, E
MLA Citation
Rabinovich, A, Cohen, JM, Cushman, M, Kahn, SR, Anderson, DR, Chagnon, I, Demers, C, Desmarais, S, Ginsberg, JS, Hanmiah, R, Kaatz, S, Kassis, J, Kearon, C, Kovacs, MJ, Lazo-Langner, A, Miron, M-J, Opatrny, L, Ortel, TL, Rathbun, S, Rodger, MA, Schulman, S, Selby, R, Smith, R, Solymoss, S, Tagalakis, V, Wells, PS, Wong, T, and Yeo, E. "Association between inflammation biomarkers, anatomic extent of deep venous thrombosis, and venous symptoms after deep venous thrombosis." Journal of Vascular Surgery: Venous and Lymphatic Disorders 3.4 (October 2015): 347-353.e1.
Source
crossref
Published In
Journal of Vascular Surgery: Venous and Lymphatic Disorders
Volume
3
Issue
4
Publish Date
2015
Start Page
347
End Page
353.e1
DOI
10.1016/j.jvsv.2015.04.005

How I treat catastrophic thrombotic syndromes.

Catastrophic thrombotic syndromes are characterized by rapid onset of multiple thromboembolic occlusions affecting diverse vascular beds. Patients may have multiple events on presentation, or develop them rapidly over days to weeks. Several disorders can present with this extreme clinical phenotype, including catastrophic antiphospholipid syndrome (APS), atypical presentations of thrombotic thrombocytopenic purpura (TTP) or heparin-induced thrombocytopenia (HIT), and Trousseau syndrome, but some patients present with multiple thrombotic events in the absence of associated prothrombotic disorders. Diagnostic workup must rapidly determine which, if any, of these syndromes are present because therapeutic management is driven by the underlying disorder. With the exception of atypical presentations of TTP, which are treated with plasma exchange, anticoagulation is the most important therapeutic intervention in these patients. Effective anticoagulation may require laboratory confirmation with anti-factor Xa levels in patients treated with heparin, especially if the baseline (pretreatment) activated partial thromboplastin time is prolonged. Patients with catastrophic APS also benefit from immunosuppressive therapy and/or plasma exchange, whereas patients with HIT need an alternative anticoagulant to replace heparin. Progressive thrombotic events despite therapeutic anticoagulation may necessitate an alternative therapeutic strategy. If the thrombotic process can be controlled, these patients can recover, but indefinite anticoagulant therapy may be appropriate to prevent recurrent events.

Authors
Ortel, TL; Erkan, D; Kitchens, CS
MLA Citation
Ortel, TL, Erkan, D, and Kitchens, CS. "How I treat catastrophic thrombotic syndromes." Blood 126.11 (September 2015): 1285-1293. (Review)
PMID
26179082
Source
epmc
Published In
Blood
Volume
126
Issue
11
Publish Date
2015
Start Page
1285
End Page
1293
DOI
10.1182/blood-2014-09-551978

Characteristics and Risk Factors of Cancer Associated Venous Thromboembolism.

The objective of this study was to examine the differences in commonly associated characteristics and risk factors of venous thromboembolism (VTE) between patients with and without cancer in a VTE population.Uniform data were collected for patients with a diagnosis of VTE obtaining care at CDC funded Thrombosis Network Centers. Patient characteristics and risk factors were compared in VTE patients with and without cancer. Logistic regression was used to calculate the unadjusted and adjusted odds ratios (ORs) and 95% confidence intervals (CIs) to assess patient characteristics and thrombotic risk factors more frequently identified among VTE patients with cancer compared to those without cancer.Between August 2003 and April 2011, 3,115 adult patients with a diagnosis of VTE including 189 (6.1%) patients with active cancer participated in the multi-site thrombosis registry. VTE patients with cancer had a higher prevalence of PE and DVT in unusual sites compared to those without cancer. Thrombophilia was more common among VTE patients without cancer than those with cancer (25.1% vs 10.6%, p<0.001). In adjusted analysis, age group≥45years (OR =5.20, 95% CI, 3.30, 8.18), surgery (OR =1.86, 95% CI, 1.19, 2.91), and hypertension (OR =1.66, 95% CI, 1.15, 2.40) were the VTE risk factors more commonly found among VTE patients with cancer.The study identified several thrombotic risk factors more likely to be found with cancer associated VTE, which may help to characterize at risk cancer patients and to develop prevention and management strategies in this population.

Authors
Faiz, AS; Khan, I; Beckman, MG; Bockenstedt, P; Heit, JA; Kulkarni, R; Manco-Johnson, M; Moll, S; Ortel, TL; Philipp, CS
MLA Citation
Faiz, AS, Khan, I, Beckman, MG, Bockenstedt, P, Heit, JA, Kulkarni, R, Manco-Johnson, M, Moll, S, Ortel, TL, and Philipp, CS. "Characteristics and Risk Factors of Cancer Associated Venous Thromboembolism." Thrombosis research 136.3 (September 2015): 535-541.
PMID
26168693
Source
epmc
Published In
Thrombosis Research
Volume
136
Issue
3
Publish Date
2015
Start Page
535
End Page
541
DOI
10.1016/j.thromres.2015.06.036

Cancer-Associated Venous Thromboembolic Disease, Version 1.2015.

The NCCN Guidelines for Cancer-Associated Venous Thromboembolic Disease outline strategies for treatment and prevention of venous thromboembolism (VTE) in adult patients with a diagnosis of cancer or for whom cancer is clinically suspected. VTE is a common complication in patients with cancer, which places them at greater risk for morbidity and mortality. Therefore, risk-appropriate prophylaxis is an essential component for the optimal care of inpatients and outpatients with cancer. Critical to meeting this goal is ensuring that patients get the most effective medication in the correct dose. Body weight has a significant impact on blood volume and drug clearance. Because obesity is a common health problem in industrialized societies, cancer care providers are increasingly likely to treat obese patients in their practice. Obesity is a risk factor common to VTE and many cancers, and may also impact the anticoagulant dose needed for safe and effective prophylaxis. These NCCN Guidelines Insights summarize the data supporting new dosing recommendations for VTE prophylaxis in obese patients with cancer.

Authors
Streiff, MB; Holmstrom, B; Ashrani, A; Bockenstedt, PL; Chesney, C; Eby, C; Fanikos, J; Fenninger, RB; Fogerty, AE; Gao, S; Goldhaber, SZ; Hendrie, P; Kuderer, N; Lee, A; Lee, JT; Lovrincevic, M; Millenson, MM; Neff, AT; Ortel, TL; Paschal, R; Shattil, S; Siddiqi, T; Smock, KJ; Soff, G; Wang, T-F; Yee, GC; Zakarija, A; McMillian, N; Engh, AM
MLA Citation
Streiff, MB, Holmstrom, B, Ashrani, A, Bockenstedt, PL, Chesney, C, Eby, C, Fanikos, J, Fenninger, RB, Fogerty, AE, Gao, S, Goldhaber, SZ, Hendrie, P, Kuderer, N, Lee, A, Lee, JT, Lovrincevic, M, Millenson, MM, Neff, AT, Ortel, TL, Paschal, R, Shattil, S, Siddiqi, T, Smock, KJ, Soff, G, Wang, T-F, Yee, GC, Zakarija, A, McMillian, N, and Engh, AM. "Cancer-Associated Venous Thromboembolic Disease, Version 1.2015." Journal of the National Comprehensive Cancer Network : JNCCN 13.9 (September 2015): 1079-1095.
PMID
26358792
Source
epmc
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
13
Issue
9
Publish Date
2015
Start Page
1079
End Page
1095
DOI
10.6004/jnccn.2015.0133

Perioperative Bridging Anticoagulation in Patients with Atrial Fibrillation.

It is uncertain whether bridging anticoagulation is necessary for patients with atrial fibrillation who need an interruption in warfarin treatment for an elective operation or other elective invasive procedure. We hypothesized that forgoing bridging anticoagulation would be noninferior to bridging with low-molecular-weight heparin for the prevention of perioperative arterial thromboembolism and would be superior to bridging with respect to major bleeding.We performed a randomized, double-blind, placebo-controlled trial in which, after perioperative interruption of warfarin therapy, patients were randomly assigned to receive bridging anticoagulation therapy with low-molecular-weight heparin (100 IU of dalteparin per kilogram of body weight) or matching placebo administered subcutaneously twice daily, from 3 days before the procedure until 24 hours before the procedure and then for 5 to 10 days after the procedure. Warfarin treatment was stopped 5 days before the procedure and was resumed within 24 hours after the procedure. Follow-up of patients continued for 30 days after the procedure. The primary outcomes were arterial thromboembolism (stroke, systemic embolism, or transient ischemic attack) and major bleeding.In total, 1884 patients were enrolled, with 950 assigned to receive no bridging therapy and 934 assigned to receive bridging therapy. The incidence of arterial thromboembolism was 0.4% in the no-bridging group and 0.3% in the bridging group (risk difference, 0.1 percentage points; 95% confidence interval [CI], -0.6 to 0.8; P=0.01 for noninferiority). The incidence of major bleeding was 1.3% in the no-bridging group and 3.2% in the bridging group (relative risk, 0.41; 95% CI, 0.20 to 0.78; P=0.005 for superiority).In patients with atrial fibrillation who had warfarin treatment interrupted for an elective operation or other elective invasive procedure, forgoing bridging anticoagulation was noninferior to perioperative bridging with low-molecular-weight heparin for the prevention of arterial thromboembolism and decreased the risk of major bleeding. (Funded by the National Heart, Lung, and Blood Institute of the National Institutes of Health; BRIDGE ClinicalTrials.gov number, NCT00786474.).

Authors
Douketis, JD; Spyropoulos, AC; Kaatz, S; Becker, RC; Caprini, JA; Dunn, AS; Garcia, DA; Jacobson, A; Jaffer, AK; Kong, DF; Schulman, S; Turpie, AGG; Hasselblad, V; Ortel, TL; BRIDGE Investigators,
MLA Citation
Douketis, JD, Spyropoulos, AC, Kaatz, S, Becker, RC, Caprini, JA, Dunn, AS, Garcia, DA, Jacobson, A, Jaffer, AK, Kong, DF, Schulman, S, Turpie, AGG, Hasselblad, V, Ortel, TL, and BRIDGE Investigators, . "Perioperative Bridging Anticoagulation in Patients with Atrial Fibrillation." The New England journal of medicine 373.9 (August 2015): 823-833.
PMID
26095867
Source
epmc
Published In
The New England journal of medicine
Volume
373
Issue
9
Publish Date
2015
Start Page
823
End Page
833
DOI
10.1056/nejmoa1501035

Recurrent venous thromboembolism in anticoagulated patients with cancer: management and short-term prognosis.

Recommendations for management of cancer-related venous thromboembolism (VTE) in patients already receiving anticoagulant therapy are based on low-quality evidence. This international registry sought to provide more information on outcomes after a breakthrough VTE in relation to anticoagulation strategies.Patients with cancer and VTE despite anticoagulant therapy were reported to the registry. Data on treatments, VTE events, major bleeding, residual thrombosis symptoms and death were collected for the following 3 months. Breakthrough VTE and subsequent recurrences were objectively verified. Outcomes with different treatment strategies were compared with Cox proportional hazards regression.We registered 212 patients with breakthrough VTE. Of those, 59% had adenocarcinoma and 73% had known metastases. At the time of the breakthrough event, 70% were on low-molecular-weight heparin (LMWH) and 27% on a vitamin K antagonist (VKA); 70% had a therapeutic or supratherapeutic dose. After breakthrough the regimen was: unchanged therapeutic dose in 33%, dose increased in 31%, switched to another drug in 24%; and other management in 11%. During the following 3 months 11% had another VTE, 8% had major bleeding and 27% died. Of the survivors, 74% had residual thrombosis symptoms. Additional VTE recurrence was less common with LMWH than with a VKA (hazard ratio [HR], 0.28; 95% confidence interval [CI], 0.11-0.70) but similar with unchanged or increased anticoagulant intensity (HR, 1.09; 95% CI, 0.45-2.63). The bleeding rate did not increase significantly with dose escalation.Morbidity and mortality are high after recurrence of cancer-related VTE despite anticoagulation. Further treatment appears to be more effective with LMWH than with a VKA.

Authors
Schulman, S; Zondag, M; Linkins, L; Pasca, S; Cheung, YW; de Sancho, M; Gallus, A; Lecumberri, R; Molnar, S; Ageno, W; Le Gal, G; Falanga, A; Hulegårdh, E; Ranta, S; Kamphuisen, P; Debourdeau, P; Rigamonti, V; Ortel, TL; Lee, A
MLA Citation
Schulman, S, Zondag, M, Linkins, L, Pasca, S, Cheung, YW, de Sancho, M, Gallus, A, Lecumberri, R, Molnar, S, Ageno, W, Le Gal, G, Falanga, A, Hulegårdh, E, Ranta, S, Kamphuisen, P, Debourdeau, P, Rigamonti, V, Ortel, TL, and Lee, A. "Recurrent venous thromboembolism in anticoagulated patients with cancer: management and short-term prognosis." Journal of thrombosis and haemostasis : JTH 13.6 (June 2015): 1010-1018.
PMID
25851122
Source
epmc
Published In
Journal of Thrombosis and Haemostasis
Volume
13
Issue
6
Publish Date
2015
Start Page
1010
End Page
1018
DOI
10.1111/jth.12955

Treatment of venous thromboembolism in cancer patients with dalteparin for up to 12 months: the DALTECAN Study.

Treatment of venous thromboembolism (VTE) in patients with cancer has a high rate of recurrence and bleeding complications. Guidelines recommend low-molecular-weight heparin (LMWH) for at least 3-6 months and possibly indefinitely for patients with active malignancy. There are, however, few data supporting treatment with LMWH beyond 6 months. The primary aim of the DALTECAN study (NCT00942968) was to determine the safety of dalteparin between 6 and 12 months in cancer-associated VTE.Patients with active cancer and newly diagnosed VTE were enrolled in a prospective, multicenter study and received subcutaneous dalteparin for 12 months. The rates of bleeding and recurrent VTE were evaluated at months 1, 2-6 and 7-12.Of 334 patients enrolled, 185 and 109 completed 6 and 12 months of therapy; 49.1% had deep vein thrombosis (DVT); 38.9% had pulmonary embolism (PE); and 12.0% had both on presentation. The overall frequency of major bleeding was 10.2% (34/334). Major bleeding occurred in 3.6% (12/334) in the first month, and 1.1% (14/1237) and 0.7% (8/1086) per patient-month during months 2-6 and 7-12, respectively. Recurrent VTE occurred in 11.1% (37/334); the incidence rate was 5.7% (19/334) for month 1, 3.4% (10/296) during months 2-6, and 4.1% (8/194) during months 7-12. One hundred and sixteen patients died, four due to recurrent VTE and two due to bleeding.Major bleeding was less frequent during dalteparin therapy beyond 6 months. The risk of developing major bleeding complications or VTE recurrence was greatest in the first month of therapy and lower over the subsequent 11 months.

Authors
Francis, CW; Kessler, CM; Goldhaber, SZ; Kovacs, MJ; Monreal, M; Huisman, MV; Bergqvist, D; Turpie, AG; Ortel, TL; Spyropoulos, AC; Pabinger, I; Kakkar, AK
MLA Citation
Francis, CW, Kessler, CM, Goldhaber, SZ, Kovacs, MJ, Monreal, M, Huisman, MV, Bergqvist, D, Turpie, AG, Ortel, TL, Spyropoulos, AC, Pabinger, I, and Kakkar, AK. "Treatment of venous thromboembolism in cancer patients with dalteparin for up to 12 months: the DALTECAN Study." Journal of thrombosis and haemostasis : JTH 13.6 (June 2015): 1028-1035.
PMID
25827941
Source
epmc
Published In
Journal of Thrombosis and Haemostasis
Volume
13
Issue
6
Publish Date
2015
Start Page
1028
End Page
1035
DOI
10.1111/jth.12923

Bridging anticoagulation in patients who require temporary interruption of warfarin therapy for an elective invasive procedure or surgery (the bridge trial)

Authors
Douketis, J; Spyropoulos, A; Kaatz, S; Caprini, J; Dunn, A; Garcia, D; Jacobson, A; Jaffer, A; Kindzelski, A; Schulman, S; Turpie, AG; Becker, R; Clark, NP; Conti, B; Ellsworth, S; Harrison, RW; Kong, D; Johnson, G; Krishnamoorthy, A; Palmeri, S; Parker, W; Saucedo, J; Schoch, P; Tallman, D; Witt, D; Hasselblad, V; Ortel, TL; Investigators, BRIDGES
MLA Citation
Douketis, J, Spyropoulos, A, Kaatz, S, Caprini, J, Dunn, A, Garcia, D, Jacobson, A, Jaffer, A, Kindzelski, A, Schulman, S, Turpie, AG, Becker, R, Clark, NP, Conti, B, Ellsworth, S, Harrison, RW, Kong, D, Johnson, G, Krishnamoorthy, A, Palmeri, S, Parker, W, Saucedo, J, Schoch, P, Tallman, D, Witt, D, Hasselblad, V, Ortel, TL, and Investigators, BRIDGES. "Bridging anticoagulation in patients who require temporary interruption of warfarin therapy for an elective invasive procedure or surgery (the bridge trial)." June 2015.
Source
wos-lite
Published In
Journal of Thrombosis and Haemostasis
Volume
13
Publish Date
2015
Start Page
83
End Page
84

Whole blood gene expression profiles distinguish clinical phenotypes of venous thromboembolism.

Recurrent venous thromboembolism (VTE) occurs infrequently following a provoked event but occurs in up to 30% of individuals following an initial unprovoked event. There is limited understanding of the biological mechanisms that predispose patients to recurrent VTE.To identify whole blood gene expression profiles that distinguished patients with clinically distinct patterns of VTE.We studied 107 patients with VTE separated into 3 groups: (1) 'low-risk' patients had one or more provoked VTE; (2) 'moderate-risk' patients had a single unprovoked VTE; (3) 'high-risk' patients had ≥2 unprovoked VTE. Each patient group was also compared to twenty-five individuals with no personal history of VTE. Total RNA from whole blood was isolated and hybridized to Illumina HT-12V4 Beadchips to assay whole genome expression.Using class prediction analysis, we distinguished high-risk patients from low-risk patients and healthy controls with good receiver operating curve characteristics (AUC=0.81 and 0.84, respectively). We also distinguished moderate-risk individuals and low-risk individuals from healthy controls with AUC's of 0.69 and 0.80, respectively. Using differential expression analysis, we identified several genes previously implicated in thrombotic disorders by genetic analyses, including SELP, KLKB1, ANXA5, and CD46. Protein levels for several of the identified genes were not significantly different between the different groups.Gene expression profiles are capable of distinguishing patients with different clinical presentations of VTE, and genes relevant to VTE risk are frequently differentially expressed in these comparisons.

Authors
Lewis, DA; Suchindran, S; Beckman, MG; Hooper, WC; Grant, AM; Heit, JA; Manco-Johnson, M; Moll, S; Philipp, CS; Kenney, K; De Staercke, C; Pyle, ME; Chi, J-T; Ortel, TL
MLA Citation
Lewis, DA, Suchindran, S, Beckman, MG, Hooper, WC, Grant, AM, Heit, JA, Manco-Johnson, M, Moll, S, Philipp, CS, Kenney, K, De Staercke, C, Pyle, ME, Chi, J-T, and Ortel, TL. "Whole blood gene expression profiles distinguish clinical phenotypes of venous thromboembolism." Thrombosis research 135.4 (April 2015): 659-665.
PMID
25684211
Source
epmc
Published In
Thrombosis Research
Volume
135
Issue
4
Publish Date
2015
Start Page
659
End Page
665
DOI
10.1016/j.thromres.2015.02.003

Platelet aggregation and mental stress induced myocardial ischemia: Results from the Responses of Myocardial Ischemia to Escitalopram Treatment (REMIT) study.

Mental stress-induced myocardial ischemia (MSIMI) is common in patients with ischemic heart disease (IHD) and associated with a poorer cardiovascular prognosis. Platelet hyperactivity is an important factor in acute coronary syndrome. This study examined associations between MSIMI and resting and mental stress-induced platelet activity.Eligible patients with clinically stable IHD underwent a battery of 3 mental stress tests during the recruitment phase of REMIT study. MSIMI was assessed by echocardiography and electrocardiography. Ex vivo platelet aggregation in response to ADP, epinephrine, collagen, serotonin, and combinations of serotonin plus ADP, epinephrine, and collagen were evaluated as was platelet serotonin transporter expression.Of the 270 participants who completed mental stress testing, and had both resting and post-stress platelet aggregation evaluation , 43.33% (n=117) met criteria for MSIMI and 18.15% (n=49) had normal left ventricular response to stress (NLVR). The MSIMI group, relative to the NLVR groups, demonstrated heightened mental stress-induced aggregation responses, as measured by area under the curve, to collagen 10μM (6.95[5.54] vs. -14.23[8.75].; P=0.045), epinephrine 10μM (12.84[4.84] vs. -6.40[7.61].; P=0.037) and to serotonin 10 μM plus ADP 1 μM (6.64[5.29] vs. -27.34[8.34]; P<.001). The resting platelet aggregation and serotonin transporter expression, however, were not different between the two groups.These findings suggest that the dynamic change of platelet aggregation caused by mental stress may underlie MSIMI. While the importance of these findings requires additional investigation, they raise concern given the recognized relationship between mental stress-induced platelet hyperactivity and cardiovascular events in patients with IHD.

Authors
Jiang, W; Boyle, SH; Ortel, TL; Samad, Z; Velazquez, EJ; Harrison, RW; Wilson, J; Kuhn, C; Williams, RB; O'Connor, CM; Becker, RC
MLA Citation
Jiang, W, Boyle, SH, Ortel, TL, Samad, Z, Velazquez, EJ, Harrison, RW, Wilson, J, Kuhn, C, Williams, RB, O'Connor, CM, and Becker, RC. "Platelet aggregation and mental stress induced myocardial ischemia: Results from the Responses of Myocardial Ischemia to Escitalopram Treatment (REMIT) study." American heart journal 169.4 (April 2015): 496-507.e1.
Website
http://hdl.handle.net/10161/15033
PMID
25819856
Source
epmc
Published In
American Heart Journal
Volume
169
Issue
4
Publish Date
2015
Start Page
496
End Page
507.e1
DOI
10.1016/j.ahj.2014.12.002

Effects of red-cell storage duration on patients undergoing cardiac surgery.

Some observational studies have reported that transfusion of red-cell units that have been stored for more than 2 to 3 weeks is associated with serious, even fatal, adverse events. Patients undergoing cardiac surgery may be especially vulnerable to the adverse effects of transfusion.We conducted a randomized trial at multiple sites from 2010 to 2014. Participants 12 years of age or older who were undergoing complex cardiac surgery and were likely to undergo transfusion of red cells were randomly assigned to receive leukocyte-reduced red cells stored for 10 days or less (shorter-term storage group) or for 21 days or more (longer-term storage group) for all intraoperative and postoperative transfusions. The primary outcome was the change in Multiple Organ Dysfunction Score (MODS; range, 0 to 24, with higher scores indicating more severe organ dysfunction) from the preoperative score to the highest composite score through day 7 or the time of death or discharge.The median storage time of red-cell units provided to the 1098 participants who received red-cell transfusion was 7 days in the shorter-term storage group and 28 days in the longer-term storage group. The mean change in MODS was an increase of 8.5 and 8.7 points, respectively (95% confidence interval for the difference, -0.6 to 0.3; P=0.44). The 7-day mortality was 2.8% in the shorter-term storage group and 2.0% in the longer-term storage group (P=0.43); 28-day mortality was 4.4% and 5.3%, respectively (P=0.57). Adverse events did not differ significantly between groups except that hyperbilirubinemia was more common in the longer-term storage group.The duration of red-cell storage was not associated with significant differences in the change in MODS. We did not find that the transfusion of red cells stored for 10 days or less was superior to the transfusion of red cells stored for 21 days or more among patients 12 years of age or older who were undergoing complex cardiac surgery. (Funded by the National Heart, Lung, and Blood Institute; RECESS ClinicalTrials.gov number, NCT00991341.).

Authors
Steiner, ME; Ness, PM; Assmann, SF; Triulzi, DJ; Sloan, SR; Delaney, M; Granger, S; Bennett-Guerrero, E; Blajchman, MA; Scavo, V; Carson, JL; Levy, JH; Whitman, G; D'Andrea, P; Pulkrabek, S; Ortel, TL; Bornikova, L; Raife, T; Puca, KE; Kaufman, RM; Nuttall, GA; Young, PP; Youssef, S; Engelman, R; Greilich, PE; Miles, R; Josephson, CD; Bracey, A; Cooke, R; McCullough, J; Hunsaker, R; Uhl, L; McFarland, JG; Park, Y; Cushing, MM; Klodell, CT; Karanam, R; Roberts, PR; Dyke, C; Hod, EA; Stowell, CP
MLA Citation
Steiner, ME, Ness, PM, Assmann, SF, Triulzi, DJ, Sloan, SR, Delaney, M, Granger, S, Bennett-Guerrero, E, Blajchman, MA, Scavo, V, Carson, JL, Levy, JH, Whitman, G, D'Andrea, P, Pulkrabek, S, Ortel, TL, Bornikova, L, Raife, T, Puca, KE, Kaufman, RM, Nuttall, GA, Young, PP, Youssef, S, Engelman, R, Greilich, PE, Miles, R, Josephson, CD, Bracey, A, Cooke, R, McCullough, J, Hunsaker, R, Uhl, L, McFarland, JG, Park, Y, Cushing, MM, Klodell, CT, Karanam, R, Roberts, PR, Dyke, C, Hod, EA, and Stowell, CP. "Effects of red-cell storage duration on patients undergoing cardiac surgery." The New England journal of medicine 372.15 (April 2015): 1419-1429.
PMID
25853746
Source
epmc
Published In
The New England journal of medicine
Volume
372
Issue
15
Publish Date
2015
Start Page
1419
End Page
1429
DOI
10.1056/nejmoa1414219

Inflammation markers and their trajectories after deep vein thrombosis in relation to risk of post-thrombotic syndrome.

Post-thrombotic syndrome (PTS) is a frequent chronic complication of deep vein thrombosis (DVT).In the BioSOX study, we investigated whether inflammation markers predict the risk of PTS after DVT.We measured C-reactive protein (CRP), ICAM-1, interleukin (IL)-6, and IL-10, at baseline, and 1 month and 6 months after a first proximal DVT, among 803 participants in the SOX trial. Participants were prospectively followed for 24 months for development of PTS.Median CRP levels at 1 month, ICAM-1 levels at baseline, 1 month and 6 months, IL-6 levels at 1 month and 6 months and IL-10 levels at 6 months were higher in patients who developed PTS than in those who did not. Multivariable regression with the median as a cutoff showed risk ratios (RRs) for PTS of 1.23 (95% confidence interval [CI] 1.05-1.45) and 1.25 (95% CI 1.05-1.48) for ICAM-1 at 1 month and 6 months, respectively, and 1.27 (95% CI 1.07-1.51) for IL-10 at 6 months. Quartile-based analysis demonstrated a dose-response association between ICAM-1 and PTS. ICAM-1 and IL-10 were also associated with PTS severity. Analysis of biomarker trajectories after DVT demonstrated an association between the highest-trajectory group of ICAM-1 and PTS.In this prospective study, ICAM-1 over time was most consistently associated with the risk of PTS. Further study is required to confirm these findings and assess their potential clinical relevance.

Authors
Rabinovich, A; Cohen, JM; Cushman, M; Wells, PS; Rodger, MA; Kovacs, MJ; Anderson, DR; Tagalakis, V; Lazo-Langner, A; Solymoss, S; Miron, MJ; Yeo, E; Smith, R; Schulman, S; Kassis, J; Kearon, C; Chagnon, I; Wong, T; Demers, C; Hanmiah, R; Kaatz, S; Selby, R; Rathbun, S; Desmarais, S; Opatrny, L; Ortel, TL; Ginsberg, JS; Kahn, SR
MLA Citation
Rabinovich, A, Cohen, JM, Cushman, M, Wells, PS, Rodger, MA, Kovacs, MJ, Anderson, DR, Tagalakis, V, Lazo-Langner, A, Solymoss, S, Miron, MJ, Yeo, E, Smith, R, Schulman, S, Kassis, J, Kearon, C, Chagnon, I, Wong, T, Demers, C, Hanmiah, R, Kaatz, S, Selby, R, Rathbun, S, Desmarais, S, Opatrny, L, Ortel, TL, Ginsberg, JS, and Kahn, SR. "Inflammation markers and their trajectories after deep vein thrombosis in relation to risk of post-thrombotic syndrome." Journal of thrombosis and haemostasis : JTH 13.3 (March 2015): 398-408.
PMID
25495610
Source
epmc
Published In
Journal of Thrombosis and Haemostasis
Volume
13
Issue
3
Publish Date
2015
Start Page
398
End Page
408
DOI
10.1111/jth.12814

Is it time for individualized thromboprophylaxis regimens in the ICU?

Authors
Welsby, I; Ortel, TL
MLA Citation
Welsby, I, and Ortel, TL. "Is it time for individualized thromboprophylaxis regimens in the ICU?." Critical care medicine 43.2 (February 2015): 500-501.
PMID
25599484
Source
epmc
Published In
Critical Care Medicine
Volume
43
Issue
2
Publish Date
2015
Start Page
500
End Page
501
DOI
10.1097/ccm.0000000000000784

Whole blood gene expression profiles distinguish clinical phenotypes of venous thromboembolism

© 2015 Elsevier Ltd. Introduction Recurrent venous thromboembolism (VTE) occurs infrequently following a provoked event but occurs in up to 30% of individuals following an initial unprovoked event. There is limited understanding of the biological mechanisms that predispose patients to recurrent VTE. Objectives To identify whole blood gene expression profiles that distinguished patients with clinically distinct patterns of VTE. Patients/Methods We studied 107 patients with VTE separated into 3 groups: (1) 'low-risk' patients had one or more provoked VTE; (2) 'moderate-risk' patients had a single unprovoked VTE; (3) 'high-risk' patients had 2 unprovoked VTE. Each patient group was also compared to twenty-five individuals with no personal history of VTE. Total RNA from whole blood was isolated and hybridized to Illumina HT-12 V4 Beadchips to assay whole genome expression. Results Using class prediction analysis, we distinguished high-risk patients from low-risk patients and healthy controls with good receiver operating curve characteristics (AUC = 0.81 and 0.84, respectively). We also distinguished moderate-risk individuals and low-risk individuals from healthy controls with AUC's of 0.69 and 0.80, respectively. Using differential expression analysis, we identified several genes previously implicated in thrombotic disorders by genetic analyses, including SELP, KLKB1, ANXA5, and CD46. Protein levels for several of the identified genes were not significantly different between the different groups. Conclusion Gene expression profiles are capable of distinguishing patients with different clinical presentations of VTE, and genes relevant to VTE risk are frequently differentially expressed in these comparisons.

Authors
Lewis, DA; Suchindran, S; Beckman, MG; Hooper, WC; Grant, AM; Heit, JA; Manco-Johnson, M; Moll, S; Philipp, CS; Kenney, K; De Staercke, C; Pyle, ME; Chi, JT; Ortel, TL
MLA Citation
Lewis, DA, Suchindran, S, Beckman, MG, Hooper, WC, Grant, AM, Heit, JA, Manco-Johnson, M, Moll, S, Philipp, CS, Kenney, K, De Staercke, C, Pyle, ME, Chi, JT, and Ortel, TL. "Whole blood gene expression profiles distinguish clinical phenotypes of venous thromboembolism." Thrombosis Research 135.4 (January 1, 2015): 659-665.
Source
scopus
Published In
Thrombosis Research
Volume
135
Issue
4
Publish Date
2015
Start Page
659
End Page
665
DOI
10.1016/j.thromres.2015.02.003

Inflammation markers and their trajectories after deep vein thrombosis in relation to risk of post-thrombotic syndrome

© 2014 International Society on Thrombosis and Haemostasis. Summary: Background: Post-thrombotic syndrome (PTS) is a frequent chronic complication of deep vein thrombosis (DVT). Objective: In the BioSOX study, we investigated whether inflammation markers predict the risk of PTS after DVT. Methods: We measured C-reactive protein (CRP), ICAM-1, interleukin (IL)-6, and IL-10, at baseline, and 1 month and 6 months after a first proximal DVT, among 803 participants in the SOX trial. Participants were prospectively followed for 24 months for development of PTS. Results: Median CRP levels at 1 month, ICAM-1 levels at baseline, 1 month and 6 months, IL-6 levels at 1 month and 6 months and IL-10 levels at 6 months were higher in patients who developed PTS than in those who did not. Multivariable regression with the median as a cutoff showed risk ratios (RRs) for PTS of 1.23 (95% confidence interval [CI] 1.05-1.45) and 1.25 (95% CI 1.05-1.48) for ICAM-1 at 1 month and 6 months, respectively, and 1.27 (95% CI 1.07-1.51) for IL-10 at 6 months. Quartile-based analysis demonstrated a dose-response association between ICAM-1 and PTS. ICAM-1 and IL-10 were also associated with PTS severity. Analysis of biomarker trajectories after DVT demonstrated an association between the highest-trajectory group of ICAM-1 and PTS. Conclusions: In this prospective study, ICAM-1 over time was most consistently associated with the risk of PTS. Further study is required to confirm these findings and assess their potential clinical relevance. Copyright

Authors
Rabinovich, A; Cohen, JM; Cushman, M; Wells, PS; Rodger, MA; Kovacs, MJ; Anderson, DR; Tagalakis, V; Lazo-Langner, A; Solymoss, S; Miron, MJ; Yeo, E; Smith, R; Schulman, S; Kassis, J; Kearon, C; Chagnon, I; Wong, T; Demers, C; Hanmiah, R; Kaatz, S; Selby, R; Rathbun, S; Desmarais, S; Opatrny, L; Ortel, TL; Ginsberg, JS; Kahn, SR
MLA Citation
Rabinovich, A, Cohen, JM, Cushman, M, Wells, PS, Rodger, MA, Kovacs, MJ, Anderson, DR, Tagalakis, V, Lazo-Langner, A, Solymoss, S, Miron, MJ, Yeo, E, Smith, R, Schulman, S, Kassis, J, Kearon, C, Chagnon, I, Wong, T, Demers, C, Hanmiah, R, Kaatz, S, Selby, R, Rathbun, S, Desmarais, S, Opatrny, L, Ortel, TL, Ginsberg, JS, and Kahn, SR. "Inflammation markers and their trajectories after deep vein thrombosis in relation to risk of post-thrombotic syndrome." Journal of Thrombosis and Haemostasis 13.3 (January 1, 2015): 398-408.
Source
scopus
Published In
Journal of Thrombosis and Haemostasis
Volume
13
Issue
3
Publish Date
2015
Start Page
398
End Page
408
DOI
10.1111/jth.12814

Platelet aggregation and mental stress induced myocardial ischemia: Results from the Responses of Myocardial Ischemia to Escitalopram Treatment (REMIT) study

© 2014 Elsevier Inc. Background Mental stress-induced myocardial ischemia (MSIMI) is common in patients with ischemic heart disease (IHD) and associated with a poorer cardiovascular prognosis. Platelet hyperactivity is an important factor in acute coronary syndrome. This study examined associations between MSIMI and resting and mental stress-induced platelet activity. Methods Eligible patients with clinically stable IHD underwent a battery of 3 mental stress tests during the recruitment phase of REMIT study. MSIMI was assessed by echocardiography and electrocardiography. Ex vivo platelet aggregation in response to ADP, epinephrine, collagen, serotonin, and combinations of serotonin plus ADP, epinephrine, and collagen were evaluated as was platelet serotonin transporter expression. Results Of the 270 participants who completed mental stress testing, and had both resting and post-stress platelet aggregation evaluation, 43.33% (n = 117) met criteria for MSIMI and 18.15% (n = 49) had normal left ventricular response to stress (NLVR). The MSIMI group, relative to the NLVR groups, demonstrated heightened mental stress-induced aggregation responses, as measured by area under the curve, to collagen 10 μM (6.95[5.54] vs. -14.23[8.75] .; P = 0.045), epinephrine 10 μM (12.84[4.84] vs. -6.40[7.61] .; P = 0.037) and to serotonin 10 μM plus ADP 1 μM (6.64[5.29] vs. -27.34[8.34] ; P < .001). The resting platelet aggregation and serotonin transporter expression, however, were not different between the two groups. Conclusions These findings suggest that the dynamic change of platelet aggregation caused by mental stress may underlie MSIMI. While the importance of these findings requires additional investigation, they raise concern given the recognized relationship between mental stress-induced platelet hyperactivity and cardiovascular events in patients with IHD.

Authors
Jiang, W; Boyle, SH; Ortel, TL; Samad, Z; Velazquez, EJ; Harrison, RW; Wilson, J; Kuhn, C; Williams, RB; O'Connor, CM; Becker, RC
MLA Citation
Jiang, W, Boyle, SH, Ortel, TL, Samad, Z, Velazquez, EJ, Harrison, RW, Wilson, J, Kuhn, C, Williams, RB, O'Connor, CM, and Becker, RC. "Platelet aggregation and mental stress induced myocardial ischemia: Results from the Responses of Myocardial Ischemia to Escitalopram Treatment (REMIT) study." American Heart Journal 169.4 (January 1, 2015): 496-507.e1.
Source
scopus
Published In
American Heart Journal
Volume
169
Issue
4
Publish Date
2015
Start Page
496
End Page
507.e1
DOI
10.1016/j.ahj.2014.12.002

Risk of venous thromboembolism occurrence among adults with selected autoimmune diseases: a study among a U.S. cohort of commercial insurance enrollees.

This study assessed the risk of venous thromboembolism (VTE) among privately insured adults in the U.S. with one or more of the following autoimmune diseases: autoimmune hemolytic anemia (AIHA), immune thrombocytopenic purpura (ITP), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE).Using the Truven Health MarketScan® Databases, patients 18-64 years of age with a diagnosis of AIHA, ITP, RA, or SLE in 2007 and a sex and age-group matched comparison group of enrollees were followed up through 2010 to identify VTE events. Survival curve and Cox proportional hazards analyses were conducted to assess differences between groups.Among patients with AIHA, ITP, RA, or SLE, or >1 of these diseases, the risk of at least one VTE event was 19.74, 7.72, 4.90, 9.89, and 13.35 per 1,000 person-years, respectively; among the comparison group, the risk was 1.91 per 1,000 person-years. The adjusted hazard ratios (aHRs) for VTE among patients with AIHA, ITP, RA, or SLE, or >1 of these diseases (when compared with the comparison group) tended to decline over follow-up time; at 1year, the aHRs were 6.30 (95% confidence interval [CI]: 4.44-8.94), 2.95 (95% CI: 2.18-4.00), 2.13 (95% CI: 1.89-2.40), 4.68 (95% CI: 4.10-5.33), and 5.11 (95% CI: 4.26-6.14), respectively.Having AIHA, ITP, RA, or SLE, or >1 of these diseases was associated with an increased likelihood of a VTE event. More research is necessary to develop better understanding of VTE occurrence among people with autoimmune diseases.

Authors
Yusuf, HR; Hooper, WC; Grosse, SD; Parker, CS; Boulet, SL; Ortel, TL
MLA Citation
Yusuf, HR, Hooper, WC, Grosse, SD, Parker, CS, Boulet, SL, and Ortel, TL. "Risk of venous thromboembolism occurrence among adults with selected autoimmune diseases: a study among a U.S. cohort of commercial insurance enrollees." Thrombosis research 135.1 (January 2015): 50-57.
PMID
25456001
Source
epmc
Published In
Thrombosis Research
Volume
135
Issue
1
Publish Date
2015
Start Page
50
End Page
57
DOI
10.1016/j.thromres.2014.10.012

Changing practice of anticoagulation: will target-specific anticoagulants replace warfarin?

The target-specific oral anticoagulants are a class of agents that inhibit factor Xa or thrombin. They are effective and safe compared to warfarin for the prevention of stroke and systemic embolism in patients with atrial fibrillation and for the treatment of venous thromboembolism, and they are comparable to low-molecular-weight heparin for thromboprophylaxis after hip or knee arthroplasty. For other indications, however, such as the prevention of stroke in patients with mechanical heart valves, initial studies have been unfavorable for the newer agents, leaving warfarin the anticoagulant of choice. Further studies are needed before the target-specific anticoagulants can be recommended for patients with cancer-associated thrombosis or heparin-induced thrombocytopenia. Concerns also persist about difficulties with the laboratory assessment of anticoagulant effect and the lack of a specific reversal agent. For these reasons, we anticipate that the vitamin K antagonists will continue to be important anticoagulants for years to come.

Authors
Arepally, GM; Ortel, TL
MLA Citation
Arepally, GM, and Ortel, TL. "Changing practice of anticoagulation: will target-specific anticoagulants replace warfarin?." Annual review of medicine 66 (January 2015): 241-253. (Review)
PMID
25587651
Source
epmc
Published In
Annual Review of Medicine
Volume
66
Publish Date
2015
Start Page
241
End Page
253
DOI
10.1146/annurev-med-051113-024633

Venous Thromboembolism (VTE) Surveillance: Incidence, Characteristics, and Initial Treatment of VTE Patients

Authors
Ortel, TL; Beckman, M; Muhlbaier, L; Reyes, N; Grant, A; Tcheng, J; Saber, I; Thames, E
MLA Citation
Ortel, TL, Beckman, M, Muhlbaier, L, Reyes, N, Grant, A, Tcheng, J, Saber, I, and Thames, E. "Venous Thromboembolism (VTE) Surveillance: Incidence, Characteristics, and Initial Treatment of VTE Patients." BLOOD 124.21 (December 6, 2014).
Source
wos-lite
Published In
Blood
Volume
124
Issue
21
Publish Date
2014

Graduated compression stockings to treat acute leg pain associated with proximal DVT. A randomised controlled trial.

Acute deep venous thrombosis (DVT) causes leg pain. Elastic compression stockings (ECS) have potential to relieve DVT-related leg pain by diminishing the diameter of distended veins and increasing venous blood flow. It was our objective to determine whether ECS reduce leg pain in patients with acute DVT. We performed a secondary analysis of the SOX Trial, a multicentre randomised placebo controlled trial of active ECS versus placebo ECS to prevent the post-thrombotic syndrome.The study was performed in 24 hospital centres in Canada and the U.S. and included 803 patients with a first episode of acute proximal DVT. Patients were randomised to receive active ECS (knee length, 30-40 mm Hg graduated pressure) or placebo ECS (manufactured to look identical to active ECS, but lacking therapeutic compression). Study outcome was leg pain severity assessed on an 11-point numerical pain rating scale (0, no pain; 10, worst possible pain) at baseline, 14, 30 and 60 days after randomisation. Mean age was 55 years and 60% were male. In active ECS patients (n=409), mean (SD) pain severity at baseline and at 60 days were 5.18 (3.29) and 1.39 (2.19), respectively, and in placebo ECS patients (n=394) were 5.38 (3.29) and 1.13 (1.86), respectively. There were no significant differences in pain scores between groups at any assessment point, and no evidence for subgroup interaction by age, sex or anatomical extent of DVT. Results were similar in an analysis restricted to patients who reported wearing stockings every day. In conclusion, ECS do not reduce leg pain in patients with acute proximal DVT.

Authors
Kahn, SR; Shapiro, S; Ducruet, T; Wells, PS; Rodger, MA; Kovacs, MJ; Anderson, D; Tagalakis, V; Morrison, DR; Solymoss, S; Miron, M-J; Yeo, E; Smith, R; Schulman, S; Kassis, J; Kearon, C; Chagnon, I; Wong, T; Demers, C; Hanmiah, R; Kaatz, S; Selby, R; Rathbun, S; Desmarais, S; Opatrny, L; Ortel, TL; Galanaud, J-P; Ginsberg, JS
MLA Citation
Kahn, SR, Shapiro, S, Ducruet, T, Wells, PS, Rodger, MA, Kovacs, MJ, Anderson, D, Tagalakis, V, Morrison, DR, Solymoss, S, Miron, M-J, Yeo, E, Smith, R, Schulman, S, Kassis, J, Kearon, C, Chagnon, I, Wong, T, Demers, C, Hanmiah, R, Kaatz, S, Selby, R, Rathbun, S, Desmarais, S, Opatrny, L, Ortel, TL, Galanaud, J-P, and Ginsberg, JS. "Graduated compression stockings to treat acute leg pain associated with proximal DVT. A randomised controlled trial." Thrombosis and haemostasis 112.6 (December 2014): 1137-1141.
PMID
25183442
Source
epmc
Published In
Thrombosis and haemostasis
Volume
112
Issue
6
Publish Date
2014
Start Page
1137
End Page
1141
DOI
10.1160/th14-05-0430

Risk of venous thromboembolism among hospitalizations of adults with selected autoimmune diseases.

Previous research has suggested autoimmune diseases are risk factors for developing venous thromboembolism (VTE). We assessed whether having diagnoses of selected autoimmune diseases associated with antiphospholipid antibodies--autoimmune hemolytic anemia (AIHA), immune thrombocytopenic purpura (ITP), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE)--were associated with having a VTE diagnosis among US adult hospitalizations. A cross-sectional study was conducted using the 2010 Nationwide Inpatient Sample of the Healthcare Cost and Utilization Project, Agency for Healthcare Research and Quality. VTE and autoimmune diseases were identified using International Classification of Diseases, Ninth Revision, Clinical Modification coded diagnoses information. The percentages of hospitalizations with a VTE diagnosis among all non-maternal adult hospitalizations without any of the four autoimmune diseases of interest and among those with AIHA, ITP, RA, and SLE diagnoses were 2.28, 4.46, 3.35, 2.65 and 2.77%, respectively. The adjusted odds ratios (OR) for having a diagnosis of VTE among non-maternal adult hospitalizations with diagnoses of AIHA, ITP, RA, and SLE were 1.25 [95% confidence interval (CI) 1.05-1.49], 1.20 (95% CI 1.07-1.34), 1.17 (95% CI 1.13-1.21), and 1.23 (95% CI 1.15-1.32), respectively, when compared to those without the corresponding conditions. The adjusted OR for a diagnosis of VTE associated with a diagnosis of any of the four autoimmune diseases was 1.20 (95% CI 1.16-1.24). The presence of a diagnosis of AIHA, ITP, RA, and SLE was associated with an increased likelihood of having a VTE diagnosis among the group of all non-maternal adult hospitalizations.

Authors
Yusuf, HR; Hooper, WC; Beckman, MG; Zhang, QC; Tsai, J; Ortel, TL
MLA Citation
Yusuf, HR, Hooper, WC, Beckman, MG, Zhang, QC, Tsai, J, and Ortel, TL. "Risk of venous thromboembolism among hospitalizations of adults with selected autoimmune diseases." Journal of thrombosis and thrombolysis 38.3 (October 2014): 306-313.
PMID
24464552
Source
epmc
Published In
Journal of Thrombosis and Thrombolysis
Volume
38
Issue
3
Publish Date
2014
Start Page
306
End Page
313
DOI
10.1007/s11239-014-1050-0

The effect of the REG2 Anticoagulation System on thrombin generation kinetics: a pharmacodynamic and pharmacokinetic first-in-human study.

The REG2 Anticoagulation System consists of pegnivacogin, a subcutaneously administered aptamer factor IXa inhibitor, and its intravenous active control agent, anivamersen. Its effect on thrombin generation is unknown. A prospectively designed thrombin generation study was conducted within the phase 1 ascending dose study of REG2 to assess the effect of REG2 on thrombin generation kinetics. A total of 32 healthy volunteers were recruited into four cohorts of ascending dose pegnivacogin for the phase 1 study. In this pre-specified substudy, blood samples were drawn in the presence or absence of corn trypsin inhibitor at specified times within each dosing cohort. Thrombin generation was initiated with tissue factor and thrombin generation kinetics were measured using the Calibrated Automated Thrombogram (CAT). REG2 attenuated thrombin generation in a dose-dependent manner. All parameters of the CAT assay, except for lag time, showed a dose and concentration-dependent response to pegnivacogin [time to peak thrombin generation (PTm), endogenous thrombin potential, peak thrombin generation, and velocity index (VIx)]. Reversal of the effect of pegnivacogin with anivamersen demonstrated restoration of thrombin generation without rebound effect. This first-in-human study of the effect of the REG2 Anticoagulation System on thrombin generation demonstrates concentration-dependent suppression of thrombin generation that is reversible without rebound effect, as measured by the CAT assay.

Authors
Vavalle, JP; Rusconi, CP; Zelenkofske, S; Wargin, WA; Ortel, TL; Alexander, JH; Povsic, TJ; Becker, RC
MLA Citation
Vavalle, JP, Rusconi, CP, Zelenkofske, S, Wargin, WA, Ortel, TL, Alexander, JH, Povsic, TJ, and Becker, RC. "The effect of the REG2 Anticoagulation System on thrombin generation kinetics: a pharmacodynamic and pharmacokinetic first-in-human study." Journal of thrombosis and thrombolysis 38.3 (October 2014): 275-284.
PMID
24880800
Source
epmc
Published In
Journal of Thrombosis and Thrombolysis
Volume
38
Issue
3
Publish Date
2014
Start Page
275
End Page
284
DOI
10.1007/s11239-014-1081-6

Sex differences in platelet reactivity and cardiovascular and psychological response to mental stress in patients with stable ischemic heart disease: insights from the REMIT study.

Although emotional stress is associated with ischemic heart disease (IHD) and related clinical events, sex-specific differences in the psychobiological response to mental stress have not been clearly identified.We aimed to study the differential psychological and cardiovascular responses to mental stress between male and female patients with stable IHD.Patients with stable IHD enrolled in the REMIT (Responses of Mental Stress-Induced Myocardial Ischemia to Escitalopram) study underwent psychometric assessments, transthoracic echocardiography, and platelet aggregation studies at baseline and after 3 mental stress tasks. Mental stress-induced myocardial ischemia (MSIMI) was defined as the development or worsening of regional wall motion abnormality, reduction of left ventricular ejection fraction (LVEF) ≥8% by transthoracic echocardiography, and/or ischemic ST-segment change on electrocardiogram during 1 or more of the 3 mental stress tasks.In the 310 participants with known IHD (18% women, 82% men), most baseline characteristics were similar between women and men (including heart rate, blood pressure, and LVEF), although women were more likely to be nonwhite, living alone (p < 0.001), and unmarried (p < 0.001); they also had higher baseline depression and anxiety (p < 0.05). At rest, women had heightened platelet aggregation responses to serotonin (p = 0.007) and epinephrine (p = 0.004) compared with men. Following mental stress, women had more MSIMI (57% vs. 41%; p < 0.04), expressed more negative (p = 0.02) and less positive emotion (p < 0.001), and demonstrated higher collagen-stimulated platelet aggregation responses (p = 0.04) than men. Men were more likely than women to show changes in traditional physiological measures, such as blood pressure (p < 0.05) and double product.In this exploratory analysis, we identified clear, measurable, and differential responses to mental stress in women and men. Further studies should test the association of sex differences in cardiovascular and platelet reactivity in response to mental stress and long-term outcomes. (Responses of Myocardial Ischemia to Escitalopram Treatment [REMIT]; NCT00574847).

Authors
Samad, Z; Boyle, S; Ersboll, M; Vora, AN; Zhang, Y; Becker, RC; Williams, R; Kuhn, C; Ortel, TL; Rogers, JG; O'Connor, CM; Velazquez, EJ; Jiang, W; REMIT Investigators,
MLA Citation
Samad, Z, Boyle, S, Ersboll, M, Vora, AN, Zhang, Y, Becker, RC, Williams, R, Kuhn, C, Ortel, TL, Rogers, JG, O'Connor, CM, Velazquez, EJ, Jiang, W, and REMIT Investigators, . "Sex differences in platelet reactivity and cardiovascular and psychological response to mental stress in patients with stable ischemic heart disease: insights from the REMIT study." Journal of the American College of Cardiology 64.16 (October 2014): 1669-1678.
PMID
25323254
Source
epmc
Published In
JACC - Journal of the American College of Cardiology
Volume
64
Issue
16
Publish Date
2014
Start Page
1669
End Page
1678
DOI
10.1016/j.jacc.2014.04.087

14th International Congress on Antiphospholipid Antibodies Task Force. Report on antiphospholipid syndrome laboratory diagnostics and trends.

Current classification criteria for definite Antiphospholipid Syndrome (APS) require the use of three laboratory assays to detect antiphospholipid antibodies (aCL, anti-β2GPI and LA) in the presence of at least one of the two major clinical manifestations (i.e. thrombosis or pregnancy morbidity) of the syndrome. However, several other autoantibodies shown to be directed to other proteins or their complex with phospholipids have been proposed to be relevant to APS but their clinical utility and their diagnostic value remains elusive. This report summarizes the findings, conclusions and recommendations of the "APS Task Force 3-Laboratory Diagnostics and Trends" meeting that took place during the 14th International Congress on Antiphospholipid Antibodies (APLA 2013, September 18-21, Rio de Janeiro, RJ, Brazil).

Authors
Bertolaccini, ML; Amengual, O; Andreoli, L; Atsumi, T; Chighizola, CB; Forastiero, R; de Groot, P; Lakos, G; Lambert, M; Meroni, P; Ortel, TL; Petri, M; Rahman, A; Roubey, R; Sciascia, S; Snyder, M; Tebo, AE; Tincani, A; Willis, R
MLA Citation
Bertolaccini, ML, Amengual, O, Andreoli, L, Atsumi, T, Chighizola, CB, Forastiero, R, de Groot, P, Lakos, G, Lambert, M, Meroni, P, Ortel, TL, Petri, M, Rahman, A, Roubey, R, Sciascia, S, Snyder, M, Tebo, AE, Tincani, A, and Willis, R. "14th International Congress on Antiphospholipid Antibodies Task Force. Report on antiphospholipid syndrome laboratory diagnostics and trends." Autoimmunity reviews 13.9 (September 2014): 917-930. (Review)
PMID
24824074
Source
epmc
Published In
Autoimmunity Reviews
Volume
13
Issue
9
Publish Date
2014
Start Page
917
End Page
930
DOI
10.1016/j.autrev.2014.05.001

14th International Congress on Antiphospholipid Antibodies Task Force. Report on antiphospholipid syndrome laboratory diagnostics and trends

Authors
Bertolaccini, ML; Amengual, O; Andreoli, L; Atsumi, T; Chighizola, CB; Forastiero, R; de Groot, P; Lakos, G; Lambert, M; Meroni, P; Ortel, TL; Petri, M; Rahman, A; Roubey, R; Sciascia, S; Snyder, M; Tebo, AE; Tincani, A; Willis, R
MLA Citation
Bertolaccini, ML, Amengual, O, Andreoli, L, Atsumi, T, Chighizola, CB, Forastiero, R, de Groot, P, Lakos, G, Lambert, M, Meroni, P, Ortel, TL, Petri, M, Rahman, A, Roubey, R, Sciascia, S, Snyder, M, Tebo, AE, Tincani, A, and Willis, R. "14th International Congress on Antiphospholipid Antibodies Task Force. Report on antiphospholipid syndrome laboratory diagnostics and trends." Autoimmunity Reviews 13.9 (September 2014): 917-930.
Source
crossref
Published In
Autoimmunity Reviews
Volume
13
Issue
9
Publish Date
2014
Start Page
917
End Page
930
DOI
10.1016/j.autrev.2014.05.001

Challenges and priorities for research: a report from the National Heart, Lung, and Blood Institute (NHLBI)/National Institutes of Health (NIH) Working Group on thrombosis in pediatric cardiology and congenital heart disease.

Authors
McCrindle, BW; Li, JS; Manlhiot, C; Tweddell, JS; Giglia, TM; Massicotte, MP; Monagle, P; Krishnamurthy, R; Mahaffey, KW; Michelson, AD; Verdun, N; Almond, CS; Newburger, JW; Brandão, LR; Esmon, CT; Manco-Johnson, MJ; Ichord, R; Ortel, TL; Chan, AK; Portman, R; Rose, M; Strony, J; Kaltman, JR
MLA Citation
McCrindle, BW, Li, JS, Manlhiot, C, Tweddell, JS, Giglia, TM, Massicotte, MP, Monagle, P, Krishnamurthy, R, Mahaffey, KW, Michelson, AD, Verdun, N, Almond, CS, Newburger, JW, Brandão, LR, Esmon, CT, Manco-Johnson, MJ, Ichord, R, Ortel, TL, Chan, AK, Portman, R, Rose, M, Strony, J, and Kaltman, JR. "Challenges and priorities for research: a report from the National Heart, Lung, and Blood Institute (NHLBI)/National Institutes of Health (NIH) Working Group on thrombosis in pediatric cardiology and congenital heart disease." Circulation 130.14 (September 2014): 1192-1203.
PMID
25266860
Source
epmc
Published In
Circulation
Volume
130
Issue
14
Publish Date
2014
Start Page
1192
End Page
1203
DOI
10.1161/circulationaha.113.008428

Pharmacometabolomics reveals that serotonin is implicated in aspirin response variability.

While aspirin is generally effective for prevention of cardiovascular disease, considerable variation in drug response exists, resulting in some individuals displaying high on-treatment platelet reactivity. We used pharmacometabolomics to define pathways implicated in variation of response to treatment. We profiled serum samples from healthy subjects pre- and postaspirin (14 days, 81 mg/day) using mass spectrometry. We established a strong signature of aspirin exposure independent of response (15/34 metabolites changed). In our discovery (N = 80) and replication (N = 125) cohorts, higher serotonin levels pre- and postaspirin correlated with high, postaspirin, collagen-induced platelet aggregation. In a third cohort, platelets from subjects with the highest levels of serotonin preaspirin retained higher reactivity after incubation with aspirin than platelets from subjects with the lowest serotonin levels preaspirin (72 ± 8 vs. 61 ± 11%, P = 0.02, N = 20). Finally, ex vivo, serotonin strongly increased platelet reactivity after platelet incubation with aspirin (+20%, P = 4.9 × 10(-4), N = 12). These results suggest that serotonin is implicated in aspirin response variability.

Authors
Ellero-Simatos, S; Lewis, JP; Georgiades, A; Yerges-Armstrong, LM; Beitelshees, AL; Horenstein, RB; Dane, A; Harms, AC; Ramaker, R; Vreeken, RJ; Perry, CG; Zhu, H; Sànchez, CL; Kuhn, C; Ortel, TL; Shuldiner, AR; Hankemeier, T; Kaddurah-Daouk, R
MLA Citation
Ellero-Simatos, S, Lewis, JP, Georgiades, A, Yerges-Armstrong, LM, Beitelshees, AL, Horenstein, RB, Dane, A, Harms, AC, Ramaker, R, Vreeken, RJ, Perry, CG, Zhu, H, Sànchez, CL, Kuhn, C, Ortel, TL, Shuldiner, AR, Hankemeier, T, and Kaddurah-Daouk, R. "Pharmacometabolomics reveals that serotonin is implicated in aspirin response variability." CPT: Pharmacometrics & Systems Pharmacology 3 (July 16, 2014): e125-.
PMID
25029353
Source
epmc
Published In
CPT: Pharmacometrics and Systems Pharmacology
Volume
3
Publish Date
2014
Start Page
e125
DOI
10.1038/psp.2014.22

14th International Congress on Antiphospholipid Antibodies: task force report on antiphospholipid syndrome treatment trends.

Antiphospholipid Syndrome (APS) is characterized by vascular thrombosis and/or pregnancy morbidity occurring in patients with persistent antiphospholipid antibodies (aPL). The primary objective of the APS Treatment Trends Task Force, created as part of the 14th International Congress on aPL, was to systematically review the potential future treatment strategies for aPL-positive patients. The task force chose as future clinical research directions: a) determining the necessity for controlled clinical trials in venous thromboembolism with the new oral direct thrombin or anti-factor Xa inhibitors pending the results of the ongoing rivaroxaban in APS (RAPS) trial, and designing controlled clinical trials in other forms of thrombotic APS; b) systematically analyzing the literature as well as aPL/APS registries, and creating specific registries for non-warfarin/heparin anticoagulants; c) increasing recruitment for an ongoing primary thrombosis prevention trial, and designing secondary thrombosis and pregnancy morbidity prevention trials with hydroxychloroquine; d) determining surrogate markers to select patients for statin trials; e) designing controlled studies with rituximab and other anti-B-cell agents; f) designing mechanistic and clinical studies with eculizumab and other complement inhibitors; and g) chemically modifying peptide therapy to improve the half-life and minimize immunogenicity. The report also includes recommendations for clinicians who consider using these agents in difficult-to-manage aPL-positive patients.

Authors
Erkan, D; Aguiar, CL; Andrade, D; Cohen, H; Cuadrado, MJ; Danowski, A; Levy, RA; Ortel, TL; Rahman, A; Salmon, JE; Tektonidou, MG; Willis, R; Lockshin, MD
MLA Citation
Erkan, D, Aguiar, CL, Andrade, D, Cohen, H, Cuadrado, MJ, Danowski, A, Levy, RA, Ortel, TL, Rahman, A, Salmon, JE, Tektonidou, MG, Willis, R, and Lockshin, MD. "14th International Congress on Antiphospholipid Antibodies: task force report on antiphospholipid syndrome treatment trends." Autoimmunity reviews 13.6 (June 2014): 685-696. (Review)
PMID
24468415
Source
epmc
Published In
Autoimmunity Reviews
Volume
13
Issue
6
Publish Date
2014
Start Page
685
End Page
696
DOI
10.1016/j.autrev.2014.01.053

Testing for antiphospholipid antibodies with solid phase assays: guidance from the SSC of the ISTH.

Authors
Devreese, KMJ; Pierangeli, SS; de Laat, B; Tripodi, A; Atsumi, T; Ortel, TL; Subcommittee on Lupus Anticoagulant/Phospholipid/Dependent Antibodies,
MLA Citation
Devreese, KMJ, Pierangeli, SS, de Laat, B, Tripodi, A, Atsumi, T, Ortel, TL, and Subcommittee on Lupus Anticoagulant/Phospholipid/Dependent Antibodies, . "Testing for antiphospholipid antibodies with solid phase assays: guidance from the SSC of the ISTH." Journal of thrombosis and haemostasis : JTH 12.5 (May 2014): 792-795.
PMID
24589091
Source
epmc
Published In
Journal of Thrombosis and Haemostasis
Volume
12
Issue
5
Publish Date
2014
Start Page
792
End Page
795
DOI
10.1111/jth.12537

Thromboprophylaxis with fondaparinux in high-risk postoperative patients with renal insufficiency.

Fondaparinux is an antithrombin-dependent factor Xa inhibitor that is used for thromboprophylaxis of patients undergoing hip fracture surgery, hip or knee replacement, or abdominal surgery. It is cleared by the kidney and should be used with caution in patients with renal impairment and avoided in patients with severe renal insufficiency. Recently, several studies have demonstrated that a lower dose of fondaparinux in patients with moderate renal impairment appears to be safe and effective. The purpose of this study was to obtain pharmacokinetic and clinical data on the use of prophylactic fondaparinux in patients with renal insufficiency undergoing major abdominal surgery for cancer (n=8) or orthopedic surgery (n=1). Anti-factor Xa levels were obtained, and a published population pharmacokinetic model for fondaparinux was fit to the data. The data were analyzed using NONMEM software. Fondaparinux did not appear to accumulate in these patients, even when the drug was administered for up to twelve days. Pharmacokinetic analysis revealed that the apparent clearance in this population, who were primarily undergoing cancer surgery, was similar to prior studies in orthopedic surgery patients. In contrast, lower estimates were obtained for volume of distribution and absorption rate constant parameters. None of the patients sustained a hemorrhagic complication attributable to fondaparinux. One patient developed hypoxia in the setting of transient atrial fibrillation and clinical suspicion for pulmonary embolism, but this was not confirmed radiographically. These results support the use of 1.5mg of fondaparinux every 24hours for thromboprophylaxis in patients with renal insufficiency undergoing high-risk surgical procedures.

Authors
Hester, W; Fry, C; Gonzalez, D; Cohen-Wolkowiez, M; Inman, BA; Ortel, TL
MLA Citation
Hester, W, Fry, C, Gonzalez, D, Cohen-Wolkowiez, M, Inman, BA, and Ortel, TL. "Thromboprophylaxis with fondaparinux in high-risk postoperative patients with renal insufficiency." Thrombosis research 133.4 (April 2014): 629-633.
PMID
24508189
Source
epmc
Published In
Thrombosis Research
Volume
133
Issue
4
Publish Date
2014
Start Page
629
End Page
633
DOI
10.1016/j.thromres.2013.11.019

Review: New oral factor Xa inhibitors reduce DVT compared with standard thromboprophylaxis after THR or TKR

Authors
Shivakumar, S; Douketis, J
MLA Citation
Shivakumar, S, and Douketis, J. "Review: New oral factor Xa inhibitors reduce DVT compared with standard thromboprophylaxis after THR or TKR." Annals of Internal Medicine 160.2 (January 21, 2014): JC3-JC3.
Source
crossref
Published In
Annals of internal medicine
Volume
160
Issue
2
Publish Date
2014
Start Page
JC3
End Page
JC3
DOI
10.7326/0003-4819-160-2-201401210-02003

Differences in thrombotic risk factors in black and white women with adverse pregnancy outcome

Introduction Black women have an increased risk of adverse pregnancy outcomes and the characteristics of thrombotic risk factors in this population are unknown. The objective of this study was to examine the racial differences in thrombotic risk factors among women with adverse pregnancy outcomes. Methods Uniform data were collected in women with adverse pregnancy outcomes (pregnancy losses, intrauterine growth restriction (IUGR), prematurity, placental abruption and preeclampsia) referred to Thrombosis Network Centers funded by the Centers for Disease Control and Prevention (CDC). Results Among 343 white and 66 black women seen for adverse pregnancy outcomes, protein S and antithrombin deficiencies were more common in black women. The prevalence of diagnosed thrombophilia was higher among whites compared to blacks largely due to Factor V Leiden mutation. The prevalence of a personal history of venous thromboembolism (VTE) did not differ significantly by race. A family history of VTE, thrombophilia, and stroke or myocardial infarction (MI) was higher among whites. Black women had a higher body mass index, and a higher prevalence of hypertension, while the prevalence of sickle cell disease was approximately 27 fold higher compared to the general US black population. Conclusions Thrombotic risk factors differ significantly in white and black women with adverse pregnancy outcomes. Such differences highlight the importance of considering race separately when assessing thrombotic risk factors for adverse pregnancy outcomes. © 2013 Elsevier Ltd. All rights reserved.

Authors
Philipp, CS; Faiz, AS; Beckman, MG; Grant, A; Bockenstedt, PL; Heit, JA; James, AH; Kulkarni, R; Manco-Johnson, MJ; Moll, S; Ortel, TL
MLA Citation
Philipp, CS, Faiz, AS, Beckman, MG, Grant, A, Bockenstedt, PL, Heit, JA, James, AH, Kulkarni, R, Manco-Johnson, MJ, Moll, S, and Ortel, TL. "Differences in thrombotic risk factors in black and white women with adverse pregnancy outcome." Thrombosis Research 133.1 (January 1, 2014): 108-111.
Source
scopus
Published In
Thrombosis Research
Volume
133
Issue
1
Publish Date
2014
Start Page
108
End Page
111
DOI
10.1016/j.thromres.2013.10.035

Compression stockings to prevent post-thrombotic syndrome: A randomised placebo-controlled trial

Background Post-thrombotic syndrome (PTS) is a common and burdensome complication of deep venous thrombosis (DVT). Previous trials suggesting benefit of elastic compression stockings (ECS) to prevent PTS were small, singlecentre studies without placebo control. We aimed to assess the efficacy of ECS, compared with placebo stockings, for the prevention of PTS. Methods We did a multicentre randomised placebo-controlled trial of active versus placebo ECS used for 2 years to prevent PTS after a first proximal DVT in centres in Canada and the USA. Patients were randomly assigned to study groups with a web-based randomisation system. Patients presenting with a first symptomatic, proximal DVT were potentially eligible to participate. They were excluded if the use of compression stockings was contraindicated, they had an expected lifespan of less than 6 months, geographical inaccessibility precluded return for follow-up visits, they were unable to apply stockings, or they received thrombolytic therapy for the initial treatment of acute DVT. The primary outcome was PTS diagnosed at 6 months or later using Ginsbergs criteria (leg pain and swelling of ≥1 month duration). We used a modified intention to treat Cox regression analysis, supplemented by a prespecified per-protocol analysis of patients who reported frequent use of their allocated treatment. This study is registered with ClinicalTrials. gov, number NCT00143598, and Current Controlled Trials, number ISRCTN71334751. Findings From 2004 to 2010, 410 patients were randomly assigned to receive active ECS and 396 placebo ECS. The cumulative incidence of PTS was 14·2% in active ECS versus 12·7% in placebo ECS (hazard ratio adjusted for centre 1·13, 95% CI 0·73-1·76; p=0·58). Results were similar in a prespecified per-protocol analysis of patients who reported frequent use of stockings. Interpretation ECS did not prevent PTS after a first proximal DVT, hence our findings do not support routine wearing of ECS after DVT.

Authors
Kahn, SR; Shapiro, S; Wells, PS; Rodger, MA; Kovacs, MJ; Anderson, DR; Tagalakis, V; Houweling, AH; Ducruet, T; Holcroft, C; Johri, M; Solymoss, S; Miron, MJ; Yeo, E; Smith, R; Schulman, S; Kassis, J; Kearon, C; Chagnon, I; Wong, T; Demers, C; Hanmiah, R; Kaatz, S; Selby, R; Rathbun, S; Desmarais, S; Opatrny, L; Ortel, TL; Ginsberg, JS
MLA Citation
Kahn, SR, Shapiro, S, Wells, PS, Rodger, MA, Kovacs, MJ, Anderson, DR, Tagalakis, V, Houweling, AH, Ducruet, T, Holcroft, C, Johri, M, Solymoss, S, Miron, MJ, Yeo, E, Smith, R, Schulman, S, Kassis, J, Kearon, C, Chagnon, I, Wong, T, Demers, C, Hanmiah, R, Kaatz, S, Selby, R, Rathbun, S, Desmarais, S, Opatrny, L, Ortel, TL, and Ginsberg, JS. "Compression stockings to prevent post-thrombotic syndrome: A randomised placebo-controlled trial." The Lancet 383.9920 (January 1, 2014): 880-888.
Source
scopus
Published In
The Lancet
Volume
383
Issue
9920
Publish Date
2014
Start Page
880
End Page
888
DOI
10.1016/S0140-6736(13)61902-9

Thromboprophylaxis with fondaparinux in high-risk postoperative patients with renal insufficiency

Fondaparinux is an antithrombin-dependent factor Xa inhibitor that is used for thromboprophylaxis of patients undergoing hip fracture surgery, hip or knee replacement, or abdominal surgery. It is cleared by the kidney and should be used with caution in patients with renal impairment and avoided in patients with severe renal insufficiency. Recently, several studies have demonstrated that a lower dose of fondaparinux in patients with moderate renal impairment appears to be safe and effective. The purpose of this study was to obtain pharmacokinetic and clinical data on the use of prophylactic fondaparinux in patients with renal insufficiency undergoing major abdominal surgery for cancer (n = 8) or orthopedic surgery (n = 1). Anti-factor Xa levels were obtained, and a published population pharmacokinetic model for fondaparinux was fit to the data. The data were analyzed using NONMEM software. Fondaparinux did not appear to accumulate in these patients, even when the drug was administered for up to twelve days. Pharmacokinetic analysis revealed that the apparent clearance in this population, who were primarily undergoing cancer surgery, was similar to prior studies in orthopedic surgery patients. In contrast, lower estimates were obtained for volume of distribution and absorption rate constant parameters. None of the patients sustained a hemorrhagic complication attributable to fondaparinux. One patient developed hypoxia in the setting of transient atrial fibrillation and clinical suspicion for pulmonary embolism, but this was not confirmed radiographically. These results support the use of 1.5 mg of fondaparinux every 24 hours for thromboprophylaxis in patients with renal insufficiency undergoing high-risk surgical procedures. © 2013 Elsevier Ltd.

Authors
Hester, W; Fry, C; Gonzalez, D; Cohen-Wolkowiez, M; Inman, BA; Ortel, TL
MLA Citation
Hester, W, Fry, C, Gonzalez, D, Cohen-Wolkowiez, M, Inman, BA, and Ortel, TL. "Thromboprophylaxis with fondaparinux in high-risk postoperative patients with renal insufficiency." Thrombosis Research 133.4 (January 1, 2014): 629-633.
Source
scopus
Published In
Thrombosis Research
Volume
133
Issue
4
Publish Date
2014
Start Page
629
End Page
633
DOI
10.1016/j.thromres.2013.11.019

The effect of the REG2 Anticoagulation System on thrombin generation kinetics: A pharmacodynamic and pharmacokinetic first-in-human study

The REG2 Anticoagulation System consists of pegnivacogin, a subcutaneously administered aptamer factor IXa inhibitor, and its intravenous active control agent, anivamersen. Its effect on thrombin generation is unknown. A prospectively designed thrombin generation study was conducted within the phase 1 ascending dose study of REG2 to assess the effect of REG2 on thrombin generation kinetics. A total of 32 healthy volunteers were recruited into four cohorts of ascending dose pegnivacogin for the phase 1 study. In this pre-specified substudy, blood samples were drawn in the presence or absence of corn trypsin inhibitor at specified times within each dosing cohort. Thrombin generation was initiated with tissue factor and thrombin generation kinetics were measured using the Calibrated Automated Thrombogram (CAT). REG2 attenuated thrombin generation in a dose-dependent manner. All parameters of the CAT assay, except for lag time, showed a dose and concentration-dependent response to pegnivacogin [time to peak thrombin generation (PTm), endogenous thrombin potential, peak thrombin generation, and velocity index (VIx)]. Reversal of the effect of pegnivacogin with anivamersen demonstrated restoration of thrombin generation without rebound effect. This first-in-human study of the effect of the REG2 Anticoagulation System on thrombin generation demonstrates concentration-dependent suppression of thrombin generation that is reversible without rebound effect, as measured by the CAT assay. © 2014 Springer Science+Business Media.

Authors
Vavalle, JP; Rusconi, CP; Zelenkofske, S; Wargin, WA; Ortel, TL; Alexander, JH; Povsic, TJ; Becker, RC
MLA Citation
Vavalle, JP, Rusconi, CP, Zelenkofske, S, Wargin, WA, Ortel, TL, Alexander, JH, Povsic, TJ, and Becker, RC. "The effect of the REG2 Anticoagulation System on thrombin generation kinetics: A pharmacodynamic and pharmacokinetic first-in-human study." Journal of Thrombosis and Thrombolysis 38.3 (January 1, 2014): 275-284.
Source
scopus
Published In
Journal of Thrombosis and Thrombolysis
Volume
38
Issue
3
Publish Date
2014
Start Page
275
End Page
284
DOI
10.1007/s11239-014-1081-6

Risk of venous thromboembolism among hospitalizations of adults with selected autoimmune diseases

Previous research has suggested autoimmune diseases are risk factors for developing venous thromboembolism (VTE). We assessed whether having diagnoses of selected autoimmune diseases associated with antiphospholipid antibodies-autoimmune hemolytic anemia (AIHA), immune thrombocytopenic purpura (ITP), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE)-were associated with having a VTE diagnosis among US adult hospitalizations. A cross-sectional study was conducted using the 2010 Nationwide Inpatient Sample of the Healthcare Cost and Utilization Project, Agency for Healthcare Research and Quality. VTE and autoimmune diseases were identified using International Classification of Diseases, Ninth Revision, Clinical Modification coded diagnoses information. The percentages of hospitalizations with a VTE diagnosis among all non-maternal adult hospitalizations without any of the four autoimmune diseases of interest and among those with AIHA, ITP, RA, and SLE diagnoses were 2.28, 4.46, 3.35, 2.65 and 2.77 %, respectively. The adjusted odds ratios (OR) for having a diagnosis of VTE among non-maternal adult hospitalizations with diagnoses of AIHA, ITP, RA, and SLE were 1.25 [95 % confidence interval (CI) 1.05-1.49], 1.20 (95 % CI 1.07-1.34), 1.17 (95 % CI 1.13-1.21), and 1.23 (95 % CI 1.15-1.32), respectively, when compared to those without the corresponding conditions. The adjusted OR for a diagnosis of VTE associated with a diagnosis of any of the four autoimmune diseases was 1.20 (95 % CI 1.16-1.24). The presence of a diagnosis of AIHA, ITP, RA, and SLE was associated with an increased likelihood of having a VTE diagnosis among the group of all non-maternal adult hospitalizations. © 2014 Springer Science+Business Media.

Authors
Yusuf, HR; Hooper, WC; Beckman, MG; Zhang, QC; Tsai, J; Ortel, TL
MLA Citation
Yusuf, HR, Hooper, WC, Beckman, MG, Zhang, QC, Tsai, J, and Ortel, TL. "Risk of venous thromboembolism among hospitalizations of adults with selected autoimmune diseases." Journal of Thrombosis and Thrombolysis 38.3 (January 1, 2014): 306-313.
Source
scopus
Published In
Journal of Thrombosis and Thrombolysis
Volume
38
Issue
3
Publish Date
2014
Start Page
306
End Page
313
DOI
10.1007/s11239-014-1050-0

Graduated compression stockings to treat acute leg pain associated with proximal DVT: A randomised controlled trial

© Schattauer 2014 Acute deep venous thrombosis (DVT) causes leg pain. Elastic compression stockings (ECS) have potential to relieve DVT-related leg pain by diminishing the diameter of distended veins and increasing venous blood flow. It was our objective to determine whether ECS reduce leg pain in patients with acute DVT. We performed a secondary analysis of the SOX Trial, a multicentre randomised placebo controlled trial of active ECS versus placebo ECS to prevent the post-thrombotic syndrome.The study was performed in 24 hospital centres in Canada and the U.S. and included 803 patients with a first episode of acute proximal DVT. Patients were randomised to receive active ECS (knee length, 30-40 mm Hg graduated pressure) or placebo ECS (manufactured to look identical to active ECS, but lacking therapeutic compression). Study outcome was leg pain severity assessed on an 11-point numerical pain rating scale (0, no pain; 10, worst possible pain) at baseline, 14, 30 and 60 days after randomisation. Mean age was 55 years and 60% were male. In active ECS patients (n=409), mean (SD) pain severity at baseline and at 60 days were 5.18 (3.29) and 1.39 (2.19), respectively, and in placebo ECS patients (n=394) were 5.38 (3.29) and 1.13 (1.86), respectively. There were no significant differences in pain scores between groups at any assessment point, and no evidence for subgroup interaction by age, sex or anatomical extent of DVT. Results were similar in an analysis restricted to patients who reported wearing stockings every day. In conclusion, ECS do not reduce leg pain in patients with acute proximal DVT.

Authors
Kahn, SR; Shapiro, S; Ducruet, T; Wells, PS; Rodger, MA; Kovacs, MJ; Anderson, D; Tagalakis, V; Morrison, DR; Solymoss, S; Miron, MJ; Yeo, E; Smith, R; Schulman, S; Kassis, J; Kearon, C; Chagnon, I; Wong, T; Demers, C; Hanmiah, R; Kaatz, S; Selby, R; Rathbun, S; Desmarais, S; Opatrny, L; Ortel, TL; Galanaud, JP; Ginsberg, JS
MLA Citation
Kahn, SR, Shapiro, S, Ducruet, T, Wells, PS, Rodger, MA, Kovacs, MJ, Anderson, D, Tagalakis, V, Morrison, DR, Solymoss, S, Miron, MJ, Yeo, E, Smith, R, Schulman, S, Kassis, J, Kearon, C, Chagnon, I, Wong, T, Demers, C, Hanmiah, R, Kaatz, S, Selby, R, Rathbun, S, Desmarais, S, Opatrny, L, Ortel, TL, Galanaud, JP, and Ginsberg, JS. "Graduated compression stockings to treat acute leg pain associated with proximal DVT: A randomised controlled trial." Thrombosis and Haemostasis 112.6 (January 1, 2014): 1137-1141.
Source
scopus
Published In
Thrombosis and haemostasis
Volume
112
Issue
6
Publish Date
2014
Start Page
1137
End Page
1141
DOI
10.1160/TH14-05-0430

14th International Congress on Antiphospholipid Antibodies Task Force. Report on antiphospholipid syndrome laboratory diagnostics and trends

© 2014 Elsevier B.V. Current classification criteria for definite Antiphospholipid Syndrome (APS) require the use of three laboratory assays to detect antiphospholipid antibodies (aCL, anti-β2GPI and LA) in the presence of at least one of the two major clinical manifestations (i.e. thrombosis or pregnancy morbidity) of the syndrome. However, several other autoantibodies shown to be directed to other proteins or their complex with phospholipids have been proposed to be relevant to APS but their clinical utility and their diagnostic value remains elusive. This report summarizes the findings, conclusions and recommendations of the "APS Task Force 3-Laboratory Diagnostics and Trends" meeting that took place during the 14th International Congress on Antiphospholipid Antibodies (APLA 2013, September 18-21, Rio de Janeiro, RJ, Brazil).

Authors
Bertolaccini, ML; Amengual, O; Andreoli, L; Atsumi, T; Chighizola, CB; Forastiero, R; de Groot, P; Lakos, G; Lambert, M; Meroni, P; Ortel, TL; Petri, M; Rahman, A; Roubey, R; Sciascia, S; Snyder, M; Tebo, AE; Tincani, A; Willis, R
MLA Citation
Bertolaccini, ML, Amengual, O, Andreoli, L, Atsumi, T, Chighizola, CB, Forastiero, R, de Groot, P, Lakos, G, Lambert, M, Meroni, P, Ortel, TL, Petri, M, Rahman, A, Roubey, R, Sciascia, S, Snyder, M, Tebo, AE, Tincani, A, and Willis, R. "14th International Congress on Antiphospholipid Antibodies Task Force. Report on antiphospholipid syndrome laboratory diagnostics and trends." Autoimmunity Reviews 13.9 (January 1, 2014): 917-930. (Review)
Source
scopus
Published In
Autoimmunity Reviews
Volume
13
Issue
9
Publish Date
2014
Start Page
917
End Page
930
DOI
10.1016/j.autrev.2014.05.001

Anticoagulation for venous thromboembolism

© Springer International Publishing Switzerland 2014. Anticoagulation is a fundamental of management in venous disease. This chapter discusses anticoagulant therapy and a variety of agents. The current treatment for a new venous thromboembolic event in a patient is anticoagulant therapy, beginning with either unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH), while warfarin is concomitantly initiated for chronic therapy.

Authors
Ortel, TL
MLA Citation
Ortel, TL. "Anticoagulation for venous thromboembolism." Phlebology, Vein Surgery and Ultrasonography: Diagnosis and Management of Venous Disease. January 1, 2014. 293-307.
Source
scopus
Publish Date
2014
Start Page
293
End Page
307
DOI
10.1007/978-3-319-01812-6_21

Differences in thrombotic risk factors in black and white women with adverse pregnancy outcome.

Black women have an increased risk of adverse pregnancy outcomes and the characteristics of thrombotic risk factors in this population are unknown. The objective of this study was to examine the racial differences in thrombotic risk factors among women with adverse pregnancy outcomes.Uniform data were collected in women with adverse pregnancy outcomes (pregnancy losses, intrauterine growth restriction (IUGR), prematurity, placental abruption and preeclampsia) referred to Thrombosis Network Centers funded by the Centers for Disease Control and Prevention (CDC).Among 343 white and 66 black women seen for adverse pregnancy outcomes, protein S and antithrombin deficiencies were more common in black women. The prevalence of diagnosed thrombophilia was higher among whites compared to blacks largely due to Factor V Leiden mutation. The prevalence of a personal history of venous thromboembolism (VTE) did not differ significantly by race. A family history of VTE, thrombophilia, and stroke or myocardial infarction (MI) was higher among whites. Black women had a higher body mass index, and a higher prevalence of hypertension, while the prevalence of sickle cell disease was approximately 27 fold higher compared to the general US black population.Thrombotic risk factors differ significantly in white and black women with adverse pregnancy outcomes. Such differences highlight the importance of considering race separately when assessing thrombotic risk factors for adverse pregnancy outcomes.

Authors
Philipp, CS; Faiz, AS; Beckman, MG; Grant, A; Bockenstedt, PL; Heit, JA; James, AH; Kulkarni, R; Manco-Johnson, MJ; Moll, S; Ortel, TL
MLA Citation
Philipp, CS, Faiz, AS, Beckman, MG, Grant, A, Bockenstedt, PL, Heit, JA, James, AH, Kulkarni, R, Manco-Johnson, MJ, Moll, S, and Ortel, TL. "Differences in thrombotic risk factors in black and white women with adverse pregnancy outcome." Thrombosis research 133.1 (January 2014): 108-111.
PMID
24246297
Source
epmc
Published In
Thrombosis Research
Volume
133
Issue
1
Publish Date
2014
Start Page
108
End Page
111
DOI
10.1016/j.thromres.2013.10.035

A pharmacogenetic versus a clinical algorithm for warfarin dosing.

BACKGROUND: The clinical utility of genotype-guided (pharmacogenetically based) dosing of warfarin has been tested only in small clinical trials or observational studies, with equivocal results. METHODS: We randomly assigned 1015 patients to receive doses of warfarin during the first 5 days of therapy that were determined according to a dosing algorithm that included both clinical variables and genotype data or to one that included clinical variables only. All patients and clinicians were unaware of the dose of warfarin during the first 4 weeks of therapy. The primary outcome was the percentage of time that the international normalized ratio (INR) was in the therapeutic range from day 4 or 5 through day 28 of therapy. RESULTS: At 4 weeks, the mean percentage of time in the therapeutic range was 45.2% in the genotype-guided group and 45.4% in the clinically guided group (adjusted mean difference, [genotype-guided group minus clinically guided group], -0.2; 95% confidence interval, -3.4 to 3.1; P=0.91). There also was no significant between-group difference among patients with a predicted dose difference between the two algorithms of 1 mg per day or more. There was, however, a significant interaction between dosing strategy and race (P=0.003). Among black patients, the mean percentage of time in the therapeutic range was less in the genotype-guided group than in the clinically guided group. The rates of the combined outcome of any INR of 4 or more, major bleeding, or thromboembolism did not differ significantly according to dosing strategy. CONCLUSIONS: Genotype-guided dosing of warfarin did not improve anticoagulation control during the first 4 weeks of therapy. (Funded by the National Heart, Lung, and Blood Institute and others; COAG ClinicalTrials.gov number, NCT00839657.).

Authors
Kimmel, SE; French, B; Kasner, SE; Johnson, JA; Anderson, JL; Gage, BF; Rosenberg, YD; Eby, CS; Madigan, RA; McBane, RB; Abdel-Rahman, SZ; Stevens, SM; Yale, S; Mohler, ER; Fang, MC; Shah, V; Horenstein, RB; Limdi, NA; Muldowney, JAS; Gujral, J; Delafontaine, P; Desnick, RJ; Ortel, TL; Billett, HH; Pendleton, RC; Geller, NL; Halperin, JL; Goldhaber, SZ; Caldwell, MD; Califf, RM; Ellenberg, JH; COAG Investigators,
MLA Citation
Kimmel, SE, French, B, Kasner, SE, Johnson, JA, Anderson, JL, Gage, BF, Rosenberg, YD, Eby, CS, Madigan, RA, McBane, RB, Abdel-Rahman, SZ, Stevens, SM, Yale, S, Mohler, ER, Fang, MC, Shah, V, Horenstein, RB, Limdi, NA, Muldowney, JAS, Gujral, J, Delafontaine, P, Desnick, RJ, Ortel, TL, Billett, HH, Pendleton, RC, Geller, NL, Halperin, JL, Goldhaber, SZ, Caldwell, MD, Califf, RM, Ellenberg, JH, and COAG Investigators, . "A pharmacogenetic versus a clinical algorithm for warfarin dosing." N Engl J Med 369.24 (December 12, 2013): 2283-2293.
PMID
24251361
Source
pubmed
Published In
The New England journal of medicine
Volume
369
Issue
24
Publish Date
2013
Start Page
2283
End Page
2293
DOI
10.1056/NEJMoa1310669

Venous Thromboembolic Disease Clinical Practice Guidelines in Oncology

Authors
Streiff, MB; Bockenstedt, PL; Cataland, SR; Chesney, C; Eby, C; Fanikos, J; Fogerty, AE; Gao, S; Goldhaber, SZ; Hassoun, H; Hendrie, P; Holmstrom, B; Kuderer, N; Lee, JT; Millenson, MM; Neff, AT; Ortel, TL; Siddiqi, T; Smith, JL; Yee, GC; Zakarija, A; McMillian, N; Naganuma, M
MLA Citation
Streiff, MB, Bockenstedt, PL, Cataland, SR, Chesney, C, Eby, C, Fanikos, J, Fogerty, AE, Gao, S, Goldhaber, SZ, Hassoun, H, Hendrie, P, Holmstrom, B, Kuderer, N, Lee, JT, Millenson, MM, Neff, AT, Ortel, TL, Siddiqi, T, Smith, JL, Yee, GC, Zakarija, A, McMillian, N, and Naganuma, M. "Venous Thromboembolic Disease Clinical Practice Guidelines in Oncology." JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK 11.11 (November 2013): 1402-1429.
PMID
24225973
Source
wos-lite
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
11
Issue
11
Publish Date
2013
Start Page
1402
End Page
1429

Depressive symptoms and mental stress-induced myocardial ischemia in patients with coronary heart disease.

OBJECTIVES: The aim of this study was to examine the associations between depressive symptoms and mental stress-induced myocardial ischemia (MSIMI) in patients with coronary heart disease (CHD). METHODS: Adult patients with documented CHD were recruited for baseline mental stress and exercise stress screening testing as a part of the enrollment process of the Responses of Myocardial Ischemia to Escitalopram Treatment trial. Patients were administered the Beck Depression Inventory II and the Center for Epidemiologic Studies Depression Scale. After a 24-48-hour β-blocker withdrawal, participants completed three mental stress tests followed by a treadmill exercise test. Ischemia was defined as a) any development or worsening of any wall motion abnormality and b) reduction of left ventricular ejection fraction at least 8% by transthoracic echocardiography and/or ischemic ST-segment change by electrocardiography during stress testing. MSIMI was considered present when ischemia occurred in at least one mental test. Data were analyzed using logistic regression adjusting for age, sex, and resting left ventricular ejection fraction. RESULTS: One hundred twenty-five (44.2%) of 283 patients were found to have MSIMI, and 93 (32.9%) had ESIMI. Unadjusted analysis showed that Beck Depression Inventory II scores were positively associated with the probability of MSIMI (odds ratio = 0.1.30: 95% confidence interval = 1.06-1.60, p = .013) and number of MSIMI-positive tasks (all p < .005). These associations were still significant after adjustment for covariates (p values <.05). CONCLUSIONS: In patients with CHD, depressive symptoms were associated with a higher probability of MSIMI. These observations may enhance our understanding of the mechanisms contributing to the association of depressive symptoms to future cardiovascular events. Trial Registration Clinicaltrials.gov identifier: NCT00574847.

Authors
Boyle, SH; Samad, Z; Becker, RC; Williams, R; Kuhn, C; Ortel, TL; Kuchibhatla, M; Prybol, K; Rogers, J; O'Connor, C; Velazquez, EJ; Jiang, W
MLA Citation
Boyle, SH, Samad, Z, Becker, RC, Williams, R, Kuhn, C, Ortel, TL, Kuchibhatla, M, Prybol, K, Rogers, J, O'Connor, C, Velazquez, EJ, and Jiang, W. "Depressive symptoms and mental stress-induced myocardial ischemia in patients with coronary heart disease." Psychosom Med 75.9 (November 2013): 822-831.
PMID
24163385
Source
pubmed
Published In
Psychosomatic Medicine
Volume
75
Issue
9
Publish Date
2013
Start Page
822
End Page
831
DOI
10.1097/PSY.0b013e3182a893ae

Aspirin exposure reveals novel genes associated with platelet function and cardiovascular events.

OBJECTIVES: The aim of this study was to develop ribonucleic acid (RNA) profiles that could serve as novel biomarkers for the response to aspirin. BACKGROUND: Aspirin reduces death and myocardial infarction (MI), suggesting that aspirin interacts with biological pathways that may underlie these events. METHODS: Aspirin was administered, followed by whole-blood RNA microarray profiling, in a discovery cohort of healthy volunteers (HV1) (n = 50) and 2 validation cohorts of healthy volunteers (HV2) (n = 53) and outpatient cardiology patients (OPC) (n = 25). Platelet function was assessed using the platelet function score (PFS) in HV1 and HV2 and the VerifyNow Aspirin Test (Accumetrics, Inc., San Diego, California) in OPC. Bayesian sparse factor analysis identified sets of coexpressed transcripts, which were examined for associations with PFS in HV1 and validated in HV2 and OPC. Proteomic analysis confirmed the association of validated transcripts in platelet proteins. Validated gene sets were tested for association with death or MI in 2 patient cohorts (n = 587 total) from RNA samples collected at cardiac catheterization. RESULTS: A set of 60 coexpressed genes named the "aspirin response signature" (ARS) was associated with PFS in HV1 (r = -0.31, p = 0.03), HV2 (r = -0.34, Bonferroni p = 0.03), and OPC (p = 0.046). Corresponding proteins for the 17 ARS genes were identified in the platelet proteome, of which 6 were associated with PFS. The ARS was associated with death or MI in both patient cohorts (odds ratio: 1.2 [p = 0.01]; hazard ratio: 1.5 [p = 0.001]), independent of cardiovascular risk factors. Compared with traditional risk factors, reclassification (net reclassification index = 31% to 37%, p ≤ 0.0002) was improved by including the ARS or 1 of its genes, ITGA2B. CONCLUSIONS: RNA profiles of platelet-specific genes are novel biomarkers for identifying patients who do not respond adequately to aspirin and who are at risk for death or MI.

Authors
Voora, D; Cyr, D; Lucas, J; Chi, J-T; Dungan, J; McCaffrey, TA; Katz, R; Newby, LK; Kraus, WE; Becker, RC; Ortel, TL; Ginsburg, GS
MLA Citation
Voora, D, Cyr, D, Lucas, J, Chi, J-T, Dungan, J, McCaffrey, TA, Katz, R, Newby, LK, Kraus, WE, Becker, RC, Ortel, TL, and Ginsburg, GS. "Aspirin exposure reveals novel genes associated with platelet function and cardiovascular events." J Am Coll Cardiol 62.14 (October 1, 2013): 1267-1276.
PMID
23831034
Source
pubmed
Published In
Journal of the American College of Cardiology
Volume
62
Issue
14
Publish Date
2013
Start Page
1267
End Page
1276
DOI
10.1016/j.jacc.2013.05.073

Antithrombotic therapy and invasive procedures.

Authors
Spyropoulos, AC; Ortel, TL
MLA Citation
Spyropoulos, AC, and Ortel, TL. "Antithrombotic therapy and invasive procedures." N Engl J Med 369.11 (September 12, 2013): 1078-. (Letter)
PMID
24024857
Source
pubmed
Published In
The New England journal of medicine
Volume
369
Issue
11
Publish Date
2013
Start Page
1078
DOI
10.1056/NEJMc1308259#SA3

Comparative effectiveness of new oral anticoagulants and standard thromboprophylaxis in patients having total hip or knee replacement: a systematic review.

BACKGROUND: Pharmacologic thromboprophylaxis reduces the risk for venous thromboembolism after total hip replacement (THR) or total knee replacement (TKR). New oral anticoagulants (NOACs), including direct thrombin inhibitors and factor Xa inhibitors, are emerging options for thromboprophylaxis after these procedures. PURPOSE: To compare the benefits and risks of NOACs versus standard thromboprophylaxis for adults having THR or TKR. DATA SOURCES: MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews from January 2009 through March 2013. STUDY SELECTION: English-language systematic reviews. DATA EXTRACTION: Two independent reviewers abstracted data and rated study quality and strength of evidence. DATA SYNTHESIS: Six good-quality systematic reviews compared NOACs with low-molecular-weight heparin (LMWH) for thromboprophylaxis after THR or TKR. Risk for symptomatic deep venous thrombosis, but not risk for death or nonfatal pulmonary embolism, was reduced with factor Xa inhibitors compared with LMWH (4 fewer events per 1000 patients). Conversely, the risk for major bleeding increased (2 more events per 1000 patients). Outcomes of dabigatran did not significantly differ from those of LMWH. Indirect evaluation of NOACs by common comparison with LMWH showed nonsignificantly reduced risks for venous thromboembolism with rivaroxaban compared with dabigatran (risk ratio [RR], 0.68 [95% CI, 0.21 to 2.23]) and apixaban (RR, 0.59 [CI, 0.26 to 1.33]) but increased major bleeding. New oral anticoagulants have not been compared with warfarin, aspirin, or unfractionated heparin. LIMITATIONS: Head-to-head comparisons among NOACs were not available. Efficacy is uncertain in routine clinical practice. CONCLUSION: New oral anticoagulants are effective for thromboprophylaxis after THR and TKR. Their clinical benefits over LMWH are marginal and offset by increased risk for major bleeding. PRIMARY FUNDING SOURCE: U.S. Department of Veterans Affairs.

Authors
Adam, SS; McDuffie, JR; Lachiewicz, PF; Ortel, TL; Williams, JW
MLA Citation
Adam, SS, McDuffie, JR, Lachiewicz, PF, Ortel, TL, and Williams, JW. "Comparative effectiveness of new oral anticoagulants and standard thromboprophylaxis in patients having total hip or knee replacement: a systematic review." Ann Intern Med 159.4 (August 20, 2013): 275-284. (Review)
PMID
24026260
Source
pubmed
Published In
Annals of internal medicine
Volume
159
Issue
4
Publish Date
2013
Start Page
275
End Page
284
DOI
10.7326/0003-4819-159-4-201308200-00008

Ticlopidine-associated ADAMTS13 activity deficient thrombotic thrombocytopenic purpura in 22 persons in Japan: a report from the Southern Network on Adverse Reactions (SONAR).

Authors
Bennett, CL; Jacob, S; Dunn, BL; Georgantopoulos, P; Zheng, XL; Kwaan, HC; McKoy, JM; Magwood, JS; Qureshi, ZP; Bandarenko, N; Winters, JL; Raife, TJ; Carey, PM; Sarode, R; Kiss, JE; Danielson, C; Ortel, TL; Clark, WF; Ablin, RJ; Rock, G; Matsumoto, M; Fujimura, Y
MLA Citation
Bennett, CL, Jacob, S, Dunn, BL, Georgantopoulos, P, Zheng, XL, Kwaan, HC, McKoy, JM, Magwood, JS, Qureshi, ZP, Bandarenko, N, Winters, JL, Raife, TJ, Carey, PM, Sarode, R, Kiss, JE, Danielson, C, Ortel, TL, Clark, WF, Ablin, RJ, Rock, G, Matsumoto, M, and Fujimura, Y. "Ticlopidine-associated ADAMTS13 activity deficient thrombotic thrombocytopenic purpura in 22 persons in Japan: a report from the Southern Network on Adverse Reactions (SONAR)." Br J Haematol 161.6 (June 2013): 896-898. (Letter)
PMID
23530950
Source
pubmed
Published In
British Journal of Haematology
Volume
161
Issue
6
Publish Date
2013
Start Page
896
End Page
898
DOI
10.1111/bjh.12303

Effect of escitalopram on mental stress-induced myocardial ischemia: results of the REMIT trial.

IMPORTANCE: Mental stress can induce myocardial ischemia and also has been implicated in triggering cardiac events. However, pharmacological interventions aimed at reducing mental stress-induced myocardial ischemia (MSIMI) have not been well studied. OBJECTIVE: To examine the effects of 6 weeks of escitalopram treatment vs placebo on MSIMI and other psychological stress-related biophysiological and emotional parameters. DESIGN, SETTING, AND PARTICIPANTS: The REMIT (Responses of Mental Stress Induced Myocardial Ischemia to Escitalopram Treatment) study, a randomized, double-blind, placebo-controlled trial of patients with clinically stable coronary heart disease and laboratory-diagnosed MSIMI. Enrollment occurred from July 24, 2007, through August 24, 2011, at a tertiary medical center. INTERVENTIONS: Eligible participants were randomized 1:1 to receive escitalopram (dose began at 5 mg/d, with titration to 20 mg/d in 3 weeks) or placebo over 6 weeks. MAIN OUTCOMES AND MEASURES: Occurrence of MSIMI, defined as development or worsening of regional wall motion abnormality; left ventricular ejection fraction reduction of 8% or more; and/or horizontal or down-sloping ST-segment depression of 1 mm or more in 2 or more leads, lasting for 3 or more consecutive beats, during 1 or more of 3 mental stressor tasks. RESULTS: Of 127 participants randomized to receive escitalopram (n = 64) or placebo (n = 63), 112 (88.2%) completed end point assessments (n = 56 in each group). At the end of 6 weeks, more patients taking escitalopram (34.2% [95% CI, 25.4%-43.0%]) had absence of MSIMI during the 3 mental stressor tasks compared with patients taking placebo (17.5% [95% CI, 10.4%-24.5%]), based on the unadjusted multiple imputation model for intention-to-treat analysis. A significant difference favoring escitalopram was observed (odds ratio, 2.62 [95% CI, 1.06-6.44]). Rates of exercise-induced ischemia were slightly lower at 6 weeks in the escitalopram group (45.8% [95% CI, 36.6%-55.0%]) than in patients receiving placebo (52.5% [95% CI, 43.3%-61.8%]), but this difference was not statistically significant (adjusted odds ratio; 1.24 [95% CI, 0.60-2.58]; P = .56). CONCLUSIONS AND RELEVANCE: Among patients with stable coronary heart disease and baseline MSIMI, 6 weeks of escitalopram, compared with placebo, resulted in a lower rate of MSIMI. There was no statistically significant difference in exercise-induced ischemia. Replication of these results in multicenter settings and investigations of other medications for reducing MSIMI are needed. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00574847.

Authors
Jiang, W; Velazquez, EJ; Kuchibhatla, M; Samad, Z; Boyle, SH; Kuhn, C; Becker, RC; Ortel, TL; Williams, RB; Rogers, JG; O'Connor, C
MLA Citation
Jiang, W, Velazquez, EJ, Kuchibhatla, M, Samad, Z, Boyle, SH, Kuhn, C, Becker, RC, Ortel, TL, Williams, RB, Rogers, JG, and O'Connor, C. "Effect of escitalopram on mental stress-induced myocardial ischemia: results of the REMIT trial." JAMA 309.20 (May 22, 2013): 2139-2149.
PMID
23695483
Source
pubmed
Published In
JAMA : the journal of the American Medical Association
Volume
309
Issue
20
Publish Date
2013
Start Page
2139
End Page
2149
DOI
10.1001/jama.2013.5566

Randomized trial of physician alerts for thromboprophylaxis after discharge.

BACKGROUND: Many hospitalized Medical Service patients are at risk for venous thromboembolism in the months after discharge. We conducted a multicenter randomized controlled trial to test whether a hospital staff member's thromboprophylaxis alert to an Attending Physician before discharge will increase the rate of extended out-of-hospital prophylaxis and, in turn, reduce the incidence of symptomatic venous thromboembolism at 90 days. METHODS: From April 2009 to January 2010, we enrolled hospitalized Medical Service patients using the point score system developed by Kucher et al to identify those at high risk for venous thromboembolism who were not ordered to receive thromboprophylaxis after discharge. There were 2513 eligible patients from 18 study sites randomized by computer in a 1:1 ratio to the alert group or the control group. RESULTS: Patients in the alert group were more than twice as likely to receive thromboprophylaxis at discharge as controls (22.0% vs 9.7%, P <.0001). Based on an intention-to-treat analysis, symptomatic venous thromboembolism at 90 days (99.9% follow-up) occurred in 4.5% of patients in the alert group, compared with 4.0% of controls (hazard ratio 1.12; 95% confidence interval, 0.74-1.69). The rate of major bleeding at 30 days in the alert group was similar to that of the control group (1.2% vs 1.2%, hazard ratio 0.94; 95% confidence interval, 0.44-2.01). CONCLUSIONS: Alerting providers to extend thromboprophylaxis after hospital discharge in Medical Service patients increased the rate of prophylaxis but did not decrease the rate of symptomatic venous thromboembolism.

Authors
Piazza, G; Anderson, FA; Ortel, TL; Cox, MJ; Rosenberg, DJ; Rahimian, S; Pendergast, WJ; McLaren, GD; Welker, JA; Akus, JJ; Stevens, SM; Elliott, CG; Freeman, AL; Patton, WF; Dabbagh, O; Wyman, A; Huang, W; Rao, AF; Goldhaber, SZ
MLA Citation
Piazza, G, Anderson, FA, Ortel, TL, Cox, MJ, Rosenberg, DJ, Rahimian, S, Pendergast, WJ, McLaren, GD, Welker, JA, Akus, JJ, Stevens, SM, Elliott, CG, Freeman, AL, Patton, WF, Dabbagh, O, Wyman, A, Huang, W, Rao, AF, and Goldhaber, SZ. "Randomized trial of physician alerts for thromboprophylaxis after discharge." Am J Med 126.5 (May 2013): 435-442.
PMID
23510945
Source
pubmed
Published In
American Journal of Medicine
Volume
126
Issue
5
Publish Date
2013
Start Page
435
End Page
442
DOI
10.1016/j.amjmed.2012.09.020

Comparative effectiveness of warfarin and new anticoagulants.

Authors
Adam, SS; Ortel, TL; Williams, JW
MLA Citation
Adam, SS, Ortel, TL, and Williams, JW. "Comparative effectiveness of warfarin and new anticoagulants." Ann Intern Med 158.8 (April 16, 2013): 637-638. (Letter)
PMID
23588759
Source
pubmed
Published In
Annals of internal medicine
Volume
158
Issue
8
Publish Date
2013
Start Page
637
End Page
638
DOI
10.7326/0003-4819-158-8-201304160-00017

Anticoagulation in the Perioperative Period

Authors
Suwanawiboon, B; Ortel, TL
MLA Citation
Suwanawiboon, B, and Ortel, TL. "Anticoagulation in the Perioperative Period." (April 1, 2013): 673-687. (Chapter)
Source
scopus
Publish Date
2013
Start Page
673
End Page
687
DOI
10.1016/B978-1-4557-2296-9.00037-3

High incidence of antibodies to protamine and protamine/heparin complexes in patients undergoing cardiopulmonary bypass.

Protamine is routinely used to reverse heparin anticoagulation during cardiopulmonary bypass (CPB). Heparin interacts with protamine to form ultralarge complexes that are immunogenic in mice. We hypothesized that patients exposed to protamine and heparin during CPB will develop antibodies (Abs) to protamine/heparin (PRT/H) complexes that are capable of platelet activation. Specimens from a recently completed prospective clinical trial (HIT [for heparin-induced thrombocytopenia] 5801 study; n = 500) of CPB patients were examined for PRT/H Abs at baseline, at time of hospital discharge (between days 3 through 7), and 30 days after CPB. PRT/H antibody features were characterized and correlated with adverse cardiovascular outcomes. We found a high incidence of PRT/H antibody formation (29%) in patients undergoing cardiac surgery. PRT/H Abs were of high titer (mean titer 1:14,744), showed heparin-dependent binding, and activated platelets in the presence of protamine. PRT/H Abs showed no cross-reactivity to platelet factor 4/heparin complexes, but were cross-reactive with protamine-containing insulin preparations. In the absence of circulating antigen at day 30, there were no complications of thrombocytopenia, thrombotic events, or long-term cardiovascular events. These studies show that Abs to PRT/H occur commonly after cardiac bypass surgery, share a number of serologic features with HIT Abs, including platelet activation, and may pose health risks to patients requiring drug reexposure.

Authors
Lee, GM; Welsby, IJ; Phillips-Bute, B; Ortel, TL; Arepally, GM
MLA Citation
Lee, GM, Welsby, IJ, Phillips-Bute, B, Ortel, TL, and Arepally, GM. "High incidence of antibodies to protamine and protamine/heparin complexes in patients undergoing cardiopulmonary bypass." Blood 121.15 (April 2013): 2828-2835.
PMID
23422751
Source
epmc
Published In
Blood
Volume
121
Issue
15
Publish Date
2013
Start Page
2828
End Page
2835
DOI
10.1182/blood-2012-11-469130

Characteristics of abdominal vein thrombosis in children and adults.

The demographic and clinical characteristics of adults and children with lower extremity deep-vein thrombosis and/or pulmonary embolism (LE DVT/PE) may differ from those with abdominal vein thrombosis (abdominal VT). Abdominal VT can be a presenting sign of an underlying prothrombotic state, and its presence in the setting of known disease might have prognostic implications different from LE DVT/PE. This study describes clinical presentations of abdominal VT compared to LE DVT/PE in adults and children. We analysed prospectively-collected data from consecutive consenting patients enrolled in one of seven Centers for Disease Control and Prevention (CDC) funded Thrombosis and Hemostasis Network Centers from August 2003 to April 2011 to compare the demographic and clinical characteristics of adults and children with abdominal VT. Both adults and children with abdominal VT tended to be younger and have a lower body mass index (BMI) than those with LE DVT/PE. Of patients with abdominal VT, children were more likely to have inferior vena cava (IVC) thrombosis than adults. For adults with venous thromboembolism (VTE), relatively more women had abdominal VT than LE DVT/PE, while the proportions with LE DVT/PE and abdominal VT by sex were similar in children. Children with abdominal VT were more likely to have diagnosed inherited thrombophilia, while trauma was more common in children with LE DVT/PE. In conclusion, both children and adults with abdominal VT were younger with a lower BMI than those with LE DVT/PE. Significant differences exist between children and adults in respect to abdominal VT compared to LE DVT/PE.

Authors
Landi, D; Beckman, MG; Shah, NR; Bockenstedt, P; Grant, AM; Heit, JA; Key, NS; Kulkarni, R; Manco-Johnson, M; Moll, S; Philipp, CS; Andersen, JC; Ortel, TL
MLA Citation
Landi, D, Beckman, MG, Shah, NR, Bockenstedt, P, Grant, AM, Heit, JA, Key, NS, Kulkarni, R, Manco-Johnson, M, Moll, S, Philipp, CS, Andersen, JC, and Ortel, TL. "Characteristics of abdominal vein thrombosis in children and adults." Thromb Haemost 109.4 (April 2013): 625-632.
PMID
23407670
Source
pubmed
Published In
Thrombosis and haemostasis
Volume
109
Issue
4
Publish Date
2013
Start Page
625
End Page
632
DOI
10.1160/TH12-08-0568

Improving clinician performance of inpatient venous thromboembolism risk assessment and prophylaxis.

Clinicians are aware of the importance of thromboprophylaxis, and that the application of measures to prevent venous thromboembolism (VTE) occurrence in hospitalized patients must be improved. To enhance clinician execution of appropriate steps to reduce the risk of inpatient VTE, a performance improvement (PI) continuing medical education (CME) initiative consisting of 3 independent tracks for hospitalized patients-patients who are medically ill, patients receiving oncology treatment, and patients undergoing major orthopedic surgery-was designed and implemented. After a baseline chart review of select evidenced-based performance measures for VTE risk stratification and prevention, participants identified ≥ 1 area of personal improvement. Participants then engaged in a period of self-improvement and reassessed their performance with a second chart review. After participating in the PI CME activity, clinician participants in the medically ill track increased their documentation of VTE risk assessments upon patient admission from baseline (56% vs 93%, n = 250; P < 0.001) and their prescription of low-molecular-weight heparin, low-dose unfractionated heparin, or fondaparinux (72% vs 88%, n = 250; P < 0.001). Orthopedic-track participants were significantly more likely to prescribe 15 to 35 days of VTE prophylaxis after total hip arthroplasty or hip fracture surgery upon patient discharge compared with baseline (51%, n = 123 vs 61%, n = 107; P < 0.001). Oncology-track participants demonstrated a nonsignificant trend for assessing and documenting bleeding risk after participation in the PI CME activity (56% vs 68%, n = 80; P = 0.143). Improvements in evidence-based strategies to reduce the risk of inpatient VTE were associated with PI CME participation. Although areas for improvement remain, increased participant identification and use of prophylactic measures can reduce the risk of VTE in hospitalized patients.

Authors
Goldhaber, SZ; Ortel, TL; Berry, CA; Stowell, SA; Gardner, AJ
MLA Citation
Goldhaber, SZ, Ortel, TL, Berry, CA, Stowell, SA, and Gardner, AJ. "Improving clinician performance of inpatient venous thromboembolism risk assessment and prophylaxis." Hosp Pract (1995) 41.2 (April 2013): 123-131.
PMID
23680743
Source
pubmed
Published In
Hospital practice (1995)
Volume
41
Issue
2
Publish Date
2013
Start Page
123
End Page
131
DOI
10.3810/hp.2013.04.1061

Molecular testing for coagulation abnormalities

© Springer Science+Business Media New York 2013. All rights are reserved. Molecular testing is frequently used in conjunction with other laboratory analyses in the evaluation of patients with hemorrhagic as well as thrombotic disorders. The most common thrombophilic defects, factor V Leiden and the prothrombin G20210A mutation, are detected by molecular testing. Functional assays are used for the less common inherited hypercoagulable states, such as antithrombin or protein C deficiency, since no single mutation has been found to predominate in these deficiency states. Functional assays are also used to identify patients with hemophilia, but genetic analysis of these individuals is frequently performed to aid in the diagnosis of carriers and identify potentially affected children. Patients with thrombotic events are treated with anticoagulant therapy, which has traditionally been warfarin, a vitamin K antagonist. Recently, polymorphisms in CYP 2C9 and VKOR1 have been shown to affect the dose of warfarin required to achieve a target international normalized ratio (INR). Similarly, polymorphisms associated with the metabolism of clopidogrel have also been identified. Prospective clinical trials will be necessary to determine the optimal use of this information.

Authors
Ramiah, V; Ortel, TL
MLA Citation
Ramiah, V, and Ortel, TL. "Molecular testing for coagulation abnormalities." Molecular Genetic Pathology: Second Edition. March 1, 2013. 955-974.
Source
scopus
Volume
9781461448006
Publish Date
2013
Start Page
955
End Page
974
DOI
10.1007/978-1-4614-4800-6-36

Prevalence and clinical characteristics of mental stress-induced myocardial ischemia in patients with coronary heart disease.

OBJECTIVES: The goal of this study was to evaluate the prevalence and clinical characteristics of mental stress-induced myocardial ischemia. BACKGROUND: Mental stress-induced myocardial ischemia is prevalent and a risk factor for poor prognosis in patients with coronary heart disease, but past studies mainly studied patients with exercise-induced myocardial ischemia. METHODS: Eligible patients with clinically stable coronary heart disease, regardless of exercise stress testing status, underwent a battery of 3 mental stress tests followed by a treadmill test. Stress-induced ischemia, assessed by echocardiography and electrocardiography, was defined as: 1) development or worsening of regional wall motion abnormality; 2) left ventricular ejection fraction reduction ≥ 8%; and/or 3) horizontal or downsloping ST-segment depression ≥ 1 mm in 2 or more leads lasting for ≥ 3 consecutive beats during at least 1 mental test or during the exercise test. RESULTS: Mental stress-induced ischemia occurred in 43.45%, whereas exercise-induced ischemia occurred in 33.79% (p = 0.002) of the study population (N = 310). Women (odds ratio [OR]: 1.88), patients who were not married (OR: 1.99), and patients who lived alone (OR: 2.24) were more likely to have mental stress-induced ischemia (all p < 0.05). Multivariate analysis showed that compared with married men or men living with someone, unmarried men (OR: 2.57) and married women (OR: 3.18), or living alone (male OR: 2.25 and female OR: 2.72, respectively) had higher risk for mental stress-induced ischemia (all p < 0.05). CONCLUSIONS: Mental stress-induced ischemia is more common than exercise-induced ischemia in patients with clinically stable coronary heart disease. Women, unmarried men, and individuals living alone are at higher risk for mental stress-induced ischemia. (Responses of Myocardial Ischemia to Escitalopram Treatment [REMIT]; NCT00574847).

Authors
Jiang, W; Samad, Z; Boyle, S; Becker, RC; Williams, R; Kuhn, C; Ortel, TL; Rogers, J; Kuchibhatla, M; O'Connor, C; Velazquez, EJ
MLA Citation
Jiang, W, Samad, Z, Boyle, S, Becker, RC, Williams, R, Kuhn, C, Ortel, TL, Rogers, J, Kuchibhatla, M, O'Connor, C, and Velazquez, EJ. "Prevalence and clinical characteristics of mental stress-induced myocardial ischemia in patients with coronary heart disease." J Am Coll Cardiol 61.7 (February 19, 2013): 714-722.
PMID
23410543
Source
pubmed
Published In
Journal of the American College of Cardiology
Volume
61
Issue
7
Publish Date
2013
Start Page
714
End Page
722
DOI
10.1016/j.jacc.2012.11.037

Depressive symptoms and mental stress-induced myocardial ischemia in patients with coronary heart disease

OBJECTIVES: The aim of this study was to examine the associations between depressive symptoms and mental stress-induced myocardial ischemia (MSIMI) in patients with coronary heart disease (CHD). METHODS: Adult patients with documented CHD were recruited for baseline mental stress and exercise stress screening testing as a part of the enrollment process of the Responses of Myocardial Ischemia to Escitalopram Treatment trial. Patients were administered the Beck Depression Inventory II and the Center for Epidemiologic Studies Depression Scale. After a 24-48-hour β-blocker withdrawal, participants completed three mental stress tests followed by a treadmill exercise test. Ischemia was defined as a) any development or worsening of any wall motion abnormality and b) reduction of left ventricular ejection fraction at least 8% by transthoracic echocardiography and/or ischemic ST-segment change by electrocardiography during stress testing. MSIMI was considered present when ischemia occurred in at least one mental test. Data were analyzed using logistic regression adjusting for age, sex, and resting left ventricular ejection fraction. RESULTS: One hundred twenty-five (44.2%) of 283 patients were found to have MSIMI, and 93 (32.9%) had ESIMI. Unadjusted analysis showed that Beck Depression Inventory II scores were positively associated with the probability of MSIMI (odds ratio = 0.1.30: 95% confidence interval = 1.06-1.60, p = .013) and number of MSIMI-positive tasks (all p < .005). These associations were still significant after adjustment for covariates (p values < .05). CONCLUSIONS: In patients with CHD, depressive symptoms were associated with a higher probability of MSIMI. These observations may enhance our understanding of the mechanisms contributing to the association of depressive symptoms to future cardiovascular events. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT00574847. Copyright © 2013 by the American Psychosomatic Society.

Authors
Boyle, SH; Samad, Z; Becker, RC; Williams, R; Kuhn, C; Ortel, TL; Kuchibhatla, M; Prybol, K; Rogers, J; O'Connor, C; Velazquez, EJ; Jiang, W
MLA Citation
Boyle, SH, Samad, Z, Becker, RC, Williams, R, Kuhn, C, Ortel, TL, Kuchibhatla, M, Prybol, K, Rogers, J, O'Connor, C, Velazquez, EJ, and Jiang, W. "Depressive symptoms and mental stress-induced myocardial ischemia in patients with coronary heart disease." Psychosomatic Medicine 75.9 (January 1, 2013): 822-831.
Source
scopus
Published In
Psychosomatic Medicine
Volume
75
Issue
9
Publish Date
2013
Start Page
822
End Page
831
DOI
10.1097/PSY.0b013e3182a893ae

Hyperreactive platelet phenotypes: relationship to altered serotonin transporter number, transport kinetics and intrinsic response to adrenergic co-stimulation.

The mechanism underlying a hyperreactive platelet phenotype remains unknown. Since serotonin has been shown to influence platelet biology and atherothrombosis, we sought to investigate the association of platelet serotonin transporter number, binding affinity, and uptake kinetics with platelet aggregation. A total of 542 healthy volunteers had light transmittance platelet aggregometry measured in response to varying concentrations of epinephrine, serotonin, epinephrine plus serotonin, ADP and collagen. Transporter-dependent serotonin uptake rate was determined (Vmax), as were serotonin transporter number (Bmax) and binding affinity (Kd) using 3H paroxetine binding in a homologous displacement assay, nonlinear regression and validated algorithms for kinetic modelling. Stimulation with submaximal (2μM) epinephrine concentration elicited a distinct, bimodal pattern of platelet aggregation in this population. In contrast, subjects exhibited minimal aggregation in response to serotonin alone. Co-stimulation with submaximal epinephrine and serotonin induced platelet aggregation to a level beyond that observed with either agonist alone and maintained a bimodal response distribution. Subjects with heightened (>60%) platelet aggregation to both epinephrine alone and epinephrine plus serotonin exhibited increased platelet serotonin uptake, and transporter number and affinity. In a population of healthy subjects, co-stimulation with submaximal concentrations of epinephrine and serotonin identifies a subset of individuals with a hyperreactive platelet aggregation profile that is associated with changes in platelet serotonin function.

Authors
Berger, JS; Becker, RC; Kuhn, C; Helms, MJ; Ortel, TL; Williams, R
MLA Citation
Berger, JS, Becker, RC, Kuhn, C, Helms, MJ, Ortel, TL, and Williams, R. "Hyperreactive platelet phenotypes: relationship to altered serotonin transporter number, transport kinetics and intrinsic response to adrenergic co-stimulation." Thromb Haemost 109.1 (January 2013): 85-92.
PMID
23223800
Source
pubmed
Published In
Thrombosis and haemostasis
Volume
109
Issue
1
Publish Date
2013
Start Page
85
End Page
92
DOI
10.1160/TH12-03-0202

Randomized trial of physician alerts for thromboprophylaxis after discharge

Background: Many hospitalized Medical Service patients are at risk for venous thromboembolism in the months after discharge. We conducted a multicenter randomized controlled trial to test whether a hospital staff member's thromboprophylaxis alert to an Attending Physician before discharge will increase the rate of extended out-of-hospital prophylaxis and, in turn, reduce the incidence of symptomatic venous thromboembolism at 90 days. Methods: From April 2009 to January 2010, we enrolled hospitalized Medical Service patients using the point score system developed by Kucher et al to identify those at high risk for venous thromboembolism who were not ordered to receive thromboprophylaxis after discharge. There were 2513 eligible patients from 18 study sites randomized by computer in a 1:1 ratio to the alert group or the control group. Results: Patients in the alert group were more than twice as likely to receive thromboprophylaxis at discharge as controls (22.0% vs 9.7%, P <.0001). Based on an intention-to-treat analysis, symptomatic venous thromboembolism at 90 days (99.9% follow-up) occurred in 4.5% of patients in the alert group, compared with 4.0% of controls (hazard ratio 1.12; 95% confidence interval, 0.74-1.69). The rate of major bleeding at 30 days in the alert group was similar to that of the control group (1.2% vs 1.2%, hazard ratio 0.94; 95% confidence interval, 0.44-2.01). Conclusions: Alerting providers to extend thromboprophylaxis after hospital discharge in Medical Service patients increased the rate of prophylaxis but did not decrease the rate of symptomatic venous thromboembolism. © 2013 Elsevier Inc.

Authors
Piazza, G; Anderson, FA; Ortel, TL; Cox, MJ; Rosenberg, DJ; Rahimian, S; Pendergast, WJ; McLaren, GD; Welker, JA; Akus, JJ; Stevens, SM; Elliott, CG; Freeman, AL; Patton, WF; Dabbagh, O; Wyman, A; Huang, W; Rao, AF; Goldhaber, SZ
MLA Citation
Piazza, G, Anderson, FA, Ortel, TL, Cox, MJ, Rosenberg, DJ, Rahimian, S, Pendergast, WJ, McLaren, GD, Welker, JA, Akus, JJ, Stevens, SM, Elliott, CG, Freeman, AL, Patton, WF, Dabbagh, O, Wyman, A, Huang, W, Rao, AF, and Goldhaber, SZ. "Randomized trial of physician alerts for thromboprophylaxis after discharge." American Journal of Medicine 126.5 (2013): 435-442.
Source
scival
Published In
The American Journal of Medicine
Volume
126
Issue
5
Publish Date
2013
Start Page
435
End Page
442
DOI
10.1016/j.amjmed.2012.09.020

RE: To the editor

Authors
Adam, SS; Ortel, TL; Jr, JWW
MLA Citation
Adam, SS, Ortel, TL, and Jr, JWW. "RE: To the editor." Annals of Internal Medicine 158.8 (2013): 637-638.
Source
scival
Published In
Annals of internal medicine
Volume
158
Issue
8
Publish Date
2013
Start Page
637
End Page
638
DOI
10.7326/0003-4819-158-8-201304160-00017

Ticlopidine-associated ADAMTS13 activity deficient thrombotic thrombocytopenic purpura in 22 persons in Japan: A report from the Southern Network on Adverse Reactions (SONAR)

Authors
Bennett, CL; Jacob, S; Dunn, BL; Georgantopoulos, P; Zheng, XL; Kwaan, HC; Mckoy, JM; Magwood, JS; Qureshi, ZP; Bandarenko, N; Winters, JL; Raife, TJ; Carey, PM; Sarode, R; Kiss, JE; Danielson, C; Ortel, TL; Clark, WF; Ablin, RJ; Rock, G; Matsumoto, M; Fujimura, Y
MLA Citation
Bennett, CL, Jacob, S, Dunn, BL, Georgantopoulos, P, Zheng, XL, Kwaan, HC, Mckoy, JM, Magwood, JS, Qureshi, ZP, Bandarenko, N, Winters, JL, Raife, TJ, Carey, PM, Sarode, R, Kiss, JE, Danielson, C, Ortel, TL, Clark, WF, Ablin, RJ, Rock, G, Matsumoto, M, and Fujimura, Y. "Ticlopidine-associated ADAMTS13 activity deficient thrombotic thrombocytopenic purpura in 22 persons in Japan: A report from the Southern Network on Adverse Reactions (SONAR)." British Journal of Haematology 161.6 (2013): 896-898.
Source
scival
Published In
British Journal of Haematology
Volume
161
Issue
6
Publish Date
2013
Start Page
896
End Page
898
DOI
10.1111/bjh.12303

Antithrombotic therapy and invasive procedures [3]

Authors
Spyropoulos, AC; Ortel, TL
MLA Citation
Spyropoulos, AC, and Ortel, TL. "Antithrombotic therapy and invasive procedures [3]." New England Journal of Medicine 369.11 (2013): 1078--.
Source
scival
Published In
The New England journal of medicine
Volume
369
Issue
11
Publish Date
2013
Start Page
1078-
DOI
10.1056/NEJMc1308259

Perioperative management of patients on chronic antithrombotic therapy.

Perioperative management of antithrombotic therapy is a situation that occurs frequently and requires consideration of the patient, the procedure, and an expanding array of anticoagulant and antiplatelet agents. Preoperative assessment must address each patient's risk for thromboembolic events balanced against the risk for perioperative bleeding. Procedures can be separated into those with a low bleeding risk, which generally do not require complete reversal of the antithrombotic therapy, and those associated with an intermediate or high bleeding risk. For patients who are receiving warfarin who need interruption of the anticoagulant, consideration must be given to whether simply withholding the anticoagulant is the optimal approach or whether a perioperative "bridge" with an alternative agent, typically a low-molecular-weight heparin, should be used. The new oral anticoagulants dabigatran and rivaroxaban have shorter effective half-lives, but they introduce other concerns for perioperative management, including prolonged drug effect in patients with renal insufficiency, limited experience with clinical laboratory testing to confirm lack of residual anticoagulant effect, and lack of a reversal agent. Antiplatelet agents must also be considered in the perioperative setting, with particular consideration given to the potential risk for thrombotic complications in patients with coronary artery stents who have antiplatelet therapy withheld.

Authors
Ortel, TL
MLA Citation
Ortel, TL. "Perioperative management of patients on chronic antithrombotic therapy." Blood 120.24 (December 6, 2012): 4699-4705. (Review)
PMID
22855600
Source
pubmed
Published In
Blood
Volume
120
Issue
24
Publish Date
2012
Start Page
4699
End Page
4705
DOI
10.1182/blood-2012-05-423228

Comparative effectiveness of warfarin and new oral anticoagulants for the management of atrial fibrillation and venous thromboembolism: a systematic review.

BACKGROUND: New oral anticoagulants (NOACs), including direct thrombin inhibitors (DTIs) and factor Xa (FXa) inhibitors, are emerging alternatives for prophylaxis and treatment of atrial fibrillation (AF) and venous thromboembolism (VTE). PURPOSE: To compare the benefits and harms of NOACs versus warfarin for AF and VTE. DATA SOURCES: MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews from January 2001 through July 2012; U.S. Food and Drug Administration (FDA) database for adverse event reports. STUDY SELECTION: English-language, randomized, controlled trials (RCTs) comparing NOACs with warfarin for management of AF or VTE and observational studies and FDA reports on adverse effects. DATA EXTRACTION: Two independent reviewers abstracted data and rated study quality and strength of evidence. DATA SYNTHESIS: Six good-quality RCTs compared NOACs (2 DTI studies, 4 FXa inhibitor studies) with warfarin. In AF, NOACs decreased all-cause mortality (risk ratio [RR], 0.88 [95% CI, 0.82 to 0.96]); in VTE, NOACs did not differ for mortality or VTE outcomes. Across indications, adverse effects of NOACs compared with warfarin were fatal bleeding (RR, 0.60 [CI, 0.46 to 0.77]), major bleeding (RR, 0.80 [CI, 0.63 to 1.01]), gastrointestinal bleeding (RR, 1.30 [CI, 0.97 to 1.73]), and discontinuation due to adverse events (RR, 1.23 [CI, 1.05 to 1.44]). Subgroup analyses suggest a higher risk for myocardial infarction with DTIs than with FXa inhibitors. Bleeding risk for NOACs may be increased in persons older than 75 years or those receiving warfarin who have good control. LIMITATION: There were no head-to-head comparisons of NOACs and limited data on harms. CONCLUSION: New oral anticoagulants are a viable option for patients receiving long-term anticoagulation. Treatment benefits compared with warfarin are small and vary depending on the control achieved by warfarin treatment. PRIMARY FUNDING SOURCE: Department of Veterans Affairs.

Authors
Adam, SS; McDuffie, JR; Ortel, TL; Williams, JW
MLA Citation
Adam, SS, McDuffie, JR, Ortel, TL, and Williams, JW. "Comparative effectiveness of warfarin and new oral anticoagulants for the management of atrial fibrillation and venous thromboembolism: a systematic review." Ann Intern Med 157.11 (December 4, 2012): 796-807. (Review)
PMID
22928173
Source
pubmed
Published In
Annals of internal medicine
Volume
157
Issue
11
Publish Date
2012
Start Page
796
End Page
807
DOI
10.7326/0003-4819-157-10-201211200-00532

Clinical causes and treatment of the thrombotic storm.

Thrombotic storm represents an extreme prothrombotic phenotype, characterized by multiple thrombotic events affecting diverse vascular beds occurring over a brief period of time. Thrombotic events involve venous and arterial circulation, including unusual locations, such as cerebral sinus venous thrombosis, intra-abdominal thromboembolic occlusions and microvascular events. Some patients will have antiphospholipid antibodies, but a significant number have no identifiable hypercoagulable state. The mainstay of treatment consists of anticoagulant therapy, although some patients appear to benefit from the addition of immunomodulatory therapies. Other disorders that share this thrombotic storm phenotype include catastrophic antiphospholipid syndrome, spontaneous heparin-induced thrombocytopenia and similar aggressive clinical disorders. Ongoing studies are focused on identifying underlying genetic factors that may predispose patients to develop this extreme clinical phenotype.

Authors
Ortel, TL; Kitchens, CS; Erkan, D; Brandão, LR; Hahn, S; James, AH; Kulkarni, R; Manco-Johnson, MJ; Pericak-Vance, M; Vance, J
MLA Citation
Ortel, TL, Kitchens, CS, Erkan, D, Brandão, LR, Hahn, S, James, AH, Kulkarni, R, Manco-Johnson, MJ, Pericak-Vance, M, and Vance, J. "Clinical causes and treatment of the thrombotic storm." Expert review of hematology 5.6 (December 1, 2012): 653-659. (Review)
Source
scopus
Published In
Expert Review of Hematology
Volume
5
Issue
6
Publish Date
2012
Start Page
653
End Page
659

Plasma proteomics of patients with non-valvular atrial fibrillation on chronic anti-coagulation with warfarin or a direct factor Xa inhibitor.

Plasma proteins mediate thrombogenesis, inflammation, endocardial injury and structural remodelling in atrial fibrillation (AF). We hypothesised that anti-coagulation with rivaroxaban, a direct factor Xa inhibitor, would differentially modulate biologically-relevant plasma proteins, compared with warfarin, a multi-coagulation protein antagonist. We performed unbiased liquid chromatography/tandem mass spectroscopy and candidate multiplexed protein immunoassays among Japanese subjects with non-valvular chronic AF who were randomly assigned to treatment with 24 weeks of rivaroxaban (n=93) or warfarin (n=94). Nine metaproteins, including fibulin-1 (p=0.0033), vitronectin (p=0.0010), haemoglobin α (p=0.0012), apolipoproteins C-II (p=0.0017) and H (p=0.0023), complement C5 precursor (p=0.0026), coagulation factor XIIIA (p=0.0026) and XIIIB (p=0.0032) subunits, and 10 candidate proteins, including thrombomodulin (p=0.0004), intercellular adhesion molecule-3 (p=0.0064), interleukin-8 (p=0.0007) and matrix metalloproteinase-3 (p=0.0003), were differentially expressed among patients with and without known clinical risk factors for stroke and bleeding in AF. Compared with warfarin, rivaroxaban treatment was associated with a greater increase in thrombomodulin (Δ 0.1 vs. 0.3 pg/ml, p=0.0026) and a trend towards a reduction in matrix metalloproteinase-9 (Δ 2.2 vs. -4.9 pg/ml, p=0.0757) over 24 weeks. Only modest correlations were observed between protein levels and prothrombin time, factor Xa activity and prothrombinase-induced clotting time. Plasma proteomics can identify distinct functional patterns of protein expression that report on known stroke and bleeding risk phenotypes in an ethnically-homogeneous AF population. The greater upregulation of thrombomodulin among patients randomised to rivaroxaban represents a proof-of-principle that pharmacoproteomics can be employed to discern novel effects of factor Xa inhibition beyond standard pharmacodynamic measures.

Authors
Chan, MY; Lin, M; Lucas, J; Moseley, A; Thompson, JW; Cyr, D; Ueda, H; Kajikawa, M; Ortel, TL; Becker, RC
MLA Citation
Chan, MY, Lin, M, Lucas, J, Moseley, A, Thompson, JW, Cyr, D, Ueda, H, Kajikawa, M, Ortel, TL, and Becker, RC. "Plasma proteomics of patients with non-valvular atrial fibrillation on chronic anti-coagulation with warfarin or a direct factor Xa inhibitor." Thromb Haemost 108.6 (December 2012): 1180-1191.
PMID
23052711
Source
pubmed
Published In
Thrombosis and haemostasis
Volume
108
Issue
6
Publish Date
2012
Start Page
1180
End Page
1191
DOI
10.1160/TH12-05-0310

Characterization of the hypercoagulable state in patients with sickle cell disease.

BACKGROUND: The pathophysiology of sickle cell disease (SCD) is complex, with increasing evidence of a pronounced prothrombotic state. OBJECTIVE: We investigated thrombin generation in SCD utilizing calibrated automated thrombography (CAT) and D-dimer, with subsequent correlation to clinical disease. PATIENT/METHODS: The study included 51 patients homozygous for hemoglobin S, either admitted for vaso-occlusive crisis (VOC) (n=34) or while in steady state and being seen in outpatient clinic (n=37). Twenty patients had blood drawn during both VOC and steady state. Mean values for CAT and D-dimer were compared between groups. Mean values for patients with and without clinical complications such as avascular necrosis and stroke were also compared. Linear regression was used to evaluate correlation to number of hospitalizations and for all pediatric patients, transcranial doppler (TCD) velocities. RESULTS: The mean D-dimer during VOC (2743 ± 3118 ng/ml) was significantly higher than during steady state (1151 ± 802, p<0.0001). Comparison of crisis and steady state by CAT also revealed a significant difference in all phases of thrombin generation, including mean endogenous thrombin potential (1381 ± 295 nM vs 923 ± 316, p<0.0001) and peak thrombin generated (284 ± 9 vs 223 ± 18, p=0.0002). There were no significant differences in mean values for the clinical outcomes examined in adults. In pediatric patients, however, increased TCD velocities correlated with steady state D-dimer (r(2)=0.32, p=0.02) and thrombin-antithrombin complex (r(2)=0.28, p=0.04. CONCLUSION: Hypercoagulable markers distinguish between patients with SCD during and between VOC, but do not correlate with specific clinical phenotypes.

Authors
Shah, N; Thornburg, C; Telen, MJ; Ortel, TL
MLA Citation
Shah, N, Thornburg, C, Telen, MJ, and Ortel, TL. "Characterization of the hypercoagulable state in patients with sickle cell disease." Thromb Res 130.5 (November 2012): e241-e245.
PMID
22959127
Source
pubmed
Published In
Thrombosis Research
Volume
130
Issue
5
Publish Date
2012
Start Page
e241
End Page
e245
DOI
10.1016/j.thromres.2012.08.307

Ticlopidine-, clopidogrel-, and prasugrel-associated thrombotic thrombocytopenic purpura: a 20-year review from the Southern Network on Adverse Reactions (SONAR).

Thienopyridine-derivatives (ticlopidine, clopidogrel, and prasugrel) are the primary antiplatelet agents. Thrombotic thrombocytopenic purpura (TTP) is a rare drug-associated syndrome, with the thienopyridines being the most common drugs implicated in this syndrome. We reviewed 20 years of information on clinical, epidemiologic, and laboratory findings for thienopyridine-associated TTP. Four, 11, and 11 cases of thienopyridine-associated TTP were reported in the first year of marketing of ticlopidine (1989), clopidogrel (1998), and prasugrel (2010), respectively. As of 2011, the FDA received reports of 97 ticlopidine-, 197 clopidogrel-, and 14 prasugrel-associated TTP cases. Severe deficiency of ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) was present in 80% and antibodies to 100% of these TTP patients on ticlopidine, 0% of the patients with clopidogrel-associated TTP (p < 0.05), and an unknown percentage of patients with prasugrel-associated TTP. TTP is associated with use of each of the three thienopyridines, although the mechanistic pathways may differ.

Authors
Jacob, S; Dunn, BL; Qureshi, ZP; Bandarenko, N; Kwaan, HC; Pandey, DK; McKoy, JM; Barnato, SE; Winters, JL; Cursio, JF; Weiss, I; Raife, TJ; Carey, PM; Sarode, R; Kiss, JE; Danielson, C; Ortel, TL; Clark, WF; Rock, G; Matsumoto, M; Fujimura, Y; Zheng, XL; Chen, H; Chen, F; Armstrong, JM; Raisch, DW; Bennett, CL
MLA Citation
Jacob, S, Dunn, BL, Qureshi, ZP, Bandarenko, N, Kwaan, HC, Pandey, DK, McKoy, JM, Barnato, SE, Winters, JL, Cursio, JF, Weiss, I, Raife, TJ, Carey, PM, Sarode, R, Kiss, JE, Danielson, C, Ortel, TL, Clark, WF, Rock, G, Matsumoto, M, Fujimura, Y, Zheng, XL, Chen, H, Chen, F, Armstrong, JM, Raisch, DW, and Bennett, CL. "Ticlopidine-, clopidogrel-, and prasugrel-associated thrombotic thrombocytopenic purpura: a 20-year review from the Southern Network on Adverse Reactions (SONAR)." Semin Thromb Hemost 38.8 (November 2012): 845-853. (Review)
PMID
23111862
Source
pubmed
Published In
Seminars in Thrombosis and Hemostasis
Volume
38
Issue
8
Publish Date
2012
Start Page
845
End Page
853
DOI
10.1055/s-0032-1328894

To bridge or not to bridge: these are the questions.

Authors
Harrison, RW; Ortel, TL; Becker, RC
MLA Citation
Harrison, RW, Ortel, TL, and Becker, RC. "To bridge or not to bridge: these are the questions." J Thromb Thrombolysis 34.1 (July 2012): 31-35. (Review)
PMID
22528332
Source
pubmed
Published In
Journal of Thrombosis and Thrombolysis
Volume
34
Issue
1
Publish Date
2012
Start Page
31
End Page
35
DOI
10.1007/s11239-012-0732-8

Antiphospholipid syndrome: laboratory testing and diagnostic strategies.

The antiphospholipid syndrome (APS) is diagnosed in patients with recurrent thromboembolic events and/or pregnancy loss in the presence of persistent laboratory evidence for antiphospholipid antibodies. Diagnostic tests for the detection of antiphospholipid antibodies include laboratory assays that detect anticardiolipin antibodies, lupus anticoagulants, and anti-β(2)-glycoprotein I antibodies. These assays have their origins beginning >60 years ago, with the identification of the biologic false positive test for syphilis, the observation of "circulating anticoagulants" in certain patients with systemic lupus erythematosus, the identification of cardiolipin as a key component in the serologic test for syphilis, and the recognition and characterization of a "cofactor" for antibody binding to phospholipids. Although these assays have been used clinically for many years, there are still problems with the accurate diagnosis of patients with this syndrome. For example, lupus anticoagulant testing can be difficult to interpret in patients receiving anticoagulant therapy, but most patients with a thromboembolic event will already be anticoagulated before the decision to perform the tests has been made. In addition to understanding limitations of the assays, clinicians also need to be aware of which patients should be tested and not obtain testing on patients unlikely to have APS. New tests and diagnostic strategies are in various stages of development and should help improve our ability to accurately diagnose this important clinical disorder.

Authors
Ortel, TL
MLA Citation
Ortel, TL. "Antiphospholipid syndrome: laboratory testing and diagnostic strategies." Am J Hematol 87 Suppl 1 (May 2012): S75-S81. (Review)
PMID
22473619
Source
pubmed
Published In
American Journal of Hematology
Volume
87 Suppl 1
Publish Date
2012
Start Page
S75
End Page
S81
DOI
10.1002/ajh.23196

Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors.

The new oral anticoagulants dabigatran, rivaroxaban and apixaban have advantages over warfarin which include no need for laboratory monitoring, less drug-drug interactions and less food-drug interactions. However, there is no established antidote for patients who are bleeding or require emergent surgery and there is a paucity of evidence to guide the clinical care during these situations. Members of thrombosis and anticoagulation groups participating in the Thrombosis and Hemostasis Summit of North America formulated expert opinion guidance for reversing the anticoagulant effect of the new oral anticoagulants and suggest: routine supportive care, activated charcoal if drug ingestion was within a couple of hours, and hemodialysis if feasible for dabigatran. Also, the pros and cons of the possible use of four factor prothrombin complex concentrate are discussed.

Authors
Kaatz, S; Kouides, PA; Garcia, DA; Spyropolous, AC; Crowther, M; Douketis, JD; Chan, AKC; James, A; Moll, S; Ortel, TL; Van Cott, EM; Ansell, J
MLA Citation
Kaatz, S, Kouides, PA, Garcia, DA, Spyropolous, AC, Crowther, M, Douketis, JD, Chan, AKC, James, A, Moll, S, Ortel, TL, Van Cott, EM, and Ansell, J. "Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors." Am J Hematol 87 Suppl 1 (May 2012): S141-S145. (Review)
PMID
22473649
Source
pubmed
Published In
American Journal of Hematology
Volume
87 Suppl 1
Publish Date
2012
Start Page
S141
End Page
S145
DOI
10.1002/ajh.23202

Time-dependent changes in non-COX-1-dependent platelet function with daily aspirin therapy.

To develop an integrated metric of non-COX-1-dependent platelet function (NCDPF) to measure the temporal response to aspirin in healthy volunteers and diabetics. NCDPF on aspirin demonstrates wide variability, despite suppression of COX-1. Although a variety of NCDPF assays are available, no standard exists and their reproducibility is not established. We administered 325 mg/day aspirin to two cohorts of volunteers (HV1, n = 52, and HV2, n = 96) and diabetics (DM, n = 74) and measured NCDPF using epinephrine, collagen, and ADP aggregometry and PFA100 (collagen/epi) before (Pre), after one dose (Post), and after several weeks (Final). COX-1 activity was assessed with arachidonic acid aggregometry (AAA). The primary outcome of the study, the platelet function score (PFS), was derived from a principal components analysis of NCDPF measures. The PFS strongly correlated with each measure of NCDPF in each cohort. After 2 or 4 weeks of daily aspirin the Final PFS strongly correlated (r > 0.7, P < 0.0001) and was higher (P < 0.01) than the Post PFS. The magnitude and direction of the change in PFS (Final–Post) in an individual subject was moderately inversely proportional to the Post PFS in HV1 (r = -0.45), HV2 (r = -0.54), DM (r = -0.68), P < 0.0001 for all. AAA remained suppressed during aspirin therapy. The PFS summarizes multiple measures of NCDPF. Despite suppression of COX-1 activity, NCDPF during aspirin therapy is predictably dynamic: those with heightened NCDPF continue to decline whereas those with low/normal NCDPF return to pre-aspirin levels over time.

Authors
Voora, D; Ortel, TL; Lucas, JE; Chi, J-T; Becker, RC; Ginsburg, GS
MLA Citation
Voora, D, Ortel, TL, Lucas, JE, Chi, J-T, Becker, RC, and Ginsburg, GS. "Time-dependent changes in non-COX-1-dependent platelet function with daily aspirin therapy." J Thromb Thrombolysis 33.3 (April 2012): 246-257.
PMID
22294277
Source
pubmed
Published In
Journal of Thrombosis and Thrombolysis
Volume
33
Issue
3
Publish Date
2012
Start Page
246
End Page
257
DOI
10.1007/s11239-012-0683-0

Periprocedural antithrombotic and bridging therapy: recommendations for standardized reporting in patients with arterial indications for chronic oral anticoagulant therapy.

Authors
Spyropoulos, AC; Douketis, JD; Gerotziafas, G; Kaatz, S; Ortel, TL; Schulman, S; Subcommittee on Control of Anticoagulation of the SSC of the ISTH,
MLA Citation
Spyropoulos, AC, Douketis, JD, Gerotziafas, G, Kaatz, S, Ortel, TL, Schulman, S, and Subcommittee on Control of Anticoagulation of the SSC of the ISTH, . "Periprocedural antithrombotic and bridging therapy: recommendations for standardized reporting in patients with arterial indications for chronic oral anticoagulant therapy." J Thromb Haemost 10.4 (April 2012): 692-694. (Review)
PMID
22934291
Source
pubmed
Published In
Journal of Thrombosis and Haemostasis
Volume
10
Issue
4
Publish Date
2012
Start Page
692
End Page
694

Laboratory diagnosis of the lupus anticoagulant.

Lupus anticoagulants are autoantibodies that are associated with an increased risk of thromboembolic events and adverse pregnancy outcomes. They are identified by a systematic, laboratory-based approach that includes the following steps: 1) prolongation of a phospholipid-dependent screening assay, 2) demonstration of an inhibitory activity by mixing studies with healthy pooled plasma, and 3) documentation that the inhibitory activity is phospholipid dependent. Laboratory testing can be complicated by several variables, however, including preanalytical factors, multiple reagents and testing platforms, and difficulties with interpreting the results. Guidelines have been developed through several professional organizations that build upon the steps listed above and provide guidance to improve the reproducibility of test results. This article reviews the guidelines developed by the Lupus Anticoagulant/Phospholipid Dependent Antibodies Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis and addresses several common issues encountered during testing for these clinically relevant autoantibodies.

Authors
Ortel, TL
MLA Citation
Ortel, TL. "Laboratory diagnosis of the lupus anticoagulant." Curr Rheumatol Rep 14.1 (February 2012): 64-70. (Review)
PMID
22134845
Source
pubmed
Published In
Current Rheumatology Reports
Volume
14
Issue
1
Publish Date
2012
Start Page
64
End Page
70
DOI
10.1007/s11926-011-0225-3

Prevention of VTE in orthopedic surgery patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.

BACKGROUND: VTE is a serious, but decreasing complication following major orthopedic surgery. This guideline focuses on optimal prophylaxis to reduce postoperative pulmonary embolism and DVT. METHODS: The methods of this guideline follow those described in Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement. RESULTS: In patients undergoing major orthopedic surgery, we recommend the use of one of the following rather than no antithrombotic prophylaxis: low-molecular-weight heparin; fondaparinux; dabigatran, apixaban, rivaroxaban (total hip arthroplasty or total knee arthroplasty but not hip fracture surgery); low-dose unfractionated heparin; adjusted-dose vitamin K antagonist; aspirin (all Grade 1B); or an intermittent pneumatic compression device (IPCD) (Grade 1C) for a minimum of 10 to 14 days. We suggest the use of low-molecular-weight heparin in preference to the other agents we have recommended as alternatives (Grade 2C/2B), and in patients receiving pharmacologic prophylaxis, we suggest adding an IPCD during the hospital stay (Grade 2C). We suggest extending thromboprophylaxis for up to 35 days (Grade 2B). In patients at increased bleeding risk, we suggest an IPCD or no prophylaxis (Grade 2C). In patients who decline injections, we recommend using apixaban or dabigatran (all Grade 1B). We suggest against using inferior vena cava filter placement for primary prevention in patients with contraindications to both pharmacologic and mechanical thromboprophylaxis (Grade 2C). We recommend against Doppler (or duplex) ultrasonography screening before hospital discharge (Grade 1B). For patients with isolated lower-extremity injuries requiring leg immobilization, we suggest no thromboprophylaxis (Grade 2B). For patients undergoing knee arthroscopy without a history of VTE, we suggest no thromboprophylaxis (Grade 2B). CONCLUSIONS: Optimal strategies for thromboprophylaxis after major orthopedic surgery include pharmacologic and mechanical approaches.

Authors
Falck-Ytter, Y; Francis, CW; Johanson, NA; Curley, C; Dahl, OE; Schulman, S; Ortel, TL; Pauker, SG; Colwell, CW
MLA Citation
Falck-Ytter, Y, Francis, CW, Johanson, NA, Curley, C, Dahl, OE, Schulman, S, Ortel, TL, Pauker, SG, and Colwell, CW. "Prevention of VTE in orthopedic surgery patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines." Chest 141.2 Suppl (February 2012): e278S-e325S.
PMID
22315265
Source
pubmed
Published In
Chest
Volume
141
Issue
2 Suppl
Publish Date
2012
Start Page
e278S
End Page
e325S
DOI
10.1378/chest.11-2404

What is the genetics of antiphospholipid antibodies/syndrome?

© Springer Science+Business Media New York 2012. An inherited risk for the occurrence of antiphospholipid antibodies (aPLs), with or without the clinical manifestations associated with antiphospholipid syndrome (APS), is supported by multiple lines of evidence. Family members of patients with APS, whether primary or associated with another autoimmune disease, are more likely to have elevated aPL levels. Multiple reports have described multiplex families with two or more family members with APS (or APS and another autoimmune disorder), and there is a strong association between aPL and APS with specific genes and gene alleles in the major histocompatibility complex. Genetic risk factors also appear to contribute to the prothrombotic risk in individual patients with aPL. The data would suggest that the development of these antibodies, as well as the clinical syndrome, reflects a complex interplay of inherited and acquired risk factors. Ongoing studies designed to identify and characterize genes associated with the development of aPL will improve our understanding of this complex autoimmune disorder and may provide a better understanding of which patients with aPL will develop clinical manifestations of the syndrome.

Authors
Ortel, TL; Meroni, PL; Alarcón-Riquelme, ME; Borghi, MO; Merrill, JT
MLA Citation
Ortel, TL, Meroni, PL, Alarcón-Riquelme, ME, Borghi, MO, and Merrill, JT. "What is the genetics of antiphospholipid antibodies/syndrome?." Antiphospholipid Syndrome: Insights and Highlights from the 13Th International Congress on Antiphospholipid Antibodies. January 1, 2012. 41-56.
Source
scopus
Publish Date
2012
Start Page
41
End Page
56
DOI
10.1007/978-1-4614-3194-7_3

Responses of mental stress-induced myocardial ischemia to escitalopram treatment: background, design, and method for the Responses of Mental Stress Induced Myocardial Ischemia to Escitalopram Treatment trial.

BACKGROUND: Mental stress-induced myocardial ischemia (MSIMI) is common in patients with clinically stable coronary heart disease (CHD) and is associated with poor outcomes. Depression is a risk factor of MSIMI. The REMIT trial investigates whether selective serotonin reuptake inhibitor (SSRI) treatment can improve MSIMI. The rationale and outline of the study are described. METHOD: In this single-center randomized clinical trial, adult patients with clinically stable CHD are recruited for baseline mental and exercise stress testing assessed by echocardiography. In addition, psychometric questionnaires are administered, and blood samples are collected for platelet activity analysis. Patients who demonstrate MSIMI, defined by new abnormal wall motion, ejection fraction reduction ≥8%, and/or development of ischemic ST change in electrocardiogram during mental stress testing, are randomized at a 1:1 ratio to escitalopram or placebo for 6 weeks. Approximately 120 patients with MSIMI are enrolled in the trial. The stress testing, platelet activity assessment, and psychometric questionnaires are repeated at the end of the 6-week intervention. The hypothesis of the study is that SSRI treatment improves MSIMI via mood regulation and modification of platelet activity. CONCLUSION: The REMIT study examines the effect of SSRI on MSIMI in vulnerable patients with CHD and probes some potential underlying mechanisms.

Authors
Jiang, W; Velazquez, EJ; Samad, Z; Kuchibhatla, M; Martsberger, C; Rogers, J; Williams, R; Kuhn, C; Ortel, TL; Becker, RC; Pristera, N; Krishnan, R; O'Connor, CM
MLA Citation
Jiang, W, Velazquez, EJ, Samad, Z, Kuchibhatla, M, Martsberger, C, Rogers, J, Williams, R, Kuhn, C, Ortel, TL, Becker, RC, Pristera, N, Krishnan, R, and O'Connor, CM. "Responses of mental stress-induced myocardial ischemia to escitalopram treatment: background, design, and method for the Responses of Mental Stress Induced Myocardial Ischemia to Escitalopram Treatment trial." Am Heart J 163.1 (January 2012): 20-26.
PMID
22172432
Source
pubmed
Published In
American Heart Journal
Volume
163
Issue
1
Publish Date
2012
Start Page
20
End Page
26
DOI
10.1016/j.ahj.2011.09.018

Clinical causes and treatment of the thrombotic storm

Thrombotic storm represents an extreme prothrombotic phenotype, characterized by multiple thrombotic events affecting diverse vascular beds occurring over a brief period of time. Thrombotic events involve venous and arterial circulation, including unusual locations, such as cerebral sinus venous thrombosis, intra-abdominal thromboembolic occlusions and microvascular events. Some patients will have antiphospholipid antibodies, but a significant number have no identifiable hypercoagulable state. The mainstay of treatment consists of anticoagulant therapy, although some patients appear to benefit from the addition of immunomodulatory therapies. Other disorders that share this thrombotic storm phenotype include catastrophic antiphospholipid syndrome, spontaneous heparin-induced thrombocytopenia and similar aggressive clinical disorders. Ongoing studies are focused on identifying underlying genetic factors that may predispose patients to develop this extreme clinical phenotype. © 2012 Expert Reviews Ltd.

Authors
Ortel, TL; Kitchens, CS; Erkan, D; Brandão, LR; Hahn, S; James, AH; Kulkarni, R; Manco-Johnson, MJ; Pericak-Vance, M; Vance, J
MLA Citation
Ortel, TL, Kitchens, CS, Erkan, D, Brandão, LR, Hahn, S, James, AH, Kulkarni, R, Manco-Johnson, MJ, Pericak-Vance, M, and Vance, J. "Clinical causes and treatment of the thrombotic storm." Expert Review of Hematology 5.6 (2012): 553-559.
PMID
23216595
Source
scival
Published In
Expert Review of Hematology
Volume
5
Issue
6
Publish Date
2012
Start Page
553
End Page
559
DOI
10.1586/ehm.12.56

Perioperative management of patients on chronic antithrombotic therapy.

Perioperative management of antithrombotic therapy is a situation that occurs frequently and requires consideration of the patient, the procedure, and an expanding array of anticoagulant and antiplatelet agents. Preoperative assessment must address each patient's risk for thromboembolic events balanced against the risk for perioperative bleeding. Procedures can be separated into those with a low bleeding risk, which generally do not require complete reversal of the antithrombotic therapy, and those associated with an intermediate or high bleeding risk. For patients who are receiving warfarin who need interruption of the anticoagulant, consideration must be given to whether simply withholding the anticoagulant is the optimal approach or whether a perioperative "bridge" with an alternative agent, typically a low-molecular-weight heparin, should be used. The new oral anticoagulants dabigatran and rivaroxaban have shorter effective half-lives, but they introduce other concerns for perioperative management, including prolonged drug effect in patients with renal insufficiency, limited experience with clinical laboratory testing to confirm lack of residual anticoagulant effect, and lack of a reversal agent. Antiplatelet agents must also be considered in the perioperative setting, with particular consideration given to the potential risk for thrombotic complications in patients with coronary artery stents who have antiplatelet therapy withheld.

Authors
Ortel, TL
MLA Citation
Ortel, TL. "Perioperative management of patients on chronic antithrombotic therapy." Hematology Am Soc Hematol Educ Program 2012 (2012): 529-535. (Review)
PMID
23233630
Source
pubmed
Published In
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program
Volume
2012
Publish Date
2012
Start Page
529
End Page
535
DOI
10.1182/asheducation-2012.1.529

Time-dependent changes in non-COX-1-dependent platelet function with daily aspirin therapy

To develop an integrated metric of non-COX-1- dependent platelet function (NCDPF) to measure the temporal response to aspirin in healthy volunteers and diabetics. NCDPF on aspirin demonstrates wide variability, despite suppression of COX-1. Although a variety of NCDPF assays are available, no standard exists and their reproducibility is not established. We administered 325 mg/day aspirin to two cohorts of volunteers (HV1, n = 52, and HV2, n = 96) and diabetics (DM, n = 74) and measured NCDPF using epinephrine, collagen, and ADP aggregometry and PFA100 (collagen/epi) before (Pre), after one dose (Post), and after several weeks (Final). COX-1 activity was assessed with arachidonic acid aggregometry (AAA). The primary outcome of the study, the platelet function score (PFS), was derived from a principal components analysis of NCDPF measures. The PFS strongly correlated with each measure of NCDPF in each cohort. After 2 or 4 weeks of daily aspirin the Final PFS strongly correlated (r>0.7, P<0.0001) and was higher (P<0.01) than the Post PFS. The magnitude and direction of the change in PFS (Final-Post) in an individual subject was moderately inversely proportional to the Post PFS in HV1 (r = -0.45), HV2 (r = -0.54), DM (r = -0.68), P<0.0001 for all. AAA remained suppressed during aspirin therapy. The PFS summarizes multiple measures of NCDPF. Despite suppression of COX-1 activity, NCDPF during aspirin therapy is predictably dynamic: those with heightened NCDPF continue to decline whereas those with low/normal NCDPF return to pre-aspirin levels over time. © Springer Science+Business Media, LLC 2012.

Authors
Voora, D; Ortel, TL; Lucas, JE; Chi, J-T; Becker, RC; Ginsburg, GS
MLA Citation
Voora, D, Ortel, TL, Lucas, JE, Chi, J-T, Becker, RC, and Ginsburg, GS. "Time-dependent changes in non-COX-1-dependent platelet function with daily aspirin therapy." Journal of Thrombosis and Thrombolysis 33.3 (2012): 246-257.
Source
scival
Published In
Journal of Thrombosis and Thrombolysis
Volume
33
Issue
3
Publish Date
2012
Start Page
246
End Page
257
DOI
10.1007/s11239-012-0683-0

Whole blood gene expression analyses in patients with single versus recurrent venous thromboembolism.

INTRODUCTION: Venous thromboembolism may recur in up to 30% of patients with a spontaneous venous thromboembolism after a standard course of anticoagulation. Identification of patients at risk for recurrent venous thromboembolism would facilitate decisions concerning the duration of anticoagulant therapy. OBJECTIVES: In this exploratory study, we investigated whether whole blood gene expression data could distinguish subjects with single venous thromboembolism from subjects with recurrent venous thromboembolism. METHODS: 40 adults with venous thromboembolism (23 with single event and 17 with recurrent events) on warfarin were recruited. Individuals with antiphospholipid syndrome or cancer were excluded. Plasma and serum samples were collected for biomarker testing, and PAXgene tubes were used to collect whole blood RNA samples. RESULTS: D-dimer levels were significantly higher in patients with recurrent venous thromboembolism, but P-selectin and thrombin-antithrombin complex levels were similar in the two groups. Comparison of gene expression data from the two groups provided us with a 50 gene probe model that distinguished these two groups with good receiver operating curve characteristics (AUC 0.75). This model includes genes involved in mRNA splicing and platelet aggregation. Pathway analysis between subjects with single and recurrent venous thromboembolism revealed that the Akt pathway was up-regulated in the recurrent venous thromboembolism group compared to the single venous thromboembolism group. CONCLUSIONS: In this exploratory study, gene expression profiles of whole blood appear to be a useful strategy to distinguish subjects with single venous thromboembolism from those with recurrent venous thromboembolism. Prospective studies with additional patients are needed to validate these results.

Authors
Lewis, DA; Stashenko, GJ; Akay, OM; Price, LI; Owzar, K; Ginsburg, GS; Chi, J-T; Ortel, TL
MLA Citation
Lewis, DA, Stashenko, GJ, Akay, OM, Price, LI, Owzar, K, Ginsburg, GS, Chi, J-T, and Ortel, TL. "Whole blood gene expression analyses in patients with single versus recurrent venous thromboembolism." Thromb Res 128.6 (December 2011): 536-540.
PMID
21737128
Source
pubmed
Published In
Thrombosis Research
Volume
128
Issue
6
Publish Date
2011
Start Page
536
End Page
540
DOI
10.1016/j.thromres.2011.06.003

Heparin-induced thrombocytopenia in cancer.

Heparin-induced thrombocytopenia is a common and clinically important drug-induced complication that can cause life- and limbthreatening thrombosis. Epidemiologically, the disease has been studied in many different clinical settings, but little is known about it in cancer patients, a population at increased risk for thrombosis and thus exposure to heparin products. Additionally, thrombocytopenia is a common finding in cancer patients. The convergence of these variables highlights the importance of an increased understanding of the disease in cancer patients.

Authors
Miriovsky, BJ; Ortel, TL
MLA Citation
Miriovsky, BJ, and Ortel, TL. "Heparin-induced thrombocytopenia in cancer." J Natl Compr Canc Netw 9.7 (July 1, 2011): 781-787. (Review)
PMID
21715724
Source
pubmed
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
9
Issue
7
Publish Date
2011
Start Page
781
End Page
787

Performance of a new, rapid, automated immunoassay for the detection of anti-platelet factor 4/heparin complex antibodies.

Heparin-induced thrombocytopenia (HIT) is a life-threatening adverse reaction to heparin that must be identified quickly to determine appropriate anticoagulant therapy strategies. The most common antibodies involved in HIT are directed against platelet factor 4/heparin (PF4/H) complexes. Many methods for anti-PF4/H detection exist such as enzyme immunoassays (EIAs), which have been shown to exhibit high-negative predictive value allowing for the exclusion of HIT in the majority of suspected patients; however, most EIAs are performed in a batch mode, thereby delaying results to the physician. HemosIL HIT-Ab(PF4-H) is a new, rapid method for the detection of total immunoglobulin against PF4/H complexes on ACL TOP Family systems. The assay was evaluated in a multicentre study at three sites with 414 HIT-suspected patients. Using a cut-off value of 1.0 U/ml for HemosIL HIT-Ab(PF4-H), the new test was compared with Asserachrom HPIA. Results showed a co-positivity of 60.2% [95% confidence interval (CI) 48.9-70.8], co-negativity of 94.6% (95% CI 91.5-96.7), and overall agreement of 87.7% (95% CI 84.1-90.7). These results are comparable to other PF4/H antibody assays available; with the added benefit of full automation and on-demand testing which provides results at the critical moment when physicians are required to make clinical decisions regarding anticoagulant therapy.

Authors
Davidson, SJ; Ortel, TL; Smith, LJ
MLA Citation
Davidson, SJ, Ortel, TL, and Smith, LJ. "Performance of a new, rapid, automated immunoassay for the detection of anti-platelet factor 4/heparin complex antibodies." Blood Coagul Fibrinolysis 22.4 (June 2011): 340-344.
PMID
21415710
Source
pubmed
Published In
Blood Coagulation and Fibrinolysis: international journal in haemostasis and thrombosis
Volume
22
Issue
4
Publish Date
2011
Start Page
340
End Page
344
DOI
10.1097/MBC.0b013e328344f7e9

Thrombotic storm revisited: preliminary diagnostic criteria suggested by the thrombotic storm study group.

Physicians periodically encounter patients with an extraordinarily accelerated course of hypercoagulability who develop thromboses in multiple organ systems over days to weeks. Such patients may harbor underlying hypercoagulable clinical conditions, but their clinical course sets them apart from most patients with similar risk factors. Underlying triggers of "thrombotic storm" include pregnancy, inflammation, trauma, surgery, and infection. Aggressive anticoagulant therapy may control thrombotic storm, yet thrombotic storm may resume with even brief interruptions of anticoagulant therapy. The authors of this communication formed the Thrombotic Storm Study Group in order to identify clinical characteristics of such patients, thus constructing preliminary criteria to better define, identify, and study the course of patients deemed to have thrombotic storm. The characteristics culled from these 10 patients are: younger age (oldest was 38 years old at time of presentation); at least 2 arterial or venous (or both) thromboembolic events, typically in unusual sites with or without microangiopathy; unexplained recurrence; and frequently proceeded by a trigger. The following characteristics were not used in defining thrombotic storm: underlying malignancies; use of acute myocardial infarction as a defining arterial event in the setting of established coronary artery disease; use of cocaine; thrombotic complications expected with various intravascular devices; known paroxysmal nocturnal hemoglobinuria or myeloproliferative disorders; severe trauma; and premorbid conditions.

Authors
Kitchens, CS; Erkan, D; Brandão, LR; Hahn, S; James, AH; Kulkarni, R; Pericak-Vance, M; Vance, J; Ortel, TL
MLA Citation
Kitchens, CS, Erkan, D, Brandão, LR, Hahn, S, James, AH, Kulkarni, R, Pericak-Vance, M, Vance, J, and Ortel, TL. "Thrombotic storm revisited: preliminary diagnostic criteria suggested by the thrombotic storm study group." Am J Med 124.4 (April 2011): 290-296. (Review)
PMID
21435416
Source
pubmed
Published In
American Journal of Medicine
Volume
124
Issue
4
Publish Date
2011
Start Page
290
End Page
296
DOI
10.1016/j.amjmed.2010.10.018

Safety and efficacy of thrombin-JMI: a multidisciplinary expert group consensus.

BACKGROUND: The use of bovine thrombin has been an effective approach to aiding hemostasis during surgery for over 60 years. Its use has a reported association with the development of antibodies to coagulation factors with limited evidence to the clinical significance. METHODS: The Collaborative Delphi survey methodology was used to develop a consensus on specified topic areas from a panel of 12 surgeons/scientists who have had experience with topical thrombins; it consisted of 2 rounds of a Web-based survey and a final live discussion. RESULTS: Some key issues that reached consensus included: bovine, human plasma-derived and recombinant human thrombin are equally effective hemostatic agents with similar adverse event rates, and immunogenicity to a topical protein rarely translate into adverse events. CONCLUSIONS: Although a risk of immunogenicity is associated with all topical thrombins, no conclusive clinical evidence is available that these antibodies have any significant effect on short- and long-term clinical consequences.

Authors
Bhandari, M; Ofosu, FA; Mackman, N; Jackson, C; Doria, C; Humphries, JE; Babu, SC; Ortel, TL; Hoffman Van Thiel, D; Walenga, JM; Wahi, R; Teoh, KHT; Fareed, J
MLA Citation
Bhandari, M, Ofosu, FA, Mackman, N, Jackson, C, Doria, C, Humphries, JE, Babu, SC, Ortel, TL, Hoffman Van Thiel, D, Walenga, JM, Wahi, R, Teoh, KHT, and Fareed, J. "Safety and efficacy of thrombin-JMI: a multidisciplinary expert group consensus." Clin Appl Thromb Hemost 17.1 (February 2011): 39-45.
PMID
21078609
Source
pubmed
Published In
Clinical and Applied Thrombosis / Hemostasis
Volume
17
Issue
1
Publish Date
2011
Start Page
39
End Page
45
DOI
10.1177/1076029610385674

Gene-expression patterns predict phenotypes of immune-mediated thrombosis (Blood (2006) 107, 4, (1391-1396))

Authors
Potti, A; Bild, A; Dressman, HK; Lewis, DA; Nevins, JR; Ortel, TL
MLA Citation
Potti, A, Bild, A, Dressman, HK, Lewis, DA, Nevins, JR, and Ortel, TL. "Gene-expression patterns predict phenotypes of immune-mediated thrombosis (Blood (2006) 107, 4, (1391-1396))." Blood 118.16 (2011): 4497--.
Source
scival
Published In
Blood
Volume
118
Issue
16
Publish Date
2011
Start Page
4497-
DOI
10.1182/blood-2011-08-375030

Venous thromboembolic disease: Clinical practice guidelines in oncology

Recognizing the increased risk of VTE in cancer patients is the first step in preventing the occurrence of VTE and promptly identifying VTE in these patients. The panel recommends VTE thromboprophylaxis for all hospitalized patients with cancer who do not have contraindications to this therapy, and also emphasizes that an increased level of clinical suspicion of VTE should be maintained for cancer patients. After hospital discharge, the panel recommends that cancer patients in a high-risk setting for VTE (e.g., patients who have undergone cancer surgery, those with multiple myeloma) continue to receive VTE prophylaxis, with the duration of anticoagulation determined by the clinical situation. Careful evaluation of cancer patients in whom VTE is suspected, and prompt treatment and follow-up for those diagnosed with VTE, is recommended after the cancer status of the patient is assessed and the risks and benefits of treatment are considered. © JNCCN-Journal of the National Comprehensive Cancer Network.

Authors
Streiff, MB; Bockenstedt, PL; Cataland, SR; Chesney, C; Eby, C; Fanikos, J; Fogarty, PF; Gao, S; Garcia-Aguilar, J; Goldhaber, SZ; al, E
MLA Citation
Streiff, MB, Bockenstedt, PL, Cataland, SR, Chesney, C, Eby, C, Fanikos, J, Fogarty, PF, Gao, S, Garcia-Aguilar, J, Goldhaber, SZ, and al, E. "Venous thromboembolic disease: Clinical practice guidelines in oncology." JNCCN Journal of the National Comprehensive Cancer Network 9.7 (2011): 714-777.
PMID
21715723
Source
scival
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
9
Issue
7
Publish Date
2011
Start Page
714
End Page
777

Antiphospholipid syndrome clinical research task force report

The Antiphospholipid Syndrome (APS) Clinical Research Task Force (CRTF) was one of six Task Forces developed by the 13th International Congress on Antiphospholipid Antibodies (aPL) organization committee with the purpose of: a) evaluating the limitations of APS clinical research and developing guidelines for researchers to help improve the quality of APS research; and b) prioritizing the ideas for a well-designed multicenter clinical trial and discussing the pragmatics of getting such a trial done. Following a systematic working algorithm, the Task Force identified five major issues that impede APS clinical research and the ability to develop evidence-based recommendations for the management of aPL-positive patients: (1) aPL detection has been based on partially or non-standardized tests, and clinical (and basic) APS research studies have included patients with heterogeneous aPL profiles with different clinical event risks; (2) clinical (and basic) APS research studies have included a heterogeneous group of patients with different aPL-related manifestations (some controversial); (3) thrombosis and/or pregnancy risk stratification and quantification are rarely incorporated in APS clinical research; (4) most APS clinical studies include patients with single positive aPL results and/or low-titer aPL ELISA results; furthermore, study designs are mostly retrospective and not population based, with limited number of prospective and/or controlled population studies; and (5) lack of the understanding the particular mechanisms of aPL-mediated clinical events limits the optimal clinical study design. The Task Force recommended that there is an urgent need for a truly international collaborative approach to design and conduct well-designed prospective large-scale multi-center clinical trials of patients with persistent and clinically significant aPL profiles. An international collaborative meeting to formulate a good research question using 'FINER' (Feasible; Interesting; Novel; Ethical; and Relevant) criteria took place in November 2010. © The Author(s), 2011.

Authors
Erkan, D; Derksen, R; Levy, R; Machin, S; Ortel, T; Pierangeli, S; Roubey, R; Lockshin, M
MLA Citation
Erkan, D, Derksen, R, Levy, R, Machin, S, Ortel, T, Pierangeli, S, Roubey, R, and Lockshin, M. "Antiphospholipid syndrome clinical research task force report." Lupus 20.2 (2011): 219-224.
PMID
21303838
Source
scival
Published In
Lupus
Volume
20
Issue
2
Publish Date
2011
Start Page
219
End Page
224
DOI
10.1177/0961203310395053

'Criteria' aPL tests: Report of a Task Force and preconference workshop at the 13th International Congress on Antiphospholipid Antibodies, Galveston, Texas, April 2010

Current classification criteria for definite antiphospholipid syndrome (APS) mandate the use of one or more of three positive 'standardized' laboratory assays to detect antiphospholipid antibodies (aPL) (viz: anticardiolipin [aCL] IgG and IgM; anti-β2glycoprotein I [anti-β2GPI] antibodies IgG and IgM; and/or a lupus anticoagulant [LAC]), when at least one of the two major clinical manifestations (thrombosis or pregnancy losses) are present. Although, efforts of standardization for these 'criteria' aPL tests have been conducted over the last 27 years, reports of inconsistencies, inter-assay and inter-laboratory variation in the results of aCL, LAC, and anti-β2GPI, and problems with the interpretation and the clinical value of the tests still exist, which affect the consistency of the diagnosis of APS. A Task Force of scientists and pioneers in the field from different countries, subdivided in three working groups, discussed and analyzed critical questions related to 'criteria' aPL tests in an evidence-based manner, during the 13th International Congress on Antiphospholipid Antibodies (APLA 2010, April 13-16, 2010, Galveston, TX). These included: review of the standardization and the need for international consensus protocol for aCL and anti-β2GPI tests; the use of monoclonal and/or polyclonal standards in the calibration curve of those tests; and the need for establishment of international units of measurement for anti- β2GPI tests. The group also reviewed the recently updated guidelines for LAC testing, and analyzed and discussed the possibility of stratification of 'criteria' aPL tests as risk factors for APS, as well as the clinical value of single positive vs. multiple aPL positivity. The group members presented, discussed, analyzed data, updated and re-defined those critical questions at a preconference workshop that was open to congress attendees. This report summarizes the findings, conclusions, and recommendations of this Task Force. © The Author(s), 2011.

Authors
Pierangeli, SS; Groot, PGD; Dlott, J; Favaloro, E; Harris, EN; Lakos, G; Ortel, T; Meroni, PL; Otomo, K; Pengo, V; Tincani, A; Wong, R; Roubey, R
MLA Citation
Pierangeli, SS, Groot, PGD, Dlott, J, Favaloro, E, Harris, EN, Lakos, G, Ortel, T, Meroni, PL, Otomo, K, Pengo, V, Tincani, A, Wong, R, and Roubey, R. "'Criteria' aPL tests: Report of a Task Force and preconference workshop at the 13th International Congress on Antiphospholipid Antibodies, Galveston, Texas, April 2010." Lupus 20.2 (2011): 182-190.
PMID
21303835
Source
scival
Published In
Lupus
Volume
20
Issue
2
Publish Date
2011
Start Page
182
End Page
190
DOI
10.1177/0961203310395055

Heparin modifies the immunogenicity of positively charged proteins.

The immune response in heparin-induced thrombocytopenia is initiated by and directed to large multimolecular complexes of platelet factor 4 (PF4) and heparin (H). We have previously shown that PF4:H multimolecular complexes assemble through electrostatic interactions and, once formed, are highly immunogenic in vivo. Based on these observations, we hypothesized that other positively charged proteins would exhibit similar biologic interactions with H. To test this hypothesis, we selected 2 unrelated positively charged proteins, protamine (PRT) and lysozyme, and studied H-dependent interactions using in vitro and in vivo techniques. Our studies indicate that PRT/H and lysozyme/H, like PF4/H, show H-dependent binding over a range of H concentrations and that formation of complexes occurs at distinct stoichiometric ratios. We show that protein/H complexes are capable of eliciting high-titer antigen-specific antibodies in a murine immunization model and that PRT/H antibodies occur in patients undergoing cardiopulmonary bypass surgery. Finally, our studies indicate that protein/H complexes, but not uncomplexed protein, directly activate dendritic cells in vitro leading to interleukin-12 release. Taken together, these studies indicate that H significantly alters the biophysical and biologic properties of positively charged compounds through formation of multimolecular complexes that lead to dendritic cell activation and trigger immune responses in vivo.

Authors
Chudasama, SL; Espinasse, B; Hwang, F; Qi, R; Joglekar, M; Afonina, G; Wiesner, MR; Welsby, IJ; Ortel, TL; Arepally, GM
MLA Citation
Chudasama, SL, Espinasse, B, Hwang, F, Qi, R, Joglekar, M, Afonina, G, Wiesner, MR, Welsby, IJ, Ortel, TL, and Arepally, GM. "Heparin modifies the immunogenicity of positively charged proteins." Blood 116.26 (December 23, 2010): 6046-6053.
PMID
20852126
Source
pubmed
Published In
Blood
Volume
116
Issue
26
Publish Date
2010
Start Page
6046
End Page
6053
DOI
10.1182/blood-2010-06-292938

The HIT Expert Probability (HEP) Score: a novel pre-test probability model for heparin-induced thrombocytopenia based on broad expert opinion.

BACKGROUND: The diagnosis of heparin-induced thrombocytopenia (HIT) is challenging. Over-diagnosis and over-treatment are common. OBJECTIVES: To develop a pre-test clinical scoring model for HIT based on broad expert opinion that may be useful in guiding clinical decisions regarding therapy. PATIENTS/METHODS: A pre-test model, the HIT Expert Probability (HEP) Score, was constructed based on the opinions of 26 HIT experts. Fifty patients referred to a reference laboratory for HIT testing comprised the validation cohort. Two hematology trainees scored each patient using the HEP Score and a previously published clinical scoring system (4 T's). A panel of three independent experts adjudicated the 50 patients and rendered a diagnosis of HIT likely or unlikely. All subjects underwent HIT laboratory testing with a polyspecific HIT ELISA and serotonin release assay (SRA). RESULTS: The HEP Score exhibited significantly greater interobserver agreement [intraclass correlation coefficient: 0.88 (95% CI 0.80-0.93) vs. 0.71 (0.54-0.83)], correlation with the results of HIT laboratory testing and concordance with the diagnosis of the expert panel (area under receiver-operating curve: 0.91 vs. 0.74, P = 0.017) than the 4 T's. The model was 100% sensitive and 60% specific for determining the presence of HIT as defined by the expert panel and would have allowed for a 41% reduction in the number of patients receiving a direct thrombin inhibitor (DTI). CONCLUSION: The HEP Score is the first pre-test clinical scoring model for HIT based on broad expert opinion, exhibited favorable operating characteristics and may permit clinicians to confidently reduce use of alternative anticoagulants. Prospective multicenter validation is warranted.

Authors
Cuker, A; Arepally, G; Crowther, MA; Rice, L; Datko, F; Hook, K; Propert, KJ; Kuter, DJ; Ortel, TL; Konkle, BA; Cines, DB
MLA Citation
Cuker, A, Arepally, G, Crowther, MA, Rice, L, Datko, F, Hook, K, Propert, KJ, Kuter, DJ, Ortel, TL, Konkle, BA, and Cines, DB. "The HIT Expert Probability (HEP) Score: a novel pre-test probability model for heparin-induced thrombocytopenia based on broad expert opinion." J Thromb Haemost 8.12 (December 2010): 2642-2650.
PMID
20854372
Source
pubmed
Published In
Journal of Thrombosis and Haemostasis
Volume
8
Issue
12
Publish Date
2010
Start Page
2642
End Page
2650
DOI
10.1111/j.1538-7836.2010.04059.x

Assays for measuring rivaroxaban: their suitability and limitations.

Several new oral anticoagulants such as rivaroxaban (which targets Factor Xa) and dabigatran etexilate (which targets thrombin) are in advanced stages of clinical development and are already available for clinical use in some countries. Although these agents do not require routine coagulation monitoring, assays to assess the level of anticoagulation may be of assistance in certain circumstances such as in case of overdose, in patients with a hemorrhagic or thromboembolic event during treatment, or to assess compliance. Moreover, the influence of the new oral anticoagulants on routine coagulation tests must be recognized. The prothrombin time is not suitable for rivaroxaban measurement for several reasons, and the routinely used international normalized ratio for monitoring the vitamin K antagonists cannot be applied to rivaroxaban. Development of universal assays is challenging because the new oral anticoagulants have different targets, and even those with the same target have variable effects on routine coagulation assays. Focusing on rivaroxaban, there is emerging evidence that an anti-Factor Xa assay that uses rivaroxaban-containing plasma calibrators may provide the optimal method for determining plasma rivaroxaban concentrations.

Authors
Lindhoff-Last, E; Samama, MM; Ortel, TL; Weitz, JI; Spiro, TE
MLA Citation
Lindhoff-Last, E, Samama, MM, Ortel, TL, Weitz, JI, and Spiro, TE. "Assays for measuring rivaroxaban: their suitability and limitations." Ther Drug Monit 32.6 (December 2010): 673-679. (Review)
PMID
20844464
Source
pubmed
Published In
Therapeutic Drug Monitoring
Volume
32
Issue
6
Publish Date
2010
Start Page
673
End Page
679
DOI
10.1097/FTD.0b013e3181f2f264

Validation of the high-dose heparin confirmatory step for the diagnosis of heparin-induced thrombocytopenia.

The diagnosis of heparin-induced thrombocytopenia (HIT) requires detection of antibodies to the heparin/platelet factor 4 (PF4) complexes via enzyme-linked immunosorbent assay. Addition of excess heparin to the sample decreases the optical density by 50% or more and confirms the presence of these antibodies. One hundred fifteen patients with anti-heparin/PF4 antibodies detected by enzyme-linked immunosorbent assay were classified as clinically HIT-positive or HIT-negative, followed by confirmation with excess heparin. A multivariate logistic regression model was fitted to estimate relationships between patient characteristics, laboratory findings, and clinical HIT status. This model was validated on an independent sample of 97 patients with anti-heparin/PF4 antibodies. No relationship between age, race, or sex and clinical HIT status was found. Maximal optical density and confirmatory positive status independently predicted HIT in multivariate analysis. Predictive accuracy on the training set (c-index 0.78, Brier score 0.17) was maintained when the algorithm was applied to the independent validation population (c-index 0.80, Brier score 0.20). This study quantifies the clinical utility of the confirmatory test to diagnose HIT. On the basis of data from the heparin/PF4 enzyme-linked immunosorbent assay and confirmatory assays, a predictive computer algorithm could distinguish patients likely to have HIT from those who do not.

Authors
Whitlatch, NL; Kong, DF; Metjian, AD; Arepally, GM; Ortel, TL
MLA Citation
Whitlatch, NL, Kong, DF, Metjian, AD, Arepally, GM, and Ortel, TL. "Validation of the high-dose heparin confirmatory step for the diagnosis of heparin-induced thrombocytopenia." Blood 116.10 (September 9, 2010): 1761-1766.
PMID
20508160
Source
pubmed
Published In
Blood
Volume
116
Issue
10
Publish Date
2010
Start Page
1761
End Page
1766
DOI
10.1182/blood-2010-01-262659

The effect of aspirin on endothelial progenitor cell biology: preliminary investigation of novel properties.

UNLABELLED: Atherosclerosis develops in an environment of endothelial injury and inflammation. Circulating endothelial progenitor cells (EPCs) are required for vascular repair and restoration of normal endothelial function. We tested the hypothesis that the nonselective cyclooxygenase (COX) inhibitor aspirin (ASA) exerts an effect on circulating EPCs. METHODS: As part of a larger study evaluating the effect of aspirin dose in primary and secondary prevention, subjects (n=32) were assigned randomly to either 81 mg or 325 mg aspirin daily for two months, and circulating mononuclear cells were enumerated at the beginning of the study and after 2 months using fluorescent antibodies against CD34 and CD133 as well as based on aldehyde dehydrogenase (ALDH) activity. Brachial artery endothelial function via flow-mediated dilation (BAFMD) and light transmittance platelet aggregometry in response to physiologic agonists was also determined. RESULTS: Subjects taking aspirin at the time of study entry had a lower numbers of CD133+/34+ cells compared to those not previously exposed (0.01% vs. 0.05% of MNCs, P<0.03). After 2 months, subjects randomized to 81 vs. 325 mg of ASA had no significant differences in the median numbers of EPCs, although mean numbers trended lower in the high dose group. Patients on chronic ASA therapy continued to have lower numbers of EPCs. Similar effects were observed in CD34 and CD 133 single-positive cells, as well as ALDH(br) cells. BAFMD did not differ nor change significantly over time between aspirin dose groups. All patients had decreased ex vivo platelet aggregation in response to arachidonic acid and ADP stimulation. CONCLUSIONS: Our preliminary studies suggest that aspirin exerts a time-dependent effect on circulating EPCs. Short-term exposure to differing doses of ASA had indeterminate effects on EPCs levels, suggesting that time of ASA exposure may play a more important role than dose. Determining the responsible mechanism(s) and the overall clinical relevance of these findings will require further investigation.

Authors
Lou, J; Povsic, TJ; Allen, JD; Adams, SD; Myles, S; Starr, AZ; Ortel, TL; Becker, RC
MLA Citation
Lou, J, Povsic, TJ, Allen, JD, Adams, SD, Myles, S, Starr, AZ, Ortel, TL, and Becker, RC. "The effect of aspirin on endothelial progenitor cell biology: preliminary investigation of novel properties." Thromb Res 126.3 (September 2010): e175-e179.
PMID
20659762
Source
pubmed
Published In
Thrombosis Research
Volume
126
Issue
3
Publish Date
2010
Start Page
e175
End Page
e179
DOI
10.1016/j.thromres.2009.11.017

Comparison of characteristics from White- and Black-Americans with venous thromboembolism: a cross-sectional study.

When compared with Whites, Black-Americans may have a 40% higher incidence venous thromboembolism (VTE) incidence. However, whether other VTE characteristics and risk factors vary by race is uncertain. To compare demographic and baseline characteristics among White- and Black-Americans with VTE, we used data prospectively collected from consecutive consenting adults enrolled in seven Centers for Disease Control (CDC) Thrombosis and Hemostasis Centers from August 2003 to March 2009. These characteristics were compared among Whites (n = 2002) and Blacks (n = 395) with objectively diagnosed VTE, both overall, and by age and gender. When compared with Whites, Blacks had a significantly higher proportion with pulmonary embolism (PE), including idiopathic PE among Black women, and a significantly higher proportion of Blacks were women. Blacks had a significantly higher mean BMI and a significantly lower proportion with recent surgery, trauma or infection, family history of VTE, and documented thrombophilia (solely from reduced factor V Leiden and prothrombin G20210A prevalence). Conversely, Blacks had a significantly higher proportion with hypertension, diabetes mellitus, chronic renal disease and dialysis, HIV, and sickle cell disease. When compared with White women, Black women had a significantly lower proportion with recent oral contraceptive use or hormone therapy. We conclude that Whites and Blacks differ significantly regarding demographic and baseline characteristics that may be risk factors for VTE. The prevalence of transient VTE risk factors and idiopathic VTE among Blacks appears to be lower and higher, respectively, suggesting that heritability may be important in the etiology of VTE among Black-Americans.

Authors
Heit, JA; Beckman, MG; Bockenstedt, PL; Grant, AM; Key, NS; Kulkarni, R; Manco-Johnson, MJ; Moll, S; Ortel, TL; Philipp, CS; CDC Thrombosis and Hemostasis Centers Research and Prevention Network,
MLA Citation
Heit, JA, Beckman, MG, Bockenstedt, PL, Grant, AM, Key, NS, Kulkarni, R, Manco-Johnson, MJ, Moll, S, Ortel, TL, Philipp, CS, and CDC Thrombosis and Hemostasis Centers Research and Prevention Network, . "Comparison of characteristics from White- and Black-Americans with venous thromboembolism: a cross-sectional study." Am J Hematol 85.7 (July 2010): 467-471.
PMID
20575037
Source
pubmed
Published In
American Journal of Hematology
Volume
85
Issue
7
Publish Date
2010
Start Page
467
End Page
471
DOI
10.1002/ajh.21735

Nephrology

The objective of this chapter is to highlight problems of hemostasis and thrombosis in regards to renal disease. The topics included are bleeding in renal disease, renal vein thrombosis, nephrotic syndrome/hypercoagulability, graft loss due to thromobosis/thrombophilias, and dose adjustment of anticoagulants in renal insufficiency. The clinical, etiologic, and treatment aspects are addressed for the first four topics and anticoagulants are discussed by degree of renal insufficiency for the final topic. © 2009 Blackwell Publishing Ltd.

Authors
Perry, S; Ortel, TL
MLA Citation
Perry, S, and Ortel, TL. "Nephrology." (May 5, 2010): 227-234. (Chapter)
Source
scopus
Publish Date
2010
Start Page
227
End Page
234
DOI
10.1002/9781444306286.ch22

Associations of depressive symptoms, trait hostility, and gender with C-reactive protein and interleukin-6 response after emotion recall.

OBJECTIVE: To examine the effects of depressive symptoms and hostility on changes in C-reactive protein (CRP) and interleukin (IL)-6 in response to an acute laboratory stressor. Depressive symptoms moderate the effect of trait hostility on circulating levels of CRP and IL-6. METHODS: The study included 307 men and 218 women, affording the opportunity to examine moderation by gender. Regression analyses were performed to examine depressive symptoms, hostility ratings, gender, and their interactions as predictors of CRP and IL-6 response to an emotion recall task. Analyses were adjusted for age, race, body mass index, and prerecall task levels of either CRP or IL-6. RESULTS: The product term for Depressive Symptoms x Hostility x Gender was not significantly related to CRP nor IL-6 response. However, Depressive Symptoms x Hostility did interact to predict CRP response (p = .002); those with the combination of high symptoms of depression and hostility had the largest CRP response. The Depressive Symptoms x Gender interaction was also a predictor of both CRP (p = .001) and IL-6 (p = .04) response; for each inflammatory marker, depressive symptoms were significantly associated with higher CRP response in women, as compared with men. Hostility did not moderate depressive symptoms, nor gender for IL-6. CONCLUSIONS: Our findings extend prior research by suggesting that, broadly speaking, depression is related to inflammatory markers; however, this relationship seems complex. Depression seems to be related to inflammation more strongly among hostile individuals and more strongly among women than among men.

Authors
Brummett, BH; Boyle, SH; Ortel, TL; Becker, RC; Siegler, IC; Williams, RB
MLA Citation
Brummett, BH, Boyle, SH, Ortel, TL, Becker, RC, Siegler, IC, and Williams, RB. "Associations of depressive symptoms, trait hostility, and gender with C-reactive protein and interleukin-6 response after emotion recall." Psychosom Med 72.4 (May 2010): 333-339.
PMID
20190126
Source
pubmed
Published In
Psychosomatic Medicine
Volume
72
Issue
4
Publish Date
2010
Start Page
333
End Page
339
DOI
10.1097/PSY.0b013e3181d2f104

Venous thromboembolism: a public health concern.

Venous thromboembolism (VTE), defined as deep vein thrombosis, pulmonary embolism, or both, affects an estimated 300,000-600,000 individuals in the U.S. each year, causing considerable morbidity and mortality. It is a disorder that can occur in all races and ethnicities, all age groups, and both genders. With many of the known risk factors-advanced age, immobility, surgery, obesity-increasing in society, VTE is an important and growing public health problem. Recently, a marked increase has occurred in federal and national efforts to raise awareness and acknowledge the need for VTE prevention. Yet, many basic public health functions-surveillance, research, and awareness-are still needed. Learning and understanding more about the burden and causes of VTE, and raising awareness among the public and healthcare providers through a comprehensive public health approach, has enormous potential to prevent and reduce death and morbidity from deep vein thrombosis and pulmonary embolism throughout the U.S.

Authors
Beckman, MG; Hooper, WC; Critchley, SE; Ortel, TL
MLA Citation
Beckman, MG, Hooper, WC, Critchley, SE, and Ortel, TL. "Venous thromboembolism: a public health concern." Am J Prev Med 38.4 Suppl (April 2010): S495-S501.
PMID
20331949
Source
pubmed
Published In
American Journal of Preventive Medicine
Volume
38
Issue
4 Suppl
Publish Date
2010
Start Page
S495
End Page
S501
DOI
10.1016/j.amepre.2009.12.017

Dose of prophylactic platelet transfusions and prevention of hemorrhage.

BACKGROUND: We conducted a trial of prophylactic platelet transfusions to evaluate the effect of platelet dose on bleeding in patients with hypoproliferative thrombocytopenia. METHODS: We randomly assigned hospitalized patients undergoing hematopoietic stem-cell transplantation or chemotherapy for hematologic cancers or solid tumors to receive prophylactic platelet transfusions at a low dose, a medium dose, or a high dose (1.1x10(11), 2.2x10(11), or 4.4x10(11) platelets per square meter of body-surface area, respectively), when morning platelet counts were 10,000 per cubic millimeter or lower. Clinical signs of bleeding were assessed daily. The primary end point was bleeding of grade 2 or higher (as defined on the basis of World Health Organization criteria). RESULTS: In the 1272 patients who received at least one platelet transfusion, the primary end point was observed in 71%, 69%, and 70% of the patients in the low-dose group, the medium-dose group, and the high-dose group, respectively (differences were not significant). The incidences of higher grades of bleeding, and other adverse events, were similar among the three groups. The median number of platelets transfused was significantly lower in the low-dose group (9.25x10(11)) than in the medium-dose group (11.25x10(11)) or the high-dose group (19.63x10(11)) (P=0.002 for low vs. medium, P<0.001 for high vs. low and high vs. medium), but the median number of platelet transfusions given was significantly higher in the low-dose group (five, vs. three in the medium-dose and three in the high-dose group; P<0.001 for low vs. medium and low vs. high). Bleeding occurred on 25% of the study days on which morning platelet counts were 5000 per cubic millimeter or lower, as compared with 17% of study days on which platelet counts were 6000 to 80,000 per cubic millimeter (P<0.001). CONCLUSIONS: Low doses of platelets administered as a prophylactic transfusion led to a decreased number of platelets transfused per patient but an increased number of transfusions given. At doses between 1.1x10(11) and 4.4x10(11) platelets per square meter, the number of platelets in the prophylactic transfusion had no effect on the incidence of bleeding. (ClinicalTrials.gov number, NCT00128713.)

Authors
Slichter, SJ; Kaufman, RM; Assmann, SF; McCullough, J; Triulzi, DJ; Strauss, RG; Gernsheimer, TB; Ness, PM; Brecher, ME; Josephson, CD; Konkle, BA; Woodson, RD; Ortel, TL; Hillyer, CD; Skerrett, DL; McCrae, KR; Sloan, SR; Uhl, L; George, JN; Aquino, VM; Manno, CS; McFarland, JG; Hess, JR; Leissinger, C; Granger, S
MLA Citation
Slichter, SJ, Kaufman, RM, Assmann, SF, McCullough, J, Triulzi, DJ, Strauss, RG, Gernsheimer, TB, Ness, PM, Brecher, ME, Josephson, CD, Konkle, BA, Woodson, RD, Ortel, TL, Hillyer, CD, Skerrett, DL, McCrae, KR, Sloan, SR, Uhl, L, George, JN, Aquino, VM, Manno, CS, McFarland, JG, Hess, JR, Leissinger, C, and Granger, S. "Dose of prophylactic platelet transfusions and prevention of hemorrhage." N Engl J Med 362.7 (February 18, 2010): 600-613.
PMID
20164484
Source
pubmed
Published In
The New England journal of medicine
Volume
362
Issue
7
Publish Date
2010
Start Page
600
End Page
613
DOI
10.1056/NEJMoa0904084

Acquired thrombotic risk factors in the critical care setting.

Acquired thrombotic risk factors include a variety of noninherited clinical conditions that can predispose an individual to an increased risk for venous thromboembolism. For patients in a critical care setting, certain acquired risk factors represent chronic conditions that the patients may have had before the current acute illness (e.g., malignancy, various cardiovascular risk factors, certain medications), whereas others may be directly related to the reason the patient is in an intensive care unit or the patient's management there (e.g., postoperative state, trauma, indwelling vascular access, certain medications). Optimal thromboprophylactic strategies depend on individual patient risk profiles including an assessment of the specific clinical setting. Treatment for patients with acquired thrombotic risk factors includes anticoagulant therapy and, if possible, resolution of the acquired risk factor(s). Heparin-induced thrombocytopenia represents a unique clinical situation in which all sources of heparin must be discontinued and the patient started on an alternative anticoagulant (e.g., a direct thrombin inhibitor) in the acute setting. The duration of anticoagulant therapy would vary depending on the specific clinical setting.

Authors
Ortel, TL
MLA Citation
Ortel, TL. "Acquired thrombotic risk factors in the critical care setting." Crit Care Med 38.2 Suppl (February 2010): S43-S50. (Review)
PMID
20083913
Source
pubmed
Published In
Critical Care Medicine
Volume
38
Issue
2 Suppl
Publish Date
2010
Start Page
S43
End Page
S50
DOI
10.1097/CCM.0b013e3181c9ccc8

Plasmapheresis and heparin reexposure as a management strategy for cardiac surgical patients with heparin-induced thrombocytopenia.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) complicates the management of patients presenting for cardiac surgery, because high-dose heparin anticoagulation for cardiopulmonary bypass is contraindicated in these patients. Alternative anticoagulants are available, but there are concerns about dosing, efficacy, monitoring, thrombosis, and hemorrhage. METHODS: A retrospective chart review between November 2004 and March 2008 retrieved perioperative clinical and laboratory data for 11 adult cardiac surgical patients with a preoperative history of HIT and a current positive antiheparin/platelet factor 4 (anti-HPF4) antibody titer, who were managed with plasmapheresis and heparin anticoagulation. RESULTS: The median (interquartile range) preoperative anti-HPF4 antibody titer was 0.8 (0.7-2.2). Three of the 11 patients (27%) died of causes unrelated to HIT and 1 of these patients (9%) developed an ischemic foot, in the setting of cardiogenic shock, not thought to be HIT-related. A single plasmapheresis treatment reduced titers by 50%-84%, and 6 patients had negative titers after treatment; none of the 3 patients with reduced titers developed clinical HIT. CONCLUSIONS: This case series describes an alternative management strategy using intraoperative plasmapheresis for patients presenting for cardiac surgery with acute or subacute HIT. Reducing antibody load can potentially decrease the thrombotic risk associated with high anti-HPF4 titers and decrease the urgency to initiate postoperative anticoagulation in this patient group at high risk of postoperative bleeding.

Authors
Welsby, IJ; Um, J; Milano, CA; Ortel, TL; Arepally, G
MLA Citation
Welsby, IJ, Um, J, Milano, CA, Ortel, TL, and Arepally, G. "Plasmapheresis and heparin reexposure as a management strategy for cardiac surgical patients with heparin-induced thrombocytopenia." Anesth Analg 110.1 (January 1, 2010): 30-35.
PMID
19933539
Source
pubmed
Published In
Anesthesia and Analgesia
Volume
110
Issue
1
Publish Date
2010
Start Page
30
End Page
35
DOI
10.1213/ANE.0b013e3181c3c1cd

Heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) is an immune-mediated hypercoagulable disorder caused by antibodies to platelet factor 4 (PF4) and heparin. HIT develops in temporal association with heparin therapy and manifests either as an unexplained thrombocytopenia or thrombocytopenia complicated by thrombosis. The propensity for thrombosis distinguishes HIT from other common drug-induced thrombocytopenias. Diagnosing HIT in hospitalized patients is often challenging because of the frequency of heparin use, occurrence of thrombocytopenia from other causes, and development of asymptomatic PF4/heparin antibodies in patients treated with heparin. This review summarizes our current understanding of the pathogenesis, clinical features, diagnostic criteria, and management approaches in HIT.

Authors
Arepally, GM; Ortel, TL
MLA Citation
Arepally, GM, and Ortel, TL. "Heparin-induced thrombocytopenia." Annu Rev Med 61 (2010): 77-90. (Review)
PMID
20059332
Source
pubmed
Published In
Annual Review of Medicine
Volume
61
Publish Date
2010
Start Page
77
End Page
90
DOI
10.1146/annurev.med.042808.171814

Comparison of characteristics from White- and Black-Americans with venous thromboembolism: A cross sectional study

Authors
Heit, JA; Beckman, M; Bockenstedt, P; Grant, A; Key, N; Kulkarni, R; Manco-Johnson, M; Moll, S; Ortel, T; Philipp, C
MLA Citation
Heit, JA, Beckman, M, Bockenstedt, P, Grant, A, Key, N, Kulkarni, R, Manco-Johnson, M, Moll, S, Ortel, T, and Philipp, C. "Comparison of characteristics from White- and Black-Americans with venous thromboembolism: A cross sectional study." American Journal of Hematology 85.11 (2010): 908-908.
Source
scival
Published In
American Journal of Hematology
Volume
85
Issue
11
Publish Date
2010
Start Page
908
End Page
908
DOI
10.1002/ajh.21844

Impact of venous thromboembolism and anticoagulation on cancer and cancer survival.

Changes in the hemostatic system and chronic hemostatic activation are frequently observed in patients with cancer, even in the absence of venous thromboembolism (VTE). VTE is a leading cause of death among patients with cancer and contributes to long-term mortality in patients with early as well as advanced-stage cancer. Mounting evidence suggests that components of the clotting cascade and associated vascular factors play an integral part in tumor progression, invasion, angiogenesis, and metastasis formation. Furthermore, there are intriguing in vitro and animal findings that anticoagulants, in particular the low molecular weight heparins (LMWHs), exert an antineoplastic effect through multiple mechanisms, including interference with tumor cell adhesion, invasion, metastasis formation, angiogenesis, and the immune system. Several relatively small randomized controlled clinical trials of anticoagulation as cancer therapy in patients without a VTE diagnosis have been completed. These comprise studies with LMWH, unfractionated heparin, and vitamin K antagonists, with overall encouraging but nonconclusive results and some limitations. Meta-analyses performed for the American Society of Clinical Oncology VTE Guidelines Committee and the Cochrane Collaboration suggest overall favorable effects of anticoagulation on survival of patients with cancer, mainly with LMWH. However, definitive clinical trials have been elusive and questions remain regarding the importance of tumor type and stage on treatment efficacy, the impact of fatal thromboembolic events, optimal anticoagulation therapy, and safety with differing chemotherapy regimens. Although the LMWHs and related agents hold promise for improving outcomes in patients with cancer, additional studies of their efficacy and safety in this setting are needed.

Authors
Kuderer, NM; Ortel, TL; Francis, CW
MLA Citation
Kuderer, NM, Ortel, TL, and Francis, CW. "Impact of venous thromboembolism and anticoagulation on cancer and cancer survival." J Clin Oncol 27.29 (October 10, 2009): 4902-4911. (Review)
PMID
19738120
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
27
Issue
29
Publish Date
2009
Start Page
4902
End Page
4911
DOI
10.1200/JCO.2009.22.4584

Update of the guidelines for lupus anticoagulant detection. Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis.

One of the conclusions of the subcommittee meeting on Lupus Anticoagulant/Phospholipid dependent antibodies, held in Geneva on 2007, was the need to update the guidelines on Lupus Anticoagulant (LA) detection. Particular emphasis was given to several aspects discussed in this official communication. A new paragraph is dedicated to the patient selection, and aims to minimize inappropriate requests for LA testing. Modalities for blood collection and processing are fully delineated and the choice of tests is limited to dRVVT and a sensitive aPTT. Calculation of cut-off values for each diagnostic step are clearly stated. A final paragraph reports the interpretation of the results in general and in particular situations.

Authors
Pengo, V; Tripodi, A; Reber, G; Rand, JH; Ortel, TL; Galli, M; De Groot, PG; Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis,
MLA Citation
Pengo, V, Tripodi, A, Reber, G, Rand, JH, Ortel, TL, Galli, M, De Groot, PG, and Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis, . "Update of the guidelines for lupus anticoagulant detection. Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis." J Thromb Haemost 7.10 (October 2009): 1737-1740.
PMID
19624461
Source
pubmed
Published In
Journal of Thrombosis and Haemostasis
Volume
7
Issue
10
Publish Date
2009
Start Page
1737
End Page
1740
DOI
10.1111/j.1538-7836.2009.03555.x

Heparin-dependent platelet factor 4 antibodies and the impact of renal function on clinical outcomes: a retrospective study in hospitalized patients.

Patients who develop thrombocytopenia and heparin-dependent platelet factor 4 antibodies while on or shortly after receiving a heparin product are often considered for alternative anticoagulation to minimize the occurrence of life and limb-threatening events. We retrospectively reviewed the hospital records of 97 patients with heparin-dependent platelet factor 4 antibodies (at least 65 of whom were felt by the primary team to have HIT) to determine the influence of renal performance on alternative anticoagulant selection and associated clinical events. For GFR > 30, approximately 30% of patients who did not receive alternative anticoagulation had documentation of concern for HIT versus 60% of patients in the GFR < 30 group. We found that a smaller proportion of patients with severe renal insufficiency, GFRs < 30 ml/min/1.73 m(2) were treated with an alternative anticoagulant-this despite their high incidence of thromboembolic events and comparable rates of HIT. Overall, rates of hemorrhage did not differ between patients when compared to those without renal insufficiency. However, there was a higher percentage of hemorrhagic events for patients with GFR < 30 ml/min/1.73 m(2) on alternative anticoagulants. This study demonstrates that patient's with GFRs < 30 ml/min/1.73 m(2) need to be assessed for overall hemorrhagic risk at the time of starting an alternative anticoagulant and need to be monitored closely to avoid hemorrhagic events.

Authors
Perry, SL; Whitlatch, NL; Ortel, TL
MLA Citation
Perry, SL, Whitlatch, NL, and Ortel, TL. "Heparin-dependent platelet factor 4 antibodies and the impact of renal function on clinical outcomes: a retrospective study in hospitalized patients." J Thromb Thrombolysis 28.2 (August 2009): 146-150.
PMID
18839279
Source
pubmed
Published In
Journal of Thrombosis and Thrombolysis
Volume
28
Issue
2
Publish Date
2009
Start Page
146
End Page
150
DOI
10.1007/s11239-008-0265-3

Recent developments in topical thrombins.

Managing blood loss is part of the surgeon's responsibility during surgical procedures, and a variety of therapeutic strategies are available to help accomplish this. Topical haemostatic agents are among the agents used to control surgical bleeding and locally arrest blood flow. Bovine thrombin is a commonly used topical haemostatic agent; however, its use has been associated with potential risks, including well-documented cases of antibody-mediated coagulopathy. This coagulopathy develops as a consequence of antibody formation directed against bovine thrombin, other bovine coagulation proteins, and their human orthologs. The fact that a coagulopathy can result in association with the use of bovine plasma-derived thrombin preparations prompted the FDA to require pharmaceutical companies to place a black-box warning in their prescribing information for products containing bovine plasma-derived thrombin. Recently, human plasma-derived thrombin and recombinant human thrombin have been approved by the FDA with the expectation that they will be less immunogenic than the bovine-derived product. In clinical studies, purified human plasma-derived thrombin and recombinant thrombin have demonstrated equivalent efficacy and safety, with improved immunogenicity profiles compared with bovine-derived thrombin agents. Well-designed and adequately powered clinical trials should be conducted to indicate whether human thrombin products would improve the risk-benefit and cost-benefit profiles for surgeries complicated by excessive bleeding.

Authors
Kessler, CM; Ortel, TL
MLA Citation
Kessler, CM, and Ortel, TL. "Recent developments in topical thrombins." Thromb Haemost 102.1 (July 2009): 15-24. (Review)
PMID
19572062
Source
pubmed
Published In
Thrombosis and haemostasis
Volume
102
Issue
1
Publish Date
2009
Start Page
15
End Page
24
DOI
10.1160/TH09-01-0034

Clinical and laboratory diagnosis of von Willebrand disease: a synopsis of the 2008 NHLBI/NIH guidelines.

Von Willebrand factor (VWF) mediates blood platelet adhesion and accumulation at sites of blood vessel injury, and also carries coagulation factor VIII (FVIII) that is important for generating procoagulant activity. Von Willebrand disease (VWD), the most common inherited bleeding disorder, affects males and females, and reflects deficiency or defects of VWF that may also cause decreased FVIII. It may also occur less commonly as an acquired disorder (acquired von Willebrand syndrome). This article briefly summarizes selected features of the March 2008 evidence-based clinical and laboratory diagnostic recommendations from the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel for assessment for VWD or other bleeding disorders or risks. Management of VWD is also addressed in the NHLBI guidelines, but is not summarized here. The VWD guidelines are available at the NHLBI Web site (http://www.nhlbi.nih.gov/guidelines/vwd).

Authors
Nichols, WL; Rick, ME; Ortel, TL; Montgomery, RR; Sadler, JE; Yawn, BP; James, AH; Hultin, MB; Manco-Johnson, MJ; Weinstein, M
MLA Citation
Nichols, WL, Rick, ME, Ortel, TL, Montgomery, RR, Sadler, JE, Yawn, BP, James, AH, Hultin, MB, Manco-Johnson, MJ, and Weinstein, M. "Clinical and laboratory diagnosis of von Willebrand disease: a synopsis of the 2008 NHLBI/NIH guidelines." Am J Hematol 84.6 (June 2009): 366-370.
PMID
19415721
Source
pubmed
Published In
American Journal of Hematology
Volume
84
Issue
6
Publish Date
2009
Start Page
366
End Page
370
DOI
10.1002/ajh.21405

Ticlopidine- and clopidogrel-associated thrombotic thrombocytopenic purpura (TTP): review of clinical, laboratory, epidemiological, and pharmacovigilance findings (1989-2008).

Thrombotic thrombocytopenic purpura (TTP) is a fulminant disease characterized by platelet aggregates, thrombocytopenia, renal insufficiency, neurologic changes, and mechanical injury to erythrocytes. Most idiopathic cases of TTP are characterized by a deficiency of ADAMTS13 (a disintegrin and metalloprotease, with thrombospondin-1-like domains) metalloprotease activity. Ironically, use of anti-platelet agents, the thienopyridine derivates clopidogrel and ticlopidine, is associated with drug induced TTP. Data were abstracted from a systematic review of English-language literature for thienopyridine-associated TTP identified in MEDLINE, EMBASE, the public website of the Food and Drug Administration, and abstracts from national scientific conferences from 1991 to April 2008. Ticlopidine and clopidogrel are the two most common drugs associated with TTP in FDA safety databases. Epidemiological studies identify recent initiation of anti-platelet agents as the most common risk factor associated with risks of developing TTP. Laboratory studies indicate that most cases of thienopyridine-associated TTP involve an antibody to ADAMTS13 metalloprotease, present with severe thrombocytopenia, and respond to therapeutic plasma exchange (TPE); a minority of thienopyridine-associated TTP presents with severe renal insufficiency, involves direct endothelial cell damage, and is less responsive to TPE. The evaluation of this potentially fatal drug toxicity can serve as a template for future efforts to comprehensively characterize other severe adverse drug reactions.

Authors
Zakarija, A; Kwaan, HC; Moake, JL; Bandarenko, N; Pandey, DK; McKoy, JM; Yarnold, PR; Raisch, DW; Winters, JL; Raife, TJ; Cursio, JF; Luu, TH; Richey, EA; Fisher, MJ; Ortel, TL; Tallman, MS; Zheng, XL; Matsumoto, M; Fujimura, Y; Bennett, CL
MLA Citation
Zakarija, A, Kwaan, HC, Moake, JL, Bandarenko, N, Pandey, DK, McKoy, JM, Yarnold, PR, Raisch, DW, Winters, JL, Raife, TJ, Cursio, JF, Luu, TH, Richey, EA, Fisher, MJ, Ortel, TL, Tallman, MS, Zheng, XL, Matsumoto, M, Fujimura, Y, and Bennett, CL. "Ticlopidine- and clopidogrel-associated thrombotic thrombocytopenic purpura (TTP): review of clinical, laboratory, epidemiological, and pharmacovigilance findings (1989-2008)." Kidney Int Suppl 112 (February 2009): S20-S24. (Review)
PMID
19180126
Source
pubmed
Published In
Kidney international. Supplement
Issue
112
Publish Date
2009
Start Page
S20
End Page
S24
DOI
10.1038/ki.2008.613

Ticlopidine- and clopidogrel-associated thrombotic thrombocytopenic purpura (TTP): Review of clinical, laboratory, epidemiological, and pharmacovigilance findings (1989-2008)

Thrombotic thrombocytopenic purpura (TTP) is a fulminant disease characterized by platelet aggregates, thrombocytopenia, renal insufficiency, neurologic changes, and mechanical injury to erythrocytes. Most idiopathic cases of TTP are characterized by a deficiency of ADAMTS13 (a disintegrin and metalloprotease, with thrombospondin-1-like domains) metalloprotease activity. Ironically, use of anti-platelet agents, the thienopyridine derivates clopidogrel and ticlopidine, is associated with drug induced TTP. Data were abstracted from a systematic review of English-language literature for thienopyridine-associated TTP identified in MEDLINE, EMBASE, the public website of the Food and Drug Administration, and abstracts from national scientific conferences from 1991 to April 2008. Ticlopidine and clopidogrel are the two most common drugs associated with TTP in FDA safety databases. Epidemiological studies identify recent initiation of anti-platelet agents as the most common risk factor associated with risks of developing TTP. Laboratory studies indicate that most cases of thienopyridine-associated TTP involve an antibody to ADAMTS13 metalloprotease, present with severe thrombocytopenia, and respond to therapeutic plasma exchange (TPE); a minority of thienopyridine-associated TTP presents with severe renal insufficiency, involves direct endothelial cell damage, and is less responsive to TPE. The evaluation of this potentially fatal drug toxicity can serve as a template for future efforts to comprehensively characterize other severe adverse drug reactions. © 2009 International Society of Nephrology.

Authors
Zakarija, A; Kwaan, HC; Moake, JL; Bandarenko, N; Pandey, DK; McKoy, JM; Yarnold, PR; Raisch, DW; Winters, JL; Raife, TJ; Cursio, JF; Luu, TH; Richey, EA; Fisher, MJ; Ortel, TL; Tallman, MS; Zheng, XL; Matsumoto, M; Fujimura, Y; Bennett, CL
MLA Citation
Zakarija, A, Kwaan, HC, Moake, JL, Bandarenko, N, Pandey, DK, McKoy, JM, Yarnold, PR, Raisch, DW, Winters, JL, Raife, TJ, Cursio, JF, Luu, TH, Richey, EA, Fisher, MJ, Ortel, TL, Tallman, MS, Zheng, XL, Matsumoto, M, Fujimura, Y, and Bennett, CL. "Ticlopidine- and clopidogrel-associated thrombotic thrombocytopenic purpura (TTP): Review of clinical, laboratory, epidemiological, and pharmacovigilance findings (1989-2008)." Kidney International 75.SUPPL. 112 (2009): S20-S24.
Source
scival
Published In
Kidney international
Volume
75
Issue
SUPPL. 112
Publish Date
2009
Start Page
S20
End Page
S24
DOI
10.1038/ki.2008.613

ASH evidence-based guidelines: is the IgG-specific anti-PF4/heparin ELISA superior to the polyspecific ELISA in the laboratory diagnosis of HIT?

You are asked to consult on a 76-year-old man admitted to the hospital with pneumonia and thrombocytopenia. Ten days before the current admission, he had undergone surgery to repair a small bowel obstruction. A preoperative platelet count had been normal. Following surgery, he received subcutaneous unfractionated heparin thromboprophylaxis until his discharge on post-operative day 5. In your differential diagnosis for the patient's thrombocytopenia, you consider heparin-induced thrombocytopenia (HIT) and wish to order laboratory testing. In addition to a polyspecific anti-PF4/heparin ELISA for the diagnosis of HIT, your laboratory has recently begun to offer an IgG-specific ELISA. You wonder which of these assays performs better in the diagnosis of HIT.

Authors
Cuker, A; Ortel, TL
MLA Citation
Cuker, A, and Ortel, TL. "ASH evidence-based guidelines: is the IgG-specific anti-PF4/heparin ELISA superior to the polyspecific ELISA in the laboratory diagnosis of HIT?." Hematology Am Soc Hematol Educ Program (2009): 250-252. (Review)
PMID
20008206
Source
pubmed
Published In
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program
Publish Date
2009
Start Page
250
End Page
252
DOI
10.1182/asheducation-2009.1.250

Heparin-induced thrombocytopenia: when a low platelet count is a mandate for anticoagulation.

Heparin-induced thrombocytopenia (HIT) is an immune-mediated disorder caused by the development of antibodies to platelet factor 4 (PF4) and heparin. The thrombocytopenia is typically moderate, with a median platelet count nadir of approximately 50 to 60 x 10(9) platelets/L. Severe thrombocytopenia has been described in patients with HIT, and in these patients antibody levels are high and severe clinical outcomes have been reported (eg, disseminated intravascular coagulation with microvascular thrombosis). The timing of the thrombocytopenia in relation to the initiation of heparin therapy is critically important, with the platelet count beginning to drop within 5 to 10 days of starting heparin. A more rapid drop in the platelet count can occur in patients who have been recently exposed to heparin (within the preceding 3 months), due to preformed anti-heparin/PF4 antibodies. A delayed form of HIT has also been described that develops within days or weeks after the heparin has been discontinued. In contrast to other drug-induced thrombocytopenias, HIT is characterized by an increased risk for thromboembolic complications, primarily venous thromboembolism. Heparin and all heparin-containing products should be discontinued and an alternative, non-heparin anticoagulant initiated. Alternative agents that have been used effectively in patients with HIT include lepirudin, argatroban, bivalirudin, and danaparoid, although the last agent is not available in North America. Fondaparinux has been used in a small number of patients with HIT and generally appears to be safe. Warfarin therapy should not be initiated until the platelet count has recovered and the patient is systemically anticoagulated, and vitamin K should be administered to patients receiving warfarin at the time of diagnosis of HIT.

Authors
Ortel, TL
MLA Citation
Ortel, TL. "Heparin-induced thrombocytopenia: when a low platelet count is a mandate for anticoagulation." Hematology Am Soc Hematol Educ Program (2009): 225-232. (Review)
PMID
20008202
Source
pubmed
Published In
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program
Publish Date
2009
Start Page
225
End Page
232
DOI
10.1182/asheducation-2009.1.225

von Willebrand factor content in Alphanate® (Laurence J. Logan) - Reply

Authors
Nichols, WL; Hultln, MB; James, AH; Manco-johnson, MJ; Montgomery, RR; Ortel, TL; Rick, ME; Sadler, JE; Weinstein, M; Yawn, BP
MLA Citation
Nichols, WL, Hultln, MB, James, AH, Manco-johnson, MJ, Montgomery, RR, Ortel, TL, Rick, ME, Sadler, JE, Weinstein, M, and Yawn, BP. "von Willebrand factor content in Alphanate® (Laurence J. Logan) - Reply." Haemophilia 15.1 (2009): 370-371.
Source
scival
Published In
Haemophilia
Volume
15
Issue
1
Publish Date
2009
Start Page
370
End Page
371
DOI
10.1111/j.1365-2516.2008.01903.x

Molecular testing for coagulopathies

Sudden and severe loss of blood can lead to shock and death. When blood vessels are damaged, Hemostasis (clot formation) will arrest bleeding. This proces is divided into primary and secondary hemostasis. © 2008 Humana Press.

Authors
Ramiah, V; Ortel, TL
MLA Citation
Ramiah, V, and Ortel, TL. "Molecular testing for coagulopathies." (December 1, 2008): 623-636. (Chapter)
Source
scopus
Publish Date
2008
Start Page
623
End Page
636
DOI
10.1007/978-1-59745-405-6_23

Anti-heparin/platelet factor 4 antibody optical density values and the confirmatory procedure in the diagnosis of heparin-induced thrombocytopenia.

Laboratory testing for heparin-induced thrombocytopenia (HIT) includes the highly sensitive, though less specific, heparin/platelet factor 4 (PF4) ELISA. A confirmatory test with excess heparin is routinely performed on positive ELISA results to improve test specificity; the significance of a negative confirmatory result is unknown. The aim was firstly to evaluate the clinical utility of the PF4 ELISA confirmatory assay, secondly to examine the relationship between ELISA optical density (OD) value and clinical diagnosis of HIT, and thirdly to assess current practice at a tertiary care medical centre regarding patients with anti-heparin/PF4 antibodies. Patients with anti-heparin/PF4 antibodies detected by commercial ELISA during 2005 were identified. A confirmatory test was performed on positive ELISA results. Patients were labeled confirmatory positive (confirm+) or confirmatory negative (confirm-). Patients were classified as HIT+ (met criteria for HIT), HIT? (HIT possible), and HIT- (did not meet criteria for HIT) utilizing ACCP guidelines. One hundred fifteen patients with anti-heparin/PF4 antibodies were identified. Ninety-eight patients were confirm+; 17 were confirm-. The majority of confirm+ patients were HIT+ or HIT?(72%); the majority of confirm- patients were HIT-(81%). Patients who were HIT+/confirm+ had higher ELISA OD values than patients who were HIT?/confirm+ or HIT-/confirm+ (p = 0.031, p = 0.001). Two confirm- patients were HIT+, one was HIT?; all had high ELISA OD values. Although confirm+ status correlated with clinical HIT, the confirmatory procedure misclassified some patients by yielding a confirm- result despite clinical HIT with high ELISA OD values. Future studies should compare higher ELISA OD values with the confirmatory procedure as strategies to improve ELISA diagnostic specificity for HIT.

Authors
Whitlatch, NL; Perry, SL; Ortel, TL
MLA Citation
Whitlatch, NL, Perry, SL, and Ortel, TL. "Anti-heparin/platelet factor 4 antibody optical density values and the confirmatory procedure in the diagnosis of heparin-induced thrombocytopenia." Thromb Haemost 100.4 (October 2008): 678-684.
PMID
18841292
Source
pubmed
Published In
Thrombosis and haemostasis
Volume
100
Issue
4
Publish Date
2008
Start Page
678
End Page
684

Direct-to-patient expert system and home INR monitoring improves control of oral anticoagulation.

BACKGROUND AND OBJECTIVE: Internet-based disease management programs have the potential to improve patient care. The objective of this study was to determine whether an interactive, internet-based system enabling supervised, patient self-management of oral anticoagulant therapy provided management comparable to an established anticoagulation clinic. PATIENTS/METHODS: Sixty patients receiving chronic oral anticoagulant therapy who had access to the internet and a printer, were enrolled into this prospective, single-group, before-after study from a single clinic and managed between March 2002 and January 2003. Patients learned how to use a home prothrombin time monitor and how to access the system through the internet. Patients used the system for six months, with daily review by the supervising physician. The primary outcome variable was the difference in time in therapeutic range prior to and following introduction of internet-supervised patient self-management. RESULTS: The mean time in therapeutic range increased from 63% in the anticoagulation clinic (control period) to 74.4% during internet-supervised patient self-management (study period). The mean difference score between control and study periods was 11.4% (P = 0.004, 95% confidence interval 5.5-17.3%). There were no hemorrhagic or thromboembolic complications. CONCLUSIONS: This novel approach of internet-supervised patient self-management improved time in therapeutic range compared to an anticoagulation clinic. This is the first demonstration of an internet-based expert system enabling remote and effective management of patients on oral anticoagulants. Expert systems may be applicable for management of other chronic diseases.

Authors
O'Shea, SI; Arcasoy, MO; Samsa, G; Cummings, SE; Thames, EH; Surwit, RS; Ortel, TL
MLA Citation
O'Shea, SI, Arcasoy, MO, Samsa, G, Cummings, SE, Thames, EH, Surwit, RS, and Ortel, TL. "Direct-to-patient expert system and home INR monitoring improves control of oral anticoagulation." J Thromb Thrombolysis 26.1 (August 2008): 14-21.
PMID
17616845
Source
pubmed
Published In
Journal of Thrombosis and Thrombolysis
Volume
26
Issue
1
Publish Date
2008
Start Page
14
End Page
21
DOI
10.1007/s11239-007-0068-y

von Willebrand disease (VWD): evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA).

von Willebrand disease (VWD) is a commonly encountered inherited bleeding disorder affecting both males and females, causing mucous membrane and skin bleeding symptoms, and bleeding with surgical or other haemostatic challenges. VWD may be disproportionately symptomatic in women of child-bearing age. It may also occur less frequently as an acquired disorder (acquired von Willebrand syndrome). VWD is caused by deficiency or dysfunction of von Willebrand factor (VWF), a plasma protein that mediates platelet haemostatic function and stabilizes blood coagulation factor VIII. The pathophysiology, classification, diagnosis and management of VWD are relatively complex, but understanding them is important for proper diagnosis and management of patients with VWD. These evidence-based guidelines for diagnosis and management of VWD from the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel (USA) review relevant publications, summarize current understanding of VWD pathophysiology and classification, and present consensus diagnostic and management recommendations based on analysis of the literature and expert opinion. They also suggest an approach for clinical and laboratory evaluation of individuals with bleeding symptoms, history of bleeding or conditions associated with increased bleeding risk. This document summarizes needs for further research in VWF, VWD and bleeding disorders, including clinical research to obtain more objective information about bleeding symptoms, advancements in diagnostic and therapeutic tools, and enhancement in the education and training of clinicians and scientists in bleeding and thrombotic disorders. The NHLBI Web site (http://www.nhlbi.nih.gov/guidelines/vwd) has a more detailed document, a synopsis of these recommendations, and patient education information.

Authors
Nichols, WL; Hultin, MB; James, AH; Manco-Johnson, MJ; Montgomery, RR; Ortel, TL; Rick, ME; Sadler, JE; Weinstein, M; Yawn, BP
MLA Citation
Nichols, WL, Hultin, MB, James, AH, Manco-Johnson, MJ, Montgomery, RR, Ortel, TL, Rick, ME, Sadler, JE, Weinstein, M, and Yawn, BP. "von Willebrand disease (VWD): evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA)." Haemophilia 14.2 (March 2008): 171-232.
PMID
18315614
Source
pubmed
Published In
Haemophilia
Volume
14
Issue
2
Publish Date
2008
Start Page
171
End Page
232
DOI
10.1111/j.1365-2516.2007.01643.x

Prevention and treatment of deep venous thrombosis.

Postoperative venous thromboembolism (VTE) is a common cause of preventable patient morbidity and mortality. Hospitalized patients have multiple risk factors for VTE, which can exert a cumulative effect on the individual patient. Although effective thromboprophylactic measures are currently available, they are not commonly used for a number of reasons, in addition to heightened concern about increasing bleeding risk. Limited data are available characterizing the incidence of symptomatic VTE following major vascular surgery in the absence of thromboprophylactic therapy. Reported rates vary according to the type of surgery, type of prophylaxis used, and diagnostic modalities used for deep venous thrombosis (DVT) and pulmonary embolism (PE). Hospital-acquired DVT in the absence of thromboprophylaxis can occur in up to 40% of patients, occurring primarily in the proximal deep veins, which elevates the risk of PE. Risk factors for VTE in vascular surgery include limb ischemia, prolonged surgery duration, localized intraoperative trauma, and atherosclerosis. Advanced patient age is also a risk factor for VTE; however, the relationship between age and risk of VTE after surgery is complex and dependent on both the type of surgery and the underlying disease process. Evidence-based guidelines for venous thrombo-prophylaxis are now available; however, adoption of and compliance with these guidelines have lagged. Effective thrombo-prophylactic strategies exist and include both pharmacologic and nonpharmacologic approaches. For those surgical patients who develop a VTE, antithrombotic therapy remains the treatment of choice.

Authors
Ortel, TL
MLA Citation
Ortel, TL. "Prevention and treatment of deep venous thrombosis." Vascular 16 Suppl 1 (March 2008): S64-S70. (Review)
PMID
18544309
Source
pubmed
Published In
Vascular
Volume
16 Suppl 1
Publish Date
2008
Start Page
S64
End Page
S70

Thrombophilias: when should we test and how does it help?

Venous thromboembolism can be a life-threatening event, occurring in ~1 in 1000 adults annually. An underlying cause for thrombosis can now be identified in up to 80% of cases, including both inherited and acquired causes of thrombophilia. In fact, it is often a combination of these risk factors that leads to the development of thrombosis. Knowing what these risk factors are for an individual patient can help with decisions regarding duration of anticoagulation, and how best to prevent a recurrent event. This article reviews both the inherited and the acquired causes of thrombophilia, focusing on the clinical scenarios in which these disorders should be suspected and on how to appropriately test for them when clinically indicated. By the conclusion of this article, the clinician should be equipped with an algorithm of how to approach a patient with a thromboembolic event, from decisions regarding which thrombophilia tests to order to how the results of these tests affect patient management.

Authors
Whitlatch, NL; Ortel, TL
MLA Citation
Whitlatch, NL, and Ortel, TL. "Thrombophilias: when should we test and how does it help?." Semin Respir Crit Care Med 29.1 (February 2008): 25-39. (Review)
PMID
18302084
Source
pubmed
Published In
Seminars in Respiratory and Critical Care Medicine
Volume
29
Issue
1
Publish Date
2008
Start Page
25
End Page
39
DOI
10.1055/s-2008-1047560

Thrombophilia screening in asymptomatic children.

Children with a family history of thrombophilia and/or thrombosis are often referred to pediatric thrombosis centers for evaluation. This article reviews the risks and benefits of thrombophilia testing in this unique population. The article also reviews an approach to testing including a step-wise evaluation and involvement of a genetic counselor.

Authors
Thornburg, CD; Dixon, N; Paulyson-Nuñez, K; Ortel, T
MLA Citation
Thornburg, CD, Dixon, N, Paulyson-Nuñez, K, and Ortel, T. "Thrombophilia screening in asymptomatic children." Thromb Res 121.5 (2008): 597-604. (Review)
PMID
17631949
Source
pubmed
Published In
Thrombosis Research
Volume
121
Issue
5
Publish Date
2008
Start Page
597
End Page
604
DOI
10.1016/j.thromres.2007.06.001

Venous thromboembolic disease

Recognizing the increased risk for VTE in cancer patients is the first step in preventing its occurrence and promptly identifying it in these patients. The panel recommends VTE thromboprophylaxis for all hospitalized patients with cancer who have no contraindications to this therapy, and also emphasizes that an increased level of clinical suspicion of VTE should be maintained for cancer patients. After hospital discharge, the panel recommends that patients at high risk for VTE (e.g., patients who have undergone surgery for cancer) continue to receive VTE prophylaxis for up to 4 weeks postoperation. Careful evaluation and follow-up of cancer patients in whom VTE is suspected, and prompt treatment and follow-up for those diagnosed with VTE is recommended after the cancer status of the patient is assessed and the risks and benefits of treatment are considered. ©Journal of the National Comprehensive Cancer Network.

Authors
Wagman, LD; Baird, MF; Bennett, CL; Bockenstedt, PL; Cataland, SR; Fanikos, J; Fogarty, PF; Goldhaber, SZ; Grover, TS; Haire, W; Hassoun, H; Hutchinson, S; Jahanzeb, M; Lee, J; Linenberger, ML; Millenson, MM; Ortel, TL; Salem, R; Smith, JL; Streiff, MB; Vedantham, S
MLA Citation
Wagman, LD, Baird, MF, Bennett, CL, Bockenstedt, PL, Cataland, SR, Fanikos, J, Fogarty, PF, Goldhaber, SZ, Grover, TS, Haire, W, Hassoun, H, Hutchinson, S, Jahanzeb, M, Lee, J, Linenberger, ML, Millenson, MM, Ortel, TL, Salem, R, Smith, JL, Streiff, MB, and Vedantham, S. "Venous thromboembolic disease." JNCCN Journal of the National Comprehensive Cancer Network 6.8 (2008): 716-753.
PMID
18926086
Source
scival
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
6
Issue
8
Publish Date
2008
Start Page
716
End Page
753

Evolution of adverse changes in stored RBCs.

Recent studies have underscored questions about the balance of risk and benefit of RBC transfusion. A better understanding of the nature and timing of molecular and functional changes in stored RBCs may provide strategies to improve the balance of benefit and risk of RBC transfusion. We analyzed changes occurring during RBC storage focusing on RBC deformability, RBC-dependent vasoregulatory function, and S-nitrosohemoglobin (SNO-Hb), through which hemoglobin (Hb) O(2) desaturation is coupled to regional increases in blood flow in vivo (hypoxic vasodilation). Five hundred ml of blood from each of 15 healthy volunteers was processed into leukofiltered, additive solution 3-exposed RBCs and stored at 1-6 degrees C according to AABB standards. Blood was subjected to 26 assays at 0, 3, 8, 24 and 96 h, and at 1, 2, 3, 4, and 6 weeks. RBC SNO-Hb decreased rapidly (1.2 x 10(-4) at 3 h vs. 6.5 x 10(-4) (fresh) mol S-nitrosothiol (SNO)/mol Hb tetramer (P = 0.032, mercuric-displaced photolysis-chemiluminescence assay), and remained low over the 42-day period. The decline was corroborated by using the carbon monoxide-saturated copper-cysteine assay [3.0 x 10(-5) at 3 h vs. 9.0 x 10(-5) (fresh) mol SNO/mol Hb]. In parallel, vasodilation by stored RBCs was significantly depressed. RBC deformability assayed at a physiological shear stress decreased gradually over the 42-day period (P < 0.001). Time courses vary for several storage-induced defects that might account for recent observations linking blood transfusion with adverse outcomes. Of clinical concern is that SNO levels, and their physiological correlate, RBC-dependent vasodilation, become depressed soon after collection, suggesting that even "fresh" blood may have developed adverse biological characteristics.

Authors
Bennett-Guerrero, E; Veldman, TH; Doctor, A; Telen, MJ; Ortel, TL; Reid, TS; Mulherin, MA; Zhu, H; Buck, RD; Califf, RM; McMahon, TJ
MLA Citation
Bennett-Guerrero, E, Veldman, TH, Doctor, A, Telen, MJ, Ortel, TL, Reid, TS, Mulherin, MA, Zhu, H, Buck, RD, Califf, RM, and McMahon, TJ. "Evolution of adverse changes in stored RBCs." Proc Natl Acad Sci U S A 104.43 (October 23, 2007): 17063-17068.
PMID
17940021
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
104
Issue
43
Publish Date
2007
Start Page
17063
End Page
17068
DOI
10.1073/pnas.0708160104

Two mechanistic pathways for thienopyridine-associated thrombotic thrombocytopenic purpura: a report from the SERF-TTP Research Group and the RADAR Project.

OBJECTIVES: We sought to describe clinical and laboratory findings for a large cohort of patients with thienopyridine-associated thrombotic thrombocytopenic purpura (TTP). BACKGROUND: The thienopyridine derivatives, ticlopidine and clopidogrel, are the 2 most common drugs associated with TTP in databases maintained by the U.S. Food and Drug Administration (FDA). METHODS: Clinical reports of TTP associated with clopidogrel and ticlopidine were identified from medical records, published case reports, and FDA case reports (n = 128). Duration of thienopyridine exposure, clinical and laboratory findings, and survival were recorded. ADAMTS13 activity (n = 39) and inhibitor (n = 30) were measured for a subset of individuals. RESULTS: Compared with clopidogrel-associated TTP cases (n = 35), ticlopidine-associated TTP cases (n = 93) were more likely to have received more than 2 weeks of drug (90% vs. 26%), to be severely thrombocytopenic (84% vs. 60%), and to have normal renal function (72% vs. 45%) (p < 0.01 for each). Compared with TTP patients with ADAMTS13 activity >15% (n = 13), TTP patients with severely deficient ADAMTS13 activity (n = 26) were more likely to have received ticlopidine (92.3% vs. 46.2%, p < 0.003). Among patients who developed TTP >2 weeks after thienopyridine, therapeutic plasma exchange (TPE) increased likelihood of survival (84% vs. 38%, p < 0.05). Among patients who developed TTP within 2 weeks of starting thienopyridines, survival was 77% with TPE and 78% without. CONCLUSIONS: Thrombotic thrombocytopenic purpura is a rare complication of thienopyridine treatment. This drug toxicity appears to occur by 2 different mechanistic pathways, characterized primarily by time of onset before versus after 2 weeks of thienopyridine administration. If TTP occurs after 2 weeks of ticlopidine or clopidogrel therapy, therapeutic plasma exchange must be promptly instituted to enhance likelihood of survival.

Authors
Bennett, CL; Kim, B; Zakarija, A; Bandarenko, N; Pandey, DK; Buffie, CG; McKoy, JM; Tevar, AD; Cursio, JF; Yarnold, PR; Kwaan, HC; De Masi, D; Sarode, R; Raife, TJ; Kiss, JE; Raisch, DW; Davidson, C; Sadler, JE; Ortel, TL; Zheng, XL; Kato, S; Matsumoto, M; Uemura, M; Fujimura, Y; SERF-TTP Research Group,
MLA Citation
Bennett, CL, Kim, B, Zakarija, A, Bandarenko, N, Pandey, DK, Buffie, CG, McKoy, JM, Tevar, AD, Cursio, JF, Yarnold, PR, Kwaan, HC, De Masi, D, Sarode, R, Raife, TJ, Kiss, JE, Raisch, DW, Davidson, C, Sadler, JE, Ortel, TL, Zheng, XL, Kato, S, Matsumoto, M, Uemura, M, Fujimura, Y, and SERF-TTP Research Group, . "Two mechanistic pathways for thienopyridine-associated thrombotic thrombocytopenic purpura: a report from the SERF-TTP Research Group and the RADAR Project." J Am Coll Cardiol 50.12 (September 18, 2007): 1138-1143.
PMID
17868804
Source
pubmed
Published In
Journal of the American College of Cardiology
Volume
50
Issue
12
Publish Date
2007
Start Page
1138
End Page
1143
DOI
10.1016/j.jacc.2007.04.093

Heparin-induced thrombocytopenia in left ventricular assist device bridge-to-transplant patients.

BACKGROUND: The presence of heparin-induced thrombocytopenia (HIT) increases the risk for thromboembolic events in ventricular assist device (VAD) patients undergoing transplantation. However, cardiopulmonary bypass with alternative anticoagulants is often complicated by bleeding. Owing to this concern, we compared outcomes of HIT-positive versus control bridge-to-transplantation VAD patients; both groups were reexposed to heparin for cardiopulmonary bypass during transplant. METHODS: From February 2000 to January 2006, data were reviewed on 92 consecutive adult patients who underwent VAD placement as a bridge to transplantation. Patients in whom thrombocytopenia developed after heparin exposure were tested for HIT with an enzyme-linked immunosorbent assay for antiheparin/platelet factor-4 (HPF4) antibody (GTI Diagnostics, Waukesha, Wisconsin). During VAD support, heparin was avoided in HIT-positive patients, but all patients were reexposed to heparin during transplantation. Comparisons between HIT-positive and control patients for survival and freedom from thromboembolic events were determined using the Kaplan-Meier method and log-rank test. Continuous and categorical variables were compared using the Wilcoxon rank-sum and Student t test. RESULTS: Twenty-four of the 92 patients (26.1%) were determined to be HIT positive by enzyme-linked immunosorbent assay. Survival to transplant was not different between the two groups. When compared with control patients, HIT-positive patients who were reexposed to heparin had a greater decrease in platelet counts immediately after transplant (postoperative days 1 to 4, p < 0.05). Despite this transient thrombocytopenia, there was no difference in posttransplant mortality or thromboembolism. CONCLUSIONS: Heparin-induced thrombocytopenia-positive VAD patients did not experience increased thromboembolism or mortality after heparin reexposure. In light of the risks of using heparin alternatives, heparin reexposure is a safe management strategy for HIT-positive VAD patients.

Authors
Schroder, JN; Daneshmand, MA; Villamizar, NR; Petersen, RP; Blue, LJ; Welsby, IJ; Lodge, AJ; Ortel, TL; Rogers, JG; Milano, CA
MLA Citation
Schroder, JN, Daneshmand, MA, Villamizar, NR, Petersen, RP, Blue, LJ, Welsby, IJ, Lodge, AJ, Ortel, TL, Rogers, JG, and Milano, CA. "Heparin-induced thrombocytopenia in left ventricular assist device bridge-to-transplant patients." Ann Thorac Surg 84.3 (September 2007): 841-845.
PMID
17720387
Source
pubmed
Published In
Annals of Thoracic Surgery
Volume
84
Issue
3
Publish Date
2007
Start Page
841
End Page
845
DOI
10.1016/j.athoracsur.2007.03.049

Influence of sample collection and storage on the detection of platelet factor 4-heparin antibodies.

Heparin-induced thrombocytopenia is a life threatening thrombotic disorder caused by antibodies to platelet factor 4 (PF4) and heparin. Commercial immunoassays are frequently used for the detection of PF4-heparin antibodies, and several studies have reported that higher antibody titers are more frequently associated with adverse events. It is not known if conditions involving sample preparation and/or storage affect the operational characteristics of PF4-heparin immunoassays. We compared the detection of PF4-heparin antibodies from 48 patient samples collected concordantly in serum separator tubes or tubes containing EDTA or sodium citrate. We also examined the effects of extended sample storage on whole blood collected in serum separator, EDTA, or citrate tubes at 4 degrees C for up to 96 hours on antibody detection. We noted that serum or plasma anticoagulated with sodium citrate or EDTA yielded comparable results. In addition, we could not demonstrate any significant sample deterioration after storage at 4 degrees C in any medium for up to 4 days. These findings suggest that PF4-heparin antibodies are largely insensitive to the effects of sample preparation and storage.

Authors
Krakow, EF; Goudar, R; Petzold, E; Suvarna, S; Last, M; Welsby, IJ; Ortel, TL; Arepally, GM
MLA Citation
Krakow, EF, Goudar, R, Petzold, E, Suvarna, S, Last, M, Welsby, IJ, Ortel, TL, and Arepally, GM. "Influence of sample collection and storage on the detection of platelet factor 4-heparin antibodies." Am J Clin Pathol 128.1 (July 2007): 150-155.
PMID
17580283
Source
pubmed
Published In
American Journal of Clinical Pathology
Volume
128
Issue
1
Publish Date
2007
Start Page
150
End Page
155
DOI
10.1309/RFQK57F5QMURQ1HY

Invited commentary.

Authors
Welsby, IJ; Ortel, TL
MLA Citation
Welsby, IJ, and Ortel, TL. "Invited commentary." Ann Thorac Surg 84.1 (July 2007): 168-169.
PMID
17588405
Source
pubmed
Published In
Annals of Thoracic Surgery
Volume
84
Issue
1
Publish Date
2007
Start Page
168
End Page
169
DOI
10.1016/j.athoracsur.2007.04.021

Age and dose sensitivities in the 2-butoxyethanol F344 rat model of hemolytic anemia and disseminated thrombosis.

In hemolytic disorders, such as sickle cell disease and beta-thalassemia, the mechanisms of thrombosis are poorly understood. Appropriate animal models would increase the understanding of the pathophysiology of thrombosis. We previously reported that rats exposed to 2-butoxyethanol (2-BE) developed hemolytic anemia and disseminated thrombosis resembling sickle cell disease and beta-thalassemia. To characterize our model further, we investigated age- and dose-related differences in sensitivity to 2-BE. We exposed groups of 6- and 12-week-old F344 rats (5 animals/group) to 62.5, 125, and 250 mg/kg/day of 2-BE for up to 4 days. Blood was collected on days 2-4 for complete blood count and measurement of intracellular adhesion molecule-1 (ICAM-1). Histopathological evaluation was performed to find evidence of disseminated thrombosis. The maximum hemolytic response, resulting in decreased erythrocyte count and higher mean cell volume (MCV) occurred in the 12-week-old rats treated with the highest dose of 2-BE (250 mg/kg, p<0.0001). The highest increase in ICAM-1 levels occurred in the 12-week-old rats treated with 125 and 250 mg/kg 2-BE (p<0.0001). No intravascular thrombi were noted in the 6-week-old 2-BE-treated animals. The majority of intravascular thrombi occurred in the 12-week-old rats treated with 250 mg/kg 2-BE. Because our findings show age- and dose-related sensitivities, we suggest that 12-week-old rats and doses of 250 mg/kg be used in the 2-BE model.

Authors
Ramot, Y; Lewis, DA; Ortel, TL; Streicker, M; Moser, G; Elmore, S; Ward, SM; Peddada, S; Nyska, A
MLA Citation
Ramot, Y, Lewis, DA, Ortel, TL, Streicker, M, Moser, G, Elmore, S, Ward, SM, Peddada, S, and Nyska, A. "Age and dose sensitivities in the 2-butoxyethanol F344 rat model of hemolytic anemia and disseminated thrombosis." Exp Toxicol Pathol 58.5 (April 2007): 311-322.
PMID
17261363
Source
pubmed
Published In
Experimental and Toxicologic Pathology
Volume
58
Issue
5
Publish Date
2007
Start Page
311
End Page
322
DOI
10.1016/j.etp.2006.11.003

The U.S. Thrombosis and Hemostasis Centers pilot sites program.

Venous thromboembolism (VTE) is a common disorder associated with significant morbidity and mortality. Despite important advances in understanding the etiology of VTE, delivery of care to patients with thrombosis and thrombophilia is frequently incomplete and highly variable. A comprehensive model of health care has been used successfully to treat and prevent complications for people with hemophilia and other chronic disorders. The effectiveness of an integrated healthcare model for patients with all coagulation disorders has yet to be evaluated. The Division of Hereditary Blood Disorders of the Centers for Disease Control and Prevention (CDC) is collaborating with eight Thrombosis and Hemostasis Centers (pilot sites) to provide health-related services and conduct research directed toward the reduction or prevention of complications of thrombosis and thrombophilia. The initial objectives of the collaboration are to (1) determine the efficacy of integrated multidisciplinary care and prevention services for people with hemostatic disorders, (2) assess unmet needs for service delivery and identify outreach strategies to improve access to care, (3) develop effective messages aimed at disease management and prevention, and (4) foster the development of training programs to enhance provider skills for the delivery of patient care. To address these objectives, the investigators and CDC have developed and implemented a web-based patient registry to follow prospectively service allocation and patient outcomes. Funding for the program began in October 2001. All eight funded centers are affiliated with U.S. medical schools. Principal investigators at the centers are hematologists (five adult, two pediatric) or cardiologists. Faculty in obstetrics-gynecology, surgery, and multiple other specialties are integral to the model of care at the centers. Other critical components at the centers are clinical laboratory services, training programs, research networks, and education and outreach programs. From August 2003 to March 2006, over 2,600 patients were enrolled in the registry, accounting for a total of more than 5,000 visits to the centers. Immediate goals of the data collection at the centers are to characterize patients receiving care at centers and document the state of health services provided. Long-term goals are to evaluate prospectively clinical outcomes for patients receiving multidisciplinary care and prevention services at centers. The network of data collection across centers will facilitate future collaborative clinical and epidemiologic investigations and enhance collective expertise in hemostasis and coagulation disorders.

Authors
Dowling, NF; Beckman, MG; Manco-Johnson, M; Hassell, K; Philipp, CS; Michaels, LA; Moll, S; Heit, JA; Penner, J; Kulkarni, R; Pipe, S; Bockenstedt, P; Andersen, J; Crudder, S; James, AH; Zimmerman, S; Ortel, TL
MLA Citation
Dowling, NF, Beckman, MG, Manco-Johnson, M, Hassell, K, Philipp, CS, Michaels, LA, Moll, S, Heit, JA, Penner, J, Kulkarni, R, Pipe, S, Bockenstedt, P, Andersen, J, Crudder, S, James, AH, Zimmerman, S, and Ortel, TL. "The U.S. Thrombosis and Hemostasis Centers pilot sites program." J Thromb Thrombolysis 23.1 (February 2007): 1-7.
PMID
17111206
Source
pubmed
Published In
Journal of Thrombosis and Thrombolysis
Volume
23
Issue
1
Publish Date
2007
Start Page
1
End Page
7
DOI
10.1007/s11239-006-9002-y

A multi-dose pharmacokinetic study of dalteparin in haemodialysis patients.

Low-molecular-weight heparins undergo renal elimination, and therefore the proper dosing in hemodialysis (HD) patients is unclear. It was the objective of this study to evaluate the pharmacokinetic (PK) parameters of dalteparin in patients receiving chronic HD for end-stage renal disease. We performed a multidose PK study with prophylactic doses of dalteparin in twelve HD patients. Dalteparin 5,000 IU was administered subcutaneously daily for four consecutive days, with HD performed on day 2 and day 4. Anti-factor Xa activity was determined daily and at multiple blood samples after the 3rd and 4th dose. Eleven of 12 patients completed the study. The mean (range) PK parameters determined after the 4th dose were as follows: i) maximum concentration (Cmax ) was 0.31 IU/ml (0.06 to 0.55 IU/ml); ii) time to Cmax was 3.55 hours (2.59 to 4.96 hr); iii) area under the curve was 3.24 IU*hr/ml (0.64 to 6.44 IU*hr/ml); iv) half-life was 3.82 hr (2.03 to 9.63 hr); and v) trough anti-factor Xa activity 0.04 IU/ml (0.02 to 0.08 IU/ml). No major bleeding was observed. In general, patients with lower body weight exhibited a higher Cmax . From this pilot PK study, we have determined initial PK parameters for dalteparin in HD patients. Although a standard prophylactic dose was used, we found that in this patient population differences in body weight influenced the Cmax. Future studies to evaluate the PK parameters of dalteparin in patients receiving chronic HD may have to use weight-based dosing and will need to be performed over a longer period of time.

Authors
Perry, SL; O'Shea, SI; Byrne, S; Szczech, LA; Ortel, TL
MLA Citation
Perry, SL, O'Shea, SI, Byrne, S, Szczech, LA, and Ortel, TL. "A multi-dose pharmacokinetic study of dalteparin in haemodialysis patients." Thromb Haemost 96.6 (December 2006): 750-755.
PMID
17139369
Source
pubmed
Published In
Thrombosis and haemostasis
Volume
96
Issue
6
Publish Date
2006
Start Page
750
End Page
755

Venous thromboembolic disease. Clinical practice guidelines in oncology.

Authors
Wagman, LD; Baird, MF; Bennett, CL; Bockenstedt, PL; Cataland, SR; Fanikos, J; Fogarty, PF; Goldhaber, SZ; Grover, TS; Haire, W; Hassoun, H; Jahanzeb, M; Leung, LL; Linenberger, ML; Millenson, MM; Ortel, TL; Salem, R; Smith, JL; Streiff, MB; National Comprehensive Cancer Network,
MLA Citation
Wagman, LD, Baird, MF, Bennett, CL, Bockenstedt, PL, Cataland, SR, Fanikos, J, Fogarty, PF, Goldhaber, SZ, Grover, TS, Haire, W, Hassoun, H, Jahanzeb, M, Leung, LL, Linenberger, ML, Millenson, MM, Ortel, TL, Salem, R, Smith, JL, Streiff, MB, and National Comprehensive Cancer Network, . "Venous thromboembolic disease. Clinical practice guidelines in oncology." J Natl Compr Canc Netw 4.9 (October 2006): 838-869.
PMID
17020664
Source
pubmed
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
4
Issue
9
Publish Date
2006
Start Page
838
End Page
869

Low-molecular-weight heparin for thromboprophylaxis in pregnant women with mechanical heart valves.

BACKGROUND: Pregnancy in a woman with a mechanical heart valve is a life-threatening situation. Due to the inability of unfractionated heparin to prevent valvular thromboses, warfarin or other vitamin K antagonists have been the preferred anticoagulants for the mother. They are, however, potentially harmful to the fetus. With the advent of low-molecular-weight heparins, clinicians were hopeful for an alternative that was safe for the fetus, but more effective than unfractionated heparin, which carries a 29-33% risk of life-threatening thromboses and a 7-15% chance of mortality. Unfortunately, fatal thromboses have occurred with low-molecular-weight heparin as well. METHODS: We searched the MEDLINE database and other sources to identify cases of the use of low-molecular-weight heparin for thromboprophylaxis in women with mechanical heart valves. RESULTS: We found 73 cases and added three of our own for a total of 76. There were 17 thrombotic events (22%). Thirteen were valve thromboses, two were strokes, and two were myocardial infarctions. There were three deaths (4%). CONCLUSIONS: While pregnant women with mechanical heart valves who receive low-molecular-weight heparin for thromboprophylaxis are at extremely high risk of life-threatening thromboses, there is no evidence that low-molecular-weight heparin is inferior to unfractionated heparin.

Authors
James, AH; Brancazio, LR; Gehrig, TR; Wang, A; Ortel, TL
MLA Citation
James, AH, Brancazio, LR, Gehrig, TR, Wang, A, and Ortel, TL. "Low-molecular-weight heparin for thromboprophylaxis in pregnant women with mechanical heart valves." J Matern Fetal Neonatal Med 19.9 (September 2006): 543-549. (Review)
PMID
16966122
Source
pubmed
Published In
Journal of Maternal-Fetal and Neonatal Medicine (Informa)
Volume
19
Issue
9
Publish Date
2006
Start Page
543
End Page
549
DOI
10.1080/14767050600886666

Clinical practice. Heparin-induced thrombocytopenia.

Authors
Arepally, GM; Ortel, TL
MLA Citation
Arepally, GM, and Ortel, TL. "Clinical practice. Heparin-induced thrombocytopenia." N Engl J Med 355.8 (August 24, 2006): 809-817. (Review)
PMID
16928996
Source
pubmed
Published In
The New England journal of medicine
Volume
355
Issue
8
Publish Date
2006
Start Page
809
End Page
817
DOI
10.1056/NEJMcp052967

The kaolin-activated Thrombelastograph predicts bleeding after cardiac surgery.

OBJECTIVE: The objective of this study was to determine the relationship of the kaolin-activated Thrombelastograph (TEG) with postoperative bleeding and laboratory tests of coagulation in the setting of cardiac surgery with the routine use of -aminocaproic acid. DESIGN: Prospective observational study. SETTING: An adult heart center at a tertiary referral, university hospital. PARTICIPANTS: Thirty adult cardiac surgical patients. INTERVENTIONS: The kaolin-activated TEG, platelet counts, prothrombin times, activated partial thromboplastin times, and fibrinogen levels were measured before induction of anesthesia, during cardiopulmonary bypass, and on arrival in the intensive care unit. Mediastinal and thoracostomy drainage were measured every hour for 4 hours after arrival in the intensive care unit. MEASUREMENTS AND MAIN RESULTS: Correlation and multivariate linear regression modeling were used to describe relationships among coagulation tests, TEG parameters, and early postoperative bleeding. The TEG maximum amplitude (MA) parameter correlated well with postoperative bleeding (r = -0.6, p = 0.0018), more so than platelet count (r = -0.45, p = 0.02), fibrinogen level (r = -0.40, p = 0.06), or prothrombin time (r = 0.43, p = 0.02). The receiver operating characteristic curve c-index describing MA as a predictor for postoperative bleeding is 0.78. Abnormalities in all the laboratory test results were associated with an abnormal MA. CONCLUSIONS: In conclusion, the kaolin-activated TEG is associated with early coagulopathic bleeding. It may reflect the severity of a global coagulopathy affecting both platelets and coagulation factors and be a guide to incremental prohemostatic therapy in this setting.

Authors
Welsby, IJ; Jiao, K; Ortel, TL; Brudney, CS; Roche, AM; Bennett-Guerrero, E; Gan, TJ
MLA Citation
Welsby, IJ, Jiao, K, Ortel, TL, Brudney, CS, Roche, AM, Bennett-Guerrero, E, and Gan, TJ. "The kaolin-activated Thrombelastograph predicts bleeding after cardiac surgery." J Cardiothorac Vasc Anesth 20.4 (August 2006): 531-535.
PMID
16884984
Source
pubmed
Published In
Journal of Cardiothoracic and Vascular Anesthesia
Volume
20
Issue
4
Publish Date
2006
Start Page
531
End Page
535
DOI
10.1053/j.jvca.2005.04.013

Gene-expression patterns predict phenotypes of immune-mediated thrombosis.

Antiphospholipid antibody syndrome (APS) is a complex autoimmune thrombotic disorder with defined clinical phenotypes. Although not all patients with elevated antiphospholipid antibody (aPLA) levels develop complications, the severity of these potential events mandates aggressive and extended lifelong anti-thrombotic therapy. One hundred twenty-nine patients (57 patients with APS and venous thromboembolism [VTE], 32 patients with VTE without aPLA, 32 patients with aPLA only, and 8 healthy patients) were enrolled. RNA from peripheral-blood collection was used for DNA microarray analysis. Patterns of gene expression that characterize APS as well as thrombosis in the presence of aPLA were identified by hierarchical clustering and binary regression methods. Gene-expression profiles identify and predict individuals with APS from patients with VTE without aPLA. Importantly, similar methods identified expression profiles that accurately predicted those patients with aPLA at high risk for thrombotic events. All profiles were validated in independent cohorts of patients. The ability to predict APS, but more importantly, those patients at risk for venous thrombosis, represents a paradigm for a genomic approach that can be applied to other populations of patients with venous thrombosis, providing for more effective clinical management of disease, while also reflecting the possible underlying biologic processes.

Authors
Potti, A; Bild, A; Dressman, HK; Lewis, DA; Nevins, JR; Ortel, TL
MLA Citation
Potti, A, Bild, A, Dressman, HK, Lewis, DA, Nevins, JR, and Ortel, TL. "Gene-expression patterns predict phenotypes of immune-mediated thrombosis." Blood 107.4 (February 15, 2006): 1391-1396.
PMID
16263789
Source
pubmed
Published In
Blood
Volume
107
Issue
4
Publish Date
2006
Start Page
1391
End Page
1396
DOI
10.1182/blood-2005-07-2669

Thrombophilia in Pregnancy: Maternal and Fetal Implications

Authors
James, A; Brancazio, L; Ortel, T
MLA Citation
James, A, Brancazio, L, and Ortel, T. "Thrombophilia in Pregnancy: Maternal and Fetal Implications." Current Women's Health Reviews 2.1 (February 1, 2006): 51-59.
Source
crossref
Published In
Current women's health reviews
Volume
2
Issue
1
Publish Date
2006
Start Page
51
End Page
59
DOI
10.2174/157340406775486265

Platelet function analyzer (PFA)-100 closure time in the evaluation of platelet disorders and platelet function.

BACKGROUND: Closure time (CT), measured by platelet function analyzer (PFA-100) device, is now available to the clinical laboratory as a possible alternative or supplement to the bleeding time test. AIM: On behalf of the Platelet Physiology Subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis (ISTH-SSC), a working Group was formed to review and make recommendations on the use of the PFA-100 CT in the evaluation of platelet function within the clinical laboratory. METHODS: The Medline database was searched to review the published information on the PFA-100 CT in the evaluation of platelet disorders and platelet function. This information, and expert opinion, was used to prepare a report and generate consensus recommendations. RESULTS: Although the PFA-100 CT is abnormal in some forms of platelet disorders, the test does not have sufficient sensitivity or specificity to be used as a screening tool for platelet disorders. A role of the PFA-100 CT in therapeutic monitoring of platelet function remains to be established. CONCLUSIONS: The PFA-100 closure time should be considered optional in the evaluation of platelet disorders and function, and its use in therapeutic monitoring of platelet function is currently best restricted to research studies and prospective clinical trials.

Authors
Hayward, CPM; Harrison, P; Cattaneo, M; Ortel, TL; Rao, AK; Platelet Physiology Subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis,
MLA Citation
Hayward, CPM, Harrison, P, Cattaneo, M, Ortel, TL, Rao, AK, and Platelet Physiology Subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis, . "Platelet function analyzer (PFA)-100 closure time in the evaluation of platelet disorders and platelet function." J Thromb Haemost 4.2 (February 2006): 312-319. (Review)
PMID
16420557
Source
pubmed
Published In
Journal of Thrombosis and Haemostasis
Volume
4
Issue
2
Publish Date
2006
Start Page
312
End Page
319
DOI
10.1111/j.1538-7836.2006.01771.x

The antiphospholipid syndrome: what are we really measuring? How do we measure it? And how do we treat it?

The antiphospholipid syndrome is described with a review of its historical development as a recognized syndrome, what constitutes an antiphospholipid antibody, how it is measured, and how the syndrome is treated. Antiphospholipid antibodies are actually antibodies to a protein, most often beta-2-glycoprotein 1, that is usually bound to a phospholipid. Some antibodies are directed towards lipid-bound prothrombin. The antibodies are measured by immunologic assays or by antibody-dependent abnormalities detected in coagulation assays. Although they prolong coagulation assays, they are associated with a thrombotic tendency rather than a bleeding disorder. There are numerous postulated mechanisms to account for the thrombotic tendency. Patients with the antiphospholipid syndrome are treated with long-term oral anticoagulation to prolong the INR to 2.0 to 3.0. For most patients, a more intense level of treatment with a higher INR is not needed.

Authors
Ortel, TL
MLA Citation
Ortel, TL. "The antiphospholipid syndrome: what are we really measuring? How do we measure it? And how do we treat it?." J Thromb Thrombolysis 21.1 (February 2006): 79-83. (Review)
PMID
16475047
Source
pubmed
Published In
Journal of Thrombosis and Thrombolysis
Volume
21
Issue
1
Publish Date
2006
Start Page
79
End Page
83
DOI
10.1007/s11239-006-5581-x

Blockade of tissue factor-factor X binding attenuates sepsis-induced respiratory and renal failure.

Tissue factor expression in sepsis activates coagulation in the lung, which potentiates inflammation and leads to fibrin deposition. We hypothesized that blockade of factor X binding to the tissue factor-factor VIIa complex would prevent sepsis-induced damage to the lungs and other organs. Acute lung injury was produced in 15 adult baboons primed with killed Escherichia coli [1 x 10(9) colony-forming units (CFU)/kg], and then 12 h later, they were given 1 x 10(10) CFU/kg live E. coli by infusion. Two hours after live E. coli, animals received antibiotics with or without monoclonal antibody to tissue factor intravenously to block tissue factor-factor X binding. The animals were monitored physiologically for 34 h before being killed and their tissue harvested. The antibody treatment attenuated abnormalities in gas exchange and lung compliance, preserved renal function, and prevented tissue neutrophil influx and bowel edema relative to antibiotics alone (all P < 0.05). It also attenuated fibrinogen depletion (P < 0.01) and decreased proinflammatory cytokines, e.g., IL-6 and -8 (P < 0.01), in systemic and alveolar compartments. Similar protective effects of the antibody on IL-6 and -8 expression and permeability were found in lipopolysaccharide-stimulated endothelial cells. Blockade of factor X binding to the tissue factor-factor VIIa complex attenuates lung and organ injuries in established E. coli sepsis by attenuating the neutrophilic response and inflammatory pathways.

Authors
Welty-Wolf, KE; Carraway, MS; Ortel, TL; Ghio, AJ; Idell, S; Egan, J; Zhu, X; Jiao, J-A; Wong, HC; Piantadosi, CA
MLA Citation
Welty-Wolf, KE, Carraway, MS, Ortel, TL, Ghio, AJ, Idell, S, Egan, J, Zhu, X, Jiao, J-A, Wong, HC, and Piantadosi, CA. "Blockade of tissue factor-factor X binding attenuates sepsis-induced respiratory and renal failure." Am J Physiol Lung Cell Mol Physiol 290.1 (January 2006): L21-L31.
PMID
16100288
Source
pubmed
Published In
American journal of physiology. Lung cellular and molecular physiology
Volume
290
Issue
1
Publish Date
2006
Start Page
L21
End Page
L31
DOI
10.1152/ajplung.00155.2005

The reactivity of paired plasma and serum samples are comparable in the anticardiolipin and anti-beta2-glycoprotein-1 ELISAs.

Authors
Lewis, DA; Pound, ML; Ortel, TL
MLA Citation
Lewis, DA, Pound, ML, and Ortel, TL. "The reactivity of paired plasma and serum samples are comparable in the anticardiolipin and anti-beta2-glycoprotein-1 ELISAs." J Thromb Haemost 4.1 (January 2006): 265-267. (Letter)
PMID
16409482
Source
pubmed
Published In
Journal of Thrombosis and Haemostasis
Volume
4
Issue
1
Publish Date
2006
Start Page
265
End Page
267
DOI
10.1111/j.1538-7836.2005.01721.x

The authors reply [21]

Authors
Arepally, GM; Ortel, TL
MLA Citation
Arepally, GM, and Ortel, TL. "The authors reply [21]." New England Journal of Medicine 355.24 (2006): 2598-2599.
Source
scival
Published In
The New England journal of medicine
Volume
355
Issue
24
Publish Date
2006
Start Page
2598
End Page
2599
DOI
10.1056/NEJMc062561

The reactivity of paired plasma and serum samples are comparable in the anticardiolipin and anti-β2-glycoprotein-1 ELISAs. Reply to a rebuttal [17]

Authors
Lewis, DA; Pound, ML; Ortel, TL
MLA Citation
Lewis, DA, Pound, ML, and Ortel, TL. "The reactivity of paired plasma and serum samples are comparable in the anticardiolipin and anti-β2-glycoprotein-1 ELISAs. Reply to a rebuttal [17]." Journal of Thrombosis and Haemostasis 4.6 (2006): 1435-1437.
Source
scival
Published In
Journal of Thrombosis and Haemostasis
Volume
4
Issue
6
Publish Date
2006
Start Page
1435
End Page
1437
DOI
10.1111/j.1538-7836.2006.01984.x

Platelet function analyzer (PFA)-100® closure time in the evaluation of platelet disorders and platelet function: Reply to a rebuttal [15]

Authors
Hayward, CPM; Harrison, P; Cattaneo, M; Ortel, TL; Rao, AK
MLA Citation
Hayward, CPM, Harrison, P, Cattaneo, M, Ortel, TL, and Rao, AK. "Platelet function analyzer (PFA)-100® closure time in the evaluation of platelet disorders and platelet function: Reply to a rebuttal [15]." Journal of Thrombosis and Haemostasis 4.6 (2006): 1433-1434.
Source
scival
Published In
Journal of Thrombosis and Haemostasis
Volume
4
Issue
6
Publish Date
2006
Start Page
1433
End Page
1434
DOI
10.1111/j.1538-7836.2006.01992.x

Platelet function analyzer (PFA)-100® closure time in the evaluation of platelet disorders and platelet function: Reply to a rebuttal [14]

Authors
Hayward, CPM; Harrison, P; Cattaneo, M; Ortel, TL; Rao, AK
MLA Citation
Hayward, CPM, Harrison, P, Cattaneo, M, Ortel, TL, and Rao, AK. "Platelet function analyzer (PFA)-100® closure time in the evaluation of platelet disorders and platelet function: Reply to a rebuttal [14]." Journal of Thrombosis and Haemostasis 4.6 (2006): 1432--.
Source
scival
Published In
Journal of Thrombosis and Haemostasis
Volume
4
Issue
6
Publish Date
2006
Start Page
1432-
DOI
10.1111/j.1538-7836.2006.01927.x

Clinical outcomes with unfractionated heparin or low-molecular-weight heparin as bridging therapy in patients on long-term oral anticoagulants: The REGIMEN registry

Background: Patients who receive long-term oral anticoagulant (OAC) therapy often require interruption of OAC for an elective surgical or an invasive procedure. Heparin bridging therapy has been used in these situations, although the optimal method has not been established. No large prospective studies have compared unfractionated heparin (UFH) withlow-molecular-weight heparin (LMWH) for the perioperative management of patients at risk of thromboembolism requiring temporary interruption of long-term OAC therapy. Patients/methods: This multicenter, observational, prospective registry conducted in North America enrolled 901 eligible patients on long-term OAC who required heparin bridging therapy for anelective surgical or invasive procedure. Practice patterns and clinical outcomeswere compared between patientswho received either UFH alone (n = 180) or LMWH alone (n = 721). Results: Overall, the majority of patients (74.5%) requiring heparin bridging therapy had arterial indications for OAC. LMWH, in mostly twice-daily treatment doses, represented approximately 80% of the study population. LMWH-bridged patients had significantly fewer arterial indications for OAC, a lower mean Charlson comorbidity score, and were less likely to undergo major or cardiothoracic surgery, receive intraprocedural anticoagulants or thrombolytics, or receive general anesthesia than UFH-bridged patients (all P < 0.05). The LMWH group had significantly more bridging therapy completed in an outpatient setting or with a < 24-h hospital stay vs. the UFH group (63.6% vs. 6.1%, P < 0.001). In the LMWH and UFH groups, similar rates of overall adverse events (16.2% vs. 17.1%, respectively, P = 0.81), major composite adverse events (arterial/venous thromboembolism, major bleed, and death; 4.2% vs. 7.9%, respectively, P = 0.07) and major bleeds (3.3% vs. 5.5%, respectively, P = 0.25) were observed. The thromboembolic event rates were 2.4% forUFH and 0.9% for LMWH. Logistic regression analysis revealed that for postoperative heparin use a Charlson comorbidity score > 1 was an independent predictor of a major bleed and that vascular, general, and major surgery were associated with nonsignificant trends towards an increased risk of major bleed. Conclusions: Treatment-dose LMWH, mostly in the outpatient setting, is used substantially more often than UFH as bridging therapy in patients with predominately arterial indications for OAC. Overall adverse events, including thromboembolism and bleeding, are similar for patients treated with LMWHor UFH. Postoperative heparin bridging should be used with caution in patients with multiple comorbidities and those undergoing vascular, general, and major surgery. These findings need to be confirmed using large randomized trials for specific patient undergoing specific procedures. © 2006 International Society on Thrombosis and Haemostasis.

Authors
Spyropoulos, AC; Turpie, A; Dunn, AS; Spandorfer, J; Douketis, J; Jacobson, A; Frost, FJ; West, M; Green, D; Campbell, M; Krasuski, R; Ortel, T; O'Shea, S; Deitelzweig, S; Muntz, J; Spencer, F; Jafri, S; Kaatz, S
MLA Citation
Spyropoulos, AC, Turpie, A, Dunn, AS, Spandorfer, J, Douketis, J, Jacobson, A, Frost, FJ, West, M, Green, D, Campbell, M, Krasuski, R, Ortel, T, O'Shea, S, Deitelzweig, S, Muntz, J, Spencer, F, Jafri, S, and Kaatz, S. "Clinical outcomes with unfractionated heparin or low-molecular-weight heparin as bridging therapy in patients on long-term oral anticoagulants: The REGIMEN registry." Journal of Thrombosis and Haemostasis 4.6 (2006): 1246-1252.
PMID
16706967
Source
scival
Published In
Journal of Thrombosis and Haemostasis
Volume
4
Issue
6
Publish Date
2006
Start Page
1246
End Page
1252
DOI
10.1111/j.1538-7836.2006.01908.x

Hemostatic activation in a chemically induced rat model of severe hemolysis and thrombosis.

INTRODUCTION: In hemolytic diseases such as sickle cell disease and beta-thalassemia, the mechanisms of thrombosis are poorly understood, however erythrocyte/endothelium interactions are thought to play an important role. Appropriate animal models would increase our understanding of the pathophysiology of thrombosis and aid in the development of new therapeutic strategies. We previously reported that rats exposed to 2-butoxyethanol (2-BE) develop hemolysis and enhanced adherence of erythrocytes to the extracellular matrix, possibly secondary to the recruitment of cellular adhesion molecules at the erythrocyte/endothelium interface. METHODS: We exposed rats to 250 mg/kg/day of 2-BE for 4 days, and collected blood for coagulation markers on each day. RESULTS: As previously observed, erythrocytes dropped precipitously (8.0 to 1.8x10(6)/microl in 48 h), and diffuse microvascular thrombosis developed in the heart, lungs, liver, bones and eyes. Prothrombin times, activated partial thromboplastin times, fibrinogen, and antithrombin-III were unchanged between treated and control rats, indicating that hemostasis is largely unperturbed. However the thrombin-antithrombin III levels in the 2-BE treated rats for all days were 3-7 times greater than the control rats. The plasma intercellular adhesion molecule-1 (ICAM-1) levels of 2-BE treated animals were approximately twice that of the controls on days 2 and 3 and 1.5 times the controls on day 4 (P<0.05). CONCLUSION: Our findings are consistent with the observations of increased erythrocyte aggregation, increased erythrocyte/endothelium interaction, and increased plasma ICAM-1 levels observed in sickle cell disease and beta-thalassemia patients. This model may be useful for studying therapeutic agents that disrupt erythrocyte/endothelium interactions.

Authors
Lewis, DA; Nyska, A; Potti, A; Hoke, HA; Klemp, KF; Ward, SM; Peddada, SD; Wu, J; Ortel, TL
MLA Citation
Lewis, DA, Nyska, A, Potti, A, Hoke, HA, Klemp, KF, Ward, SM, Peddada, SD, Wu, J, and Ortel, TL. "Hemostatic activation in a chemically induced rat model of severe hemolysis and thrombosis." Thromb Res 118.6 (2006): 747-753.
PMID
16405975
Source
pubmed
Published In
Thrombosis Research
Volume
118
Issue
6
Publish Date
2006
Start Page
747
End Page
753
DOI
10.1016/j.thromres.2005.11.010

Continuing anticoagulation following venous thromboembolism.

Authors
Krakow, E; Ortel, TL
MLA Citation
Krakow, E, and Ortel, TL. "Continuing anticoagulation following venous thromboembolism." JAMA 294.24 (December 28, 2005): 3088-. (Letter)
PMID
16380585
Source
pubmed
Published In
JAMA : the journal of the American Medical Association
Volume
294
Issue
24
Publish Date
2005
Start Page
3088
DOI
10.1001/jama.294.24.3088-a

Preoperative anti-PF4/heparin antibody level predicts adverse outcome after cardiac surgery.

OBJECTIVE: Preexisting serum antibodies to heparin/platelet factor 4 complexes may predispose adult cardiac surgical patients to increased perioperative morbidity and mortality. We sought to determine the association between preoperative serum antibodies directed against platelet factor 4/heparin complexes and major complications (in-hospital death or length of stay >10 days) in adult cardiac surgical patients. METHODS: In a prospective observational study of 466 patients undergoing elective coronary artery bypass grafting, valvular heart surgery, or both, preoperative serum was assayed for anti-platelet factor 4/heparin antibody by using a commercially available enzyme-linked immunosorbent assay (Asserachrom HPIA). Known preoperative risk factors were assessed, and patients were assigned a risk score by using the validated method of Parsonnet and colleagues. RESULTS: Major complications (death or postoperative hospitalization >10 days) occurred in 108 patients (23%). Overall, 59 (13%) patients had a positive preoperative anti-platelet factor 4/heparin antibody screen (upper limit of normal is 0.5 optical density units). A positive assay result independently predicted an increased risk of major complications (P = .0284; odds ratio, 1.98; 95% confidence interval, 1.06-3.62) over and above the effect of the Parsonnet risk score (P < .001; odds ratio, 1.07; 95% confidence interval, 1.05-1.10). The level of preoperative anti-platelet factor 4/heparin antibody was also significantly associated with major complications (P = .036; odds ratio, 1.31; 95% confidence interval, 1.02-1.68) independently of the Parsonnet risk score. No association (P > .75) existed between the Parsonnet risk score and preoperative anti-platelet factor 4/heparin antibody level. CONCLUSIONS: Serum antibodies directed against platelet factor 4/heparin complexes are prevalent in the adult patient population undergoing cardiac surgery. The presence of these antibodies before surgery is an independent predictor for death or prolonged hospitalization after adult cardiac surgery.

Authors
Bennett-Guerrero, E; Slaughter, TF; White, WD; Welsby, IJ; Greenberg, CS; El-Moalem, H; Ortel, TL
MLA Citation
Bennett-Guerrero, E, Slaughter, TF, White, WD, Welsby, IJ, Greenberg, CS, El-Moalem, H, and Ortel, TL. "Preoperative anti-PF4/heparin antibody level predicts adverse outcome after cardiac surgery." J Thorac Cardiovasc Surg 130.6 (December 2005): 1567-1572.
PMID
16308000
Source
pubmed
Published In
Journal of Thoracic and Cardiovascular Surgery
Volume
130
Issue
6
Publish Date
2005
Start Page
1567
End Page
1572
DOI
10.1016/j.jtcvs.2005.07.052

Point-of-care testing of the international normalized ratio in patients with antiphospholipid antibodies.

Antiphospholipid antibodies can influence the results of clotting tests in a subset of patients, which can be a major obstacle in monitoring warfarin. The aim was to determine if point-of-care testing of the International Normalized Ratio (INR) is influenced by antiphospholipid antibodies. We compared 59 patients receiving warfarin for a diagnosis of antiphospholipid antibody syndrome (APS) to 49 patients receiving warfarin for atrial fibrillation to evaluate the consistency between INR results obtained by different methods. INR results obtained by finger stick (capillary whole-blood) and venipuncture (non-citrated and citrated whole-blood) were compared with our laboratory plasma-based prothrombin time assay. Five patients (8%) with APS and both elevated anti-beta2glycoprotein I levels and positive lupus anticoagulants had non-measurable ProTime INR results and generally higher Hemochron Signature INR results than the plasma-based method, but the corresponding chromogenic factor X results were not supratherapeutic. For the remaining patients, differences between the plasma-based INR and the point-of-care INR results ranged from 0.2 +/- 0.2 to 0.4 +/- 0.3. The differences were similar for patients with APS and atrial fibrillation for all INR comparisons with the exception of the plasma-based method compared with the ProTime, which showed a mean absolute difference of 0.4 +/- 0.3 for APS patients and of 0.2 +/- 0.2 for atrial fibrillation patients (p = 0.02). In a subset ofAPS patients, the ProTime system will not yield an INR result and the HEMochron Signature (citrate and non-citrate whole-blood) INR results will exhibit elevated INR results. For this subset of APS patients, we suggest using an alternative method to monitor warfarin.

Authors
Perry, SL; Samsa, GP; Ortel, TL
MLA Citation
Perry, SL, Samsa, GP, and Ortel, TL. "Point-of-care testing of the international normalized ratio in patients with antiphospholipid antibodies." Thromb Haemost 94.6 (December 2005): 1196-1202.
PMID
16411394
Source
pubmed
Published In
Thrombosis and haemostasis
Volume
94
Issue
6
Publish Date
2005
Start Page
1196
End Page
1202
DOI
10.1160/TH05-06-0400

Thrombophilia and thrombosis in thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disorder characterized by microangiopathic hemolytic anemia and thrombocytopenia often accompanied by microvascular ischemia, which may manifest as sensorimotor signs, visual changes, renal impairment, cardiac ischemia, and abdominal pain, depending on the organs affected. Until a few decades ago, TTP remained an almost universally fatal disorder. The introduction of plasma exchange therapy (PE) with replacement of fresh frozen plasma has improved the survival of patients with acute TTP dramatically from less than 10% to approximately 80 to 90% and is now considered the therapy of choice. During the last decade, the understanding of the pathophysiology of thrombotic microangiopathies, especially TTP, has increased considerably. The clinical features of thrombotic sequelae in TTP are diverse and usually secondary to microvascular thrombosis. Clinical and laboratory evidence for disruption of primary and secondary hemostasis, the role of endothelial integrity and fibrinolysis, the relevance of large vessel thrombosis, and the prevalence of thrombophilic states in TTP are discussed in this review. In summary, although the syndrome of TTP can sometimes be confused with other thrombotic diatheses, it is clear that the phenomenon of thrombosis in TTP appears to be distinctly different, both biologically and clinically, from other causes of microangiopathy and/or antibody-mediated thrombosis. Traditional anticoagulant and antiplatelet strategies are generally not effective in patients with TTP, despite the predominance of thrombotic manifestations, and common prothrombotic polymorphisms detected in patients with venous thromboembolism are seldom present.

Authors
Potti, A; Ramiah, V; Ortel, TL
MLA Citation
Potti, A, Ramiah, V, and Ortel, TL. "Thrombophilia and thrombosis in thrombotic thrombocytopenic purpura." Semin Thromb Hemost 31.6 (December 2005): 652-658. (Review)
PMID
16388416
Source
pubmed
Published In
Seminars in Thrombosis and Hemostasis
Volume
31
Issue
6
Publish Date
2005
Start Page
652
End Page
658
DOI
10.1055/s-2005-925471

Cardiolipin polyspecific autoreactivity in two broadly neutralizing HIV-1 antibodies.

The design of a human immunodeficiency virus-1 (HIV-1) immunogen that can induce broadly reactive neutralizing antibodies is a major goal of HIV-1 vaccine development. Although rare human monoclonal antibodies (mAbs) exist that broadly neutralize HIV-1, HIV-1 envelope immunogens do not induce these antibody specificities. Here we demonstrate that the two most broadly reactive HIV-1 envelope gp41 human mAbs, 2F5 and 4E10, are polyspecific autoantibodies reactive with the phospholipid cardiolipin. Thus, current HIV-1 vaccines may not induce these types of antibodies because of autoantigen mimicry of the conserved membrane-proximal epitopes of the virus. These results may have important implications for generating effective neutralizing antibody responses by using HIV-1 vaccines.

Authors
Haynes, BF; Fleming, J; St Clair, EW; Katinger, H; Stiegler, G; Kunert, R; Robinson, J; Scearce, RM; Plonk, K; Staats, HF; Ortel, TL; Liao, H-X; Alam, SM
MLA Citation
Haynes, BF, Fleming, J, St Clair, EW, Katinger, H, Stiegler, G, Kunert, R, Robinson, J, Scearce, RM, Plonk, K, Staats, HF, Ortel, TL, Liao, H-X, and Alam, SM. "Cardiolipin polyspecific autoreactivity in two broadly neutralizing HIV-1 antibodies." Science 308.5730 (June 24, 2005): 1906-1908.
PMID
15860590
Source
pubmed
Published In
Science
Volume
308
Issue
5730
Publish Date
2005
Start Page
1906
End Page
1908
DOI
10.1126/science.1111781

von Willebrand's disease diagnosed after menorrhagia worsened from levonorgestrel intrauterine system.

BACKGROUND: Adult females with menorrhagia may have unrecognized mild von Willebrand's disease. Most females with known von Willebrand's disease report menorrhagia. CASE: A 38-year-old healthy female desired contraception. She described heavy menses lasting 8 days since menarche. History included uncomplicated vaginal deliveries. Physical examination was normal. The levonorgestrel intrauterine system was placed. Her menorrhagia then worsened to 14 successive days each month. Evaluation revealed mild von Willebrand's disease. At 19 months of follow-up, she retained her levonorgestrel intrauterine system and avoided pregnancy. Her menses slowly improved to spotting for 8 days each month. CONCLUSION: Von Willebrand's disease is a likely cause of menorrhagia that goes unrecognized as well as a potential cause for "failed" conservative treatment for menorrhagia. Understanding the cause of menorrhagia is an important aspect of evaluating this common symptom.

Authors
Lukes, AS; Perry, S; Ortel, TL
MLA Citation
Lukes, AS, Perry, S, and Ortel, TL. "von Willebrand's disease diagnosed after menorrhagia worsened from levonorgestrel intrauterine system." Obstet Gynecol 105.5 Pt 2 (May 2005): 1223-1226.
PMID
15863590
Source
pubmed
Published In
Obstetrics & Gynecology (Elsevier)
Volume
105
Issue
5 Pt 2
Publish Date
2005
Start Page
1223
End Page
1226
DOI
10.1097/01.AOG.0000157758.94890.59

Antihuman factor V antibodies after use of relatively pure bovine thrombin.

Although bovine thrombin is commonly used in the operating room, there is evidence that exposure to bovine thrombin can result in the development of autoimmune antibodies, usually against factor V, which can lead to a profound coagulopathy. It is thought that impurities in bovine thrombin preparations are responsible for the adverse reactions in patients. Here we describe a case in which exposure to a relatively pure bovine thrombin preparation resulted in the development of an antihuman factor V antibody-associated coagulopathy. This report calls into question the safety of even relatively pure bovine thrombin.

Authors
Lawson, JH; Lynn, KA; Vanmatre, RM; Domzalski, T; Klemp, KF; Ortel, TL; Niklason, LE; Parker, W
MLA Citation
Lawson, JH, Lynn, KA, Vanmatre, RM, Domzalski, T, Klemp, KF, Ortel, TL, Niklason, LE, and Parker, W. "Antihuman factor V antibodies after use of relatively pure bovine thrombin." Ann Thorac Surg 79.3 (March 2005): 1037-1038.
PMID
15734434
Source
pubmed
Published In
Annals of Thoracic Surgery
Volume
79
Issue
3
Publish Date
2005
Start Page
1037
End Page
1038
DOI
10.1016/j.athoracsur.2003.09.110

Thrombosis, thrombophilia, and thromboprophylaxis in pregnancy.

Normal pregnancy is accompanied by changes in coagulation that have likely evolved to protect women from the bleeding challenges of miscarriage and childbirth. Consequently, pregnant women are at an increased risk of thrombosis. The most important risk factors are thrombophilia and a history of thrombosis. Most thromboses in pregnancy occur in the left lower extremity, but pelvic vein thromboses are not uncommon. Thrombophilia increases not only the risk of maternal thrombosis but also the risk of poor pregnancy outcome. All pregnant women should be asked about a personal or family history of thrombosis and the details of their obstetrical history. Some women should undergo laboratory testing, particularly those with a personal history of thrombosis or a history of poor pregnancy outcome. The purpose of testing is to help determine which women should receive anticoagulation therapy, which is used not only to treat venous thromboembolism, but also to prevent thromboembolism and reduce the risk of poor pregnancy outcome in women with thrombophilia. Low-molecular-weight heparins are preferred over unfractionated heparin because they have a longer half-life and are presumed to have fewer side effects. Their longer half-life is a disadvantage around the time of delivery when unfractionated heparin, with its shorter half-life, is easier to manage. The risk of thrombosis is higher postpartum than during pregnancy, so anticoagulation therapy is usually continued for at least 6 weeks after delivery.

Authors
James, AH; Brancazio, LR; Ortel, TL
MLA Citation
James, AH, Brancazio, LR, and Ortel, TL. "Thrombosis, thrombophilia, and thromboprophylaxis in pregnancy." Clinical advances in hematology & oncology : H&O 3.3 (March 2005): 187-197. (Academic Article)
PMID
16166990
Source
manual
Published In
Clinical advances in hematology & oncology : H&O
Volume
3
Issue
3
Publish Date
2005
Start Page
187
End Page
197

Warfarin in antiphospholipid syndrome--time to explore new horizons.

Authors
Erkan, D; Ortel, TL; Lockshin, MD
MLA Citation
Erkan, D, Ortel, TL, and Lockshin, MD. "Warfarin in antiphospholipid syndrome--time to explore new horizons." J Rheumatol 32.2 (February 2005): 208-212.
PMID
15693072
Source
pubmed
Published In
The Journal of rheumatology
Volume
32
Issue
2
Publish Date
2005
Start Page
208
End Page
212

Phospholipid vesicles interfere with binding of antibody fragments to the light chain of factor VIII

Factor VIII binds to phospholipid membranes through the C2 domain (S2173-Y2332). Residues M2199, F2200, L2251, L2252, V2223,W2313 andV2314 at the tips of β-hairpins and loops are thought to contribute to phospholipid membrane binding. Similarly, residues in the C2 domain of the homologous protein factorV form a phospholipid binding site, but residues in the A3 and CI domains are also thought to contribute to membrane binding. Phage display technology was previously used to isolate factor VIII light chain specific single-chain variable domain fragments (scFv) from patients with factorVIII inhibitors. Phospholipid vesicles inhibited the binding of factorVIII to scFvsWRI and WR16 (epitope: E2181-M2199) with half saturation values of 23 and 47 μM respectively.The single point mutant F2200A factor VIII light chain bound to WRI and WR16 with a much lower affinity than wild type protein suggesting that residue F2200 is also included in the epitopes of these scFvs. Binding of factorVIII to C2-specific scFvs WR13 and EL14 (epitope: K2207-M2321) was not inhibited by phospholipid vesicles. Consistent with this, F2200A factor VIII light chain bound to these scFvs with the same affinity as the wild type protein. However, phospholipid vesicles also inhibited the binding of factorVIII to theA3-CI-specific scFvs KM36 (epitope: Q1778-D1840) and KM38 (epitope: S1690-N1777 and/or V1841-N2172) with half saturation values of 84 and 165 μM, respectively, suggesting that the A3 and/or CI domains may contribute to membrane binding of the cofactor. © 2005 Schattauer GmbH, Stuttgart.

Authors
Lewis, DA; Bovenschen, N; Mertens, K; Voorberg, J; Ortel, TL
MLA Citation
Lewis, DA, Bovenschen, N, Mertens, K, Voorberg, J, and Ortel, TL. "Phospholipid vesicles interfere with binding of antibody fragments to the light chain of factor VIII." Thrombosis and Haemostasis 93.5 (2005): 833-841.
PMID
15886796
Source
scival
Published In
Thrombosis and Haemostasis
Volume
93
Issue
5
Publish Date
2005
Start Page
833
End Page
841
DOI
10.1160/TH04-11-0729

Highlights from the 46th annual meeting of the American Society of Hematology

Authors
Fassas, A; Barlogie, B; Feusner, J; Kay, NE; Wingard, JR; Ortel, TL
MLA Citation
Fassas, A, Barlogie, B, Feusner, J, Kay, NE, Wingard, JR, and Ortel, TL. "Highlights from the 46th annual meeting of the American Society of Hematology." Clinical Advances in Hematology and Oncology 3.2 (2005): 111-116.
PMID
16166978
Source
scival
Published In
Clinical Advances in Hematology and Oncology
Volume
3
Issue
2
Publish Date
2005
Start Page
111
End Page
116

Dialogue with patient care organizations.

Authors
Costello, R; Young, J; Burkholder, R; Cranston, J; Ortel, TL; Dentali, S; Cotter, R; O'sullivan Maillet, J; Hawkins, B; Craig Hooper, W
MLA Citation
Costello, R, Young, J, Burkholder, R, Cranston, J, Ortel, TL, Dentali, S, Cotter, R, O'sullivan Maillet, J, Hawkins, B, and Craig Hooper, W. "Dialogue with patient care organizations." Thromb Res 117.1-2 (2005): 211-222.
PMID
16125754
Source
pubmed
Published In
Thrombosis Research
Volume
117
Issue
1-2
Publish Date
2005
Start Page
211
End Page
222
DOI
10.1016/j.thromres.2005.07.004

Thrombosis and the antiphospholipid syndrome.

The antiphospholipid syndrome is an antibody-mediated hypercoagulable state characterized by recurrent venous and arterial thromboembolic events. Several studies have determined that the frequency of antiphospholipid syndrome in patients presenting with a venous thromboembolic event is between 4% and 14%. Because of the high risk for recurrent thromboembolism in these patients, current recommendations suggest a longer, potentially lifelong, course of antithrombotic therapy following an initial event. Although most authorities agree on an extended course of therapy, considerable controversy surrounds the optimal target therapeutic INR for patients with antiphospholipid syndrome. For an initial venous thromboembolic event, a target INR of 2.0 to 3.0 is supported by two prospective, randomized clinical trials. In contrast, relatively limited data exist for an initial arterial thromboembolic event in patients who have the antiphospholipid syndrome, and therapeutic recommendations range from aspirin to warfarin with a high target INR. Recurrent thromboembolic events can be extremely difficult to treat, and some patients may benefit from the addition of immunosuppressive therapies. Importantly, as many as 50% of the initial thromboembolic events sustained by patients with antiphospholipid antibodies occur in the setting of additional, coincident prothrombotic risk factors, indicating the importance of addressing any additional risk factors, such as hypercholesterolemia, in these patients. Prospective studies are needed to address the role of thromboprophylactic strategies in asymptomatic individuals with antiphospholipid antibodies in the absence of additional risk factors.

Authors
Ortel, TL
MLA Citation
Ortel, TL. "Thrombosis and the antiphospholipid syndrome." Hematology Am Soc Hematol Educ Program (2005): 462-468.
PMID
16304421
Source
pubmed
Published In
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program
Publish Date
2005
Start Page
462
End Page
468
DOI
10.1182/asheducation-2005.1.462

Thrombosis Research: Preface

Authors
Marder, VJ; Ortel, TL; Grollman, A; Hasan, AAK
MLA Citation
Marder, VJ, Ortel, TL, Grollman, A, and Hasan, AAK. "Thrombosis Research: Preface." Thrombosis Research 117.1-2 (2005): 1-3.
Source
scival
Published In
Thrombosis Research
Volume
117
Issue
1-2
Publish Date
2005
Start Page
1
End Page
3
DOI
10.1016/j.thromres.2005.09.002

Clinical implications for patients on antithrombotic therapy while taking supplements.

Authors
Ortel, TL
MLA Citation
Ortel, TL. "Clinical implications for patients on antithrombotic therapy while taking supplements." Thromb Res 117.1-2 (2005): 75-80.
PMID
15961141
Source
pubmed
Published In
Thrombosis Research
Volume
117
Issue
1-2
Publish Date
2005
Start Page
75
End Page
80
DOI
10.1016/j.thromres.2005.04.032

Detection of antibody-mediated reduction of annexin A5 anticoagulant activity in plasmas of patients with the antiphospholipid syndrome.

Annexin A5 (A5) forms 2-dimensional crystals over phospholipid bilayers, blocking their availability for coagulation reactions. Recently, human antiphospholipid (aPL) monoclonal antibodies (mAbs) have been demonstrated by atomic force microscopy (AFM) to disrupt this crystallization and accelerate coagulation. We therefore performed a study with small, well-defined groups of patients to investigate whether these effects on A5 binding and activity are also detectable in plasmas from patients with the aPL syndrome. A5 binding to phospholipid was significantly reduced by plasmas of patients with the aPL syndrome and thromboembolism compared with healthy controls (mean +/- SD, 26.7 +/- 4.3 ng/well [n = 25] vs 30.5 +/- 3.1 ng/well [n = 20], P < .01) and the non-aPL thromboembolism group (29.9 +/- 3.2 ng/well [n = 15], P < .05). A5 anticoagulant activity was reduced by plasmas of patients with aPL syndrome and thromboembolism compared with aPL antibodies without thrombosis (182 +/- 31% [n = 25] vs 210 +/- 35% [n = 26], P < .01), non-aPL thromboembolism (229 +/- 16% [n = 15], P < .001), and healthy controls (231 +/- 14% [n = 30], P < .001). In conclusion, in accordance with recent AFM data with monoclonal human aPL antibodies, plasmas from patients with aPL antibodies with thromboembolism reduce both A5 binding to phospholipid and A5 anticoagulant activity. This "annexin A5 resistance" identifies a novel mechanism for thrombosis in the aPL syndrome.

Authors
Rand, JH; Wu, X-X; Lapinski, R; van Heerde, WL; Reutelingsperger, CP; Chen, PP; Ortel, TL
MLA Citation
Rand, JH, Wu, X-X, Lapinski, R, van Heerde, WL, Reutelingsperger, CP, Chen, PP, and Ortel, TL. "Detection of antibody-mediated reduction of annexin A5 anticoagulant activity in plasmas of patients with the antiphospholipid syndrome." Blood 104.9 (November 1, 2004): 2783-2790.
PMID
15242878
Source
pubmed
Published In
Blood
Volume
104
Issue
9
Publish Date
2004
Start Page
2783
End Page
2790
DOI
10.1182/blood-2004-01-0203

Regulatable aptamers in medicine: focus on antithrombotic strategies.

Proteins generally execute the key physiological activities required for normal growth and homeostasis. As such, many different classes of proteins, including proteases, kinases, cellular receptors and signalling proteins, represent attractive targets for diagnosis or therapy. Aptamers are small nucleic acid molecules that function as direct protein inhibitors, much like monoclonal antibodies. After a decade of intensive research, technology development and initial clinical evaluation, aptamers have now demonstrated broad potential as direct protein ligands and inhibitors, and thus represent an exciting class of compounds for the development of new therapeutic and diagnostic agents. This review will discuss the basic properties and isolation of aptamers, their use in animals and the clinic, and describe an exciting recent advance in the development of antidotes to certain aptamers, which will add a repertoire of new agents with regulatable activity for clinical use.

Authors
Potti, A; Rusconi, CP; Sullenger, BA; Ortel, TL
MLA Citation
Potti, A, Rusconi, CP, Sullenger, BA, and Ortel, TL. "Regulatable aptamers in medicine: focus on antithrombotic strategies." Expert Opin Biol Ther 4.10 (October 2004): 1641-1647. (Review)
PMID
15461575
Source
pubmed
Published In
Expert Opinion on Biological Therapy
Volume
4
Issue
10
Publish Date
2004
Start Page
1641
End Page
1647
DOI
10.1517/14712598.4.10.1641

Use of a new platelet function analyzer to detect von Willebrand disease in women with menorrhagia.

OBJECTIVE: The purpose of this study was to assess the usefulness of a new platelet function analyzer in the detection of von Willebrand disease and platelet dysfunction in women with menorrhagia. STUDY DESIGN: Women with menorrhagia and control subjects were tested with a platelet function analyzer. If the results were abnormal, further testing was performed for possible von Willebrand disease or platelet dysfunction. Results were compared. RESULTS: Of the 108 women with menorrhagia, 28 had an abnormal platelet function analysis results: 7 results were suggestive of von Willebrand disease; 17 results were suggestive of platelet dysfunction, and 4 results were inconclusive. Of the 100 control subjects, 18 subjects had an abnormal platelet function analysis result: 2 results were suggestive of von Willebrand disease; 12 results were suggestive of platelet dysfunction, and 4 results were inconclusive. The prevalence of suspected von Willebrand disease was 6% among women with menorrhagia and 2% among control subjects. Among white women, the prevalence was 10% compared with 1% among control subjects. CONCLUSION: We demonstrated that the platelet function analyzer could be used to detect von Willebrand disease in women with menorrhagia.

Authors
James, AH; Lukes, AS; Brancazio, LR; Thames, E; Ortel, TL
MLA Citation
James, AH, Lukes, AS, Brancazio, LR, Thames, E, and Ortel, TL. "Use of a new platelet function analyzer to detect von Willebrand disease in women with menorrhagia." Am J Obstet Gynecol 191.2 (August 2004): 449-455.
PMID
15343220
Source
pubmed
Published In
American Journal of Obstetrics & Gynecology
Volume
191
Issue
2
Publish Date
2004
Start Page
449
End Page
455
DOI
10.1016/j.ajog.2004.03.009

Coagulation abnormalities in patients with hip osteonecrosis.

The relatively high frequency of coagulation abnormalities in patients with hip osteonecrosis might represent increased risk factors for the development of bone necrosis by predisposing these patients to thromboembolic phenomena. The recognition of this association may increase as more patients with osteonecrotic lesions are tested for haemostatic abnormalities. Early diagnosis of hypercoagulability in the group of patients at risk may allow pharmacologic intervention that may prevent this devastating process from developing.

Authors
Korompilias, AV; Ortel, TL; Urbaniak, JR
MLA Citation
Korompilias, AV, Ortel, TL, and Urbaniak, JR. "Coagulation abnormalities in patients with hip osteonecrosis." Orthop Clin North Am 35.3 (July 2004): 265-vii.
PMID
15271534
Source
pubmed
Published In
Orthopedic Clinics of North America
Volume
35
Issue
3
Publish Date
2004
Start Page
265
End Page
vii
DOI
10.1016/j.ocl.2004.02.004

A review of the therapeutic uses of thrombin.

Thrombin is the product of the hemostatic response essential to the conversion of fibrinogen to fibrin. In addition, it is also responsible for the aggregation of blood platelets in the formation of the "platelet plug" as well as the activation of factor VIII, factor V, factor XI, factor XIII and protein C. The action of thrombin is not confined to the hemostatic response as it also has a critical function in the wound healing process by stimulating 'mitogenic' events through interaction with cell surface receptors. In this review, we consider the various biological activities of thrombin as they relate to current therapeutic use. While there has been considerable interest in the development of fibrin sealant products, there has been considerably less interest in documenting the continuing use of thrombin as a therapeutic. The use of thrombin for topical hemostasis and the treatment of pseudoaneurysms will be discussed in detail. It is concluded that the use of thrombin as a drug will not only continue but also will significantly increase. However, the availability of a safe human thrombin preparation will be critical for the continued use of thrombin as a therapeutic.

Authors
Lundblad, RL; Bradshaw, RA; Gabriel, D; Ortel, TL; Lawson, J; Mann, KG
MLA Citation
Lundblad, RL, Bradshaw, RA, Gabriel, D, Ortel, TL, Lawson, J, and Mann, KG. "A review of the therapeutic uses of thrombin." Thromb Haemost 91.5 (May 2004): 851-860. (Review)
PMID
15116244
Source
pubmed
Published In
Thrombosis and haemostasis
Volume
91
Issue
5
Publish Date
2004
Start Page
851
End Page
860
DOI
10.1160/TH03-12-0792

A review of the therapeutic uses of thrombin

Thrombin is the product of the hemostatic response essential to the conversion of fibrinogen to fibrin. In addition, it is also responsible for the aggregation of blood platelets in the formation of the "platelet plug" as well as the activation of factor VIII, factor V, factor XI, factor XIII and protein C. The action of thrombin is not confined to the hemostatic response as it also has a critical function in the wound healing process by stimulating 'mitogenic' events through interaction with cell surface receptors. In this review, we consider the various biological activities of thrombin as they relate to current therapeutic use. While there has been considerable interest in the development of fibrin sealant products, there has been considerably less interest in documenting the continuing use of thrombin as a therapeutic. The use of thrombin for topical hemostasis and the treatment of pseudoaneurysms will be discussed in detail. It is concluded that the use of thrombin as a drug will not only continue but also will significantly increase. However, the availability of a safe human thrombin preparation will be critical for the continued use of thrombin as a therapeutic. © 2004 Schattauer GmbH, Stuttgart.

Authors
Lundblad, RL; Bradshaw, RA; Gabriel, D; Ortel, TL; Lawson, J; Mann, KG
MLA Citation
Lundblad, RL, Bradshaw, RA, Gabriel, D, Ortel, TL, Lawson, J, and Mann, KG. "A review of the therapeutic uses of thrombin." Thrombosis and Haemostasis 92.REV. (2004): 143-152.
Source
scival
Published In
Thrombosis and haemostasis
Volume
92
Issue
REV.
Publish Date
2004
Start Page
143
End Page
152
DOI
10.1160/TH03-12-0792

Potassium homeostasis in patients receiving prophylactic dose enoxaparin therapy [10]

Authors
Potti, A; Danielson, B; Badreddine, R; Ortel, T
MLA Citation
Potti, A, Danielson, B, Badreddine, R, and Ortel, T. "Potassium homeostasis in patients receiving prophylactic dose enoxaparin therapy [10]." Journal of Thrombosis and Haemostasis 2.7 (2004): 1208-1209.
PMID
15219219
Source
scival
Published In
Journal of Thrombosis and Haemostasis
Volume
2
Issue
7
Publish Date
2004
Start Page
1208
End Page
1209
DOI
10.1111/j.1538-7836.2004.00791.x

Management of lepirudin therapy for a patient with antiphospholipid antibody syndrome using the whole blood ecarin clot time and activated partial thromboplastin time.

A patient with antiphospholipid antibody syndrome (APS) and a history of heparin-induced thrombocytopenia required lepirudin therapy. The patient had an abnormal baseline activated partial thromboplastin time (aPTT), complicating management of his therapy. We investigated whether an alternative monitoring system, using a dry reagent technology [Thrombolytic Assessment System (TAS)], could be used to monitor the patient's whole blood ecarin clot time (ECT) and aPTT. Baseline values for the ECT and aPTT were normal with this system. During a continuous infusion of lepirudin, the patient's whole blood ECT was maintained between a desired range of 150-200 s for 73% of the time. Similarly, his whole blood aPTT was maintained between 60 and 80 s for 80% of the time. In contrast, the patient's plasma-based aPTT by standard methods was consistently > 150 s. The patient underwent surgical procedures without complications. To further investigate the finding that the patient's antibody did not affect the aPTT with this system, we performed the ECT and the aPTT assays on the TAS Analyzer with plasma samples from 10 patients with APS and abnormal aPTTs. All 10 samples had plasma ECT values within the normal range. Four patients had normalization of the aPTT, suggesting that a subset of patients with APS may benefit from the TAS aPTT assay when monitoring heparin or other anticoagulation therapy.

Authors
Perry, SL; O'Shea, SI; Ortel, TL
MLA Citation
Perry, SL, O'Shea, SI, and Ortel, TL. "Management of lepirudin therapy for a patient with antiphospholipid antibody syndrome using the whole blood ecarin clot time and activated partial thromboplastin time." Blood Coagul Fibrinolysis 14.6 (September 2003): 601-604.
PMID
12960616
Source
pubmed
Published In
Blood Coagulation and Fibrinolysis
Volume
14
Issue
6
Publish Date
2003
Start Page
601
End Page
604
DOI
10.1097/01.mbc.0000061338.72909.23

Hypercoagulable states and antithrombotic strategies in recurrent vascular access site thrombosis.

Vascular access site thrombosis is a major cause of morbidity in patients receiving hemodialysis. The role of hypercoagulable states in recurrent vascular access site thrombosis remains poorly understood. Data are limited regarding systemic anticoagulation to improve access graft patency, because of concern about hemorrhagic complications. We determined the prevalence of hypercoagulable states and clinical outcome (thrombotic and hemorrhagic) after initiation of antithrombotic therapy in a series of patients with recurrent vascular access site thrombosis. We evaluated 31 patients who had sustained 119 thrombotic events that resulted in vascular access graft failure during the year before evaluation. Sixty-eight percent of patients tested had elevated concentrations of antibody to anticardiolipin or topical bovine thrombin, and 18% of patients tested had heparin-induced antibodies. More than 90% of patients had elevated factor VIII concentration, 62% had elevated fibrinogen concentrations, and 42% had elevated C-reactive protein concentrations. Twenty-nine patients were given antithrombotic therapy: 13 with warfarin sodium, 12 with unfractionated heparin (UFH), and 11 with low molecular weight heparin (LMWH). Seven patients received more than one antithrombotic agent, sequentially. Nineteen patients have had no thrombotic events since beginning antithrombotic therapy (10 with warfarin, 3 with UFH, 6 with LMWH). Mean follow-up was 8.6 months (median, 7 months). Eight patients sustained 10 bleeding complications (5 with warfarin, 3 with UFH, and 2 with LMWH). In conclusion, hypercoagulable states are common in patients with recurrent vascular access site thrombosis. Antithrombotic therapy may increase vascular access graft patency, but is associated with significant risk for hemorrhage. Prospective studies are needed to evaluate the role and safety of antithrombotic agents in improving vascular access graft patency.

Authors
O'shea, SI; Lawson, JH; Reddan, D; Murphy, M; Ortel, TL
MLA Citation
O'shea, SI, Lawson, JH, Reddan, D, Murphy, M, and Ortel, TL. "Hypercoagulable states and antithrombotic strategies in recurrent vascular access site thrombosis." J Vasc Surg 38.3 (September 2003): 541-548.
PMID
12947274
Source
pubmed
Published In
Journal of Vascular Surgery
Volume
38
Issue
3
Publish Date
2003
Start Page
541
End Page
548

Prothrombin and beta 2-glycoprotein I frequently contribute to antiphospholipid antibody interactions with phospholipids and the generation of abnormal waveform profiles in coagulation assays.

Transmittance waveforms are generated during clot formation on photo-optical coagulation analyzers. We previously showed that 61.5% of patients with antiphospholipid antibodies (APLA) exhibited a negative deflection in the pre-coagulation phase of the prothrombin time (PT slope 1). The current studies investigated the 'molecular basis' of this abnormal parameter. We found that the negative PT slope 1 is IgG-mediated and is not dependent on the presence of fibrinogen or thrombin activity. We also found that IgG from most of the patients required a specific thromboplastin and the presence of prothrombin or beta(2)-glycoprotein I beta(2) GPI) to produce an abnormal IgG wave-form assay. In addition, the abnormal IgG waveform required cofactor binding to phospholipids when beta(2) GPI was the cofactor, and annexin V could partially block this interaction. In conclusion, these results showed that the interactions of IgG with phospholipids via beta(2) GPI or prothrombin constitute the core mechanisms of the abnormal waveforms.

Authors
Su, Z; Izumi, T; Ortel, TL
MLA Citation
Su, Z, Izumi, T, and Ortel, TL. "Prothrombin and beta 2-glycoprotein I frequently contribute to antiphospholipid antibody interactions with phospholipids and the generation of abnormal waveform profiles in coagulation assays." Thromb Haemost 90.2 (August 2003): 218-226.
PMID
12888868
Source
pubmed
Published In
Thrombosis and haemostasis
Volume
90
Issue
2
Publish Date
2003
Start Page
218
End Page
226
DOI
10.1160/TH02-09-0052

Binding of factor VIII inhibitors to discrete regions of the factor VIII C2 domain disrupt phospholipid binding.

We characterized seven factor VIII inhibitors with epitopes in the C2 domain of factor VIII using a series of factor V C2 domain chimeras that substituted exon-sized fragments of the C2 domain of factor VIII for the corresponding regions of factor V. All inhibited co-factor activity of factor VIII and six inhibited binding of factor VIII to phosphatidylserine. Inhibitors Hz, JN and GK32 bound epitopes within amino acids S2173-K2281; inhibitors GK24 and TO bound epitopes within amino acids V2223-Y2332; and inhibitors UNC11 and UNC12 bound epitopes throughout the C2 domain (amino acids S2173-Y2332). Inhibitors Hz, JN and UNC12 inhibited the co-factor activity of chimera 5A, which substituted amino acids S2173-Q2222 of factor VIII for the corresponding region of factor V, in a prothrombinase assay. This inhibition could be partially reversed by pre-incubation of chimera 5A with phospholipid vesicles, suggesting that these antibodies interfered with phospholipid binding. Inhibitors UNC11 and UNC12, on the other hand, did not inhibit the binding of chimera 1 A to phosphatidylserine, suggesting that binding to the segment spanning amino acids V2282-Y2332 does not necessarily block phospholipid binding. These results agree with the model of the phospholipid-binding site determined by crystal structure of the C2 domain of factor VIII.

Authors
Lewis, DA; Moore, KD; Ortel, TL
MLA Citation
Lewis, DA, Moore, KD, and Ortel, TL. "Binding of factor VIII inhibitors to discrete regions of the factor VIII C2 domain disrupt phospholipid binding." Blood Coagul Fibrinolysis 14.4 (June 2003): 361-368.
PMID
12945878
Source
pubmed
Published In
Blood Coagulation and Fibrinolysis
Volume
14
Issue
4
Publish Date
2003
Start Page
361
End Page
368

Heparin-induced thrombocytopenia: clinical presentations and therapeutic management.

With increasing indications for heparin usage, an understanding of heparin-induced thrombocytopenia (HIT) as a complication of heparin therapy is more essential than ever. Complications of HIT can result in significant morbidity and mortality. We review the clinical presentations of HIT, laboratory and diagnostic workup, and treatment agents available or being evaluated.

Authors
Larned, ZL; O'Shea, SI; Ortel, TL
MLA Citation
Larned, ZL, O'Shea, SI, and Ortel, TL. "Heparin-induced thrombocytopenia: clinical presentations and therapeutic management." Clin Adv Hematol Oncol 1.6 (June 2003): 356-364. (Review)
PMID
16224435
Source
pubmed
Published In
Clinical advances in hematology & oncology : H&O
Volume
1
Issue
6
Publish Date
2003
Start Page
356
End Page
364

Blockade of tissue factor: treatment for organ injury in established sepsis.

Blockade of tissue factor before lethal sepsis prevents acute lung injury and renal failure in baboons, indicating that activation of coagulation by tissue factor is an early event in the pathogenesis of acute lung injury and organ dysfunction. We hypothesized that blockade of tissue factor would also attenuate these injuries in established sepsis by prevention of further fibrin deposition and inflammation. Twelve male baboons received heat-killed Escherichia coli intravenously followed 12 hours later by live E. coli infusion. Six animals were treated 2 hours after the live bacteria with site-inactivated Factor VIIa, a competitive tissue factor inhibitor, and six animals were vehicle-treated sepsis control subjects. Animals were ventilated and monitored for 48 hours. Physiologic and hematologic parameters were measured every 6 hours, and pathologic evaluation was performed after 48 hours. Animals treated with site inactivated Factor VIIa had less severe lung injury, with preserved gas exchange, better lung compliance and histology scores, and decreased lung wet/dry weight. In treated animals, urine output was higher, metabolic acidosis was attenuated, and renal tubular architecture was protected. Coagulopathy was attenuated, and plasma interleukin-6, interleukin-8, and soluble tumor necrosis factor receptor-1 levels were significantly lower in the treated animals. These results show that blockade of coagulation attenuates acute lung and renal injury in established Gram-negative sepsis accompanied by antiinflammatory effects of therapy.

Authors
Carraway, MS; Welty-Wolf, KE; Miller, DL; Ortel, TL; Idell, S; Ghio, AJ; Petersen, LC; Piantadosi, CA
MLA Citation
Carraway, MS, Welty-Wolf, KE, Miller, DL, Ortel, TL, Idell, S, Ghio, AJ, Petersen, LC, and Piantadosi, CA. "Blockade of tissue factor: treatment for organ injury in established sepsis." Am J Respir Crit Care Med 167.9 (May 1, 2003): 1200-1209.
PMID
12714343
Source
pubmed
Published In
American journal of respiratory and critical care medicine
Volume
167
Issue
9
Publish Date
2003
Start Page
1200
End Page
1209
DOI
10.1164/rccm.200204-287OC

Contributions of Asn2198, Met2199, and Phe2200 in the factor VIII C2 domain to cofactor activity, phospholipid-binding, and von Willebrand factor-binding.

The crystal structure of the factor VIII C2 domain consists of a beta-sandwich core from which beta-hairpins and loops extend to form a hydrophobic surface. The hydrophobic surface includes M2199 and F2200 at the tip of the 1(st) beta-hairpin. To determine the individual contributions of residues N2198, M2199, and F2200 to phospholipid and von Willebrand factor (vWF) binding properties of factor VIII, we prepared mutant proteins with single alanine substitutions. We found that single mutations at N2198 and M2199 had relatively little impact on cofactor activity, or phospholipid and vWF binding. However the F2200A mutant had slightly lower cofactor activity at subsaturating phospholipid concentrations. Competitive ELISAs suggested that F2200 plays a more important role in both phospholipid-binding and vWF-binding than N2198 and M2199. All mutant proteins were still recognized by a monoclonal antibody and two factor VIII inhibitors that neutralized cofactor activity and blocked factor VIII binding to phospholipids.

Authors
Lewis, DA; Pound, ML; Ortel, TL
MLA Citation
Lewis, DA, Pound, ML, and Ortel, TL. "Contributions of Asn2198, Met2199, and Phe2200 in the factor VIII C2 domain to cofactor activity, phospholipid-binding, and von Willebrand factor-binding." Thromb Haemost 89.5 (May 2003): 795-802.
PMID
12719775
Source
pubmed
Published In
Thrombosis and haemostasis
Volume
89
Issue
5
Publish Date
2003
Start Page
795
End Page
802

Clinical and laboratory evaluation of thrombophilia.

Thrombophilia is the predisposition to venous thromboembolism and is caused by inherited and acquired factors, alone or in combination. With the discovery of APC resistance and the prothrombin gene mutation, more than half of all patients with clinical characteristics of thrombophilia are now diagnosed with an inherited disorder. The hypercoagulable work-up of patients with venous thromboembolism is important, because the causes can influence the duration and management of anticoagulation therapy, as well as affect other decisions regarding life and health issues.

Authors
Perry, SL; Ortel, TL
MLA Citation
Perry, SL, and Ortel, TL. "Clinical and laboratory evaluation of thrombophilia." Clin Chest Med 24.1 (March 2003): 153-170. (Review)
PMID
12685062
Source
pubmed
Published In
Clinics in Chest Medicine
Volume
24
Issue
1
Publish Date
2003
Start Page
153
End Page
170

Alternative methods of anticoagulation for dialysis-dependent patients with heparin-induced thrombocytopenia.

Dialysis patients who are continually exposed to heparin are at risk for heparin-induced thrombocytopenia (HIT). Heparin-induced antibodies have been reported to occur in 0-12% of hemodialysis (HD) patients. The diagnosis or suspicion of HIT in this patient population requires careful confirmation of the diagnosis and substitution of heparin with an alternate anticoagulant for dialysis. Alternate agents such as the direct thrombin inhibitors (hirudin and argatroban) are available, but careful dosing and monitoring of the anticoagulant effect are required. Despite careful dosing, hemorrhagic complications have occurred with these agents. Unfortunately there are limited options for treatment of hemorrhagic complications and no specific antidotes are available for the direct thrombin inhibitors. In this report the currently available alternatives to heparin for dialysis, including dosing and monitoring recommendations, are reviewed.

Authors
O'Shea, SI; Ortel, TL; Kovalik, EC
MLA Citation
O'Shea, SI, Ortel, TL, and Kovalik, EC. "Alternative methods of anticoagulation for dialysis-dependent patients with heparin-induced thrombocytopenia." Semin Dial 16.1 (January 2003): 61-67. (Review)
PMID
12535303
Source
pubmed
Published In
Seminars in Dialysis
Volume
16
Issue
1
Publish Date
2003
Start Page
61
End Page
67

Anti-β2-glycoprotein I antibody-mediated inhibition of activated protein C requires binding of β2-glycoprotein I to phospholipids

To clarify the role(s) of anti-β 2 GPI antibodies on thrombosis in antiphospholipid antibody syndromes (APS), the effect of IgG from three patients on activated protein C (APC) was investigated using phospholipid vesicles and purified proteins. Two of the total IgG inhibited APC activity in the presence of β 2 GPI, whereas the third IgG did not. In addition, one IgG inhibited APC activity without β 2 GPI. Anti-β 2 GPI IgG from the two inhibitory IgG preparations inhibited APC activity only in the presence of β 2 GPI. Inhibition was suppressed partially by excess APC and almost completely by excess phospholipid vesicles. Cleaved β 2 GPI, a non-phospholipid-binding form, did not support inhibitory activity, even though the anti-β 2 GPI IgG bound to the cleaved molecule. This study confirms that anti-β 2 GPI antibodies from APS patients inhibit APC activity, and demonstrates the requirement of phospholipid binding of β 2 GPI for expression of the inhibitory activity of these antibodies.

Authors
Izumi, T; Pound, ML; Su, Z; Iverson, GM; Ortel, TL
MLA Citation
Izumi, T, Pound, ML, Su, Z, Iverson, GM, and Ortel, TL. "Anti-β2-glycoprotein I antibody-mediated inhibition of activated protein C requires binding of β2-glycoprotein I to phospholipids." Thrombosis and Haemostasis 88.4 (October 1, 2002): 620-626.
Source
scopus
Published In
Thrombosis and haemostasis
Volume
88
Issue
4
Publish Date
2002
Start Page
620
End Page
626

Anti-beta(2)-glycoprotein I antibody-mediated inhibition of activated protein C requires binding of beta(2)-glycoprotein I to phospholipids.

To clarify the role(s) of anti-beta(2) GPI antibodies on thrombosis in anti-phospholipid antibody syndromes (APS), the effect of IgG from three patients on activated protein C (APC) was investigated using phospholipid vesicles and purified proteins. Two of the total IgG inhibited APC activity in the presence of beta(2)GPI, whereas the third IgG did not. In addition, one IgG inhibited APC activity without beta(2)GPI. Anti-beta(2)GPI IgG from the two inhibitory IgG preparations inhibited APC activity only in the presence of beta(2)GPI. Inhibition was suppressed partially by excess APC and almost completely by excess phospholipid vesicles. Cleaved beta(2)GPI, a non-phospholipid-binding form, did not support inhibitory activity, even though the anti-beta(2)GPI IgG bound to the cleaved molecule. This study confirms that anti-beta(2)GPI antibodies from APS patients inhibit APC activity, and demonstrates the requirement of phospholipid binding of beta(2)GPI for expression of the inhibitory activity of these antibodies.

Authors
Izumi, T; Pound, ML; Su, Z; Iverson, GM; Ortel, TL
MLA Citation
Izumi, T, Pound, ML, Su, Z, Iverson, GM, and Ortel, TL. "Anti-beta(2)-glycoprotein I antibody-mediated inhibition of activated protein C requires binding of beta(2)-glycoprotein I to phospholipids." Thromb Haemost 88.4 (October 2002): 620-626.
PMID
12362233
Source
pubmed
Published In
Thrombosis and haemostasis
Volume
88
Issue
4
Publish Date
2002
Start Page
620
End Page
626

RNA aptamers as reversible antagonists of coagulation factor IXa.

Many therapeutic agents are associated with adverse effects in patients. Anticoagulants can engender acute complications such as significant bleeding that increases patient morbidity and mortality. Antidote control provides the safest means to regulate drug action. For this reason, despite its known limitations and toxicities, heparin use remains high because it is the only anticoagulant that can be controlled by an antidote, the polypeptide protamine. To date, no generalizable strategy for developing drug-antidote pairs has been described. We investigated whether drug-antidote pairs could be rationally designed by taking advantage of properties inherent to nucleic acids to make antidote-controlled anticoagulant agents. Here we show that protein-binding oligonucleotides (aptamers) against coagulation factor IXa are potent anticoagulants. We also show that oligonucleotides complementary to these aptamers can act as antidotes capable of efficiently reversing the activity of these new anticoagulants in plasma from healthy volunteers and from patients who cannot tolerate heparin. This generalizable strategy for rationally designing a drug-antidote pair thus opens up the way for developing safer regulatable therapeutics.

Authors
Rusconi, CP; Scardino, E; Layzer, J; Pitoc, GA; Ortel, TL; Monroe, D; Sullenger, BA
MLA Citation
Rusconi, CP, Scardino, E, Layzer, J, Pitoc, GA, Ortel, TL, Monroe, D, and Sullenger, BA. "RNA aptamers as reversible antagonists of coagulation factor IXa." Nature 419.6902 (September 5, 2002): 90-94.
PMID
12214238
Source
pubmed
Published In
Nature
Volume
419
Issue
6902
Publish Date
2002
Start Page
90
End Page
94
DOI
10.1038/nature00963

Antiphospholipid antibodies.

Authors
Moll, S; Ortel, TL
MLA Citation
Moll, S, and Ortel, TL. "Antiphospholipid antibodies." Arch Intern Med 162.15 (August 12, 2002): 1783-1784. (Letter)
PMID
12153392
Source
pubmed
Published In
Archives of internal medicine
Volume
162
Issue
15
Publish Date
2002
Start Page
1783
End Page
1784

Issues in the utilization of low molecular weight heparins.

Low molecular weight heparins (LMWHs) are parenteral anticoagulants that are widely used for the prevention and treatment of thromboembolic disease. These agents possess several advantages compared to standard heparin, including a more predictable anticoagulant response, better bioavailability allowing for subcutaneous therapy, and a longer half-life. Laboratory monitoring of the LMWHs uses an anti-factor Xa assay, but monitoring is generally not necessary for most patients. However, certain patient populations do benefit from an individualized approach to therapy and, in some cases, therapeutic monitoring, because of an increased bleeding risk and/or relative contraindications to anticoagulant therapy. For example, since LMWHs are cleared by the kidney, they must be used with caution in renal insufficiency. LMWHs are safe and effective during pregnancy but may not be the optimal antithrombotic agent in pregnant women with prosthetic valves. In addition, management around the time of delivery can be difficult because of the bleeding risk, particularly associated with epidural anesthesia. Therapeutic monitoring also may be useful for the morbidly obese, in children, and for patients with malignancy.

Authors
O'Shea, SI; Ortel, TL
MLA Citation
O'Shea, SI, and Ortel, TL. "Issues in the utilization of low molecular weight heparins." Semin Hematol 39.3 (July 2002): 172-178. (Review)
PMID
12124679
Source
pubmed
Published In
Seminars in Hematology
Volume
39
Issue
3
Publish Date
2002
Start Page
172
End Page
178

Coagulation and inflammation in acute lung injury.

The acute respiratory distress syndrome (ARDS) is a severe lung injury in patients with sepsis and other acute inflammatory insults, which is characterized by fibrin deposition in the pulmonary parenchyma, vasculature, and airspaces. Recent evidence suggests that progressive ARDS is closely linked to activation of inflammation and coagulation. Coagulation becomes activated by circulating endotoxin or bacteria, and a procoagulant state develops in the vascular and the alveolar compartments of the lung. This state is Tissue Factor (TF)-dependent and associated with increased elaboration of inflammatory cytokines. A similar procoagulant state is found in bronchoalveolar lavage of patients with ARDS, suggesting that extravascular coagulation contributes to lung inflammation. TF and other coagulation proteins, including Factor Xa, thrombin, and fibrin, also contribute to the pathogenesis of acute lung injury through multi-level interactions with inflammatory effectors, in which these proteins coordinately act as regulators of tissue injury responses. Each coagulation protein has direct and independent effects on inflammatory events that influences lung injury through changes in cytokine elaboration, inflammatory cell migration and activation, surfactant function, and repair mechanisms. New interventional strategies directed at procoagulant activity highlight the importance of the coagulation system to acute lung injury and suggest that blockade of initiation of coagulation may have therapeutic benefit in patients with ARDS.

Authors
Welty-Wolf, KE; Carraway, MS; Ortel, TL; Piantadosi, CA
MLA Citation
Welty-Wolf, KE, Carraway, MS, Ortel, TL, and Piantadosi, CA. "Coagulation and inflammation in acute lung injury." Thromb Haemost 88.1 (July 2002): 17-25. (Review)
PMID
12152667
Source
pubmed
Published In
Thrombosis and haemostasis
Volume
88
Issue
1
Publish Date
2002
Start Page
17
End Page
25

Antiphospholipid antibodies after surgical exposure to topical bovine thrombin.

Exposure to topical bovine thrombin during surgery frequently results in the development of antibodies to multiple protein and carbohydrate antigens. We investigated the frequency of increased levels of antibodies to cardiolipin and beta(2)-glycoprotein I (beta(2)-GPI) in two groups of patients, one exposed to bovine thrombin during cardiovascular surgery (n = 151) and a "control" group undergoing cardiovascular surgery but without exposure to bovine thrombin (n = 11). Anticardiolipin antibody levels were increased before surgery in 10 of the 151 patients exposed to topical thrombin (6.6%). Four to 8 weeks after surgery, 84 patients (55.6%) had increased anticardiolipin antibody levels (P <.0001). In the control group, an increased anticardiolipin antibody level was present in a single patient before and after surgery (9%). Increased levels of antibodies to bovine and human beta(2)-GPI were also observed after surgery in the patients exposed to topical thrombin (37.7% and 38.2%, respectively). Increased anticardiolipin levels correlated with higher levels of antibody to bovine, but not human, beta(2)-GPI. In addition, increased levels of anticardiolipin antibody were associated with higher levels of antibodies to bovine factor V and prothrombin, as well as human factor V. Antibody binding on an enzyme-linked immunosorbent assay conducted to detect anticardiolipin antibody was dependent on the presence of anionic phospholipid, indicating that binding was not linked to the fetal bovine serum in the blocking buffer alone. Seven of 8 patients with delayed thromboembolic complications had increased anticardiolipin IgG antibody levels after surgery, but this association was not statistically significant. Nevertheless, our findings support the recommendation that the clinical safety of these commonly used hemostatic agents should be reassessed.

Authors
Su, Z; Izumi, T; Thames, EH; Lawson, JH; Ortel, TL
MLA Citation
Su, Z, Izumi, T, Thames, EH, Lawson, JH, and Ortel, TL. "Antiphospholipid antibodies after surgical exposure to topical bovine thrombin." J Lab Clin Med 139.6 (June 2002): 349-356.
PMID
12066133
Source
pubmed
Published In
Journal of Laboratory and Clinical Medicine
Volume
139
Issue
6
Publish Date
2002
Start Page
349
End Page
356

Two classes of germline genes both derived from the V(H)1 family direct the formation of human antibodies that recognize distinct antigenic sites in the C2 domain of factor VIII.

Most plasmas from patients with inhibitors contain antibodies that are reactive with the C2 domain of factor VIII. Previously, we have shown that the variable heavy chain (V(H)) regions of antibodies to the C2 domain are encoded by the closely related germline gene segments DP-10, DP-14, and DP-88, which all belong to the V(H)1 gene family. Here, we report on the isolation and characterization of additional anti-C2 antibodies that are derived from V(H) gene segments DP-88 and DP-5. Competition experiments using murine monoclonal antibodies CLB-CAg 117 and ESH4 demonstrated that antibodies derived from DP-5 and DP-88 bound to different sites within the C2 domain. Epitope mapping studies using a series of factor VIII/factor V hybrids revealed that residues 2223 to 2332 of factor VIII are required for binding of the DP-10-, DP-14-, and DP-88-encoded antibodies. In contrast, binding of the DP-5-encoded antibodies required residues in both the amino- and carboxy-terminus of the C2 domain. Inspection of the reactivity of the antibodies with a series of human/porcine hybrids yielded similar data. Binding of antibodies derived from germline gene segments DP-10, DP-14, and DP-88 was unaffected by replacement of residues 2181 to 2243 of human factor VIII for the porcine sequence, whereas binding of the DP-5-encoded antibodies was abrogated by this replacement. Together these data indicate that antibodies assembled from V(H) gene segments DP-5 and the closely related germline gene segments DP-10, DP-14, and DP-88 target 2 distinct antigenic sites in the C2 domain of factor VIII.

Authors
van den Brink, EN; Bril, WS; Turenhout, EAM; Zuurveld, M; Bovenschen, N; Peters, M; Yee, TT; Mertens, K; Lewis, DA; Ortel, TL; Lollar, P; Scandella, D; Voorberg, J
MLA Citation
van den Brink, EN, Bril, WS, Turenhout, EAM, Zuurveld, M, Bovenschen, N, Peters, M, Yee, TT, Mertens, K, Lewis, DA, Ortel, TL, Lollar, P, Scandella, D, and Voorberg, J. "Two classes of germline genes both derived from the V(H)1 family direct the formation of human antibodies that recognize distinct antigenic sites in the C2 domain of factor VIII." Blood 99.8 (April 15, 2002): 2828-2834.
PMID
11929772
Source
pubmed
Published In
Blood
Volume
99
Issue
8
Publish Date
2002
Start Page
2828
End Page
2834

Abnormal optical waveform profiles in coagulation assays from patients with antiphospholipid antibodies.

Transmittance waveforms are the optical data generated during clot formation on photo-optical coagulation analyzers and are used to define specific events of the clotting reactions. Thus, a prothrombin time (PT) or an activated partial thromboplastin time (aPTT) can be divided into a pre-coagulation phase, a coagulation phase, and a post-coagulation phase. These phases are further characterized by parameters that define the timing, the rate, the 'slope', and the magnitude of the signal change of the reactions. We investigated the transmittance waveform parameters obtained during PT and aPTT of patients with antiphospholipid antibodies (APLA) who were or were not taking warfarin, normal donors, and non-APLA patients taking warfarin. An abnormal deflection in the pre-coagulation phase of the PT (called slope 1) was observed in 61.5% of the patients with APLA, in contrast to 5.9% of non-APLA patients taking warfarin (P= 0.0015). The presence of an abnormal PT slope 1 was reagent specific and was inversely correlated with the anticardiolipin antibody immunoglobulin G (IgG) level, which suggests that the abnormal PT slope 1 may reflect interactions between patient IgG and components from the thromboplastin, possibly phospholipids. The abnormal PT slope 1 values may be of diagnostic utility in the identification of patients with antiphospholipid syndromes.

Authors
Su, Z; Braun, PJ; Klemp, KF; Baker, KR; Thames, EH; Ortel, TL
MLA Citation
Su, Z, Braun, PJ, Klemp, KF, Baker, KR, Thames, EH, and Ortel, TL. "Abnormal optical waveform profiles in coagulation assays from patients with antiphospholipid antibodies." Blood Coagul Fibrinolysis 13.1 (January 2002): 7-17.
PMID
11994562
Source
pubmed
Published In
Blood Coagulation and Fibrinolysis
Volume
13
Issue
1
Publish Date
2002
Start Page
7
End Page
17

Frequency of anti-heparin-platelet factor 4 antibodies in hemodialysis patients and correlation with recurrent vascular access thrombosis.

Heparin-induced thrombocytopenia (HIT), characterized by the formation of antibodies to a complex of platelet factor 4 (PF4) and heparin, is a well-recognized risk factor for thromboembolic complications. The frequency of antibody development varies among patient populations. Hemodialysis patients have repeated heparin exposure and should be at risk of developing HIT. This might, contribute to the development of vascular access thrombosis. We prospectively evaluated 88 hemodialysis patients for the presence of anti-PF4/heparin antibodies. Eighteen patients (20%) had a prior history of 1 or more prior access thrombosis. One patient (1.14%), without a history of graft thrombosis, tested positive for anti-PF4/heparin antibodies. In our study, the presence of anti-PF4/heparin antibodies was rare and was not increased in patients with a history of vascular access thrombosis.

Authors
O'Shea, SI; Sands, JJ; Nudo, SA; Ortel, TL
MLA Citation
O'Shea, SI, Sands, JJ, Nudo, SA, and Ortel, TL. "Frequency of anti-heparin-platelet factor 4 antibodies in hemodialysis patients and correlation with recurrent vascular access thrombosis." Am J Hematol 69.1 (January 2002): 72-73.
PMID
11835336
Source
pubmed
Published In
American Journal of Hematology
Volume
69
Issue
1
Publish Date
2002
Start Page
72
End Page
73

Anti-β2-glycoprotein I antibody-mediated inhibition of activated protein C requires binding of β2-glycoprotein I to phospholipids

To clarify the role(s) of anti-β2GPI antibodies on thrombosis in antiphospholipid antibody syndromes (APS), the effect of IgG from three patients on activated protein C (APC) was investigated using phospholipid vesicles and purified proteins. Two of the total IgG inhibited APC activity in the presence of β2GPI, whereas the third IgG did not. In addition, one IgG inhibited APC activity without β2GPI. Anti-β2GPI IgG from the two inhibitory IgG preparations inhibited APC activity only in the presence of β2GPI. Inhibition was suppressed partially by excess APC and almost completely by excess phospholipid vesicles. Cleaved β2GPI, a non-phospholipid-binding form, did not support inhibitory activity, even though the anti-β2GPI IgG bound to the cleaved molecule. This study confirms that anti-β2GPI antibodies from APS patients inhibit APC activity, and demonstrates the requirement of phospholipid binding of β2GPI for expression of the inhibitory activity of these antibodies.

Authors
Izumi, T; Pound, ML; Su, Z; Iverson, GM; Ortel, TL
MLA Citation
Izumi, T, Pound, ML, Su, Z, Iverson, GM, and Ortel, TL. "Anti-β2-glycoprotein I antibody-mediated inhibition of activated protein C requires binding of β2-glycoprotein I to phospholipids." Thrombosis and Haemostasis 88.4 (2002): 620-626.
Source
scival
Published In
Thrombosis and Haemostasis
Volume
88
Issue
4
Publish Date
2002
Start Page
620
End Page
626

Mutation of bcl-x gene in non-Hodgkin's lymphoma

The bcl-x gene product has two forms, bcl-xl and bcl-xs. The bcl-xl form, similar to bcl-2, inhibits apoptosis. Reverse transcriptase-polymerase chain reaction-single-stranded conformation polymorphism (RT-PCR-SSCP) gel analysis was used to screen for mutations of the bcl-xl transcript of 50 non-Hodgkin's lymphoma (NHL) cases. One missense mutation in a patient with diffuse large B-cell lymphoma was found. Sequence analysis of this case showed that AGC (Ser) was mutated to GGC (Gly) in codon 154. An examination of mutation and/or polymorphism in born marrow samples of this case and 50 normal controls by the RT-PCR-SSCP method could not detect bandshifts. Mutation of the bcl-x gene in NHL has not been reported previously. There is a possibility that mutation of the bcl-x gene play a role in the tumorigenesis of NHL. © 2002 Wiley-Liss, Inc.

Authors
O'Shea, SI; Sands, JJ; Nudo, SA; Ortel, TL
MLA Citation
O'Shea, SI, Sands, JJ, Nudo, SA, and Ortel, TL. "Mutation of bcl-x gene in non-Hodgkin's lymphoma." American Journal of Hematology 69.1 (2002): 74-76.
PMID
11835337
Source
scival
Published In
American Journal of Hematology
Volume
69
Issue
1
Publish Date
2002
Start Page
74
End Page
76
DOI
10.1002/ajh.10030

Coagulation blockade prevents sepsis-induced respiratory and renal failure in baboons.

Sepsis-induced tissue factor (TF) expression activates coagulation in the lung and leads to a procoagulant environment, which results in fibrin deposition and potentiates inflammation. We hypothesized that preventing initiation of coagulation at TF-Factor VIIa (FVIIa) complex would block fibrin deposition and control inflammation in sepsis, thereby limiting acute lung injury (ALI) and other organ damage in baboons. A model of ALI was used in which adult baboons were primed with killed Escherichia coli (1 x 10(9) CFU/kg), and bacteremic sepsis was induced 12 h later by infusion of live E. coli at 1 x 10(10) CFU/kg. Animals in the treatment group were given a competitive inhibitor of TF, site-inactivated FVIIa (FVIIai), intravenously at the time of the infusion of live bacteria and monitored physiologically for another 36 h. FVIIai dramatically protected gas exchange and lung compliance, prevented lung edema and pulmonary hypertension, and preserved renal function relative to vehicle (all p < 0.05). Treatment attenuated sepsis-induced fibrinogen depletion (p < 0.01) and decreased systemic proinflammatory cytokine responses, for example, interleukin 6 (p < 0.01). The protective effects of TF blockade in sepsis-induced ALI were confirmed by using tissue factor pathway inhibitor. The results show that TF-FVIIa complex contributes to organ injury in septic primates in part through selective stimulation of proinflammatory cytokine release and fibrin deposition.

Authors
Welty-Wolf, KE; Carraway, MS; Miller, DL; Ortel, TL; Ezban, M; Ghio, AJ; Idell, S; Piantadosi, CA
MLA Citation
Welty-Wolf, KE, Carraway, MS, Miller, DL, Ortel, TL, Ezban, M, Ghio, AJ, Idell, S, and Piantadosi, CA. "Coagulation blockade prevents sepsis-induced respiratory and renal failure in baboons." Am J Respir Crit Care Med 164.10 Pt 1 (November 15, 2001): 1988-1996.
PMID
11734456
Source
pubmed
Published In
American journal of respiratory and critical care medicine
Volume
164
Issue
10 Pt 1
Publish Date
2001
Start Page
1988
End Page
1996
DOI
10.1164/ajrccm.164.10.2105027

Exposure of mice to topical bovine thrombin induces systemic autoimmunity.

Bovine thrombin is used as an aid to hemostasis in medical and surgical procedures. At least 500,000 Americans are exposed to this therapeutic annually and reports suggest that exposure is associated with the development of autoreactive antibodies. To determine whether bovine thrombin can induce pathological autoimmunity we exposed nonautoimmune-prone galactose-alpha1-3-galactose-deficient mice to the two bovine thrombin preparations currently approved for use in the United States. We found that, like humans exposed to bovine thrombin, mice developed an immune response against the therapeutic and the xenogeneic carbohydrate galactose-alpha1-3-galactose, and some mice developed autoantibodies against clotting factors. Further, unexpectedly, a single exposure to this therapeutic also induced autoimmunity with features characteristic of systemic lupus erythematosus including antibodies against nuclear antigens, native DNA, double-stranded DNA, and cardiolipin. High levels of these autoantibodies correlated with glomerulonephritis in all mice evaluated. This autoimmune syndrome was detected in mice 15 weeks after a secondary exposure to bovine thrombin and female mice were found to develop the syndrome at a significantly greater frequency than males. Thus, these studies indicate that exposure to bovine thrombin preparations can induce a pathological systemic autoimmune syndrome with lupus-like serology.

Authors
Schoenecker, JG; Johnson, RK; Lesher, AP; Day, JD; Love, SD; Hoffman, MR; Ortel, TL; Parker, W; Lawson, JH
MLA Citation
Schoenecker, JG, Johnson, RK, Lesher, AP, Day, JD, Love, SD, Hoffman, MR, Ortel, TL, Parker, W, and Lawson, JH. "Exposure of mice to topical bovine thrombin induces systemic autoimmunity." Am J Pathol 159.5 (November 2001): 1957-1969.
PMID
11696457
Source
pubmed
Published In
The American journal of pathology
Volume
159
Issue
5
Publish Date
2001
Start Page
1957
End Page
1969
DOI
10.1016/S0002-9440(10)63043-X

Tissue factor in experimental acute lung injury.

Acute lung injury (ALI) is characterized by fibrin deposition in the tissue and vascular spaces. Coagulation is activated after exposure to endotoxin or bacteria, and a procoagulant environment rapidly develops in the vascular, interstitial, and alveolar spaces of the lung. These changes are tissue factor (TF)-dependent and associated with increases in inflammatory cytokines. Procoagulant changes also occur in the lungs of patients with the acute respiratory distress syndrome (ARDS), suggesting that epithelial inflammation activates the extrinsic pathway. Many inflammatory mediators have specific effects on coagulation; however, the role of TF in regulation of pulmonary inflammatory responses is less clear. Here we report initial data on blockade of TF-initiated coagulation in baboons with Escherichia coli sepsis-induced ALI, using active site-inactivated FVIIa (FVIIai ASIS). Treatment with FVIIai prevented plasma fibrinogen depletion and attenuated fibrin deposition in the tissues. The drug also decreased systemic cytokine responses and inflammatory changes in the lung, including neutrophil infiltration, and decreased edema. Coagulation blockade with FVIIai improved lung function by preserving gas exchange and compliance, decreased pulmonary hypertension, and enhanced renal function. These results show that TF-FVIIa complex is an important regulatory site for the pathologic response of the lung to sepsis.

Authors
Welty-Wolf, KE; Carraway, MS; Idell, S; Ortel, TL; Ezban, M; Piantadosi, CA
MLA Citation
Welty-Wolf, KE, Carraway, MS, Idell, S, Ortel, TL, Ezban, M, and Piantadosi, CA. "Tissue factor in experimental acute lung injury." Semin Hematol 38.4 Suppl 12 (October 2001): 35-38. (Review)
PMID
11735108
Source
pubmed
Published In
Seminars in Hematology
Volume
38
Issue
4 Suppl 12
Publish Date
2001
Start Page
35
End Page
38

Risk factors associated with thrombosis in patients with antiphospholipid antibodies.

OBJECTIVE: To define risk factors associated with thrombosis in patients with antiphospholipid antibodies (aPL). METHODS: Ninety-nine patients with aPL, most of whom had prior thrombosis, were evaluated for the presence of acquired and inherited thrombophilic states. Genomic testing was performed for factor V(R506Q), 3' prothrombin (PTG) and methylene tetrahydrofolate reductase (MTHFR) polymorphisms. Clinical records were reviewed for the presence of acquired risk factors (RF) for thrombosis and events associated with aPL. Univariate statistical analysis was performed using Fisher's exact testing. A neural network statistical model was also used to identify which thrombophilic risk factors were most important in development of arterial and venous thrombosis. RESULTS: For arterial thrombosis, hypertension, tobacco use, hyperlipidemia, and diabetes mellitus were the most important predictors of thrombosis. By contrast, tobacco use, the 3' PTG and factor V(R506Q) polymorphisms, and previous cardiac surgery were the most important predictors of venous thrombosis. CONCLUSION: In this hypothesis-generating retrospective study, acquired risk factors were most important in arterial thrombosis, while the presence of factor V(R506Q) and 3' PTG polymorphisms were more important in the development of venous thrombosis. These findings are being validated in an ongoing, prospective study.

Authors
Hansen, KE; Kong, DF; Moore, KD; Ortel, TL
MLA Citation
Hansen, KE, Kong, DF, Moore, KD, and Ortel, TL. "Risk factors associated with thrombosis in patients with antiphospholipid antibodies." J Rheumatol 28.9 (September 2001): 2018-2024.
PMID
11550969
Source
pubmed
Published In
The Journal of rheumatology
Volume
28
Issue
9
Publish Date
2001
Start Page
2018
End Page
2024

Antibodies to prothrombin, factor V, and beta2-glycoprotein I and vascular access thrombosis.

We studied 88 hemodialysis patients for the presence of antibodies to human factor II (hFII), bovine factor V (bFV), and human beta2-glycoprotein 1 (beta2GPI). Forty-one patients had elevated anti-hFII antibodies, 17 had elevated anti-bFV antibodies, and 9 had elevated anti-beta2GPI antibodies. Fifty-two patients had elevated antibodies to one or more protein. Patients with PTFE grafts had elevated antibodies most frequently (21 [75%] vs. 20 fistulas [45%; p = 0.016 compared with PTFE] and 11 tunneled catheters [68.8%]). Twelve of 13 patients (92.3%) with PTFE grafts and thrombosis had elevated antibody levels, compared with 9 of 15 without thrombosis (60%; p = 0.049). The number of thromboses and mean thrombosis rates were significantly higher in PTFE patients with antibodies (1.24 vs. 0.14 thromboses, p < 0.01; 42.67 vs. 6.44 thromboses/100 patient years, p < 0.05). When analyzed individually, thrombotic complications occurred more frequently in patients with PTFE grafts and elevated anti-bFV antibodies (p = 0.016), but did not correlate with anti-hFII or anti-beta2GPI antibodies. Thrombotic complications did not correlate with elevated antibody levels in patients with AV fistulas or cuffed catheters. In conclusion, hemodialysis patients with PTFE grafts frequently have elevated antibodies to FII, FV, and beta2GPI, and the presence of elevated antibody levels to one or more of these proteins is associated with an increased thrombotic risk. Further studies are necessary to determine whether limiting exposure to bovine thrombin preparations will decrease the incidence of these antibodies and PTFE graft thrombosis.

Authors
Sands, JJ; Nudo, SA; Moore, KD; Ortel, TL
MLA Citation
Sands, JJ, Nudo, SA, Moore, KD, and Ortel, TL. "Antibodies to prothrombin, factor V, and beta2-glycoprotein I and vascular access thrombosis." ASAIO J 47.5 (September 2001): 507-510.
PMID
11575827
Source
pubmed
Published In
ASAIO Journal
Volume
47
Issue
5
Publish Date
2001
Start Page
507
End Page
510

Beta2-glycoprotein I-dependent anticardiolipin antibodies preferentially bind the amino terminal domain of beta2-glycoprotein I.

Many of the autoantibodies in antiphospholipid syndrome (APS) are directed against beta2-glycoprotein I (beta2-GPI). Recent studies from our laboratories have indicated that the immunodominant binding epitope(s) for high titer, affinity purified antibodies from 11 APS patients are localized to the amino terminal domain (domain 1) of beta2-GPI. The present study employed surface plasmon resonance to localize the immunodominant domain in serum samples from a large cohort of patients with GPL values ranging from 21 to 230 units (n = 106 patients). Eighty-eight percent of patients showed > or = threefold selectivity for beta2-GPI containing domain 1 relative to the domain deletion mutant that lacked domain 1. The domain 1 binding activity in patient serum was abolished by removing the IgG fraction from the serum and the binding activity could be fully reconstituted with the IgG fraction. Thus, analysis of serum samples from a large cohort of APS patients indicates that the immunodominant binding epitope(s) for anti-beta2 antibodies are localized to the amino terminal domain of beta2-GPI.

Authors
McNeeley, PA; Dlott, JS; Furie, RA; Jack, RM; Ortel, TL; Triplett, DA; Victoria, EJ; Linnik, MD
MLA Citation
McNeeley, PA, Dlott, JS, Furie, RA, Jack, RM, Ortel, TL, Triplett, DA, Victoria, EJ, and Linnik, MD. "Beta2-glycoprotein I-dependent anticardiolipin antibodies preferentially bind the amino terminal domain of beta2-glycoprotein I." Thromb Haemost 86.2 (August 2001): 590-595.
PMID
11522008
Source
pubmed
Published In
Thrombosis and haemostasis
Volume
86
Issue
2
Publish Date
2001
Start Page
590
End Page
595

Fine mapping of inhibitory anti-factor V antibodies using factor V C2 domain mutants. Identification of two antigenic epitopes involved in phospholipid binding.

Hemorrhagic factor V inhibitors frequently bind to the second C-type (C2) domain of factor V and interfere with phospholipid binding. To define specific residues recognized by inhibitors from four patients (one bovine thrombin-induced and three spontaneous antibodies), epitope mapping was performed using recombinant human factor V lacking most of the B-type domain (FV des B) and alanine-substituted mutants within the C2 domain (FV des B C2 mutants). FV des B C2 mutants located in the region between Lys2060 and Glu2069 were resistant to inhibition by three IgG preparations including the bovine thrombin-induced antibody in both prothrombinase and phospholipid-binding assays. In contrast, mutations at Lys2087 and Lys2092/Glu2096 were significantly resistant to inhibition by the fourth IgG preparation in both prothrombinase and phospholipid-binding assays. These results confirm interference of phospholipid binding by hemorrhagic factor V inhibitors and support the role(s) of these residues in phospholipid binding.

Authors
Izumi, T; Kim, SW; Greist, A; Macedo-Ribeiro, S; Fuentes-Prior, P; Bode, W; Kane, WH; Ortel, TL
MLA Citation
Izumi, T, Kim, SW, Greist, A, Macedo-Ribeiro, S, Fuentes-Prior, P, Bode, W, Kane, WH, and Ortel, TL. "Fine mapping of inhibitory anti-factor V antibodies using factor V C2 domain mutants. Identification of two antigenic epitopes involved in phospholipid binding." Thromb Haemost 85.6 (June 2001): 1048-1054.
PMID
11434683
Source
pubmed
Published In
Thrombosis and haemostasis
Volume
85
Issue
6
Publish Date
2001
Start Page
1048
End Page
1054

Factor VIII Arg2304 --> His binds to phosphatidylserine and is a functional cofactor in the factor X-ase complex.

Four factor VIII light chain constructs containing hemophilia A mutations at R2304 and R2307 were prepared and expressed in mammalian cells. These mutations are located in a putative phosphatidylserine binding site identified by peptide studies (spanning amino acids 2303-2332). The levels of all four mutants in conditioned medium were significantly less than wild type by immunoprecipitation and ELISA. R2304H and wild type factor VIII light chains were concentrated by cation exchange chromatography from medium. R2304H and wild type factor VIII light chains bound immobilized phosphatidylserine similarly. The reconstituted cofactor activity of R2304H factor VIII light chain was slightly greater than wild type factor VIII light chain. These results are consistent with the recently reported crystal structure of factor VIII C2 domain that suggests R2304H is not directly involved in phospholipid binding. The observed clinical phenotype is probably due to decreased circulating levels of a functional protein.

Authors
Lewis, DA; Moore, KD; Ortel, TL
MLA Citation
Lewis, DA, Moore, KD, and Ortel, TL. "Factor VIII Arg2304 --> His binds to phosphatidylserine and is a functional cofactor in the factor X-ase complex." Thromb Haemost 85.2 (February 2001): 260-264.
PMID
11246544
Source
pubmed
Published In
Thrombosis and haemostasis
Volume
85
Issue
2
Publish Date
2001
Start Page
260
End Page
264

β2-Glycoprotein I-dependent anticardiolipin antibodies preferentially bind the amino terminal domain of β2-glycoprotein I

Many of the autoantibodies in antiphospholipid syndrome (APS) are directed against β 2 -glycoprotein I (β 2 -GPI). Recent studies from our laboratories have indicated that the immunodominant binding epitope(s) for high titer, affinity purified antibodies from 11 APS patients are localized to the amino terminal domain (domain 1) of β 2 -GPI. The present study employed surface plasmon resonance to localize the immunodominant domain in serum samples from a large cohort of patients with GPL values ranging from 21 to 230 units (n = 106 patients). Eighty-eight percent of patients showed ≥ threefold selectivity for β 2 -GPI containing domain 1 relative to the domain deletion mutant that lacked domain 1. The domain 1 binding activity in patient serum was abolished by removing the IgG fraction from the serum and the binding activity could be fully reconstituted with the IgG fraction. Thus, analysis of serum samples from a large cohort of APS patients indicates that the immunodominant binding epitope(s) for anti-β 2 antibodies are localized to the amino terminal domain of β 2 -GPI.

Authors
McNeeley, PA; Dlott, JS; Furie, RA; Jack, RM; Ortel, TL; Triplett, DA; Victoria, EJ; Linnik, MD
MLA Citation
McNeeley, PA, Dlott, JS, Furie, RA, Jack, RM, Ortel, TL, Triplett, DA, Victoria, EJ, and Linnik, MD. 2-Glycoprotein I-dependent anticardiolipin antibodies preferentially bind the amino terminal domain of β2-glycoprotein I." Thrombosis and Haemostasis 86.2 (January 1, 2001): 590-595.
Source
scopus
Published In
Thrombosis and haemostasis
Volume
86
Issue
2
Publish Date
2001
Start Page
590
End Page
595

Immunologic impact and clinical outcomes after surgical exposure to bovine thrombin.

OBJECTIVE: To determine prospectively the immunologic response and adverse clinical events in surgical patients exposed to bovine thrombin during cardiac surgical procedures. SUMMARY BACKGROUND DATA: Topical bovine thrombin is used extensively as a hemostatic agent during cardiovascular surgery. Antibodies developing after exposure to bovine thrombin have been anecdotally associated with hemorrhagic complications. METHODS: One hundred fifty-one patients undergoing cardiac surgical procedures were prospectively recruited for this study before surgical exposure with topical bovine thrombin. Immunoassays were used to determine antibody levels against both bovine and human coagulation proteins before and after exposure to bovine thrombin. Alterations in coagulation assay parameters and adverse clinical events were followed in all patients enrolled in the study. RESULTS: Baseline elevated antibody levels to one or more bovine coagulation proteins were observed most frequently in patients with a prior history of a surgical procedure during which bovine thrombin is frequently used. More than 95% of patients developed a seropositive response to bovine coagulation proteins, and 51% manifested elevated antibody levels to the corresponding human coagulation proteins after bovine thrombin exposure. Postoperative coagulation abnormalities were more common in patients with antibodies to human coagulation proteins. Patients with multiple elevated antibody levels to bovine proteins before surgery were more likely to sustain an adverse clinical outcome after surgery. Using a logistic regression model, the adjusted odds ratio for sustaining an adverse event with multiple elevated antibody levels to bovine proteins before surgery was 5.40. CONCLUSIONS: Bovine thrombin preparations are highly immunogenic and appear to be associated with an increased risk for adverse clinical outcomes during subsequent surgical procedures. The clinical safety of these commonly used preparations needs to be reassessed, and reexposure to these agents should likely be avoided.

Authors
Ortel, TL; Mercer, MC; Thames, EH; Moore, KD; Lawson, JH
MLA Citation
Ortel, TL, Mercer, MC, Thames, EH, Moore, KD, and Lawson, JH. "Immunologic impact and clinical outcomes after surgical exposure to bovine thrombin." Ann Surg 233.1 (January 2001): 88-96.
PMID
11141230
Source
pubmed
Published In
Annals of Surgery
Volume
233
Issue
1
Publish Date
2001
Start Page
88
End Page
96

Anticoagulation therapy.

Despite refinements and standardization in the use of anticoagulants, many problems remain for clinicians. Dr. Crowther describes appropriate starting and maintenance doses of warfarin, factors accounting for inter- and intra-observer variability and importantly, the management of the over-anticoagulated patients and bleeding patients. Dr. White compares unfractionated heparin (UFH) and low molecular weight heparin (LMWH) and addresses whether there truly are differences in the efficacy and safety of different LMWH's for both arterial and venous indications. Dr. Ortel discusses the management of the problem patient who requires anticoagulants, the management of heparin-induced thrombocytopenia, the pregnant patient, the obese patient, patients who have renal insufficiency and/or liver disease, patients with malignant disease, and other challenging patient populations.

Authors
Ginsberg, JA; Crowther, MA; White, RH; Ortel, TL
MLA Citation
Ginsberg, JA, Crowther, MA, White, RH, and Ortel, TL. "Anticoagulation therapy." Hematology Am Soc Hematol Educ Program (2001): 339-357. (Review)
PMID
11722992
Source
pubmed
Published In
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program
Publish Date
2001
Start Page
339
End Page
357

Coagulation blockade prevents sepsis-induced respiratory and renal failure in baboons

Sepsis-induced tissue factor (TF) expression activates coagulation in the lung and leads to a procoagulant environment, which results in fibrin deposition and potentiates inflammation. We hypothesized that preventing initiation of coagulation at TF-Factor VIIa (FVIIa) complex would block fibrin deposition and control inflammation in sepsis, thereby limiting acute lung injury (ALI) and other organ damage in baboons. A model of ALI was used in which adult baboons were primed with killed Escherichia coli (1 × 109 CFU/kg), and bacteremic sepsis was induced 12 h later by infusion of live E. coli at 1 × 1010 CFU/kg. Animals in the treatment group were given a competitive inhibitor of TF, site-inactivated FVIIa (FVIIai), intravenously at the time of the infusion of live bacteria and monitored physiologically for another 36 h. FVIIai dramatically protected gas exchange and lung compliance, prevented lung edema and pulmonary hypertension, and preserved renal function relative to vehicle (all p < 0.05). Treatment attenuated sepsis-induced fibrinogen depletion (p < 0.01) and decreased systemic proinflammatory cytokine responses, for example, interleukin 6 (p < 0.01). The protective effects of TF blockade in sepsis-induced ALI were confirmed by using tissue factor pathway inhibitor. The results show that TF-FVIIa complex contributes to organ injury in septic primates in part through selective stimulation of proinflammatory cytokine release and fibrin deposition.

Authors
Welty-Wolf, KE; Carraway, MS; Miller, DL; Ortel, TL; Ezban, M; Ghio, AJ; Idell, S; Piantadosi, CA
MLA Citation
Welty-Wolf, KE, Carraway, MS, Miller, DL, Ortel, TL, Ezban, M, Ghio, AJ, Idell, S, and Piantadosi, CA. "Coagulation blockade prevents sepsis-induced respiratory and renal failure in baboons." American Journal of Respiratory and Critical Care Medicine 164.10 I (2001): 1988-1996.
Source
scival
Published In
American journal of respiratory and critical care medicine
Volume
164
Issue
10 I
Publish Date
2001
Start Page
1988
End Page
1996

Tissue factor in experimental acute lung injury

Acute lung injury (ALI) is characterized by fibrin deposition in the tissue and vascular spaces. Coagulation is activated after exposure to endotoxin or bacteria, and a procoagulant environment rapidly develops in the vascular, interstitial, and alveolar spaces of the lung. These changes are tissue factor (TF)-dependent and associated with increases in inflammatory cytokines. Procoagulant changes also occur in the lungs of patients with the acute respiratory distress syndrome (ARDS), suggesting that epithelial inflammation activates the extrinsic pathway. Many inflammatory mediators have specific effects on coagulation; however, the role of TF in regulation of pulmonary inflammatory responses is less clear. Here we report initial data on blockade of TF-initiated coagulation in baboons with Escherichia coli sepsis-induced ALI, using active site-inactivated FVIIa (FVIIai ASIS). Treatment with FVIIai prevented plasma fibrinogen depletion and attenuated fibrin deposition in the tissues. The drug also decreased systemic cytokine responses and inflammatory changes in the lung, including neutrophil infiltration, and decreased edema. Coagulation blockade with FVIIai improved lung function by preserving gas exchange and compliance, decreased pulmonary hypertension, and enhanced renal function. These results show that TF-FVIIa complex is an important regulatory site for the pathologic response of the lung to sepsis. Copyright © 2001 by W.B. Saunders Company.

Authors
Welty-Wolf, KE; Carraway, MS; Idell, S; Ortel, TL; Ezban, M; Piantadosi, CA
MLA Citation
Welty-Wolf, KE, Carraway, MS, Idell, S, Ortel, TL, Ezban, M, and Piantadosi, CA. "Tissue factor in experimental acute lung injury." Seminars in Hematology 38.4 SUPPL. 12 (2001): 35-38.
Source
scival
Published In
Seminars in Hematology
Volume
38
Issue
4 SUPPL. 12
Publish Date
2001
Start Page
35
End Page
38

β2-Glycoprotein I-dependent anticardiolipin antibodies preferentially bind the amino terminal domain of β2-glycoprotein I

Many of the autoantibodies in antiphospholipid syndrome (APS) are directed against β2-glycoprotein I (β2-GPI). Recent studies from our laboratories have indicated that the immunodominant binding epitope(s) for high titer, affinity purified antibodies from 11 APS patients are localized to the amino terminal domain (domain 1) of β2-GPI. The present study employed surface plasmon resonance to localize the immunodominant domain in serum samples from a large cohort of patients with GPL values ranging from 21 to 230 units (n = 106 patients). Eighty-eight percent of patients showed ≥ threefold selectivity for β2-GPI containing domain 1 relative to the domain deletion mutant that lacked domain 1. The domain 1 binding activity in patient serum was abolished by removing the IgG fraction from the serum and the binding activity could be fully reconstituted with the IgG fraction. Thus, analysis of serum samples from a large cohort of APS patients indicates that the immunodominant binding epitope(s) for anti-β2 antibodies are localized to the amino terminal domain of β2-GPI.

Authors
McNeeley, PA; Dlott, JS; Furie, RA; Jack, RM; Ortel, TL; Triplett, DA; Victoria, EJ; Linnik, MD
MLA Citation
McNeeley, PA, Dlott, JS, Furie, RA, Jack, RM, Ortel, TL, Triplett, DA, Victoria, EJ, and Linnik, MD. 2-Glycoprotein I-dependent anticardiolipin antibodies preferentially bind the amino terminal domain of β2-glycoprotein I." Thrombosis and Haemostasis 86.2 (2001): 590-595.
Source
scival
Published In
Thrombosis and Haemostasis
Volume
86
Issue
2
Publish Date
2001
Start Page
590
End Page
595

Mutation of MYH9, encoding non-muscle myosin heavy chain A, in May-Hegglin anomaly.

May-Hegglin anomaly (MHA) is an autosomal dominant macrothrombocytopenia of unclear pathogenesis characterized by thrombocytopenia, giant platelets and leukocyte inclusions. Studies have indicated that platelet structure and function are normal, suggesting a defect in megakaryocyte fragmentation. The disorder has been linked to chromosome 22q12-13. Here we screen a candidate gene in this region, encoding non-muscle myosin heavy chain A (MYH9), for mutations in ten families. In each family, we identified one of three sequence variants within either the -helical coiled coil or the tailpiece domain that co-segregated with disease status. The E1841K mutation was found in 5 families and occurs at a conserved site in the rod domain. This mutation was not found in 40 normal individuals. Four families had a nonsense mutation that resulted in truncation of most of the tailpiece. One family had a T1155I mutation present in an affected mother and daughter, but not in the mother's parents, thus representing a new mutation. Among the 30 affected individuals, 21 unaffected individuals and 13 spouses in the 10 families, there was correlation of a variant of MYH9 with the presence of MHA. The identification of MYH9 as the disease gene for MHA establishes the pathogenesis of the disorder, should provide further insight into the processes of normal platelet formation and may facilitate identification of the genetic basis of related disorders.

Authors
Kelley, MJ; Jawien, W; Ortel, TL; Korczak, JF
MLA Citation
Kelley, MJ, Jawien, W, Ortel, TL, and Korczak, JF. "Mutation of MYH9, encoding non-muscle myosin heavy chain A, in May-Hegglin anomaly." Nat Genet 26.1 (September 2000): 106-108.
PMID
10973260
Source
pubmed
Published In
Nature Genetics
Volume
26
Issue
1
Publish Date
2000
Start Page
106
End Page
108
DOI
10.1038/79069

Assessment of primary hemostasis by PFA-100 analysis in a tertiary care center.

We evaluated the utility of the PFA-100 platelet function analyzer in identifying disorders in platelet function and/or von Willebrand factor (vWF) in patients with various systemic disorders being followed at a tertiary care center. Closure times were determined with collagen/ ADP (CADP) and collagen/epinephrine (CEPI) cartridges for 305 patients, and abnormal results were further evaluated with platelet aggregometry and vWF analysis. Prolonged CADP and/or CEPI closure times were identified in 114 patients (37.3%), but most were isolated prolonged CEPI closure times predominantly due to aspirin therapy (79 patients). Prolonged CADP closure times were most frequently due to qualitative platelet defects and/or decreased vWF levels. Prolonged CADP closure times were encountered most frequently in patients with sickle cell disease and were associated with a decreased hematocrit. This study demonstrated that the PFA-100 analyzer can accurately assess vWF-dependent platelet function and detect other platelet defects under high shear stress in complex patient populations.

Authors
Ortel, TL; James, AH; Thames, EH; Moore, KD; Greenberg, CS
MLA Citation
Ortel, TL, James, AH, Thames, EH, Moore, KD, and Greenberg, CS. "Assessment of primary hemostasis by PFA-100 analysis in a tertiary care center." Thromb Haemost 84.1 (July 2000): 93-97.
PMID
10928477
Source
pubmed
Published In
Thrombosis and haemostasis
Volume
84
Issue
1
Publish Date
2000
Start Page
93
End Page
97

Antibodies to topical bovine thrombin correlate with access thrombosis.

Bovine thrombin is often used topically to promote hemostasis during vascular surgery, including dialysis-access placement. Patients frequently develop antibodies to bovine thrombin preparations, and some may develop antiphospholipid antibodies. We evaluated 88 hemodialysis patients for the presence of antibodies to topical bovine thrombin to determine if elevated antibody levels correlated with vascular access thrombosis. Twenty-seven patients (30.7%) had elevated antibody levels to topical bovine thrombin. More patients with elevated antibody levels had prior vascular access thrombosis than patients with normal antibody levels (13 of 27 versus 5 of 61 patients; P < 0.001). This difference was almost entirely the result of greater levels of thrombosis in patients with polytetrafluoroethylene (PTFE) grafts and elevated antibody levels. In these patients, 11 of 13 patients (84.6%) with elevated antibody levels had a previous thrombosis compared with 2 of 15 patients (13. 3%) with normal antibody levels (P < 0.001). Patients with elevated antibody levels and PTFE grafts also had more prior thromboses (1.92 +/- 1.60 versus 0.133 +/- 0.35 thromboses; P < 0.01) and a greater thrombosis rate (66.89 +/- 63.71 versus 4.65 +/- 12.05 thromboses/100 patient-years; P < 0.01) than patients with normal antibody levels. There were no differences in the frequency of myocardial infarction, coronary artery bypass, access age, presence of diabetes mellitus, platelet counts, anticardiolipin antibody, albumin, lactate dehydrogenase, or C-reactive protein levels. In conclusion, patients with PTFE grafts and elevated antibody levels to topical bovine thrombin had significantly more vascular access thrombosis.

Authors
Sands, JJ; Nudo, SA; Ashford, RG; Moore, KD; Ortel, TL
MLA Citation
Sands, JJ, Nudo, SA, Ashford, RG, Moore, KD, and Ortel, TL. "Antibodies to topical bovine thrombin correlate with access thrombosis." Am J Kidney Dis 35.5 (May 2000): 796-801.
PMID
10793011
Source
pubmed
Published In
American Journal of Kidney Diseases
Volume
35
Issue
5
Publish Date
2000
Start Page
796
End Page
801

Antibodies to prothrombin and factor V correlate-with PTFE graft thrombosis

In this study, 88 hemodialysis patients (44 AV fistulas [AVF], 28 PTFE grafts [PTFE], 16 cuffed catheters [CC]) were studied for the presence of antibodies to human and bovine prothrombin (FII), bovine factor V (bFV), and human β2-glycoprotein I (β2GPI). Antibody levels were measured by ELISA. The results were correlated with the patients' access history.

Authors
Sands, JJ; Nudo, S; Ortel, TL
MLA Citation
Sands, JJ, Nudo, S, and Ortel, TL. "Antibodies to prothrombin and factor V correlate-with PTFE graft thrombosis." ASAIO Journal 46.2 (2000): 209--.
Source
scival
Published In
ASAIO Journal
Volume
46
Issue
2
Publish Date
2000
Start Page
209-

Crystal structures of the membrane-binding C2 domain of human coagulation factor V.

Rapid and controlled clot formation is achieved through sequential activation of circulating serine proteinase precursors on phosphatidylserine-rich procoagulant membranes of activated platelets and endothelial cells. The homologous complexes Xase and prothrombinase, each consisting of an active proteinase and a non-enzymatic cofactor, perform critical steps within this coagulation cascade. The activated cofactors VIIIa and Va, highly specific for their cognate proteinases, are each derived from precursors with the same A1-A2-B-A3-C1-C2 architecture. Membrane binding is mediated by the C2 domains of both cofactors. Here we report two crystal structures of the C2 domain of human factor Va. The conserved beta-barrel framework provides a scaffold for three protruding loops, one of which adopts markedly different conformations in the two crystal forms. We propose a mechanism of calcium-independent, stereospecific binding of factors Va and VIIIa to phospholipid membranes, on the basis of (1) immersion of hydrophobic residues at the apices of these loops in the apolar membrane core; (2) specific interactions with phosphatidylserine head groups in the groove enclosed by these loops; and (3) favourable electrostatic contacts of basic side chains with negatively charged membrane phosphate groups.

Authors
Macedo-Ribeiro, S; Bode, W; Huber, R; Quinn-Allen, MA; Kim, SW; Ortel, TL; Bourenkov, GP; Bartunik, HD; Stubbs, MT; Kane, WH; Fuentes-Prior, P
MLA Citation
Macedo-Ribeiro, S, Bode, W, Huber, R, Quinn-Allen, MA, Kim, SW, Ortel, TL, Bourenkov, GP, Bartunik, HD, Stubbs, MT, Kane, WH, and Fuentes-Prior, P. "Crystal structures of the membrane-binding C2 domain of human coagulation factor V." Nature 402.6760 (November 25, 1999): 434-439.
PMID
10586886
Source
pubmed
Published In
Nature
Volume
402
Issue
6760
Publish Date
1999
Start Page
434
End Page
439
DOI
10.1038/46594

Antiphospholipid antibodies in patients with Wegener's granulomatosis and polyarteritis nodosa.

Authors
Hansen, KE; Moore, KD; Ortel, TL; Allen, NB
MLA Citation
Hansen, KE, Moore, KD, Ortel, TL, and Allen, NB. "Antiphospholipid antibodies in patients with Wegener's granulomatosis and polyarteritis nodosa." Arthritis Rheum 42.10 (October 1999): 2250-2252.
PMID
10524702
Source
pubmed
Published In
Arthritis and Rheumatism
Volume
42
Issue
10
Publish Date
1999
Start Page
2250
End Page
2252
DOI
10.1002/1529-0131(199910)42:10<2250::AID-ANR32>3.0.CO;2-7

Partial glycosylation at asparagine-2181 of the second C-type domain of human factor V modulates assembly of the prothrombinase complex.

Thrombin-activated factor Va exists as two isoforms, factor Va(1) and factor Va(2), which differ in the size of their light chains and their affinity for biological membranes. The heterogeneity of the light chain remained following incubation of factor Va with N-glycanase. However, we found that the factor V C2 domain, which contains a single potential glycosylation site at Asn-2181, was partially glycosylated when expressed in COS cells. To confirm the structural basis for factor Va(1) and factor Va(2), we mutated Asn-2181 to glutamine (N2181Q) and expressed this mutant using a B domain deletion construct (rHFV des B) in COS cells. Thrombin activation of N2181Q released a light chain with mobility identical to that of factor Va(2) on SDS-PAGE. The functional properties of purified N2181Q were similar to those of factor Va(2) in prothrombinase assays carried out in the presence of limiting concentrations of phosphatidylserine. The binding of human factor Va(1) and factor Va(2) to 75:25 POPC/POPS vesicles was also investigated in equilibrium binding assays using proteins containing a fluorescein-labeled heavy chain. The affinity of human factor Va(2) binding to POPC/POPS vesicles was approximately 3-fold higher than that of factor Va(1). These results indicate that partial glycosylation of factor V at asparagine-2181 is the structural basis of the light chain doublet and that the presence of this oligosaccharide reduces the affinity of factor Va for biological membranes.

Authors
Kim, SW; Ortel, TL; Quinn-Allen, MA; Yoo, L; Worfolk, L; Zhai, X; Lentz, BR; Kane, WH
MLA Citation
Kim, SW, Ortel, TL, Quinn-Allen, MA, Yoo, L, Worfolk, L, Zhai, X, Lentz, BR, and Kane, WH. "Partial glycosylation at asparagine-2181 of the second C-type domain of human factor V modulates assembly of the prothrombinase complex." Biochemistry 38.35 (August 31, 1999): 11448-11454.
PMID
10471296
Source
pubmed
Published In
Biochemistry
Volume
38
Issue
35
Publish Date
1999
Start Page
11448
End Page
11454
DOI
10.1021/bi991275y

Clinical and laboratory manifestations of anti-factor V antibodies.

Factor V is a large, multi-domain glycoprotein that exhibits both procoagulant and anticoagulant activity. Anti-factor V antibodies may develop by several mechanisms and, depending on their epitope specificity, may produce hemorrhagic or thromboembolic complications. The clinical laboratory is an essential component in diagnosing these antibodies, and therapeutic management depends on the predominant clinical manifestations.

Authors
Ortel, TL
MLA Citation
Ortel, TL. "Clinical and laboratory manifestations of anti-factor V antibodies." J Lab Clin Med 133.4 (April 1999): 326-334. (Review)
PMID
10218762
Source
pubmed
Published In
Journal of Laboratory and Clinical Medicine
Volume
133
Issue
4
Publish Date
1999
Start Page
326
End Page
334

Two instruments to determine activated partial thromboplastin time: implications for heparin monitoring.

STUDY OBJECTIVE: To measure the difference in therapeutic ranges of activated partial thromboplastin time (APTT) between two laboratory devices. DESIGN: Prospective, controlled laboratory study. SETTING: University-affiliated hospital. PATIENTS: Thirty inpatients receiving intravenous unfractionated heparin for treatment of myocardial infarction, unstable angina, deep venous thrombosis, or pulmonary embolism. INTERVENTIONS: Therapeutic APTT ranges were determined by a portable (whole blood assay) and a central laboratory device (plasma assay) based on heparin serum concentrations. They were compared with APTT ranges equivalent to 1.5-2.5 times the mean normal determination. MEASUREMENTS AND MAIN RESULTS: The central laboratory and portable devices produced therapeutic ranges of 61-93 and 56-73 seconds, respectively. Both differed from conventional therapeutic ratios of 1.5-2.5 times the mean normal (41-68 sec). Mean absolute APTT differences between instruments were statistically significant (12 +/- 20 sec, p<0.006), and 58% of paired APTT values differed by more than 10 seconds. CONCLUSION: A fixed APTT ratio as a goal for monitoring unfractionated heparin may result in significant underanticoagulation. Individual therapeutic APTT ranges must be reported for each instrument if more than one is used for heparin monitoring.

Authors
Taylor, CT; Petros, WP; Ortel, TL
MLA Citation
Taylor, CT, Petros, WP, and Ortel, TL. "Two instruments to determine activated partial thromboplastin time: implications for heparin monitoring." Pharmacotherapy 19.4 (April 1999): 383-387.
PMID
10212007
Source
pubmed
Published In
Pharmacotherapy
Volume
19
Issue
4
Publish Date
1999
Start Page
383
End Page
387

Familial antiphospholipid antibody syndrome: criteria for disease and evidence for autosomal dominant inheritance.

OBJECTIVE: To develop diagnostic criteria for a familial form of antiphospholipid antibody syndrome (APS), identify families with >1 affected member, examine possible modes of inheritance, and determine linkage to potential candidate genes. METHODS: Family members of probands with primary APS were analyzed for clinical and laboratory abnormalities associated with APS. Families with > or =2 affected members were analyzed by segregation analysis and typed for candidate genetic markers. RESULTS: Seven families were identified. Thirty of 101 family members met diagnostic criteria for APS. Segregation studies rejected both environmental and autosomal recessive models, and the data were best fit by either a dominant or codominant model. Linkage analysis showed independent segregation of APS and several candidate genes. CONCLUSION: Clinical and laboratory criteria are essential to identify the spectrum of disease associated with APS. We believe a set of criteria was developed that can precisely define affected family members with APS. Modeling studies utilizing these criteria strongly support a genetic basis for disease in families with APS and suggest that a susceptibility gene is inherited in an autosomal dominant pattern. However, in these families, APS was not linked with HLA, Fas, or other candidate genes, including beta2-glycoprotein 1, HLA, T cell receptor beta chain, Ig heavy chain, antithrombin III, Fas ligand, factor V, complement factor H, IgK, and Fas.

Authors
Goel, N; Ortel, TL; Bali, D; Anderson, JP; Gourley, IS; Smith, H; Morris, CA; DeSimone, M; Branch, DW; Ford, P; Berdeaux, D; Roubey, RA; Kostyu, DD; Kingsmore, SF; Thiel, T; Amos, C; Seldin, MF
MLA Citation
Goel, N, Ortel, TL, Bali, D, Anderson, JP, Gourley, IS, Smith, H, Morris, CA, DeSimone, M, Branch, DW, Ford, P, Berdeaux, D, Roubey, RA, Kostyu, DD, Kingsmore, SF, Thiel, T, Amos, C, and Seldin, MF. "Familial antiphospholipid antibody syndrome: criteria for disease and evidence for autosomal dominant inheritance." Arthritis Rheum 42.2 (February 1999): 318-327.
PMID
10025927
Source
pubmed
Published In
Arthritis and Rheumatism
Volume
42
Issue
2
Publish Date
1999
Start Page
318
End Page
327
DOI
10.1002/1529-0131(199902)42:2<318::AID-ANR15>3.0.CO;2-5

Two instruments to determine activated partial thromboplastin lime: Implications for heparin monitoring

Study Objective. To measure the difference in therapeutic ranges of activated partial thromboplastin time (APTT) between two laboratory devices. Design. Prospective, controlled laboratory study. Setting. University- affiliated hospital. Patients. Thirty inpatients receiving intravenous unfractionated heparin for treatment of myocardial infarction, unstable angina, deep venous thrombosis, or pulmonary embolism. Interventions. Therapeutic APTT ranges were determined by a portable (whole blood assay) and a central laboratory device (plasma assay) based on heparin serum concentrations. They were compared with APTT ranges equivalent to 1.5-2.5 times the mean normal determination. Measurements and Main Results. The central laboratory and portable devices produced therapeutic ranges of 61-93 and 56-73 seconds, respectively. Both differed from conventional therapeutic ratios of 1.5-2.5 times the mean normal (41-68 sec). Mean absolute APTT differences between instruments were statistically significant (12 ± 20 sec, p<0.006), and 58% of paired APTT values differed by more than 10 seconds. Conclusion. A fixed APTT ratio as a goal for monitoring unfractionated heparin may result in significant underanticoagulation. Individual therapeutic APTT ranges must be reported for each instrument if more than one is used for heparin monitoring.

Authors
Taylor, CT; Petros, WP; Ortel, TL
MLA Citation
Taylor, CT, Petros, WP, and Ortel, TL. "Two instruments to determine activated partial thromboplastin lime: Implications for heparin monitoring." Pharmacotherapy 19.4 I (1999): 383-387.
Source
scival
Published In
Pharmacotherapy
Volume
19
Issue
4 I
Publish Date
1999
Start Page
383
End Page
387

Diagnosis of pulmonary embolism.

Authors
Moll, S; Ortel, TL
MLA Citation
Moll, S, and Ortel, TL. "Diagnosis of pulmonary embolism." N Engl J Med 339.15 (October 8, 1998): 1084-. (Letter)
PMID
9767002
Source
pubmed
Published In
The New England journal of medicine
Volume
339
Issue
15
Publish Date
1998
Start Page
1084

New treatment options for heparin-induced thrombocytopenia.

A rapidly acting anticoagulant that can either inhibit thrombin generation or inhibit thrombin itself is the optimum therapy for acute thrombosis associated with heparin-induced thrombocytopenia (HIT). In this review, the newer treatment approaches that fulfill this requirement are discussed. These newer treatments include hirudin and argatroban, direct thrombin inhibitors, and danaparoid, which inhibits thrombin generation. Preliminary outcome results from the extensive compassionate-use program for danaparoid in HIT and from a recently completed randomized clinical trial that compared danaparoid with dextran in patients with HIT are provided. Based on these data, danaparoid appears to be a useful and safe replacement for heparin in patients who develop HIT.

Authors
Ortel, TL; Chong, BH
MLA Citation
Ortel, TL, and Chong, BH. "New treatment options for heparin-induced thrombocytopenia." Semin Hematol 35.4 Suppl 5 (October 1998): 26-34. (Review)
PMID
9855181
Source
pubmed
Published In
Seminars in Hematology
Volume
35
Issue
4 Suppl 5
Publish Date
1998
Start Page
26
End Page
34

Heparin-induced thrombocytopenia.

Authors
Ortel, TL
MLA Citation
Ortel, TL. "Heparin-induced thrombocytopenia." Semin Hematol 35.4 Suppl 5 (October 1998): 1-2. (Review)
PMID
9855177
Source
pubmed
Published In
Seminars in Hematology
Volume
35
Issue
4 Suppl 5
Publish Date
1998
Start Page
1
End Page
2

Recurrent thrombosis of the superior vena cava associated with activated protein C resistance: imaging findings.

The purpose of this report is to describe imaging findings in activated protein C resistance, a hereditary cause of recurrent thrombosis. The case described was unusual in that a neonate was affected, whereas the vast majority of cases occur in adulthood. This entity is important to diagnose because of the recurrent nature of thromboses and the fact that relatives are often affected.

Authors
Provenzale, JM; Frush, DP; Ortel, TL
MLA Citation
Provenzale, JM, Frush, DP, and Ortel, TL. "Recurrent thrombosis of the superior vena cava associated with activated protein C resistance: imaging findings." Pediatr Radiol 28.8 (August 1998): 597-598.
PMID
9716630
Source
pubmed
Published In
Pediatric Radiology
Volume
28
Issue
8
Publish Date
1998
Start Page
597
End Page
598
DOI
10.1007/s002470050424

Inhibitory anti-factor V antibodies bind to the factor V C2 domain and are associated with hemorrhagic manifestations.

Factor V inhibitors may develop as spontaneous autoantibodies, as alloantibodies after exposure to bovine thrombin preparations, or in factor V-deficient patients after plasma therapy. Clinical manifestations range from asymptomatic laboratory abnormalities to life-threatening hemorrhage. We have characterized the anti-factor V antibodies from 12 patients diagnosed with factor V inhibitors. In 8 patients, hemorrhagic complications (5 autoantibodies and 3 bovine thrombin-induced alloantibodies) developed, and 4 were asymptomatic (2 autoantibodies and 2 alloantibodies). The IgG fractions from all 12 patients immunoprecipitated the factor Va light chain, but only the 8 IgG fractions associated with hemorrhage inhibited factor V activity in a prothrombinase assay. Nine IgG fractions, including the 8 patients with hemorrhage, immunoprecipitated the isolated second C-type domain (C2). The 8 IgG fractions from the symptomatic patients also immunoprecipitated recombinant chimeras containing only the N-terminal third of the factor V C2 domain, and isolated recombinant C2 domain abrogated the inhibitory effect of the antibodies. Five of the inhibitory IgG fractions blocked binding of factor V to phosphatidylserine. These results suggest that inhibitory anti-factor V antibodies are associated with hemorrhagic manifestations and frequently bind to a common region within the C2 domain, whether originating spontaneously or after exposure to bovine thrombin.

Authors
Ortel, TL; Moore, KD; Quinn-Allen, MA; Okamura, T; Sinclair, AJ; Lazarchick, J; Govindan, R; Carmagnol, F; Kane, WH
MLA Citation
Ortel, TL, Moore, KD, Quinn-Allen, MA, Okamura, T, Sinclair, AJ, Lazarchick, J, Govindan, R, Carmagnol, F, and Kane, WH. "Inhibitory anti-factor V antibodies bind to the factor V C2 domain and are associated with hemorrhagic manifestations." Blood 91.11 (June 1, 1998): 4188-4196.
PMID
9596666
Source
pubmed
Published In
Blood
Volume
91
Issue
11
Publish Date
1998
Start Page
4188
End Page
4196

Monitoring oral anticoagulant therapy in patients with lupus anticoagulants.

Authors
Ortel, TL; Moll, S
MLA Citation
Ortel, TL, and Moll, S. "Monitoring oral anticoagulant therapy in patients with lupus anticoagulants." Br J Haematol 101.2 (May 1998): 390-392. (Letter)
PMID
9609541
Source
pubmed
Published In
British Journal of Haematology
Volume
101
Issue
2
Publish Date
1998
Start Page
390
End Page
392

Cerebrovascular disease risk factors: neuroradiologic findings in patients with activated protein C resistance.

PURPOSE: To assess the patterns of abnormal neuroradiologic findings in patients with a hypercoagulable state related to activated protein C (APC) resistance. MATERIALS AND METHODS: Records in 23 patients with a hypercoagulable state related to APC resistance (18 women, five men; average age, 44.5 years) were reviewed for cerebrovascular disease risk factors and other causes of a hypercoagulable state. Computed tomographic scans, magnetic resonance (MR) images, angiograms, and transesophageal echocardiograms were also reviewed. RESULTS: Stroke risk factors or other causes of a hypercoagulable state were found in 12 patients. Arterial infarcts were seen in 18 patients. Hyperintense white matter foci were seen on MR images in six patients. Dural sinus thrombosis was found in four patients. Angiograms of intracranial circulation in six patients showed major artery occlusions in four. MR angiograms in four patients showed internal carotid artery occlusion in one. No major abnormalities were seen in extracranial cerebral vasculature in 15 patients. Transesophageal echocardiograms in 11 patients showed a patent foramen ovale in one patient but no systemic source of embolism. Seven patients had non-central nervous system thrombotic events. CONCLUSION: Patients with APC resistance and stroke appear to differ from the general stroke population in terms of age and frequency of extracranial sources of cerebrovascular disease.

Authors
Provenzale, JM; Barboriak, DP; Davey, IC; Ortel, TL
MLA Citation
Provenzale, JM, Barboriak, DP, Davey, IC, and Ortel, TL. "Cerebrovascular disease risk factors: neuroradiologic findings in patients with activated protein C resistance." Radiology 207.1 (April 1998): 85-89.
PMID
9530303
Source
pubmed
Published In
Radiology
Volume
207
Issue
1
Publish Date
1998
Start Page
85
End Page
89
DOI
10.1148/radiology.207.1.9530303

Antiphospholipid antibodies: findings at arteriography.

PURPOSE: The purpose of this study was to determine the frequency and types of abnormalities at arteriography in patients with antiphospholipid antibodies (APA) and ischemic cerebrovascular events. METHODS: Twenty-three patients with APA and ischemic cerebrovascular events who underwent arteriography were identified. Patients over the age of 65 years were excluded. No patients met diagnostic criteria for systemic lupus erythematosus. All angiograms were reviewed by two neuroradiologists. RESULTS: Seventeen patients (74%) between the ages of 28 and 64 years (average age, 40 years) had abnormal angiograms. Sixteen patients had arterial abnormalities and one had dural sinus thrombosis. Ten had solely intracranial abnormalities (nine arterial and one venous), six had solely extracranial arterial abnormalities, and one had both intracranial and extracranial arterial abnormalities. Intracranial arterial abnormalities included stem or branch occlusions of the cerebral or basilar arteries, which were generally solitary (six patients), and findings suggestive of vasculitis (four patients). Four patients had stenoses of the origins of two or more great vessels. Two patients had extracranial internal carotid artery stenoses or occlusions that were not typical of atheromatous disease, considered to be embolic in one patient. In another patient, a stenosis of the origin of the internal carotid artery was present that appeared typical of atheromatous disease. Infarctions were seen on CT or MR studies in 13 of 17 patients with abnormal angiograms. CONCLUSION: In our group of patients, typical atheromatous lesions at the common carotid artery bifurcation were rare. Some lesions that are infrequent in the general stroke population (eg, vasculitis-like findings and stenoses at the origin of great vessels) were common. Patients with APA and cerebrovascular events appear to differ from the general stroke population with regard to types of arterial abnormalities seen at arteriography.

Authors
Provenzale, JM; Barboriak, DP; Allen, NB; Ortel, TL
MLA Citation
Provenzale, JM, Barboriak, DP, Allen, NB, and Ortel, TL. "Antiphospholipid antibodies: findings at arteriography." AJNR Am J Neuroradiol 19.4 (April 1998): 611-616.
PMID
9576644
Source
pubmed
Published In
American Journal of Neuroradiology
Volume
19
Issue
4
Publish Date
1998
Start Page
611
End Page
616

Dural sinus thrombosis associated with activated protein C resistance: MR imaging findings and proband identification.

OBJECTIVE: The purpose of this study was to report the association of dural sinus thrombosis with a hypercoagulable state associated with activated protein C resistance. CONCLUSION: In our small study population, hemorrhagic venous infarction was common (three of four patients) among patients with dural sinus thrombosis and activated protein C resistance. Four of five patients with dural sinus thrombosis had positive tests for activated protein C resistance. This finding, in conjunction with data from other studies, suggests that patients with dural sinus thrombosis may need to be studied for the presence of activated protein C resistance. A positive finding for activated protein C resistance can be important not only in helping to explain the cause of thrombosis in affected individuals but also in identifying families at risk for thrombosis.

Authors
Provenzale, JM; Barboriak, DP; Ortel, TL
MLA Citation
Provenzale, JM, Barboriak, DP, and Ortel, TL. "Dural sinus thrombosis associated with activated protein C resistance: MR imaging findings and proband identification." AJR Am J Roentgenol 170.2 (February 1998): 499-502.
PMID
9456973
Source
pubmed
Published In
AJR. American journal of roentgenology
Volume
170
Issue
2
Publish Date
1998
Start Page
499
End Page
502
DOI
10.2214/ajr.170.2.9456973

Disseminated thrombosis in primary antiphospholipid syndrome: MR findings.

We report the MR imaging findings in a patient with primary antiphospholipid syndrome, adrenal infarction and widespread thrombosis involving abdominal, pelvic, and pulmonary vessels. This syndrome should be suspected in patients with thromboses and organ infarctions of otherwise undetermined etiology.

Authors
Provenzale, JM; Spritzer, CE; Nelson, RC; Ortel, TL
MLA Citation
Provenzale, JM, Spritzer, CE, Nelson, RC, and Ortel, TL. "Disseminated thrombosis in primary antiphospholipid syndrome: MR findings." Eur J Radiol 26.3 (February 1998): 244-247.
PMID
9587749
Source
pubmed
Published In
European Journal of Radiology
Volume
26
Issue
3
Publish Date
1998
Start Page
244
End Page
247

Systemic thrombosis in patients with antiphospholipid antibodies: lesion distribution and imaging findings.

OBJECTIVE: The purpose of this study was to determine the patterns of non-CNS thromboses in patients with a hypercoagulable state associated with antiphospholipid antibodies (APA). MATERIALS AND METHODS: A search of our institution's clinical coagulation and immunology laboratories' records of patients examined from January 1993 to January 1996 revealed 1290 patients with APA. Computerized records of radiologic studies were reviewed for evidence of thrombotic events, which were found in 93 patients (49 males and 44 females; average age, 40 years). The anatomic distribution of thrombotic events was recorded. RESULTS: Fifty-five patients (59%; 29 males and 26 females; average age, 44.2 years) had solely venous thromboses, 26 patients (28%; 15 males and 11 females; average age, 33.1 years) had solely arterial thromboses, and 12 (13%; 5 males and 7 females; average age, 35.4 years) had both types of events. Deep vein thrombosis (DVT) of the legs was the most common finding, occurring in 45 patients (48%). Six patients had recurrent DVT. Other sites of venous thrombotic events included pulmonary embolism, 30 patients (32%); thoracic veins (superior vena cava, subclavian vein, or jugular vein), 10 patients (11%); and abdominal or pelvic veins, 18 events in 11 patients (12%). Sites of arterial thromboses included arteries supplying the upper limbs (great vessels arising from the aorta or the brachial, radial, ulnar, or digital arteries), 15 events in 12 patients (13%); aorta, one patient (1%); abdominal or pelvic arteries, 11 events in eight patients (9%); and arteries supplying the lower limbs (femoral or popliteal arteries), seven patients (8%). CONCLUSION: Venous thromboses were more common than arterial thromboses in our patient group, with DVT being the most common. However, thromboses in sites that are unusual for the general population were also relatively common. APA should be suspected in patients with thromboses in unusual sites or recurrent thromboses of an otherwise unexplained cause.

Authors
Provenzale, JM; Ortel, TL; Allen, NB
MLA Citation
Provenzale, JM, Ortel, TL, and Allen, NB. "Systemic thrombosis in patients with antiphospholipid antibodies: lesion distribution and imaging findings." AJR Am J Roentgenol 170.2 (February 1998): 285-290.
PMID
9456930
Source
pubmed
Published In
AJR. American journal of roentgenology
Volume
170
Issue
2
Publish Date
1998
Start Page
285
End Page
290
DOI
10.2214/ajr.170.2.9456930

Diagnosis of pulmonary embolism [5] (multiple letters)

Authors
Schwartz, MA; Zimhony, O; Moll, S; Ortel, TL; Pechlaner, C; Gritsch, W; Wiedermann, C; Yu, DR; Miller, R; Bray, PF
MLA Citation
Schwartz, MA, Zimhony, O, Moll, S, Ortel, TL, Pechlaner, C, Gritsch, W, Wiedermann, C, Yu, DR, Miller, R, and Bray, PF. "Diagnosis of pulmonary embolism [5] (multiple letters)." New England Journal of Medicine 339.15 (1998): 1084-1085.
PMID
9767005
Source
scival
Published In
New England Journal of Medicine
Volume
339
Issue
15
Publish Date
1998
Start Page
1084
End Page
1085
DOI
10.1056/NEJM199810083391515

Monitoring warfarin therapy in patients with lupus anticoagulants [1] (multiple letters)

Authors
Manoharan, A; D'Angelo, A; Valle, PD; Crippa, L; Moll, S; Ortel, TL
MLA Citation
Manoharan, A, D'Angelo, A, Valle, PD, Crippa, L, Moll, S, and Ortel, TL. "Monitoring warfarin therapy in patients with lupus anticoagulants [1] (multiple letters)." Annals of Internal Medicine 128.6 (1998): 504-505.
PMID
9499338
Source
scival
Published In
Annals of Internal Medicine
Volume
128
Issue
6
Publish Date
1998
Start Page
504
End Page
505

Monitoring oral anticoagulant therapy in patients with lupus anticoagulants [3] (multiple letters)

Authors
Ortel, TL; Moll, S; Lawrie, AS; Purdy, G; Mackie, IJ; Machin, SJ
MLA Citation
Ortel, TL, Moll, S, Lawrie, AS, Purdy, G, Mackie, IJ, and Machin, SJ. "Monitoring oral anticoagulant therapy in patients with lupus anticoagulants [3] (multiple letters)." British Journal of Haematology 101.2 (1998): 390-392.
Source
scival
Published In
British Journal of Haematology
Volume
101
Issue
2
Publish Date
1998
Start Page
390
End Page
392

New treatment options for heparin-induced thrombocytopenia

A rapidly acting anticoagulant that can either inhibit thrombin generation or inhibit thrombin itself is the optimum therapy for acute thrombosis associated with heparin-induced thrombocytopenia (HIT). In this review, the newer treatment approaches that fulfill this requirement are discussed. These newer treatments include hirudin and argatroban, direct thrombin inhibitors, and danaparoid, which inhibits thrombin generation. Preliminary outcome results from the extensive compassionate-use program for danaparoid in HIT and from a recently completed randomized clinical trial that compared danaparoid with dextran in patients with HIT are provided. Based on these data, danaparoid appears to be a useful and safe replacement for heparin in patients who develop HIT.

Authors
Ortel, TL; Chong, BH
MLA Citation
Ortel, TL, and Chong, BH. "New treatment options for heparin-induced thrombocytopenia." Seminars in Hematology 35.4 SUPPL. 5 (1998): 26-34.
Source
scival
Published In
Seminars in Hematology
Volume
35
Issue
4 SUPPL. 5
Publish Date
1998
Start Page
26
End Page
34

Anticardiolipin antibodies and osteonecrosis of the femoral head.

The current study evaluated the prevalence of anticardiolipin antibodies, which have been associated with thrombotic phenomena, in patients with nontraumatic osteonecrosis of the hip and assessed whether the presence of such antibodies is associated with an increased risk for the development of bone necrosis. Forty consecutive patients (25 men and 15 women) with nontraumatic osteonecrosis of the hip were studied. Their ages ranged from 19 to 56 years (average, 34.3 years). Anticardiolipin antibodies were present in 37.5% (15 of 40) of the tested patients, a significantly higher rate than is seen in healthy subjects, of whom only one of 100 had low titer anticardiolipin antibodies (1%). Six of 40 patients tested positive for immunoglobulin M alone, and six of 40 patients tested positive for immunoglobulin A alone. Three of 40 patients tested positive for immunoglobulin M and immunoglobulin A isotype. The results of the current study indicate an increased incidence of anticardiolipin antibodies in patients with nontraumatic osteonecrosis of the femoral head, which may reflect that anticardiolipin antibodies play a role in the pathogenesis of bone necrosis by predisposing to thrombotic phenomena.

Authors
Korompilias, AV; Gilkeson, GS; Ortel, TL; Seaber, AV; Urbaniak, JR
MLA Citation
Korompilias, AV, Gilkeson, GS, Ortel, TL, Seaber, AV, and Urbaniak, JR. "Anticardiolipin antibodies and osteonecrosis of the femoral head." Clin Orthop Relat Res 345 (December 1997): 174-180.
PMID
9418637
Source
pubmed
Published In
Clinical Orthopaedics and Related Research ®
Issue
345
Publish Date
1997
Start Page
174
End Page
180

Monitoring warfarin therapy in patients with lupus anticoagulants.

BACKGROUND: Recommended therapeutic international normalized ratios (INRs) for oral anticoagulation in patients with lupus anticoagulants who sustain a thromboembolic event are controversial. Patients with lupus anticoagulants often have a prolonged prothrombin time, which may complicate management of anticoagulant therapy. OBJECTIVES: To determine the validity of the INR as a monitor for warfarin therapy in patients with lupus anticoagulants and to investigate alternate approaches to monitoring warfarin therapy in these patients. DESIGN: Prospective case series. SETTING: Tertiary care hospital. PATIENTS: 34 patients with lupus anticoagulants. MEASUREMENTS: Prothrombin times were determined by using several thromboplastins, and INRs were calculated for the patients receiving warfarin. Factor II levels, chromogenic factor X levels, and prothrombin-proconvertin times were determined for patients receiving warfarin. RESULTS: For patients with lupus anticoagulants who were not receiving warfarin, prothrombin times were often elevated and varied significantly with different thromboplastins. Individual thromboplastins differed in sensitivity to the presence of a lupus anticoagulant. For patients receiving warfarin, INRs obtained by using different thromboplastins greatly varied and often overestimated the extent of anticoagulation. Chromogenic factor X levels and prothrombin-proconvertin times correlated well with each other and with established therapeutic ranges. CONCLUSIONS: Lupus anticoagulants can influence prothrombin times and lead to INRs that do not accurately reflect the true level of anticoagulation. Use of the INR to standardize prothrombin times is invalid for some patients with lupus anticoagulants. To prevent supratherapeutic or subtherapeutic anticoagulation, these patients must be individually monitored with a test that is insensitive to lupus anticoagulants.

Authors
Moll, S; Ortel, TL
MLA Citation
Moll, S, and Ortel, TL. "Monitoring warfarin therapy in patients with lupus anticoagulants." Ann Intern Med 127.3 (August 1, 1997): 177-185.
PMID
9245222
Source
pubmed
Published In
Annals of internal medicine
Volume
127
Issue
3
Publish Date
1997
Start Page
177
End Page
185

Combined factor IX and XI deficiency discovered at liver biopsy.

Authors
Hunt, CM; Carson, KL; Ortel, TL
MLA Citation
Hunt, CM, Carson, KL, and Ortel, TL. "Combined factor IX and XI deficiency discovered at liver biopsy." Dig Dis Sci 42.8 (August 1997): 1731-1733.
PMID
9286241
Source
pubmed
Published In
Digestive Diseases and Sciences
Volume
42
Issue
8
Publish Date
1997
Start Page
1731
End Page
1733

Subdural hematoma and lupus anticoagulants.

BACKGROUND AND PURPOSE: Patients with lupus anticoagulants do not typically have a bleeding tendency. However, a few reports of hemorrhage in patients with lupus anticoagulants in the absence of known risk factors for bleeding have been published, raising the question of an etiologic connection between lupus anticoagulants and certain types of hemorrhage. The presentation of three patients with subdural hematoma and lupus anticoagulants within only 1 year at our institutions and the report of two such patients in the literature led us to conduct a retrospective study to determine whether patients with lupus anticoagulants may have an increased risk for the development of subdural hematoma. CASE DESCRIPTIONS: All patients with a discharge diagnosis of nontraumatic subdural hematoma and lupus anticoagulant at three medical institutions between 1985 and 1996 were identified, and their medical histories and laboratory evaluations were reviewed. Of 733 patients with a discharge diagnosis of nontraumatic subdural hematoma, 5 were diagnosed as having a lupus anticoagulant (0.7%). All had known risk factors for the development of subdural hematoma: thrombocytopenia, hypoprothrombinemia, intracerebral venous hemorrhage, warfarin therapy, and advanced age with a history of a fall. CONCLUSIONS: This study suggests that presence of a lupus anticoagulant by itself is not associated with an increased incidence of nontraumatic subdural hematoma.

Authors
Moll, S; McCloud, M; Ortel, TL
MLA Citation
Moll, S, McCloud, M, and Ortel, TL. "Subdural hematoma and lupus anticoagulants." Stroke 28.3 (March 1997): 646-648.
PMID
9056625
Source
pubmed
Published In
Stroke
Volume
28
Issue
3
Publish Date
1997
Start Page
646
End Page
648

Plasma levels of factors II, VII and X and their relationship to the international normalized ratio during chronic warfarin therapy.

Monitoring of oral anticoagulant therapy is usually undertaken with the prothrombin time (PT), which is influenced by factors II, X, and VII. A number of studies have suggested that the prothrombin (factor II) level may be the most important determinant of the therapeutic efficacy of these drugs. Although some studies suggest that oral anticoagulants induce a similar residual level of plasma vitamin K-dependent proteins, others have called this into question. We therefore measured plasma levels of factors II, X, and VII in 50 patients undergoing chronic Warfarin therapy. The plasma levels of factors II, X, and VII were significantly different. Although the factor X levels of all plasmas were < 30%, levels of factors II and VII were > 30% in 14% and 50% of the samples, respectively. Multivariable analysis showed factor II levels to be the least significant of the three factors measured in determining the international normalized ratio of plasma or whole blood. Thus, plasma levels of the vitamin K-dependent coagulation factors are not equal in patients on chronic Warfarin therapy. If factor II (prothrombin) levels are indeed the major determinants of the therapeutic efficacy of Warfarin, alternative means of monitoring that more accurately reflects prothrombin levels should be evaluated.

Authors
Lind, SE; Callas, PW; Golden, EA; Joyner, KA; Ortel, TL
MLA Citation
Lind, SE, Callas, PW, Golden, EA, Joyner, KA, and Ortel, TL. "Plasma levels of factors II, VII and X and their relationship to the international normalized ratio during chronic warfarin therapy." Blood Coagul Fibrinolysis 8.1 (January 1997): 48-53.
PMID
9105637
Source
pubmed
Published In
Blood Coagulation and Fibrinolysis
Volume
8
Issue
1
Publish Date
1997
Start Page
48
End Page
53

Helical computed tomography and magnetic resonance imaging in the diagnosis of venous thromboembolic disease: Case report and review of the literature

Pulmonary embolism (PE) remains a common cause of morbidity and mortality. Appropriate therapy requires timely diagnosis, but currently available noninvasive modalities lack adequate sensitivity and specificity. In particular, the vast majority of ventilation-perfusion scans are unable to confirm or reliably exclude PE, cannot differentiate acute from chronic PE, and do not provide clues to possible alternative explanations of the patient's presenting symptoms (even if PE can be excluded). The case presented here illustrates the potential utility of two new noninvasive tests for PE, magnetic resonance imaging and helical computed tomography. In addition, the available literature on these modalities with emphasis on their clinical accuracy and limitations is reviewed.

Authors
Layish, DT; Spritzer, CE; Ortel, TL; Tapson, VF
MLA Citation
Layish, DT, Spritzer, CE, Ortel, TL, and Tapson, VF. "Helical computed tomography and magnetic resonance imaging in the diagnosis of venous thromboembolic disease: Case report and review of the literature." Clinical Pulmonary Medicine 4.3 (1997): 170-173.
Source
scival
Published In
Clinical Pulmonary Medicine
Volume
4
Issue
3
Publish Date
1997
Start Page
170
End Page
173

Annals of Internal Medicine: Monitoring warfarin therapy in patients with lupus anticoagulants

Background: Recommended therapeutic international normalized ratios (INRs) for oral anticoagulation in patients with lupus anticoagulants who sustain a thromboembolic event are controversial. Patients with lupus anticoagulants often have a prolonged prothrombin time, which may complicate management of anticoagulant therapy. Objectives: To determine the validity of the INR as a monitor for warfarin therapy in patients with lupus anticoagulants and to investigate alternate approaches to monitoring warfarin therapy in these patients. Design: Prospective case series. Setting: Tertiary care hospital. Patients: 34 patients with lupus anticoagulants. Measurements: Prothrombin times were determined by using several thromboplastins, and INRs were calculated for the patients receiving warfarin. Factor II levels, chromogenic factor X levels, and prothrombin-proconvertin times were determined for patients receiving warfarin. Results: For patients with lupus anticoagulants who were not receiving warfarin, prothrombin times were often elevated and varied significantly with different thromboplastins. Individual thromboplastins differed in sensitivity to the presence of a lupus anticoagulant. For patients receiving warfarin, INRs obtained by using different thromboplastins greatly varied and often overestimated the extent of anticoagulation. Chromogenic factor X levels and prothrombin-proconvertin times correlated well with each other and with established therapeutic ranges. Conclusions: Lupus anticoagulants can influence prothrombin times and lead to INRs that do not accurately reflect the true level of anticoagulation. Use of the INR to standardize prothrombin times is invalid for some patients with lupus anticoagulants. To prevent supratherapeutic or subtherapeutic anticoagulation, these patients must be individually monitored with a test that is insensitive to lupus anticoagulants.

Authors
Moll, S; Ortel, TL
MLA Citation
Moll, S, and Ortel, TL. "Annals of Internal Medicine: Monitoring warfarin therapy in patients with lupus anticoagulants." Annals of Internal Medicine 127.3 (1997): 177-185.
Source
scival
Published In
Annals of Internal Medicine
Volume
127
Issue
3
Publish Date
1997
Start Page
177
End Page
185

Thrombocytopenia in association with a wandering spleen.

An ectopic, so-called wandering spleen is an uncommon occurrence. We present the case of a young woman who presented with abdominal pain and was found to have an enlarged spleen, located in the lower abdomen and pelvis. The possibility of lymphoma was entertained because of concomitant findings of thrombocytopenia and a possible mesenteric mass. The mass was subsequently found at laparotomy to be the tail of the malpositioned pancreas, and the thrombocytopenia resolved with splenectomy. Review of the literature indicates that lymphoma is an uncommon finding in wandering spleens, that wandering spleens are enlarged in most cases, and that thrombocytopenia, while uncommon, can be seen, in particular when associated with torsion of an elongated splenic pedicle.

Authors
Moll, S; Igelhart, JD; Ortel, TL
MLA Citation
Moll, S, Igelhart, JD, and Ortel, TL. "Thrombocytopenia in association with a wandering spleen." Am J Hematol 53.4 (December 1996): 259-263. (Review)
PMID
8948667
Source
pubmed
Published In
American Journal of Hematology
Volume
53
Issue
4
Publish Date
1996
Start Page
259
End Page
263
DOI
10.1002/(SICI)1096-8652(199612)53:4<259::AID-AJH11>3.0.CO;2-7

Patients with antiphospholipid antibodies: CT and MR findings of the brain.

OBJECTIVE: The purpose of this study was to determine the spectrum of neuroradiologic findings in patients with antiphospholipid antibodies (APA) and to compare findings in systemic lupus erythematosus (SLE) and non-SLE patients. MATERIALS AND METHODS: We identified 110 patients with APA who underwent CT or MR imaging, of whom 59 (54%) had abnormal studies. Of these 59 patients, abnormalities were categorized as large infarcts, cortical infarcts, lacunar infarcts, hyperintense white matter foci on T2-weighted images, or dural sinus thrombosis. White matter foci were designated as small (< 5mm) or large (> 5 mm). RESULTS: Large infarcts were the most common abnormality, seen in 24 of 110 (22%) patients, followed in frequency by hyperintense white matter foci, seen in 19 of 110 (17%) patients. Ninety-five percent of patients with hyperintense white matter foci had at least one large lesion, and 76% had five or more small foci, three or more large foci, or both. Small cortical infarcts and lacunar infarcts were seen in 11 of 110 (10%) and 10 of 110 (9%) patients, respectively. Dural sinus thrombosis was seen in five patients. The frequency of abnormalities was high in both the SLE (57%) and the non-SLE (41%) groups. Large infarcts were more common in the non-SLE group (26%) than in the SLE group (5%). Although hyperintense white matter foci and cortical infarcts were more common in SLE patients, the differences were not statistically significant. CONCLUSION: Infarcts of various sizes and hyperintense white matter foci are the most common abnormalities seen on CT and MR imaging in patients with APA. We found no significant differences in frequencies of abnormalities seen between non-SLE and SLE patients.

Authors
Provenzale, JM; Barboriak, DP; Allen, NB; Ortel, TL
MLA Citation
Provenzale, JM, Barboriak, DP, Allen, NB, and Ortel, TL. "Patients with antiphospholipid antibodies: CT and MR findings of the brain." AJR Am J Roentgenol 167.6 (December 1996): 1573-1578.
PMID
8956600
Source
pubmed
Published In
AJR. American journal of roentgenology
Volume
167
Issue
6
Publish Date
1996
Start Page
1573
End Page
1578
DOI
10.2214/ajr.167.6.8956600

Effect of heterologous factor V heavy chain sequences on the secretion of recombinant human factor VIII.

Factor VIII and factor V share a repetitive domain structure of A1-A2-B-A3-C1-C2. To define the region(s) within the factor VIII heavy chain that result in inefficient expression of the recombinant protein, we expressed a series of factor VIII/factor V chimeras that contained heterologous sequences from the A1 and/or A2 domains. Substitution of the factor VIII A1 domain dramatically reduced secretion of factor V approximately 500-fold, whereas substitution of the factor VIII A2 domain had minimal effect on secretion. Conversely, substitution of the factor V A1 domain increased secretion of factor VIII approximately 3-fold, whereas substitution of the factor V A2 domain actually reduced secretion approximately 4-fold. Pulse chase experiments confirmed that reduced expression levels were due to decreased secretion rather than instability of secreted protein. Smaller substitutions did not further localize within the A1 domain the regions responsible for inefficient secretion.

Authors
Ortel, TL; Moore, KD; Ezban, M; Kane, WH
MLA Citation
Ortel, TL, Moore, KD, Ezban, M, and Kane, WH. "Effect of heterologous factor V heavy chain sequences on the secretion of recombinant human factor VIII." Thromb Haemost 75.1 (January 1996): 36-44.
PMID
8713777
Source
pubmed
Published In
Thrombosis and haemostasis
Volume
75
Issue
1
Publish Date
1996
Start Page
36
End Page
44

Factor v inhibitors associated with hemorrhagic symptoms bind to a limited region of the factor va light chain

Factor V inhibitors most commonly occur as (1 ) spontaneously arising autoantibodies in previously normal patients, or (2) cross-reacting alloantibodies arising after exposure to topical bovine thrombin preparations containing bovine factor V. We previously demonstrated that a spontaneous factor V inhibitor associated with hemorrhagic symptoms bound to the aminoterminal region of the second C-type domain (C2) of the light chain of factor V. This resulted in loss of procoagulant activity as well as phosphatidylserine-specHic binding. We have now investigated a total of twelve patients with factor V inhibitors, including seven autoantibodies and five antibodies arising after exposure to bovine thrombin preparations. Eight patients presented with hemorrhagic manifestations (five autoantibodies and three alloantibodies). Four had no clinical manifestations, but were found to have a factor V inhibitor during evaluation of abnormal screening coagulation assays. Using recombinant human factor V (rHFV) deletion mutants, all twelve inhibitors were found to bind epitopes contained within the light chain of factor Va. All eight hemorrhagic inhibitors and one non-hemorrhagic inhibitor were further mapped to the C2 domain. One of the remaining non-hemorrhagic antibodies appeared to recognize an epitope in the C1 domain, but the other two antibodies did not bind to any construct smaller than the light chain. Using recombinant factor V/factor VIII chimeras, we found that seven of the eight hemorrhagic inhibitors bound to the amino terminal third of the 02 domain, while the eighth antibody bound to a larger epitope in the same region. The non-hemorrhagic inhibitor did not bind to any of the chimeras. IgQ preparations from the hemorrhagic Inhibitors neutralized factor Va procoagulant activity in a prothrombinase assay, but this inhibitory effect could be abrogated by pre-incubation of the inhibitor with purified rHFV C2 domain. In addition, none of the inhibitors neutralized the procoagulant activity of a recombinant chimera that replaced the epitope(s) recognized by the inhibitors with the corresponding region of the factor VIII molecule. IgG fractions from the non-hemorrhagic inhibitors had no effect on factor V activity in the same assay system. In summary, inhibitors associated with hemorrhagic symptoms bound to the amino terminal region of the 02 domain, regardless of whether they were autoantibodies or alloantibodies. Interestingly, this region of the bovine factor V 02 domain, spanning 51 amino acids, is identical in primary sequence to the human protein with the exception of 3 amino acids.

Authors
Ortel, TL; Moore, KD; Quinn-Allen, M; Kane, WH
MLA Citation
Ortel, TL, Moore, KD, Quinn-Allen, M, and Kane, WH. "Factor v inhibitors associated with hemorrhagic symptoms bind to a limited region of the factor va light chain." Journal of Investigative Medicine 44.3 (1996): 233a-.
Source
scival
Published In
Journal of Investigative Medicine
Volume
44
Issue
3
Publish Date
1996
Start Page
233a

Anatomic distribution of venous thrombosis in patients with antiphospholipid antibody: imaging findings.

OBJECTIVE: Antiphospholipid antibodies are immunoglobulins that cross-react with phospholipid within cell membranes. These antibodies have been associated with a hypercoagulable state manifested by early stroke, frequent arterial and venous thromboses, recurrent fetal loss, thrombocytopenia, and livedo reticularis (antiphospholipid syndrome). The purpose of this study was to determine the anatomic distribution of venous thrombosis in patients with antiphospholipid antibodies as seen on imaging examinations. MATERIALS AND METHODS: We retrospectively reviewed the laboratory results of patients tested for antiphospholipid antibodies at a tertiary referral center during the period January 1992 to April 1994. This review revealed 228 patients with antiphospholipid antibodies. We excluded patients with systemic lupus erythematosus or any other medical condition associated with a hypercoagulable state and patients over 65 years old. Thirty-one of the remaining 73 patients had undergone imaging studies of the CNS or non-CNS venous system. Radiologic studies (contrast angiography or venography, MR angiography or venography, or Doppler sonography) were examined for the presence of venous thrombosis. Nineteen patients--11 men and eight women, 18-62 years old (average age, 38 years)--with venous thromboses were identified. RESULTS: Twelve patients had non-CNS thrombosis alone, three had CNS thrombosis alone, and four had both CNS and non-CNS thromboses. Locations of non-CNS thromboses included deep veins of the legs (nine occurrences), pulmonary vessels (five), and large veins in the thorax or abdomen (six). Three of these patients had documented thromboses at other sites. Twelve patients had recurrent thrombotic events (six with multiple recurrences), including five with arterial thromboses and two with both venous and arterial thromboses and stroke. Among patients with CNS involvement, five had documented thromboses (four dural sinus, one arterial) and two had arterial distribution strokes demonstrated by CT. Two patients with only non-CNS thromboses had either seizures or migraines. CONCLUSION: Deep veins of the leg were the most common site of venous thrombosis. The thoracic and abdominal venous system and the dural sinuses--unusual sites of thrombosis in the general population--are other common sites. Antiphospholipid antibodies should be suspected when thromboses are found in these locations in the absence of other known risk factors, or when found in combination with arterial thromboses or CNS ischemic disease in young or middle-aged patients.

Authors
Provenzale, JM; Ortel, TL
MLA Citation
Provenzale, JM, and Ortel, TL. "Anatomic distribution of venous thrombosis in patients with antiphospholipid antibody: imaging findings." AJR Am J Roentgenol 165.2 (August 1995): 365-368.
PMID
7618558
Source
pubmed
Published In
AJR. American journal of roentgenology
Volume
165
Issue
2
Publish Date
1995
Start Page
365
End Page
368
DOI
10.2214/ajr.165.2.7618558

Adrenal hemorrhage in patients with primary antiphospholipid syndrome: imaging findings.

OBJECTIVE: The primary antiphospholipid syndrome consists of recurrent thromboses, early stroke, recurrent fetal loss, and livedo reticularis in patients with antiphospholipid antibodies and without systemic lupus erythematosus. The purpose of this study was to analyze the imaging findings in patients who had this syndrome as well as adrenal hemorrhage. MATERIALS AND METHODS: The medical records and reports of radiologic examinations of 228 patients with elevated titers of lupus anticoagulant or anticardiolipin antibodies from January 1992 to April 1994 were examined for indications of adrenal hemorrhage. Four patients (two men and two women 38-78 years old) were identified as having adrenal hemorrhage. The abdominal CT and MR imaging findings for three patients and autopsy data for the fourth patient were analyzed. RESULTS: Adrenal hemorrhage was seen in all three patients who underwent abdominal CT and in one patient who underwent MR imaging. Adrenal hemorrhage was bilateral in three patients. Extension of hemorrhage into the perinephric space was present in two patients. Associated clinical findings probably attributable to the presence of antiphospholipid antibodies included amaurosis fugax (two patients), deep venous thrombosis (three patients), and transient ischemic attacks or stroke (two patients). CONCLUSION: Antiphospholipid antibodies appear to be a risk factor for adrenal hemorrhage. The presence of these antibodies should be suspected in patients who have adrenal hemorrhage as well as recurrent thromboses and early stroke.

Authors
Provenzale, JM; Ortel, TL; Nelson, RC
MLA Citation
Provenzale, JM, Ortel, TL, and Nelson, RC. "Adrenal hemorrhage in patients with primary antiphospholipid syndrome: imaging findings." AJR Am J Roentgenol 165.2 (August 1995): 361-364.
PMID
7618557
Source
pubmed
Published In
AJR. American journal of roentgenology
Volume
165
Issue
2
Publish Date
1995
Start Page
361
End Page
364
DOI
10.2214/ajr.165.2.7618557

Clinical and laboratory evaluation of the hypercoagulable states.

In summary, every patient presenting with a new (or recurrent) thromboembolic event should be carefully assessed for potential predisposing factors. This starts with a thorough patient history and complete physical examination. If indicated, the clinical assessment is then used to guide the clinical laboratory evaluation for a potential hypercoagulable state. Identification of a specific hypercoagulable state, primary or secondary, is extremely important in the prognosis and therapeutic management of the individual patient.

Authors
Macik, BG; Ortel, TL
MLA Citation
Macik, BG, and Ortel, TL. "Clinical and laboratory evaluation of the hypercoagulable states." Clin Chest Med 16.2 (June 1995): 375-387. (Review)
PMID
7656547
Source
pubmed
Published In
Clinics in Chest Medicine
Volume
16
Issue
2
Publish Date
1995
Start Page
375
End Page
387

Thrombin-catalyzed activation of recombinant human factor V.

Proteolytic activation of human factor V by thrombin results from the cleavage of three peptide bonds at Arg709, Arg1018, and Arg1545. In order to define the functional importance of these sites, mutants with isoleucine substitutions blocking thrombin cleavage at one, two, or all three activation sites were expressed in COS-7 cells. The wild type protein is activated approximately 10-fold by thrombin or Russell's viper venom (RVV-V). Thrombin cleavage at Arg709 alone did not result in an increase in procoagulant activity. Cleavage at both Arg709 and Arg1018 resulted in an approximately 3.4-fold increase in activity. Cleavage at these sites was required for rapid cleavage by thrombin at Arg1545, however, which resulted in maximal activation of the factor V molecule. In contrast, isolated cleavage at Arg1545 by RVV-V was sufficient for efficient and complete activation of factor V. The effect of isoleucine substitutions at one or both thrombin cleavage sites in a B-domain deletion mutant lacking amino acids 811-1491 was also investigated. The specific activity of all four mutants was approximately 30% compared to thrombin activated factor V, indicating that these isoleucine substitutions do not drastically alter the structure of the protein and that cleavage at these sites is not required for the expression of partial procoagulant activity.

Authors
Keller, FG; Ortel, TL; Quinn-Allen, MA; Kane, WH
MLA Citation
Keller, FG, Ortel, TL, Quinn-Allen, MA, and Kane, WH. "Thrombin-catalyzed activation of recombinant human factor V." Biochemistry 34.12 (March 28, 1995): 4118-4124.
PMID
7696276
Source
pubmed
Published In
Biochemistry
Volume
34
Issue
12
Publish Date
1995
Start Page
4118
End Page
4124

A Sensitive DRVVT Reagent System for the Detection of Lupus Anticoagulants

Authors
Joyner, KA; Ortel, TL
MLA Citation
Joyner, KA, and Ortel, TL. "A Sensitive DRVVT Reagent System for the Detection of Lupus Anticoagulants." Clinical and Applied Thrombosis/Hemostasis 1.1 (January 1995): 73-75.
Source
crossref
Published In
Clinical and Applied Thrombosis/Hemostasis
Volume
1
Issue
1
Publish Date
1995
Start Page
73
End Page
75
DOI
10.1177/107602969500100112

Evaluation of preanalytical variables associated with measurement of prothrombin fragment 1.2.

We have used a monoclonal antibody-based ELISA for plasma prothrombin fragment 1.2 (F1.2) to establish appropriate sample collection and storage conditions for this biomarker of thrombin generation. F1.2 concentrations were not altered by exogenous factor Xa, thrombin, or thromboplastin if blood was collected by routine venipuncture into tubes containing heparin as anticoagulant (but not citrate, acid-citrate-dextrose, EDTA, or oxalate) and if plasma antithrombin III concentration was > or = 30% of normal. Heparinized plasma F1.2 was stable for > or = 8 h at 20-25 degrees C, and if premixed with a stabilizing reagent, for > or = 4 years at -70 degrees C. Mean values for heparinized plasma F1.2 collected and stored by recommended procedures were increased in patients with thrombosis and conditions of increased thrombotic risk, and were sensitive to heparin and oral anticoagulant therapies. We conclude that plasma obtained by routine venipuncture into tubes with heparin as anticoagulant is an appropriate specimen for F1.2 measurements for most patients.

Authors
Greenberg, CS; Hursting, MJ; Macik, BG; Ortel, TL; Kane, WH; Moore, BM
MLA Citation
Greenberg, CS, Hursting, MJ, Macik, BG, Ortel, TL, Kane, WH, and Moore, BM. "Evaluation of preanalytical variables associated with measurement of prothrombin fragment 1.2." Clin Chem 40.10 (October 1994): 1962-1969.
PMID
7923780
Source
pubmed
Published In
Clinical chemistry
Volume
40
Issue
10
Publish Date
1994
Start Page
1962
End Page
1969

Evaluation of a modified procedure for Staclot LA for the confirmation of lupus anticoagulants.

Staclot LA is a hexagonal (II) phase phospholipid clotting assay used to confirm the presence of lupus anticoagulants (LA). However, there have been complaints that the procedure contains several incubation steps requiring 15 min of operator time. The authors were able to shorten this procedure to a single 5 min incubation without affecting assay sensitivity. Both procedures were performed on 45 known lupus anticoagulant positive specimens, 25 normal donors, eleven plasmas from patients with known factor VIII or factor V inhibitors and ten other specimens submitted for lupus anticoagulant or anticardiolipin antibody testing but without complete testing to confirm the presence of LA prior to testing with Staclot LA. Excellent agreement was observed between the two procedures with concurrence in 87 of 91 specimens (95.6%). Each method detected 39 of 45 LA positive specimens giving a sensitivity of 86.7%. This modification shortens technologist time by two-thirds without compromising assay sensitivity, which will allow for automation on commonly used coagulation analysers.

Authors
Charles, LA; McGlasson, DL; Hawksworth, BA; Ashcraft, JH; Ortel, TL
MLA Citation
Charles, LA, McGlasson, DL, Hawksworth, BA, Ashcraft, JH, and Ortel, TL. "Evaluation of a modified procedure for Staclot LA for the confirmation of lupus anticoagulants." Blood Coagul Fibrinolysis 5.4 (August 1994): 601-604.
PMID
7841317
Source
pubmed
Published In
Blood Coagulation and Fibrinolysis
Volume
5
Issue
4
Publish Date
1994
Start Page
601
End Page
604

Antiphospholipid antibodies in patients without systemic lupus erythematosus: neuroradiologic findings.

PURPOSE: To study neuroradiologic findings in patients with hypercoagulability due to antiphospholipid antibodies (APAs). MATERIALS AND METHODS: Retrospective review of abnormal angiographic, computed tomographic, and magnetic resonance imaging findings was performed over a 14-month period in patients with APAs, no diagnosis of systemic lupus erythematosus, age less than 65 years, and no other cause of a hypercoagulable state. RESULTS: Fourteen patients (age range, 22-62 years) with APAs had abnormal results at neuroradiologic examination. Abnormal findings on cross-sectional imaging studies included large-artery (n = 3), lacunar (n = 5), and venous infarctions (n = 2); cortical atrophy (n = 5); white matter abnormalities (n = 3); and dural sinus thrombosis (n = 4). Abnormal angiographic findings included large-artery occlusions (n = 2), arterial narrowing that simulated vasculitis (n = 2), and transverse sinus thrombosis (n = 1). CONCLUSION: Presence of APAs should be suspected when no cause is apparent for either (a) an ischemic cerebrovascular event in young and middle-aged adults or (b) dural sinus or cerebral venous thrombosis (c) in patients with recurrent systemic arterial or venous thromboses, especially women with recurrent miscarriages.

Authors
Provenzale, JM; Heinz, ER; Ortel, TL; Macik, BG; Charles, LA; Alberts, MJ
MLA Citation
Provenzale, JM, Heinz, ER, Ortel, TL, Macik, BG, Charles, LA, and Alberts, MJ. "Antiphospholipid antibodies in patients without systemic lupus erythematosus: neuroradiologic findings." Radiology 192.2 (August 1994): 531-537.
PMID
8029427
Source
pubmed
Published In
Radiology
Volume
192
Issue
2
Publish Date
1994
Start Page
531
End Page
537
DOI
10.1148/radiology.192.2.8029427

Localization of functionally important epitopes within the second C-type domain of coagulation factor V using recombinant chimeras.

Coagulation factor V, an integral component of the prothrombinase complex, possesses two C-type domains at the carboxyl-terminal end of the molecule. Homologous C-type domains are present in factor VIII as well as several non-coagulation proteins. Deletion of the second C-type domain of factor V results in the loss of procoagulant activity and the ability to bind phosphatidylserine. We now report the effect of substitution of all or a portion of the C2 domain of factor V with the corresponding regions of factor VIII or the human breast carcinoma protein BA46. Substitution of the entire domain with a heterologous C2 domain does not restore significant procoagulant activity, although smaller, exon-size substitutions do result in chimeras with partial activity (approximately 10% of factor Va). Using chimeras with partial substitutions, we determined that the amino-terminal region of the domain is involved in binding to phosphatidylserine. In contrast, the central region of the domain is not involved in phosphatidylserine binding, but an antibody binding at or near this site inhibits procoagulant activity, suggesting that this region is involved in a separate function. Lastly, the molecular basis for the light chain doublet, which is important in the expression of full procoagulant activity, is located within the carboxyl-terminal region of the C2 domain.

Authors
Ortel, TL; Quinn-Allen, MA; Keller, FG; Peterson, JA; Larocca, D; Kane, WH
MLA Citation
Ortel, TL, Quinn-Allen, MA, Keller, FG, Peterson, JA, Larocca, D, and Kane, WH. "Localization of functionally important epitopes within the second C-type domain of coagulation factor V using recombinant chimeras." J Biol Chem 269.22 (June 3, 1994): 15898-15905.
PMID
7515064
Source
pubmed
Published In
The Journal of biological chemistry
Volume
269
Issue
22
Publish Date
1994
Start Page
15898
End Page
15905

Topical thrombin and acquired coagulation factor inhibitors: clinical spectrum and laboratory diagnosis.

Topical bovine thrombin preparations are used extensively in cardiovascular, neurosurgical, and otolaryngologic procedures. Patients who are treated with these topical thrombin preparations may develop antibodies to bovine coagulation factors that may cross-react with the endogenous human clotting proteins. We have identified four patients with acquired factor inhibitors following exposure to topical thrombin at Duke University Medical Center and summarize these cases in addition to 13 patients previously reported in the literature. In most cases, the inhibitor developed following a second (or subsequent) exposure to topical thrombin. The clinical course was extremely variable, ranging from totally asymptomatic to life-threatening hemorrhage. The most consistent laboratory abnormality was a prolonged bovine thrombin clotting time, which corrected, at least partially, when human thrombin was substituted for bovine thrombin. Some of these patients also developed factor V inhibitors with prolonged prothrombin and activated partial thromboplastin times. Although these patients have prolonged clotting times, they should not be considered "autoanticoagulated," since thromboembolic complications can still occur. Therapeutic intervention is largely empirical and depends on the clinical manifestations of the individual patient.

Authors
Ortel, TL; Charles, LA; Keller, FG; Marcom, PK; Oldham, HN; Kane, WH; Macik, BG
MLA Citation
Ortel, TL, Charles, LA, Keller, FG, Marcom, PK, Oldham, HN, Kane, WH, and Macik, BG. "Topical thrombin and acquired coagulation factor inhibitors: clinical spectrum and laboratory diagnosis." Am J Hematol 45.2 (February 1994): 128-135. (Review)
PMID
8141118
Source
pubmed
Published In
American Journal of Hematology
Volume
45
Issue
2
Publish Date
1994
Start Page
128
End Page
135

Complement-induced vesiculation and exposure of membrane prothrombinase sites in platelets of paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired stem-cell disorder in which the glycolipid-anchored membrane proteins, including the cell-surface complement inhibitors, CD55 and CD59, are partially or completely deleted from the plasma membranes of mature blood cells. To gain insight into the pathogenesis of thrombosis that is frequently observed in this disorder, the procoagulant responses of PNH platelets exposed to the human terminal complement proteins C5b-9 were investigated. C5b-9 complexes were assembled on gel-filtered platelets by incubation with purified C5b6, C7, C9, and limiting amounts of C8. Platelet microparticle formation and exposure of plasma membrane-binding sites for coagulation factor Va were then analyzed by flow cytometry. PNH platelets exhibiting undetectable levels of surface CD59 antigen showed an approximately 10-fold increase in sensitivity to C5b-9-stimulated expression of membrane-binding sites for factor Va when compared with platelets from normal controls. Expression of catalytic surface for the prothrombinase complex (VaXa) paralleled the exposure of factor Va-binding sites; the rate of prothrombin conversion by C5b-9-treated PNH platelets exceeded that of C5b-9-treated normal controls by approximately 10-fold at the maximal input of C8 tested (500 ng/mL). These data indicate that PNH platelets deficient in plasma membrane CD59 antigen are exquisitely sensitive to C5b-9-induced expression of prothrombinase activity, and suggest that the tendency toward thrombosis in these patients may be due, at least in part, to the deletion of this complement inhibitor from the platelet plasma membrane.

Authors
Wiedmer, T; Hall, SE; Ortel, TL; Kane, WH; Rosse, WF; Sims, PJ
MLA Citation
Wiedmer, T, Hall, SE, Ortel, TL, Kane, WH, Rosse, WF, and Sims, PJ. "Complement-induced vesiculation and exposure of membrane prothrombinase sites in platelets of paroxysmal nocturnal hemoglobinuria." Blood 82.4 (August 15, 1993): 1192-1196.
PMID
7688991
Source
pubmed
Published In
Blood
Volume
82
Issue
4
Publish Date
1993
Start Page
1192
End Page
1196

Characterization of an acquired inhibitor to coagulation factor V. Antibody binding to the second C-type domain of factor V inhibits the binding of factor V to phosphatidylserine and neutralizes procoagulant activity.

Coagulation Factor V is an essential component of the prothrombinase complex, which activates the zymogen prothrombin to thrombin. A patient was described who developed a Factor V inhibitor that neutralized the procoagulant activity of Factor V and resulted in a fatal hemorrhagic diathesis (Coots, M. C., A. F. Muhleman, and H. I. Glueck. 1978. Am. J. Hematol. 4:193-206). This inhibitor was shown to be an IgG antibody that bound to the light chain of Factor V. Using a series of light chain deletion mutants, we have found that this antibody binds to the second C-type domain of the light chain. Both inhibitor IgG and Fab fragments rapidly neutralized the procoagulant activity of Factor Va, implying that the neutralization resulted from specific binding to the C2 domain. We have previously demonstrated that deletion of the C2 domain results in loss of procoagulant activity, as well as loss of phosphatidylserine-specific binding. Confirming these results, both inhibitor IgG and Fab fragments interfered with phosphatidylserine-specific binding of Factor V. Conversely, preincubation of Factor Va with procoagulant phospholipids protected the cofactor from inactivation by the inhibitor. Our results suggest that this inhibitor neutralizes the procoagulant activity of Factor Va by interfering with the C2-mediated interaction with phospholipid surfaces, thereby disrupting formation of the prothrombinase complex.

Authors
Ortel, TL; Quinn-Allen, MA; Charles, LA; Devore-Carter, D; Kane, WH
MLA Citation
Ortel, TL, Quinn-Allen, MA, Charles, LA, Devore-Carter, D, and Kane, WH. "Characterization of an acquired inhibitor to coagulation factor V. Antibody binding to the second C-type domain of factor V inhibits the binding of factor V to phosphatidylserine and neutralizes procoagulant activity." J Clin Invest 90.6 (December 1992): 2340-2347.
PMID
1281831
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
90
Issue
6
Publish Date
1992
Start Page
2340
End Page
2347
DOI
10.1172/JCI116123

Parenteral anticoagulation with the heparinoid Lomoparan (Org 10172) in patients with heparin induced thrombocytopenia and thrombosis.

Progressive thrombocytopenia may develop in as many as 5% of patients receiving heparin anticoagulation. In these patients, the risk of thromboembolic complications as well as continued thrombocytopenia necessitates discontinuation of heparin and initiation of an alternative anticoagulant when indicated. The heparinoid Lomoparan (Org 10172) is a mixture of several non-heparin low molecular weight glycosaminoglycans with proven anticoagulant efficacy that is generally non-reactive with platelets in the presence of plasma from patients with heparin induced thrombocytopenia, whereas standard heparin will induce platelet aggregation. We evaluated the role of heparinoid as a potential alternative anticoagulant in patients with heparin induced thrombocytopenia. During a 6 month period, we identified six patients with heparin induced thrombocytopenia who required an alternative parenteral anticoagulant, four as primary treatment for specific medical problem, and two as anticoagulation during a necessary surgical procedure. Heparinoid was used successfully in both medical and surgical patients requiring parenteral anticoagulation. In no case was there an exacerbation of the thrombocytopenia nor thromboembolic complications while on heparinoid therapy. Three of our patients sustained hemorrhagic complications, predominantly in the post-surgical setting in association with elevated anti-factor Xa levels and additional anticoagulant agents. We feel that these results confirm the utility of heparinoid anticoagulation in a select subset of patients with heparin induced thrombocytopenia who require continued parenteral anticoagulation.

Authors
Ortel, TL; Gockerman, JP; Califf, RM; McCann, RL; O'Connor, CM; Metzler, DM; Greenberg, CS
MLA Citation
Ortel, TL, Gockerman, JP, Califf, RM, McCann, RL, O'Connor, CM, Metzler, DM, and Greenberg, CS. "Parenteral anticoagulation with the heparinoid Lomoparan (Org 10172) in patients with heparin induced thrombocytopenia and thrombosis." Thromb Haemost 67.3 (March 2, 1992): 292-296.
PMID
1379384
Source
pubmed
Published In
Thrombosis and haemostasis
Volume
67
Issue
3
Publish Date
1992
Start Page
292
End Page
296

Deletion analysis of recombinant human factor V. Evidence for a phosphatidylserine binding site in the second C-type domain.

Human coagulation factor V is an integral component of the prothrombinase complex. Rapid activation of prothrombin is dependent on the interactions of this nonenzymatic cofactor with factor Xa and prothrombin in the presence of calcium ions and a phospholipid or platelet surface. Factor V is similar structurally and functionally to the homologous cofactor, factor VIII, which interacts with factor IXa to accelerate factor X activation in the presence of calcium and phospholipids. Both of these cofactors, when activated, possess homologous heavy and light chains. Binding to anionic phospholipids is mediated by the light chains of these two cofactors. In bovine factor Va, a phosphatidylserine-specific binding site has been localized to the amino-terminal A3 domain of the light chain. In human factor VIII, on the other hand, a region within the carboxyl-terminal C2 domain of the light chain has been shown to interact with anionic phospholipids. We have constructed a series of recombinant deletion mutants lacking domain-size fragments of the light chain of human factor V (rHFV). These mutants are expressed and secreted as single-chain proteins by COS cells. Thrombin and the factor V activator from Russell's viper venom process these deletion mutants as expected. The light chain deletion mutants possess essentially no procoagulant activity, nor are they activated by treatment with factor V activator from Russell's viper venom. Deletion of the second C-type domain results in essentially complete loss of phosphatidylserine-specific binding whereas the presence of the C2 domain alone (rHFV des-A3C1, which lacks the A3 and C1 domains of the light chain) results in significant phosphatidylserine-specific binding. The presence of the A3 domain alone (rHFV des-C1C2) does not mediate binding to immobilized phosphatidylserine. Increasing calcium ion concentrations result in decreased binding of recombinant human factor V and the mutant rHFV des-A3C1 to phosphatidylserine, similar to previous studies with purified plasma factor V and phospholipid vesicles. These results indicate that human factor V, similar to human factor VIII, possesses a phosphatidylserine-specific binding site within the C2 domain of the light chain.

Authors
Ortel, TL; Devore-Carter, D; Quinn-Allen, M; Kane, WH
MLA Citation
Ortel, TL, Devore-Carter, D, Quinn-Allen, M, and Kane, WH. "Deletion analysis of recombinant human factor V. Evidence for a phosphatidylserine binding site in the second C-type domain." J Biol Chem 267.6 (February 25, 1992): 4189-4198.
PMID
1740460
Source
pubmed
Published In
The Journal of biological chemistry
Volume
267
Issue
6
Publish Date
1992
Start Page
4189
End Page
4198

"Heparin-free" cardiopulmonary bypass: first reported use of heparinoid (Org 10172) to provide anticoagulation for cardiopulmonary bypass.

Org 10172 provided adequate anticoagulation for this patient. An excellent correlation between anti-factor Xa activity and ACT was observed at the doses used for CPB. If high-dose Org 10172 is used, these data suggest that it may be possible to circumvent the measurement of anti-factor Xa activity by using the ACT as an index of this heparinoid's anticoagulant effect. Because postoperative bleeding may be excessive, however, development of a method of reversal of Org 10172 is desirable. Although the optimal ACT, dose, plasma concentration, and means of reversal (e.g., protamine vs. heparinase) remains to be determined, heparinoids provide an alternate means of anticoagulation for CPB in patients unable to receive standard heparin.

Authors
Doherty, DC; Ortel, TL; de Bruijn, N; Greenberg, CS; Van Trigt, P
MLA Citation
Doherty, DC, Ortel, TL, de Bruijn, N, Greenberg, CS, and Van Trigt, P. ""Heparin-free" cardiopulmonary bypass: first reported use of heparinoid (Org 10172) to provide anticoagulation for cardiopulmonary bypass." Anesthesiology 73.3 (September 1990): 562-565.
PMID
1697448
Source
pubmed
Published In
Anesthesiology
Volume
73
Issue
3
Publish Date
1990
Start Page
562
End Page
565

Group C streptococcal arthritis: case report and review.

Streptococci account for approximately 15%-20% of cases of nongonococcal septic arthritis. The majority of these are due to group A streptococci, but group B and group G streptococci are being isolated more frequently. We present a case of group C streptococcal arthritis and summarize nine additional cases reported in the literature. The group C streptococci include the large colony of Voges-Proskauer-negative bacteria (Streptococcus equi, Streptococcus equisimilis, Streptococcus zooepidemicus, and Streptococcus dysgalactiae) as well as as the minute colony of Voges-Proskauer-positive Streptococcus anginosus ("Streptococcus milleri") group C organisms. Any joint may become infected, but joints affected by preexisting rheumatologic abnormalities are more frequently involved. Bacteremia was documented in five of the 10 patients. One patient had an associated pneumonia, and another patient had an associated acute aortic valve endocarditis. None of the infections involved a prosthetic joint or an overlying cellulitis, associations reported for group G streptococcal arthritis. Surgical drainage of the infected joint was required in six of the 10 patients. We concluded that the presence of two groups of organisms sharing the same Lancefield group antigen necessitates the careful identification of isolates to determine potential clinical differences.

Authors
Ortel, TL; Kallianos, J; Gallis, HA
MLA Citation
Ortel, TL, Kallianos, J, and Gallis, HA. "Group C streptococcal arthritis: case report and review." Rev Infect Dis 12.5 (September 1990): 829-837. (Review)
PMID
2237126
Source
pubmed
Published In
Reviews of Infectious Diseases
Volume
12
Issue
5
Publish Date
1990
Start Page
829
End Page
837

Expression and characterization of recombinant human factor V and a mutant lacking a major portion of the connecting region.

Human coagulation factor V is a protein cofactor that is an essential component of the prothrombinase complex. A full-length factor V cDNA has been subcloned into the mammalian expression vector pDX and used to transfect COS cells. Approximately 95 +/- 4% of the recombinant human factor V (rHFV) synthesized in COS cells is secreted into the culture medium. Forty-eight hours after transfection rHFV antigen levels in the conditioned medium were 70 +/- 15 ng/mL. Factor V activity determined by fibrometer assay increased approximately 5-fold from 0.027 +/- 0.012 to 0.124 +/- 0.044 unit/mL following activation by the factor V activating enzyme from Russell's viper venom (RVV-V). A chromogenic assay specific for factor Va indicated that recombinant factor V had 3.8 +/- 1.3% of the activity of the activated protein. The estimated specific activity of the recombinant factor Va was approximately 1800 +/- 500 units/mg, which is similar to the specific activity of purified plasma factor Va of 1700-2000 units/mg. Immunoprecipitation of [35S]methionine-labeled rHFV revealed a single high molecular mass component (approximately 330 kDa). Treatment of rHFV with thrombin or RVV-V resulted in the formation of proteolytic products that were similar to those seen with plasma factor V. We have also expressed a mutant, rHFV-des-B811-1441, that lacks a large portion of the highly glycosylated connecting region that is present in factor V. Immunoprecipitation of [35S]methionine-labeled rHFV-des-B811-1441 revealed a single-chain polypeptide with Mr approximately 230 kDa. This mutant constitutively expressed 38 +/- 7% of the activity of the RVV-V-activated protein.(ABSTRACT TRUNCATED AT 250 WORDS)

Authors
Kane, WH; Devore-Carter, D; Ortel, TL
MLA Citation
Kane, WH, Devore-Carter, D, and Ortel, TL. "Expression and characterization of recombinant human factor V and a mutant lacking a major portion of the connecting region." Biochemistry 29.29 (July 24, 1990): 6762-6768.
PMID
2397212
Source
pubmed
Published In
Biochemistry
Volume
29
Issue
29
Publish Date
1990
Start Page
6762
End Page
6768

Author's reply

Authors
Ortel, TL
MLA Citation
Ortel, TL. "Author's reply." American Journal of Hematology 31.3 (July 1989): 220-220.
Source
crossref
Published In
American Journal of Hematology
Volume
31
Issue
3
Publish Date
1989
Start Page
220
End Page
220
DOI
10.1002/ajh.2830310317

High-dose intravenous methylprednisolone for Kasabach-Merritt syndrome

Authors
Ozsoylu, S; Ortel, TL
MLA Citation
Ozsoylu, S, and Ortel, TL. "High-dose intravenous methylprednisolone for Kasabach-Merritt syndrome." American Journal of Hematology 31.3 (1989): 219-220.
PMID
2741917
Source
scival
Published In
American Journal of Hematology
Volume
31
Issue
3
Publish Date
1989
Start Page
219
End Page
220

Antifibrinolytic therapy in the management of the Kasabach Merritt syndrome.

The Kasabach Merritt syndrome consists of thrombocytopenia, microangiopathic hemolytic anemia, and a localized consumption coagulopathy that develops within the abnormal vascular channels of a hemangioma. In general, these patients demonstrate only mild abnormalities of screening clotting tests, but they can potentially develop life-threatening complications. We present a patient who developed a severe anemia that was refractory to erythrocyte transfusions. Treatment with epsilon-aminocaproic acid to inhibit fibrinolysis and cryoprecipitate to replenish his deficient circulating fibrinogen interrupted the cycle of his systemic coagulopathy and enabled us to transfuse him to a normal hematocrit.

Authors
Ortel, TL; Onorato, JJ; Bedrosian, CL; Kaufman, RE
MLA Citation
Ortel, TL, Onorato, JJ, Bedrosian, CL, and Kaufman, RE. "Antifibrinolytic therapy in the management of the Kasabach Merritt syndrome." Am J Hematol 29.1 (September 1988): 44-48.
PMID
3177369
Source
pubmed
Published In
American Journal of Hematology
Volume
29
Issue
1
Publish Date
1988
Start Page
44
End Page
48

Arsenic poisoning and seizures.

Authors
Ortel, TL; Bedrosian, CL; Simel, DL
MLA Citation
Ortel, TL, Bedrosian, CL, and Simel, DL. "Arsenic poisoning and seizures." N C Med J 48.12 (December 1987): 627-630.
PMID
3480434
Source
pubmed
Published In
North Carolina Medical Journal
Volume
48
Issue
12
Publish Date
1987
Start Page
627
End Page
630

Purification of glycopeptides of human plasma proteins by high-performance liquid chromatography.

The combination of gel permeation chromatography and high-performance liquid chromatography proves to be very effective for the purification of high-molecular-weight glycopeptides containing a single glycan, that have been difficult to separate by other procedures. In order to facilitate comparison of the chromatographic properties of glycopeptides derived from a variety of proteins and having different structures, identical procedures were used for their purification. The method was applied to a series of human plasma proteins, including immunoglobulin D, ceruloplasmin, hemopexin, beta-2-glycoprotein I, 3.1S alpha-2-leucine-rich glycoprotein, and alpha-1-B-glycoprotein. All the purified glycopeptides were placed in the protein structure of these plasma proteins. In several cases the carbohydrate structure has been determined by collaborating groups. Immunoglobulin D is the first example of a glycoprotein whose entire primary structure has been defined by utilizing a a single protein source. Furthermore, hemopexin and 3.1S alpha-2-leucine-rich glycoprotein were both found to contain GalN oligosaccharide, which had not previously been identified in these proteins. The method was also used to identify the oligosaccharide that is missing in a carbohydrate variant of ceruloplasmin.

Authors
Takahashi, N; Takahashi, Y; Ortel, TL; Lozier, JN; Ishioka, N; Putnam, FW
MLA Citation
Takahashi, N, Takahashi, Y, Ortel, TL, Lozier, JN, Ishioka, N, and Putnam, FW. "Purification of glycopeptides of human plasma proteins by high-performance liquid chromatography." J Chromatogr 317 (December 28, 1984): 11-26.
PMID
6530429
Source
pubmed
Published In
J Chromatogr
Volume
317
Publish Date
1984
Start Page
11
End Page
26

Structural model of human ceruloplasmin based on internal triplication, hydrophilic/hydrophobic character, and secondary structure of domains.

A molecular model for the structure of human ceruloplasmin is proposed that is based on the determination of the complete amino acid sequence, studies of the products of limited proteolytic cleavage, calculations of the hydrophilic/hydrophobic character (hydropathy profile), and predictions of the local secondary structure. This multicopper oxidase (Mr approximately 132,000) consists of a single polypeptide chain (1046 amino acid residues) with four attached glucosamine oligosaccharides. Computer-assisted statistical analysis of the internal repetition in the amino acid sequence confirms that the entire polypeptide chain is divided into three contiguous homology units, each containing about 350 amino acid residues. Each homology unit is subdivided into three domains, designated A1, A2, and B, that differ in structure and probably in function. Calculations of the hydropathy profile and predictions of the secondary structure support a molecular model based on internal repetition of three homology units and help to identify characteristic features of the interdomain junctions. The alignment scores for internal duplication of pairings of the three homology units of ceruloplasmin exceed the scores yet reported for contiguous internal duplication of any other protein. This highly significant evidence for intragenic repetition suggests that the ceruloplasmin molecule evolved by tandem triplication of ancestral genes coding for a primordial copper oxidase.

Authors
Ortel, TL; Takahashi, N; Putnam, FW
MLA Citation
Ortel, TL, Takahashi, N, and Putnam, FW. "Structural model of human ceruloplasmin based on internal triplication, hydrophilic/hydrophobic character, and secondary structure of domains." Proc Natl Acad Sci U S A 81.15 (August 1984): 4761-4765.
PMID
6589622
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
81
Issue
15
Publish Date
1984
Start Page
4761
End Page
4765

Single-chain structure of human ceruloplasmin: the complete amino acid sequence of the whole molecule.

We have determined the amino acid sequence of the amino-terminal 67,000-dalton (67-kDa) fragment of human ceruloplasmin and have established overlapping sequences between the 67-kDa and 50-kDa fragments and between the 50-kDa and 19-kDa fragments. The 67-kDa fragment contains 480 amino acid residues and three glucosamine oligosaccharides. These results together with our previous sequence data for the 50-kDa and 19-kDa fragments complete the amino acid sequence of human ceruloplasmin. The polypeptide chain has a total of 1,046 amino acid residues (Mr 120,085) and has attachment sites for four glucosamine oligosaccharides; together these account for the total molecular mass of human ceruloplasmin (132 kDa). The sequence analysis of the peptides overlapping the fragments showed that one additional amino acid, arginine, is present between the 67-kDa and 50-kDa fragments, and another, lysine, is between the 50-kDa and 19-kDa fragments. Only two apparent sites of amino acid interchange have been identified in the polypeptide chain. Both involve a single-point interchange of glycine and lysine that would result in a difference in charge. The results of the complete sequence analysis verified that human ceruloplasmin is composed of a single polypeptide chain and that the subunit-like fragments are produced by proteolytic cleavage during purification (and possibly also in vivo).

Authors
Takahashi, N; Ortel, TL; Putnam, FW
MLA Citation
Takahashi, N, Ortel, TL, and Putnam, FW. "Single-chain structure of human ceruloplasmin: the complete amino acid sequence of the whole molecule." Proc Natl Acad Sci U S A 81.2 (January 1984): 390-394.
PMID
6582496
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
81
Issue
2
Publish Date
1984
Start Page
390
End Page
394

Structural model of human ceruloplasmin based on internal triplication, hydrophilic/hydrophobic character, and secondary structure of domains

A molecular model for the structure of human ceruloplasmin is proposed that is based on the determination of the complete amino acid sequence, studies of the products of limited proteolytic cleavage, calculations of the hydrophilic/hydrophobic character (hydropathy profile), and predictions of the local secondary structure. This multicopper oxidase (M(r) ~ 132,000) consists of a single polypeptide chain (1046 amino acid residues) with four attached glucosamine oligosaccharides. Computer-assisted statistical analysis of the internal repetition in the amino acid sequence confirms that the entire polypeptide chain is divided into three contiguous homology units, each containing about 350 amino acid residues. Each homology unit is subdivided into three domains, designated A1, A2, and B, that differ in structure and probably in function. Calculations of the hydropathy profile and predictions of the secondary structure support a molecular model based on internal repetition of three homology units and help to identify characteristic features of the interdomain junctions. The alignment scores for internal duplication of pairings of the three homology units of ceruloplasmin exceed the scores yet reported for contiguous internal duplication of any other protein. This highly significant evidence for intragenic repetition suggests that the ceruloplasmin molecule evolved by tandem triplication of ancestral genes coding for a primordial copper oxidase.

Authors
Ortel, TL; Takahashi, N; Putnam, FW
MLA Citation
Ortel, TL, Takahashi, N, and Putnam, FW. "Structural model of human ceruloplasmin based on internal triplication, hydrophilic/hydrophobic character, and secondary structure of domains." Proceedings of the National Academy of Sciences of the United States of America 81.15 I (1984): 4761-4765.
Source
scival
Published In
Proceedings of the National Academy of Sciences of the United States of America
Volume
81
Issue
15 I
Publish Date
1984
Start Page
4761
End Page
4765

Single-chain structure of human ceruloplasmin: The complete amino acid sequence of the whole molecule

We have determined the amino acid sequence of the amino-terminal 67,000-dalton (67-kDa) fragment of human ceruloplasmin and have established overlapping sequences between the 67-kDa and 50-kDa fragments and between the 50-kDa and 19-kDa fragments. The 67-kDa fragment contains 480 amino acid residues and three glucosamine oligosaccharides. These results together with our previous sequence data for the 50-kDa and 19-kDa fragments complete the amino acid sequence of human ceruloplasmin. The polypeptide chain has a total of 1,046 amino acid residues (M(r) 120,085) and has attachment sites for four glucosamine oligosaccharides; together these account for the total molecular mass of human ceruloplasmin (132 kDa). The sequence analysis of the peptides overlapping the fragments showed that one additional amino acid, arginine, is present between the 67-kDa and 50-kDa fragments, and another, lysine, is between the 50-kDa and 19-kDa fragments. Only two apparent sites of amino acid interchange have been identified in the polypeptide chain. Both involve a single-point interchange of glycine and lysine that would result in a difference in charge. The results of the complete sequence analysis verified that human ceruloplasmin is composed of a single polypeptide chain and that the subunitlike fragments are produced by proteolytic cleavage during purification (and possibly also in vivo).

Authors
Takahashi, N; Ortel, TL; Putnam, FW
MLA Citation
Takahashi, N, Ortel, TL, and Putnam, FW. "Single-chain structure of human ceruloplasmin: The complete amino acid sequence of the whole molecule." Proceedings of the National Academy of Sciences of the United States of America 81.2 I (1984): 390-394.
Source
scival
Published In
Proceedings of the National Academy of Sciences of the United States of America
Volume
81
Issue
2 I
Publish Date
1984
Start Page
390
End Page
394

Separation of limited tryptic fragments of human ceruloplasmin by gel-permeation high-performance liquid chromatography.

Limited tryptic proteolysis of human ceruloplasmin rapidly produces several large, protease-resistant fragments, suggesting that the molecule consists of several domains. In order to locate the sites of proteolytic cleavage in the whole molecule, we used gel-permeation high-performance liquid chromatography to determine the optimum conditions for fragment separation. Using a buffer containing 8 M urea, the 67,000-daltons tryptic fragment from single-chain ceruloplasmin was isolated in a sufficiently pure state for amino acid sequence analysis to determine its location in the uncleaved molecule. These results have been used in conjunction with amino acid sequence data to develop a schematic model of the domain structure of human ceruloplasmin.

Authors
Ortel, TL; Takahashi, N; Putnam, FW
MLA Citation
Ortel, TL, Takahashi, N, and Putnam, FW. "Separation of limited tryptic fragments of human ceruloplasmin by gel-permeation high-performance liquid chromatography." J Chromatogr 266 (August 26, 1983): 257-263.
PMID
6630352
Source
pubmed
Published In
J Chromatogr
Volume
266
Publish Date
1983
Start Page
257
End Page
263

Internal triplication in the structure of human ceruloplasmin.

Amino acid sequence analysis of the 67,000-dalton (67-kDal) fragment that is the amino-terminal half of human ceruloplasmin has revealed internal triplication in the primary structure of the entire molecule. This is illustrated by comparison of 620 residues representing homologous domains of the 67-kDal fragment and of the 50-kDal and 19-kDal fragments that together comprise the carboxyl-terminal half of the molecule. The polypeptide chain is divided into three covalently linked homologous segments, each of about 340 residues. All three homology units have about 30% identity in sequence, and each pair exhibits at least 40% identity. The statistical significance of the 3-fold internal duplication was established by computerized analysis of the sequence. These results and studies of the sites of limited proteolytic cleavage support a model for the ceruloplasmin molecule consisting of an alternating structure of six domains of two different kinds (or possibly nine domains of three kinds). The 3-fold internal homology suggests that the ceruloplasmin molecule evolved by tandem triplication of ancestral genes.

Authors
Takahashi, N; Bauman, RA; Ortel, TL; Dwulet, FE; Wang, CC; Putnam, FW
MLA Citation
Takahashi, N, Bauman, RA, Ortel, TL, Dwulet, FE, Wang, CC, and Putnam, FW. "Internal triplication in the structure of human ceruloplasmin." Proc Natl Acad Sci U S A 80.1 (January 1983): 115-119.
PMID
6571985
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
80
Issue
1
Publish Date
1983
Start Page
115
End Page
119
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