The Laboratory Diagnosis and Clinical Management of Patients with Heparin-Induced Thrombocytopenia: An Update

ABSTRACT

Heparin-induced thrombocytopenia (HIT) is a serious adverse effect of heparin exposure that can progress to severe thrombosis, amputation, or death. HIT is an immune response in which antibodies cause platelet activation, platelet aggregation, the generation of procoagulant platelet microparticles, and activation of leukocytes and endothelial cells. Early diagnosis based on a comprehensive interpretation of clinical and laboratory information is important to improve clinical outcomes. However, limitations of the laboratory assays and atypical clinical presentations can make the diagnosis difficult. Clinical management of patients with HIT is with a non-heparin anticoagulant such as a direct thrombin inhibitor or danaparoid followed by a vitamin K antagonist for long-term treatment. The new anti-factor Xa drugs (fondaparinux, rivaroxaban, apixaban) and other non-heparin antithrombotic agents can potentially be used for the treatment of HIT if clinically validated. Important drug-specific limitations and dosing and monitoring guidelines must be respected for patient safety. Issues still exist regarding the optimal clinical management of HIT.

Heparin - thrombocytopenia - antibody - assays - thrombin inhibitor

REFERENCES

• 1 Kelton J G, Sheridan D, Santos A et al.. Heparin-induced thrombocytopenia: laboratory studies.  Blood. 1988;  72 925-930
• 2 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 95-96
• 3 Greinacher A, Potzsch B, Amiral J, Dummel V, Eichner A, Mueller-Eckhardt C. Heparin-associated thrombocytopenia: isolation of the antibody and characterization of a multimolecular PF4-heparin complex as the major antigen.  Thromb Haemost. 1994;  71 247-251
• 4 Maccarana M, Lindahl U. Model of interaction between platelet factor 4 and heparin.  Glycobiology. 1993;  3 271-277
• 5 Mayo K H, Ilyina E, Roongta V et al.. Heparin binding to platelet factor-4. An NMR and site-directed mutagenesis study: arginine residues are crucial for binding.  Biochem J. 1995;  312 357-365
• 6 Newman P M, Chong B H. Heparin-induced thrombocytopenia: new evidence for the dynamic binding of purified anti-PF4-heparin antibodies to platelets and the resultant platelet activation.  Blood. 2000;  96 182-187
• 7 Suh J S, Aster R H, Visentin G P. Antibodies from patients with heparin-induced thrombocytopenia/thrombosis recognize different epitopes on heparin:platelet factor 4.  Blood. 1998;  91 916-922
• 8 Visentin G P. Heparin-induced thrombocytopenia: molecular pathogenesis.  Thromb Haemost. 1999;  82 448-456
• 9 Rauova L, Poncz M, McKenzie S E et al.. Ultralarge complexes of PF4 and heparin are central to the pathogenesis of heparin-induced thrombocytopenia.  Blood. 2005;  105 131-138
• 10 Visentin G P, Ford S E, Scott P J, Aster R H. Antibodies from patients with heparin-induced thrombocytopenia/thrombosis are specific for platelet factor 4 complexed with heparin or bound to endothelial cells.  J Clin Invest. 1994;  93 81-88
• 11 Newman P M, Chong W J. Further characterization of antibody and antigen in heparin-induced thrombocytopenia.  Br J Haematol. 1999;  107 303-309
• 12 Amiral J, Marfaing-Koka M, Wolf M et al.. Presence of autoantibodies to interleukin-8 or neutrophil-activating peptide-2 in patients with heparin-associated thrombocytopenia.  Blood. 1996;  88 410-416
• 13 Regnault V, deMaistre E, Carteaux J, Gruel Y, Nguyen P. Platelet activation induced by human antibodies to interleukin-8.  Blood. 2003;  101 1419-1421
• 14 Walenga J M, Prechel M M, Jeske W P, Bakhos M. Unfractionated heparin compared with low-molecular-weight heparin as related to heparin-induced thrombocytopenia.  Curr Opin Pulm Med. 2005;  11 385-391
• 15 Fareed J, Bick R L, Rao G et al.. The immunogenic potential of generic versions of low-molecular weight heparins may not be the same as the branded products.  Clin Appl Thromb Hemost. 2008;  14 5-7
• 16 Jeske W P, Walenga J M, Szatkowski E et al.. Effect of glycoprotein IIb/IIIa antagonists on the HIT serum induced activation of platelets.  Thromb Res. 1997;  88 271-281
• 17 Warkentin T E, Hayward C P, Boshkov L K et al.. Sera from patients with heparin-induced thrombocytopenia generate platelet-derived microparticles with procoagulant activity: an explanation for the thrombotic complications of heparin-induced thrombocytopenia.  Blood. 1994;  84 3691-3699
• 18 Walenga J M, Jeske W P, Prechel M M, Bakhos M. Newer insights on the mechanism of heparin-induced thrombocytopenia.  Semin Thromb Hemost. 2004;  30(Suppl 1) 57-67
• 19 Jeske W P, Vasaiwala S, Schlenker R, Wallis E, Walenga J M. Leukocyte activation in heparin-induced thrombocytopenia.  Blood. 2000;  96 29b
• 20 Pouplard C, Iochmann S, Renard B et al.. Induction of monocyte tissue factor expression by antibodies to heparin-platelet factor 4 complexes developed in heparin-induced thrombocytopenia.  Blood. 2001;  97 3300-3302
• 21 Herbert J M, Savi P, Jeske W P, Walenga J M. Effect of SR121566A, a potent GP IIb-IIIa antagonist, on the HIT serum/heparin-induced platelet mediated activation of human endothelial cells.  Thromb Haemost. 1998;  80 326-331
• 22 Walenga J M, Michal K, Hoppensteadt D, Wood J J, Bick R L, Robinson J A. Vascular damage correlates between heparin-induced thrombocytopenia and the antiphospholipid syndrome.  Clin Appl Thromb Hemost. 1999;  5(Suppl 1) S76-S84
• 23 Fareed J, Walenga J M, Hoppensteadt D A et al.. Selectins in the HIT syndrome: pathophysiologic role and therapeutic modulation.  Semin Thromb Hemost. 1999;  25(Suppl 1) 37-42
• 24 Blank M, Shoenfeld Y, Tavor S et al.. Anti-platelet factor 4/heparin antibodies from patients with heparin-induced thrombocytopenia provoke direct activation of microvascular endothelial cells.  Int Immunol. 2002;  14 121-129
• 25 Matsuo T, Tomaru T, Kario K, Hirokawa T. Incidence of heparin-PF4 complex antibody formation and heparin-induced thrombocytopenia in acute coronary syndrome.  Thromb Res. 2005;  115 475-481
• 26 Opatrny L, Warner M N. Risk of thrombosis in patients with malignancy and heparin-induced thrombocytopenia.  Am J Hematol. 2004;  76 240-244
• 27 Reininger C B, Greinacher A, Graf J, Lassila R, Steckmeier B, Schwieberer L. Platelets of patients with peripheral arterial disease are hypersensitive to heparin.  Thromb Res. 1996;  81 641-649
• 28 Warkentin T E, Sheppard J A, Horsewood P, Simpson P J, Moore J C. Impact of the patient population on the risk for heparin-induced thrombocytopenia.  Blood. 2000;  96 1703-1708
• 29 Shuster T A, Silliman W R, Coats R D, Mureebe L, Silver D. Heparin-induced thrombocytopenia: twenty-nine years later.  J Vasc Surg. 2003;  38 1316-1322
• 30 Warkentin T E, Greinacher A. Heparin-induced thrombocytopenia: recognition, treatment, and prevention.  Chest. 2004;  126 311S-337S
• 31 Warkentin T E, Crowther M A. When is HIT really HIT?.  Ann Thorac Surg. 2007;  83 21-23
• 32 Lo G K, Juhl D, Warkentin T E, Sigouin C S, Eichler P, Greinacher A. Evaluation of pretest clinical score (4 T's) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings.  J Thromb Haemost. 2006;  4 759-765
• 33 Pouplard C, Amiral J, Borg J Y, Laporte-Simitsidis S, Delahousse B, Gruel Y. Decision analysis for use of platelet aggregation test, carbon 14-serotonin release assay, and heparin-platelet factor 4 enzyme-linked immunosorbent assay for diagnosis of heparin-induced thrombocytopenia.  Am J Clin Pathol. 1999;  111 700-706
• 34 Parker R I. Measurement of heparin-dependent platelet antibodies in the diagnosis of heparin-induced thrombocytopenia: fact or fiction?.  Crit Care Med. 2007;  35 1784-1785
• 35 Walenga J M, Jeske W P, Fasanella A R, Wood J J, Bakhos M. Laboratory tests for the diagnosis of heparin-induced thrombocytopenia.  Semin Thromb Hemost. 1999;  25(Suppl. 1) 43-49
• 36 Chong B H, Burgess J, Ismail F. The clinical usefulness of the platelet aggregation test for the diagnosis of heparin-induced thrombocytopenia.  Thromb Haemost. 1993;  69 344-350
• 37 Warkentin T E, Hayward C PM, Smith C A, Kelly P M, Kelton J G. Determinants of donor platelet variability when testing for heparin-induced thrombocytopenia.  J Lab Clin Med. 1992;  120 371-379
• 38 Eichler P, Budde U, Haas S et al.. First workshop for detection of heparin-induced antibodies: validation of the heparin-induced platelet-activation test (HIPA) in comparison with a PF4/heparin ELISA.  Thromb Haemost. 1999;  81 625-629
• 39 Izban K F, Lietz J W, Hoppensteadt D A et al.. Comparison of two PF4/heparin ELISA assays for the laboratory diagnosis of heparin-induced thrombocytopenia.  Semin Thromb Hemost. 1999;  25(Suppl 1) 51-56
• 40 Warkentin T E, Greinacher A. Laboratory testing for heparin-induced thrombocytopenia. In: Warkentin TE, Greinacher A Heparin-Induced Thrombocytopenia. 4th ed. New York, NY; Informa Healthcare 2007: 227-260
• 41 Martin-Toutain I, Piette J C, Diemert M C, Faucher C, Jobic L, Ankri A. High prevalence of antibodies to platelet factor 4 heparin in patients with antiphospholipid antibodies in absence of heparin-induced thrombocytopenia.  Lupus. 2007;  16 79-83
• 42 Warkentin T E, Sheppard J A, Moore J C, Moore K M, Sigouin C S, Kelton J G. Laboratory testing for the antibodies that cause heparin-induced thrombocytopenia: how much class to we need?.  J Lab Clin Med. 2005;  146 341-346
• 43 Juhl D, Eichler P, Lubenow N, Strobel U, Wessel A, Greinacher A. Incidence and clinical significance of anti-PF4/heparin antibodies of the IgG, IgM, and IgA class in 755 consecutive patients samples referred for diagnostic testing for heparin-induced thrombocytopenia.  Eur J Haematol. 2006;  76 420-426
• 44 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 95-96
• 45 Platelet Immunology ISTH Scientific Subcommittee .Chairs: Warkentin T, Chong B, Greinacher A, Gruel Y, Kiefel V, Kroll H. 6 July 2007. Palexpo, Geneva, Switzerland. http://Available at www.isth2007.com. Accessed December 6, 2007
• 46 Pouplard C, Gueret P, Fouassier M, Ternisien C, Trossaert M, Regina S. Prospective evaluation of the ‘4Ts’ score and particle gel immunoassay specific to heparin/PF4 for the diagnosis of heparin-induced thrombocytopenia.  J Thromb Haemost. 2007;  5 1373-1379
• 47 Warkentin T E. Platelet count monitoring and laboratory testing for heparin-induced thrombocytopenia.  Arch Pathol Lab Med. 2002;  126 1415-1423
• 48 Zwicker J I, Uhl L, Huang W-Y, Shaz B H, Bauer K A. Thrombosis and ELISA optical density values in hospitalized patients with heparin-induced thrombocytopenia.  J Thromb Haemost. 2004;  2 2133-2137
• 49 Refaai M A, Laposata M, VanCott E M. Clinical significance of a borderline titer in a negative ELISA test for heparin-induced thrombocytopenia.  Am J Clin Pathol. 2003;  119 61-65
• 50 Smythe M A, Koerber J M, Mattson J C. An evaluation of heparin platelet factor 4 antibody testing.  J Thromb Haemost. 2005;  3(Suppl 1) 1516
• 51 Messmore H L, Jeske W P, Wehrmacher W, Walenga J M. Benefit-risk assessment of treatments for heparin-induced thrombocytopenia.  Drug Safety. 2003;  26 625-641
• 52 Wallis D E, Workman D L, Lewis B F, Pifarré R, Moran J F. Failure of early heparin cessation as a treatment for heparin-induced thrombocytopenia.  Am J Med. 1999;  106 629-635
• 53 Lewis B E, Wallis D E, Berkowitz S D for the ARG-911 Study Investigators et al.. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia.  Circulation. 2001;  103 1838-1843
• 54 Lewis B E, Wallis D E, Leya F, Hursting M J, Kelton J G. for the Argatroban-915 Investigators. Argatroban anticoagulation in patients with heparin-induced thrombocytopenia.  Arch Intern Med. 2003;  163 1849-1856
• 55 Greinacher A, Völpel H, Janssens U et al.. for the HIT Investigators Group. Recombinant hirudin (lepirudin) provides safe and effective anticoagulation in patients with heparin-induced thrombocytopenia: a prospective study.  Circulation. 1999;  99 73-80
• 56 Greinacher A, Janssens U, Berg G for the HAT Investigataors et al.. Lepirudin (recombinant hirudin) for parenteral anticoagulation in patients with heparin-induced thrombocytopenia.  Circulation. 1999;  100 587-593
• 57 Walenga J M, Fasanella A R, Iqbal O et al.. Coagulation laboratory testing in patients treated with argatroban.  Semin Thromb Hemost. 1999;  25(Suppl 1) 61-66
• 58 Walenga J M, Drenth A F, Mayuga M et al.. Transition from argatroban to oral anticoagulation with phenprocoumon or acenocoumarol: effect on coagulation factor testing.  Clin Appl Thromb Hemost. 2008;  , in press
• 59 Hirsh J, Heddle N, Kelton J G. Treatment of heparin-induced thrombocytopenia.  Arch Intern Med. 2004;  164 361-369
• 60 Warkentin T E. Management of heparin-induced thrombocytopenia: a critical comparison of lepirudin and argatroban.  Thromb Res. 2003;  110 73-82
• 61 Walenga J M, Fareed D, Schultz C, Neville B, Hoppensteadt D. Argatroban, not lepirudin or bivalirudin, treatment results in the generation of nitric oxide during parenteral administration.  Blood. 2004;  104 512a
• 62 Lewis B E, Walenga J M, Hursting M J. Argatroban anticoagulation in patients with heparin-induced thrombocytopenia.  Cardiovasc Rev Rep. 2002;  23 445-457
• 63 Swan S K, Hursting M J. The pharmacokinetics and pharmacodynamics of argatroban: effects of age, gender, and hepatic or renal dysfunction.  Pharmacotherapy. 2000;  20 318-329
• 64 Swan S K, St. Peter J V, Lambrecht L J, Hursting M J. Comparison of anticoagulant effects and safety of argatroban and heparin in healthy subjects.  Pharmacotherapy. 2000;  20 756-770
• 65 La Monte M P, Brown P M, Hursting M J. Alternative parenteral anticoagulation with argatroban, a direct thrombin inhibitor.  Expert Rev Cardiovasc Ther. 2005;  3 31-41
• 66 Matthai Jr W H, Hursting M J, Lewis B E, Kelton J G. Argatroban anticoagulation in patients with a history of heparin-induced thrombocytopenia.  Thromb Res. 2005;  116 121-126
• 67 Walenga J M, Ahmad S, Hoppensteadt D, Iqbal O, Hursting M J, Lewis B E. Argatroban therapy does not generate antibodies that alter its anticoagulant activity in patients with heparin-induced thrombocytopenia.  Thromb Res. 2002;  105 401-405
• 68 Lewis B E, Matthai W H, Cohen M, Moses J, Hursting M J, Leya F. Argatroban anticoagulation during percutaneous coronary intervention in patients with heparin-induced thrombocytopenia.  Catheter Cardiovasc Interv. 2002;  57 177-184
• 69 Jang I K, Hurstings M J. When heparins promote thrombosis: review of heparin-induced thrombocytopenia.  Circulation. 2005;  111 2671-2683
• 70 Cetta F, Graham L C, Wrona L L, Arruda M J, Walenga J M. Argatroban use during pediatric interventional cardiac catheterization.  Catheter Cardiovasc Interv. 2004;  61 147-149
• 71 Jang I K, Lewis B E, Matthai W H, Kleiman N S. Argatroban anticoagulation in conjunction with glycoprotein IIb/IIIa inhibition in patients undergoing percutaneous coronary intervention: an open-label, nonrandomized pilot study.  J Thromb Thrombolysis. 2004;  18 31-37
• 72 LaMonte M P, Brown P M, Hursting M J. Stroke in patients with heparin-induced thrombocytopenia and the effect of argatroban therapy.  Crit Care Med. 2004;  32 976-980
• 73 Cochran K, DeMartini T J, Lewis B E et al.. Use of lepirudin during percutaneous vascular interventions in patients with heparin-induced thrombocytopenia.  J Invasive Cardiol. 2003;  15 617-621
• 74 Eichler P, Friesen H J, Lubenow N, Jaeger B, Greinacher A. Anti-hirudin antibodies in patients with heparin-induced thrombocytopenia treated with lepirudin: incidence, effects on aPTT, and clinical relevance.  Blood. 2000;  96 2373-2378
• 75 Greinacher A, Eichler P, Albrecht D, Strobel U, Potzsch B, Eriksson B I. Anti-hirudin antibodies following low-dose subcutaneous treatment with desirudin for thrombosis prophylaxis after hip-replacement surgery: incidence and clinical relevance.  Blood. 2003;  101 2617-2619
• 76 Fischer K G, Liebe V, Hudek R et al.. Anti-hirudin antibodies alter pharmacokinetics and pharmacodynamics of recombinant hirudin.  Thromb Haemost. 2003;  89 973-982
• 77 Greinacher A, Lubenow N, Eichler P. Anaphylactic and anaphylactoid reactions associated with lepirudin in patients with heparin-induced thrombocytopenia (HIT).  Circulation. 2003;  108 2062-2065
• 78 Mahaffey K W, Lewis B E, Wildermann N M for the ATBAT Investigators et al. The anticoagulant therapy with bivalirudin to assist in the performance of PCI in patients with heparin-induced thrombocytopenia (ATBAT) study.  J Invasive Cardiol. 2003;  15 611-616
• 79 Merry A F, Raudkivi P J, Middleton N G et al.. Bivalirudin versus heparin and protamine in off-pump coronary artery bypass surgery.  Ann Thorac Surg. 2004;  77 925-931
• 80 Koster A, Spiess B, Chew D P et al.. Effectiveness of bivalirudin as a replacement for heparin during cardiopulmonary bypass in patients undergoing coronary artery bypass grafting.  Am J Cardiol. 2004;  93 356-359
• 81 Pötzsch B, Klovekorn W P. Use of heparin during cardiopulmonary bypass in patients with a history of heparin-induced thrombocytopenia.  N Engl J Med. 2000;  343 515-516
• 82 Magnani H N, Gallus A. Heparin-induced thrombocytopenia (HIT). A report of 1,478 clinical outcomes of patients treated with danaparoid (Orgaran) from 1982 to mid-2004.  Thromb Haemost. 2006;  95 967-981
• 83 Lindhoff-Last E, Kreutzenbeck H-J, Magnani H N. Treatment of 51 pregnancies with danaparoid because of heparin intolerance.  Thromb Haemost. 2005;  93 63-69
• 84 Chong B H, Gallus A S, Cade J F, Magnani H, Manoharan A, Oldmeadow M. for the Australian HIT Study Group . Prospective randomized open-label comparison of danaparoid with dextran 70 in the treatment of heparin-induced thrombocytopenia with thrombosis.  Thromb Haemost. 2001;  86 1170-1175
• 85 Farner B, Eichler P, Kroll H, Greinacher A. A comparison of danaparoid and lepirudin in heparin-induced thrombocytopenia.  Thromb Haemost. 2001;  85 950-957
• 86 Walenga J M, Koza M J, Lewis B E, Pifarré R. Relative heparin-induced thrombocytopenic potential of low molecular weight heparins and new antithrombotic agents.  Clin Appl Thromb Hemost. 1996;  2(Suppl 1) S21-S27
• 87 Elalamy I, Lecrubier C, Horellou M H, Conard J, Samama M M. Heparin-induced thrombocytopenia: laboratory management.  Ann Med. 2000;  32(Suppl 1) 60-67
• 88 Wallis D E, Quintos R, Wehrmacher W, Messmore H L. Safety of warfarin anticoagulation in patients with heparin-induced thrombocytopenia.  Chest. 1999;  116 1333-1338
• 89 Gosselin R C, Dager W E, King J H et al.. Effect of direct thrombin inhibitors, bivalirudin, lepirudin, and argatroban, on prothrombin time and INR values.  Am J Clin Pathol. 2004;  121 593-599
• 90 Sheth S B, DiCicco R A, Hursting M J, Montague T, Jorkasky D K. Interpreting the international normalized ratio (INR) in individuals receiving argatroban and warfarin.  Thromb Haemost. 2001;  85 435-440
• 91 Harder S, Graff J, Klinkhardt U et al.. Transition from argatroban to oral anticoagulation with phenprocoumon or acenocoumarol: effects on PT, aPTT, and ecarin clotting time.  Thromb Haemost. 2004;  91 1137-1145
• 92 Hursting M J, Lewis B E, Macfarlane D E. Transitioning from argatroban to warfarin therapy in patients with heparin-induced thrombocytopenia.  Clin Appl Thromb Hemost. 2005;  11 279-287
• 93 Parody R, Oliver A, Souto J C, Fontcuberta J. Fondaparinux (Arixtra) as an alternative anti-thrombotic prophylaxis when there is hypersensitivity to low molecular weight and unfractionated heparins.  Haematologica. 2003;  88 ECR32
• 94 D'Amico E A, Villaca P R, Gualandro S F, Bassitt R P, Chamone D A. Successful use of Arixtra in a patient with paroxysmal nocturnal hemoglobinuria, Budd-Chiari syndrome and heparin-induced thrombocytopenia.  J Thromb Haemost. 2003;  1 2452-2453
• 95 Bradner J, Hallisey R K, Kuter D J. Fondaparinux in the treatment of heparin-induced thrombocytopenia.  Blood. 2004;  104 , abstract 1775
• 96 Warkentin T E, Maurer B T, Aster R H. Heparin-induced thrombocytopenia associated with fondaparinux.  N Engl J Med. 2007;  356 2653-2655
• 97 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 3791-3796
• 98 Walenga J M, Jeske W P, Wallis D E et al.. Clinical experience with combined treatment of thrombin inhibitors and GPIIb/IIIa inhibitors in patients with HIT.  Semin Thromb Hemost. 1999;  25(Suppl 1) 77-81
• 99 Walenga J M, Lewis B E, Jeske W P et al.. Combined thrombin and platelet inhibition treatment for HIT patients.  Haemostaseologie. 1999;  19 128-133
• 100 Haas S, Walenga J M, Jeske W P, Fareed J. Heparin-induced thrombocytopenia: the role of platelet activation and therapeutic implications.  Semin Thromb Hemost. 1999;  25(Suppl 1) 67-75