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Semin Thromb Hemost 2011; 37(6): 653-663
DOI: 10.1055/s-0031-1291375
© Thieme Medical Publishers

Heparin-Induced Thrombocytopenia: Real-World Issues

Lori-Ann Linkins1 , Theodore E. Warkentin1 , 2
  • 1Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada
  • 2Pathology and Molecular Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada
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Publication History

Publication Date:
18 November 2011 (online)

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ABSTRACT

Heparin-induced thrombocytopenia (HIT) is a prothrombotic drug reaction caused by platelet-activating antibodies. HIT sera often activate platelets without needing heparin—such heparin-“independent” platelet activation can be associated with HIT beginning or worsening despite stopping heparin (“delayed-onset HIT”). We address important issues in HIT diagnosis and therapy, using a recent cohort of HIT patients to illustrate influences of heparin type; triggers for HIT investigation; serological features of heparin-independent platelet activation; and treatment. In our cohort of recent HIT cases (n = 13), low-molecular-weight heparin (dalteparin) was a common causative agent (n = 8, 62%); most patients were diagnosed after HIT-thrombosis had occurred; and danaparoid was the most frequently selected treatment. Heparin-independent platelet activation was common (7/13 [54%]) and predicted slower platelet count recovery (>1 week) among evaluable patients (5/5 vs 1/6; p = 0.015). In our experience with argatroban-treated patients, HIT-associated consumptive coagulopathy confounds anticoagulant monitoring. Our observations provide guidance on practical aspects of HIT diagnosis and management.

KEYWORDS

Heparin-induced thrombocytopenia - prothrombotic - danaparoid - fondaparinux - direct thrombin inhibitors

REFERENCES

  • 1 Amiral J, Bridey F, Dreyfus M et al.. Platelet factor 4 complexed to heparin is the target for antibodies generated in heparin-induced thrombocytopenia.  Thromb Haemost. 1992;  68 (1) 95-96
    Search in Google Scholar
  • 2 Warkentin T E. Agents for the treatment of heparin-induced thrombocytopenia.  Hematol Oncol Clin North Am. 2010;  24 (4) 755-775 ix
    Search in Google Scholar
  • 3 Warkentin T E, Chong B H, Greinacher A. Heparin-induced thrombocytopenia: towards consensus.  Thromb Haemost. 1998;  79 (1) 1-7
    Search in Google Scholar
  • 4 Sheridan D, Carter C, Kelton J G. A diagnostic test for heparin-induced thrombocytopenia.  Blood. 1986;  67 (1) 27-30
    Search in Google Scholar
  • 5 Warkentin T E, Kelton J G. A 14-year study of heparin-induced thrombocytopenia.  Am J Med. 1996;  101 (5) 502-507
    Search in Google Scholar
  • 6 Warkentin T E. Management of heparin-induced thrombocytopenia: a critical comparison of lepirudin and argatroban.  Thromb Res. 2003;  110 (2-3) 73-82
    Search in Google Scholar
  • 7 Warkentin T E, Kelton J G. Delayed-onset heparin-induced thrombocytopenia and thrombosis.  Ann Intern Med. 2001;  135 (7) 502-506
    Search in Google Scholar
  • 8 Socher I, Kroll H, Jorks S, Santoso S, Sachs U J. Heparin-independent activation of platelets by heparin-induced thrombocytopenia antibodies: a common occurrence.  J Thromb Haemost. 2008;  6 (1) 197-200
    Search in Google Scholar
  • 9 Prechel M M, McDonald M K, Jeske W P, Messmore H L, Walenga J M. Activation of platelets by heparin-induced thrombocytopenia antibodies in the serotonin release assay is not dependent on the presence of heparin.  J Thromb Haemost. 2005;  3 (10) 2168-2175
    Search in Google Scholar
  • 10 Warkentin T E, Bernstein R A. Delayed-onset heparin-induced thrombocytopenia and cerebral thrombosis after a single administration of unfractionated heparin.  N Engl J Med. 2003;  348 (11) 1067-1069
    Search in Google Scholar
  • 11 Greinacher A, Warkentin T E. The direct thrombin inhibitor hirudin.  Thromb Haemost. 2008;  99 (5) 819-829
    Search in Google Scholar
  • 12 Warkentin T E, Levine M N, Hirsh J et al.. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin.  N Engl J Med. 1995;  332 (20) 1330-1335
    Search in Google Scholar
  • 13 Warkentin T E, Roberts R S, Hirsh J, Kelton J G. An improved definition of immune heparin-induced thrombocytopenia in postoperative orthopedic patients.  Arch Intern Med. 2003;  163 (20) 2518-2524
    Search in Google Scholar
  • 14 Warkentin T E. Clinical picture of heparin-induced thrombocytopenia. In: Warkentin T E, Greinacher A, eds. Heparin-Induced Thrombocytopenia. 4th ed. New York: Informa Healthcare USA; 2007: 21-66
    Search in Google Scholar
  • 15 Warkentin T E, Elavathil L J, Hayward C PM, Johnston M A, Russett J I, Kelton J G. The pathogenesis of venous limb gangrene associated with heparin-induced thrombocytopenia.  Ann Intern Med. 1997;  127 (9) 804-812
    Search in Google Scholar
  • 16 Srinivasan A F, Rice L, Bartholomew J R et al.. Warfarin-induced skin necrosis and venous limb gangrene in the setting of heparin-induced thrombocytopenia.  Arch Intern Med. 2004;  164 (1) 66-70
    Search in Google Scholar
  • 17 Warkentin T E. Should vitamin K be administered when HIT is diagnosed after administration of coumarin?.  J Thromb Haemost. 2006;  4 (4) 894-896
    Search in Google Scholar
  • 18 Warkentin T E, Sheppard J A, Sigouin C S, Kohlmann T, Eichler P, Greinacher A. Gender imbalance and risk factor interactions in heparin-induced thrombocytopenia.  Blood. 2006;  108 (9) 2937-2941
    Search in Google Scholar
  • 19 Warkentin T E, Cook R J, Marder V J et al.. Anti-platelet factor 4/heparin antibodies in orthopedic surgery patients receiving antithrombotic prophylaxis with fondaparinux or enoxaparin.  Blood. 2005;  106 (12) 3791-3796
    Search in Google Scholar
  • 20 Salem M, Elrefai S, Shrit M A, Warkentin T E. Fondaparinux thromboprophylaxis-associated heparin-induced thrombocytopenia syndrome complicated by arterial thrombotic stroke.  Thromb Haemost. 2010;  104 (5) 1071-1072
    Search in Google Scholar
  • 21 Greinacher A, Gopinadhan M, Günther J U et al.. Close approximation of two platelet factor 4 tetramers by charge neutralization forms the antigens recognized by HIT antibodies.  Arterioscler Thromb Vasc Biol. 2006;  26 (10) 2386-2393
    Search in Google Scholar
  • 22 Greinacher A, Alban S, Omer-Adam M A, Weitschies W, Warkentin T E. Heparin-induced thrombocytopenia: a stoichiometry-based model to explain the differing immunogenicities of unfractionated heparin, low-molecular-weight heparin, and fondaparinux in different clinical settings.  Thromb Res. 2008;  122 (2) 211-220
    Search in Google Scholar
  • 23 Pouplard C, May M A, Regina S, Marchand M, Fusciardi J, Gruel Y. Changes in platelet count after cardiac surgery can effectively predict the development of pathogenic heparin-dependent antibodies.  Br J Haematol. 2005;  128 (6) 837-841
    Search in Google Scholar
  • 24 Lubenow N, Hinz P, Thomaschewski S et al.. The severity of trauma determines the immune response to PF4/heparin and the frequency of heparin-induced thrombocytopenia.  Blood. 2010;  115 (9) 1797-1803
    Search in Google Scholar
  • 25 Warkentin T E, Sheppard J A, Moore J C, Cook R J, Kelton J G. Studies of the immune response in heparin-induced thrombocytopenia.  Blood. 2009;  113 (20) 4963-4969
    Search in Google Scholar
  • 26 Warkentin T E, Greinacher A, Koster A, Lincoff A M. 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 Erratum in: Chest. 2011;139(5):1261. Dosage error in article text.
    Search in Google Scholar
  • 27 ten Berg M J, van den Bemt PMLA, Huisman A, Schobben AFAM, Egberts T CG, van Solinge W W. Compliance with platelet count monitoring recommendations and management of possible heparin-induced thrombocytopenia in hospitalized patients receiving low-molecular-weight heparin.  Ann Pharmacother. 2009;  43 (9) 1405-1412
    Search in Google Scholar
  • 28 Riggio J M, Cooper M K, Leiby B E, Walenga J M, Merli G J, Gottlieb J E. Effectiveness of a clinical decision support system to identify heparin induced thrombocytopenia.  J Thromb Thrombolysis. 2009;  28 (2) 124-131
    Search in Google Scholar
  • 29 Rogers B A, Cowie A S. The monitoring of heparin induced thrombocytopenia following surgery: an audit and international survey.  J Perioper Pract. 2010;  20 (2) 66-69
    Search in Google Scholar
  • 30 Chong B H, Magnani H N. Danaparoid for the treatment of heparin-induced thrombocytopenia. In: Warkentin T E, Greinacher A, eds. Heparin-Induced Thrombocytopenia. 4th ed. New York: Informa Healthcare USA; 2007: 319-343
    Search in Google Scholar
  • 31 Lubenow N, Warkentin T E, Greinacher A et al.. Results of a systematic evaluation of treatment outcomes for heparin-induced thrombocytopenia in patients receiving danaparoid, ancrod, and/or coumarin explain the rapid shift in clinical practice during the 1990s.  Thromb Res. 2006;  117 (5) 507-515
    Search in Google Scholar
  • 32 Warkentin T E. Fondaparinux: does it cause HIT? Can it treat HIT?.  Expert Rev Hematol. 2010;  3 (5) 567-581
    Search in Google Scholar
  • 33 Greinacher A. Lepirudin for the treatment of heparin-induced thrombocytopenia. In: Warkentin T E, Greinacher A, eds. Heparin-Induced Thrombocytopenia. 4th ed. New York: Informa Healthcare USA; 2007: 345-378
    Search in Google Scholar
  • 34 Lewis B E, Hursting M J. Argatroban therapy in heparin-induced thrombocytopenia. In: Warkentin T E, Greinacher A, eds. Heparin-Induced Thrombocytopenia. 4th ed. New York: Informa Healthcare USA; 2007: 379-408
    Search in Google Scholar
  • 35 Farner B, Eichler P, Kroll H, Greinacher A. A comparison of danaparoid and lepirudin in heparin-induced thrombocytopenia.  Thromb Haemost. 2001;  85 (6) 950-957
    Search in Google Scholar
  • 36 Warkentin T E, Sheppard J I, Moore J C, Sigouin C S, Kelton J G. Quantitative interpretation of optical density measurements using PF4-dependent enzyme-immunoassays.  J Thromb Haemost. 2008;  6 (8) 1304-1312
    Search in Google Scholar
  • 37 Warkentin T E, Kelton J G. Temporal aspects of heparin-induced thrombocytopenia.  N Engl J Med. 2001;  344 (17) 1286-1292
    Search in Google Scholar
  • 38 Lee A Y, Levine M N, Baker R I Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer.  N Engl J Med. 2003;  349 (2) 146-153
    Search in Google Scholar
  • 39 Amiral J, Vissac A M. Role of heparin-dependent antigens in immune heparin-induced thrombocytopenia. In: Warkentin T E, Greinacher A, eds. Heparin-Induced Thrombocytopenia. 4th ed. New York: Informa Healthcare USA; 2007: 131-147
    Search in Google Scholar
  • 40 Girolami B, Prandoni P, Stefani P M et al.. The incidence of heparin-induced thrombocytopenia in hospitalized medical patients treated with subcutaneous unfractionated heparin: a prospective cohort study.  Blood. 2003;  101 (8) 2955-2959
    Search in Google Scholar
  • 41 Prandoni P, Siragusa S, Girolami B, Fabris F. BELZONI Investigators Group . The incidence of heparin-induced thrombocytopenia in medical patients treated with low-molecular-weight heparin: a prospective cohort study.  Blood. 2005;  106 (9) 3049-3054
    Search in Google Scholar
  • 42 Prandoni P, Falanga A, Piccioli A. Cancer, thrombosis and heparin-induced thrombocytopenia.  Thromb Res. 2007;  120 (Suppl 2) S137-S140
    Search in Google Scholar
  • 43 Opatrny L, Warner M N. Risk of thrombosis in patients with malignancy and heparin-induced thrombocytopenia.  Am J Hematol. 2004;  76 (3) 240-244
    Search in Google Scholar
  • 44 ten Cate H, Falanga A. Overview of the postulated mechanisms linking cancer and thrombosis.  Pathophysiol Haemost Thromb. 2008;  36 (3-4) 122-130
    Search in Google Scholar
  • 45 Gruel Y, Pouplard C, Nguyen P French Heparin-Induced Thrombocytopenia Study Group et al. Biological and clinical features of low-molecular-weight heparin-induced thrombocytopenia.  Br J Haematol. 2003;  121 (5) 786-792
    Search in Google Scholar
  • 46 Warkentin T E. HIT paradigms and paradoxes.  J Thromb Haemost. 2011;  9 (Supp. 1) 105-117
    Search in Google Scholar

Theodore E WarkentinM.D. 

Hamilton Regional Laboratory Medicine Program, Room 1-270B, Hamilton Health Sciences, Hamilton General Site

237 Barton Street East, Hamilton, ON L8L 2X2, Canada

Email: twarken@mcmaster.ca