Semin Thromb Hemost 2009; 35(3): 337-343
DOI: 10.1055/s-0029-1222612
© Thieme Medical Publishers

An Update on the Prevalence and Characterization of H-PF4 Antibodies in Asian-Indian Patients

Meganathan Kannan1 , Renu Saxena2 , Cafer Adiguzel3 , Jawed Fareed4
  • 1Postdoctoral fellow, Department of Hematology, All India Institute of Medical Sciences, New Delhi, India; and Division of Hematology, U.S. Food and Drug Administration, NIH, Bethesda, Maryland
  • 2Professor and Head, Department of Hematology, All India Institute of Medical Sciences, New Delhi, India
  • 3Research fellow, Department of Pharmacology, Loyola University Medical Center, Chicago, Illinois; and Department of Hematology, Marmara University School of Medicine, Istanbul, Turkey
  • 4Professor, Department of Pharmacology, Loyola University Medical Center, Chicago, Illinois
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Publikationsverlauf

Publikationsdatum:
18. Mai 2009 (online)

ABSTRACT

Heparin is the second most widely used anticoagulant/antithrombotic agent besides warfarin and is commonly used for various purposes such as treatment and surgical indications. A significant adverse effect of heparin treatment can occur when heparin binds platelet factor 4 (H-PF4) to form a complex that results in formation of H-PF4 antibodies, which in turn leads to platelet/endothelial cell activation followed by heparin-induced thrombocytopenia (HIT). Based on the heparin-induced platelet aggregation and enzyme-linked immunosorbent assay tests, the H-PF4 antibody (HIT antibody) was diagnosed in 6% of Indian patients undergoing cardiovascular surgery who received unfractionated heparin, but the frequency of occurrence rose to 15% when the patients were tested with the 14C-serotonin release assay. This highlights some methodological variations in the diagnosis of HIT antibodies. It was also found that all the HIT-positive patients were either homozygous or heterozygous for the FcγRIIa polymorphism, which also highlights the role of this polymorphism in the occurrence of HIT. Very recent studies show that increases in HIT antibody production may also be due to heparin contaminants. Although these antibodies do not result in thrombocytopenia, contaminants in heparin may be capable of triggering a differential immunogenic response in comparison with contaminant-free heparin. Here we discuss the methodological differences in diagnosing HIT, the potential impact of contaminants in heparin, as well as future considerations.

REFERENCES

  • 1 Amiral J, Marfaing-Koka A, Poncz M, Meyer D. The biological basis of heparin-induced thrombocytopenia.  Platelets. 1998;  9 77-91
  • 2 Ahmad S, Untch B, Haas S et al.. Differential prevalence of anti-heparin-PF4 immunoglobulin subtypes in patients treated with clivarin and heparin: implications in the HIT pathogenesis.  Mol Cell Biochem. 2004;  258 163-170
  • 3 Warkentin T E, Greinacher A. Heparin-induced thrombocytopenia: recognition, treatment, and prevention. The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.  Chest. 2004;  126(Suppl. 3) 311S-337S
  • 4 Fabris F, Ahmad S, Cella G, Jeske W P, Walenga J M, Fareed J. Pathophysiology of heparin-induced thrombocytopenia: clinical and diagnostic implications – a review.  Arch Pathol Lab Med. 2000;  124 1657-1666
  • 5 Chong B H. Heparin-induced thrombocytopenia.  J Thromb Haemost. 2003;  1 1471-1478
  • 6 Castelli R, Cassinerio E, Cappellini M D, Porro F, Graziadei G, Fabris F. Heparin induced thrombocytopenia: pathogenetic, clinical, diagnostic and therapeutic aspects.  Cardiovasc Hematol Disord Drug Targets. 2007;  7 153-162
  • 7 Brieger D B, Mak K H, Kottke-Marchant K. Heparin-induced thrombocytopenia.  J Am Coll Cardiol. 1998;  31 1449-1459
  • 8 Fabris F, Ahmad S, Cella G, Jeske W P, Walenga J M, Fareed J. Pathophysiology of heparin-induced thrombocytopenia: clinical and diagnostic implications—a review.  Arch Pathol Lab Med. 1966;  124 1657-1666
  • 9 Brandt J T, Isenhart C E, Osborne J M, Ahmed A, Anderson C L. On the role of platelet Fc gamma RIIa phenotype in heparin-induced thrombocytopenia.  Thromb Haemost. 1995;  74 1564-1572
  • 10 Lehrnbecher T L, Foster C B, Zhu S et al.. Variant genotypes of FcγRIIA influence the development of Kaposi's sarcoma in HIV-infected men.  Blood. 2000;  95 2386-2390
  • 11 Ohno H, Yokoi M. Intraoperative management for a patient with heparin-induced thrombocytopenia (HIT) undergoing off-pump coronary bypass surgery using argatroban, a direct thrombin inhibitor.  Masui. 2002;  51 30-33
  • 12 Selleng K, Selleng S, Greinacher A. Heparin-induced thrombocytopenia in intensive care patients.  Semin Thromb Hemost. 2008;  34 425-438
  • 13 Prechel M, Walenga J M. The laboratory diagnosis and clinical management of patients with heparin-induced thrombocytopenia: an update.  Semin Thromb Hemost. 2008;  34 86-96
  • 14 Greinacher A, Kohlmann T, Strobel U, Sheppard J A, Warkentin T E. The temporal profile of the anti-PF4/heparin immune response.  Blood. 2008;  , December 23 (Epub ahead of print)
  • 15 Krauel K, Fürll B, Warkentin T E et al.. Heparin-induced thrombocytopenia–therapeutic concentrations of danaparoid, unlike fondaparinux and direct thrombin inhibitors, inhibit formation of platelet factor 4-heparin complexes.  J Thromb Haemost. 2008;  6 2160-2167
  • 16 DiGiovanni C W. Current concepts review: heparin-induced thrombocytopenia.  Foot Ankle Int. 2008;  29 1158-1167
  • 17 Kannan M, Ahmad F, Ahmad S, Kale S, Fareed J, Saxena R. Heparin-PF4 antibodies in heparin induced thrombocytopenia: its relationship with FcgRIIa polymorphism.  Am J Immunol.. 2005;  1 55-59
  • 18 Hursting M J, Verme-Gibboney C N. Risk factors for major bleeding in patients with heparin-induced thrombocytopenia treated with argatroban: a retrospective study.  J Cardiovasc Pharmacol. 2008;  52 561-566
  • 19 Kawano H, Toyoda K, Miyata S et al.. Heparin-induced thrombocytopenia: a serious complication of heparin therapy for acute stroke.  Cerebrovasc Dis. 2008;  26 641-649
  • 20 Jiji R S, Michaels A D. Heparin-induced thrombocytopenia (HIT) causing pulmonary emboli during coronary intervention.  Catheter Cardiovasc Interv. 2008;  72 819-822
  • 21 Kannan M, Ahmad S, Ahmad F et al.. Functional characterization of antibodies against heparin-PF4 complex in heparin-induced thrombocytopenia patients in Asian-Indians: relevance to inflammatory markers.  Blood Coagul Fibrinolysis. 2005;  16 487-490
  • 22 Walenga J M, Jeske W P, Wood J J, Ahmad S, Lewis B E, Bakhos M. Laboratory tests for heparin-induced thrombocytopenia: a multicenter study.  Semin Hematol. 1999;  36(Suppl 1) 22-28
  • 23 Lee D H, Warkentin T E, Denomme G A, Hayward C P, Kelton J G. A diagnostic test for heparin-induced thrombocytopenia: detection of platelet microparticles using flow cytometry.  Br J Haematol. 1996;  95 724-731
  • 24 Kannan M, Ahmed R, Kale S, Ahmad S, Fareed J, Saxena R. Laboratory diagnosis of heparin-induced thrombocytopenia in Asian Indians as investigated with functional and immunologic methods.  Clin Appl Thromb Hemost. 2004;  10 51-54
  • 25 Barginear M F, Donahue L, Allen S L et al.. Heparin-induced thrombocytopenia complicating hemodialysis.  Clin Appl Thromb Hemost. 2008;  14 105-107
  • 26 Bansal V, Cunanan J, Adiguzel C, Litinas E, Nelson K, Fareed J. A higher prevalence of HIT antibodies in patients may be due to contaminated heparin.  Blood. 2008;  112 3022
  • 27 Zhang Z, Weïwer M, Li B, Kemp M M, Daman T H, Linhardt R J. Oversulfated chondroitin sulfate: impact of a heparin impurity, associated with adverse clinical events, on low-molecular-weight heparin preparation.  J Med Chem. 2008;  51 5498-5501
  • 28 Kishimoto T K, Viswanathan K, Ganguly T et al.. Contaminated heparin associated with adverse clinical events and activation of the contact system.  N Engl J Med. 2008;  358 2457-2467
  • 29 Bell W R, Royall R M. Heparin-associated thrombocytopenia: a comparison of three heparin preparations.  N Engl J Med. 1980;  303 902-907
  • 30 Harenberg J, Wehling M. Current and future prospects for anticoagulant therapy: inhibitors of factor Xa and factor IIa.  Semin Thromb Hemost. 2008;  34 39-57
  • 31 Fareed J, Hoppensteadt D A, Fareed D et al.. Survival of heparins, oral anticoagulants, and aspirin after the year 2010.  Semin Thromb Hemost. 2008;  34 58-73
  • 32 Warkentin T E, Greinacher A, Koster A, Lincoff A M. on behalf of the American College of Chest Physicians . Treatment and prevention of heparin-induced thrombocytopenia: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).  Chest. 2008;  133(6, Suppl) 340S-380S
  • 33 Fareed J, Walenga J, Messmore H, Baker W, Bick M. In memoriam: Rodger L. Bick, MD, PhD, FACP–a wonderful friend, great clinician, and brilliant educator.  Clin Appl Thromb Hemost. 2009;  15 5-7
  • 34 Nand S, Wong W, Yuen B, Yetter A, Schmulbach E, Gross Fisher S. Heparin-induced thrombocytopenia with thrombosis: incidence, analysis of risk factors, and clinical outcomes in 108 consecutive patients treated at a single institution.  Am J Hematol. 1997;  56 12-16
  • 35 Warkentin T E. Heparin-induced thrombocytopenia: a ten-year retrospective.  Annu Rev Med. 1999;  50 129-147

Prof. Jawed FareedPh.D. 

Director, Hemostasis and Thrombosis Research Program, Departments of Pathology and Pharmacology

Loyola University Medical Center, 2160 S. First Ave., Maywood, IL 60153

eMail: jfareed@lumc.edu

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