Recent advances in heparin-induced thrombocytopenia

Current Opinion in Hematology

Volumn 18, Issue 5, 2011, Pages 315-322

  Cuker, Adam ^a  

^a UNIVERSITY OF PENNSYLVANIA   (United States)

Author keywords

diagnosis; epidemiology; heparin induced thrombocytopenia; management

Indexed keywords

ANTIVITAMIN K; ARGATROBAN; DANAPAROID; DESULFATOHIRUDIN; FONDAPARINUX; HEPARIN; HIRULOG; LEPIRUDIN; LOW MOLECULAR WEIGHT HEPARIN;

ACUTE CORONARY SYNDROME; ANTICOAGULANT THERAPY; BLEEDING; CLINICAL DECISION MAKING; CLINICAL FEATURE; CONTINUOUS INFUSION; CREATININE CLEARANCE; DRUG CONTRAINDICATION; DRUG DOSE REDUCTION; DRUG DOSE TITRATION; DRUG WITHDRAWAL; ENZYME LINKED IMMUNOSORBENT ASSAY; HEPARIN INDUCED PLATELET ACTIVATION ASSAY; HEPARIN INDUCED THROMBOCYTOPENIA; HUMAN; IMMUNOASSAY; LABORATORY TEST; MORBIDITY; MULTIPLE ORGAN FAILURE; PARTIAL THROMBOPLASTIN TIME; PARTICLE GEL IMMUNOASSAY; PRIORITY JOURNAL; REVIEW; RISK FACTOR; SCORING SYSTEM; SENSITIVITY AND SPECIFICITY; SEROTONIN RELEASE ASSAY; THROMBOCYTE ACTIVATION; THROMBOCYTE COUNT; THROMBOCYTE TRANSFUSION; THROMBOSIS; TREATMENT DURATION; VENOUS THROMBOEMBOLISM;

HEPARIN; HUMANS; THROMBOCYTOPENIA;

EID: 80051786280     PISSN: 10656251     EISSN: 15317048     Source Type: Journal    
DOI: 10.1097/MOH.0b013e3283497ef2     Document Type: Review

References (72)

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;68:95-96.
2. Martel N, Lee J, Wells PS. Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: a meta-analysis. Blood 2005;106:2710-2715. (Pubitemid 41510744)
3. Warkentin TE, Sheppard JA, Sigouin CS, et al. Gender imbalance and risk factor interactions in heparin-induced thrombocytopenia. Blood 2006;108:2937-2941.
4. Cuker A. Heparin-induced thrombocytopenia: present and future. J Thromb Thrombolysis 2011;31:353-366.
5. Lubenow N, Hinz P, Thomaschewski S, et al. The severity of trauma determines the immune response to PF4/heparin and the frequency of heparininduced thrombocytopenia. Blood 2010;115:1797-1803. This randomized trial comparing UFH with LMWH for thromboprophylaxis in trauma patients is the first study to identify severity of trauma as a risk factor for both anti-PF4/heparin antibody formation and HIT.
6. Motokawa S, Torigoshi T, Maeda Y, et al. IgG-class anti-PF4/heparin antibodies and symptomatic DVT in orthopedic surgery patients receiving different antithromboembolic prophylaxis therapeutics. BMC Musculoskelet Disord 2011;12:22.
7. Smythe MA, Koerber JM, Mattson JC. The incidence of recognized heparininduced thrombocytopenia in a large, tertiary care teaching hospital. Chest 2007;131:1644-1649. (Pubitemid 46981615)
8. Bauer TL, Arepally G, Konkle BA, et al. Prevalence of heparin-associated antibodies without thrombosis in patients undergoing cardiopulmonary bypass surgery. Circulation 1997;95:1242-1246. (Pubitemid 27097836)
9. Warkentin TE, Sheppard JA, Horsewood P, et al. Impact of the patient population on the risk of heparin-induced thrombocytopenia. Blood 2000;96:1703-1708. (Pubitemid 30661052)
10. Pouplard C, May MA, Iochmann S, et al. Antibodies to platelet factor 4-heparin after cardiopulmonary bypass in patients anticoagulated with heparin or lowmolecular-weight heparin: clinical implications for heparin-induced thrombocytopenia. Circulation 1999;99:2530-2536. (Pubitemid 29228283)
11. Warkentin TE, Cook RJ, Marder VJ, Greinacher A. Anti-PF4/heparin antibody formation postorthopedic surgery thromboprophylaxis: the role of nondrug risk factors and evidence for a stoichiometry-based model. J Thromb Haemost 2010;8:504-512. This large study of more than 6000 orthopedic surgery patients provides evidence for several novel host-related risk factors for HIT including type of surgery, timing of first anticoagulant dose in relation to surgery, and BMI.
12. Stein PD, Hull RD, Matta F, et al. Incidence of thrombocytopenia in hospitalized patients with venous thromboembolism. Am J Med 2009;122:919-930.
13. Burgess JK, Lindeman R, Chesterman CN, Chong BH. Single amino acid mutation of Fc gamma receptor is associated with the development of heparin-induced thrombocytopenia. Br J Haematol 1995;91:761-766.
14. Gruel Y, Pouplard C, Lasne D, et al. The homozygous FcgammaRIIIa-158 V genotype is a risk factor for heparin-induced thrombocytopenia in patients with antibodies to heparin-platelet factor 4 complexes. Blood 2004;104:2791-2793. (Pubitemid 39434963)
15. Harris K, Nguyen P, Van Cott EM. Platelet PlA2 polymorphism and the risk for thrombosis in heparin-induced thrombocytopenia. Am J Clin Pathol 2008;129:282-286. (Pubitemid 352029319)
16. Warkentin TE. New approaches to the diagnosis of heparin-induced thrombocytopenia. Chest 2005;127:35S-45S. (Pubitemid 40224080)
17. Oliveira GB, Crespo EM, Becker RC, et al. Incidence and prognostic significance of thrombocytopenia in patients treated with prolonged heparin therapy. Arch Intern Med 2008;168:94-102.
18. Selleng S, Malowsky B, Strobel U, et al. Early-onset and persisting thrombocytopenia in postcardiac surgery patients is rarely due to heparin-induced thrombocytopenia, even when antibody tests are positive. J Thromb Haemost 2010;8:30-36. This prospective study demonstrates the rarity of HIT after cardiac surgery, the potential for overdiagnosis in this setting, and differences in the platelet profile between patients with true HIT and those with thrombocytopenia due to other causes.
19. Warkentin TE, Greinacher A. Heparin-induced anaphylactic and anaphylactoid reactions: two distinct but overlapping syndrome. Expert Opin Drug Saf 2009;8:129-144.
20. Teh CH, Robertson MN, Warkentin TE, et al. Transient global amnesia as the presenting feature of heparin-induced thrombocytopenia. J Card Surg 2010;25:386.
21. Warkentin TE. Heparin-induced skin lesions. Br J Haematol 1996;92:494-497. (Pubitemid 26042948)
22. Schinderwolf M, Kroll H, Ackermann H, et al. Heparin-induced nonnecrotizing skin lesions: rarely associated with heparin-induced thrombocytopenia. J Thromb Haemost 2010;8:1486-1491. This is the first study to show that nonnecrotizing skin lesions at subcutaneous injection sites, which were previously thought to be manifestations of HIT, are almost always due to delayed hypersensitivity reactions rather than HIT.
23. Lo GK, Juhl D, Warkentin TE, et al. Evaluation of a pretest clinical score (4T's) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings. J Thromb Haemost 2006;4:759-765.
24. Lillo Le-Louet A, Boutouyrie P, Alhenc-Gelas M, et al. Diagnostic score for heparin-induced thrombocytopenia after cardiopulmonary bypass. J Thromb Haemost 2004;2:1882-1888. (Pubitemid 40192738)
25. Cuker A, Arepally G, Crowther MA, et al. The HIT Expert Probability (HEP) Score: a novel pretest probability model for heparin-induced thrombocytopenia based on broad expert opinion. J Thromb Haemost 2010;8:2642-2650. In this single-center retrospective study, the HEP Score, the first clinical scoring model for HIT based on broad expert opinion, proved superior to the 4Ts with respect to interobserver agreement, correlation with the results of HIT laboratory testing, and agreement with expert diagnosis.
26. Messmore HL, Fabbrini N, Bird ML, et al. Simple scoring system for the early management of heparin-induced thrombocytopenia. Clin Appl Thromb Haemost 2011;17:197-201.
27. Crowther MA, Cook DJ, Albert M, et al. The 4Ts scoring system for heparininduced thrombocytopenia in medical-surgical intensive care unit patients. J Crit Care 2010;25:287-293.
28. Strutt JK, Mackey JE, Johnson SM, Sylvia LM. Assessment of the 4Ts pretest clinical scoring system as a predictor of heparin-induced thrombocytopenia. Pharmacotherapy 2011;31:138-145.
29. Sachan D, Gupta N, Agarwal P, Chaudhary R. The utility of pretest clinical scoring for clinical diagnosis of heparin-induced thrombocytopenia in cardiac surgery patients of a tertiary care centre in North India. Transfus Med 2011 [Epub ahead of print]. doi: 10.1111/j.1365-3148.2010.01068.x.
30. Wirth SM, Macaulay TE, Armistead JA, et al. Evaluation of a clinical scoring scale to direct early appropriate therapy in heparin-induced thrombocytopenia. J Oncol Pharm Pract 2010;16:161-166.
31. Khan MM, Noble DW, Watson HG. Heparin-induced thrombocytopenia and the utility of the 4Ts score in the Intensive Care Unit. Br J Haematol 2011;152:672-674.
32. Pouplard C, Amiral J, Borg JY, et al. 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 heparininduced thrombocytopenia. Am J Clin Pathol 1999;111:700-706. (Pubitemid 29200959)
33. Lo GK, Sigouin CS, Warkentin TE. What is the potential for overdiagnosis of heparin-induced thrombocytopenia? Am J Hematol 2007;82:1037-1043. (Pubitemid 350209843)
34. Martin-Toutain I, Settegrana C, Ankri A. High levels of heparin-platelet factor 4 antibodies in patients with pseudothrombocytopenia: risk of misdiagnosis. J Thromb Haemost 2009;7:1416-1418.
35. Pauzner R, Greinacher A, Selleng K, et al. False-positive tests for heparininduced thrombocytopenia in patients with antiphospholipid syndrome and systemic lupus erythematosus. J Thromb Haemost 2009;7:1070-1074.
36. Zwicker JI, Uhl L, Huang WY, et al. Thrombosis and ELISA optical density values in hospitalized patients with heparin-induced thrombocytopenia. J Thromb Haemost 2005;2:2133-2137.
37. Denys B, Stove V, Philippe J, Devreese K. A clinical-laboratory approach contributing to a rapid and reliable diagnosis of heparin-induced thrombocytopenia. Thromb Res 2008;123:137-145.
38. Greinacher A, Itterman T, Bagemuhl J, et al. Heparin-induced thrombocytopenia: towards standardization of platelet factor 4/heparin antigen tests. J Thromb Haemost 2010;8:2025-2031.
39. Ruf KM, Bensadoun ES, Davis GA, et al. A clinical-laboratory algorithm incorporating optical density value to predict heparin-induced thrombocytopenia. Thromb Haemost 2011;105:553-559.
40. Javela K, Kekomaki R, Koskinen S. Significance of quantitative measurement of heparin-induced platelet antibodies. Eur J Haematol 2010;84:169-174.
41. Warkentin TE, Sheppard JI, Moore JC, Kelton JG. The use of well characterized sera for the assessment of new diagnostic enzyme-immunoassays for the diagnosis of heparin-induced thrombocytopenia. J Thromb Haemost 2010;8:216-218.
42. Morel-Kopp MC, Aboud M, Tan CW, et al. Heparin-induced thrombocytopenia: evaluation of IgG and IgGAM ELISA assays. Int J Lab Hematol 2011;33:245-250.
43. Pouplard C, Leroux D, Regina S, et al. Effectiveness of a new immunoassay for the diagnosis of heparin-induced thrombocytopenia and improved specificity when detecting IgG antibodies. Thromb Haemost 2010;103:145-150.
44. Cuker A, 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;2009:250-252.
45. Selleng S, Schreier N, Wollert HG, Greinacher A. Brief Report: The diagnostic value of the anti-PF4/heparin immunoassay high-dose heparin confirmatory test in cardiac surgery patients. Anesth Analg 2011;112:774-776.
46. Bakchoul T, Giptner A, Bein G, et al. Performance characteristics of two commercially available IgG-specific immunoassays in the assessment of heparin-induced thrombocytopenia (HIT). Thromb Res 2011;127:345-348.
47. Rissoul K, Madani M, Nougier C, et al. Assessment of the interest of using confirmatory test in ELISA with use of high concentration of heparin-induced thrombocytopenia. Ann Biol Clin 2010;68:555-560.
48. Whitlatch NL, Kong DF, Metjian AD, et al. Validation of the high-dose heparin confirmatory step for the diagnosis of heparin-induced thrombocytopenia. Blood 2010;116:1761-1766. This study provides a nomogram for the determination of the probability of HIT based on the results of the HIT ELISA and the high heparin confirmatory test.
49. Legnani C, Cini M, Pili C, et al. Evaluation of a new automated panel of assays for the detection of anti-PF4/heparin antibodies in patients suspected of having heparin-induced thrombocytopenia. Thromb Haemost 2010;104:402-409.
50. Davidson SJ, Ortel TL, Smith LJ. Performance of a new, rapid, automated assay for the detection of antiplatelet factor 4/heparin complex antibodies. Blood Coagul Fibrinolysis 2011;22:340-344.
51. Selleng K, Schutt A, Selleng S, et al. Studies of the antiplatelet factor 4/heparin immune response: adapting the enzyme-linked immunosorbent spot assay for detection of memory B cells against complex antigens. Transfusion 2010;50:32-39. HIT is often diagnosed only after thrombosis occurs. This study represents the first reported attempt to develop an ELISPOT for the early detection of HIT prior to development of pathogenic antibodies and onset of clinical sequelae.
52. Morel-Kopp MC, Aboud M, Tan CW, et al. Whole blood impedance aggregometry detects heparin-induced thrombocytopenia antibodies. Thromb Res 2010;125:e234-e239.
53. Mullier F, Bailly N, Cornet Y, et al. Contribution of platelet microparticles generation assay to the diagnosis of type II heparin-induced thrombocytopenia. Thromb Haemost 2010;103:1277-1281.
54. Jy W, Mao WW, Horstman LL, et al. A flow cytometric assay of platelet activation marker P-selectin (CD62P) distinguished heparin-induced thrombocytopenia (HIT) from HIT with thrombosis (HITT). Thromb Haemost 1999;82:1255-1259. (Pubitemid 29473788)
55. Tomer A. A sensitive and specific functional flow cytometric assay for the diagnosis of heparin-induced thrombocytopenia. Br J Haematol 1997;98:648-656. (Pubitemid 27386546)
56. Warkentin TE, Greinacher A, Koster A, et al. Treatment and prevention of heparin-induced thrombocytopenia: American College of Chest Physicians Evidence-Based Clinical Practice Guideline (8th edition). Chest 2008;133:340S-380S. (Pubitemid 351892970)
57. Pappalardo F, Scandroglio A, Maj G, et al. Treatment of heparin-induced thrombocytopenia after cardiac surgery: preliminary experience with fondaparinux. J Thorac Cardiovasc Surg 2010;139:790-792.
58. Grouzi E, Kyriakou E, Panagou I, Spiliotopoulou I. Fondaparinux for the treatment of acute heparin-induced thrombocytopenia: a single-center experience. Clin Appl Thromb Haemost 2010;16:663-667.
59. Warkentin TE. Fondaparinux: does it cause HIT? Can it treat HIT? Expert Rev Hematol 2010;3:567-581. This is an outstanding review on a timely topic - fondaparinux and its role in both the cause and management of HIT. A pooled analysis of case series of fondaparinux for the treatment of acute HIT is presented.
60. Warkentin TE, Davidson BL, Buller HR, et al. Prevalence and risk of preexisting heparin-induced thrombocytopenia antibodies in patients with acute venous thromboembolism. Chest 2011 [Epub ahead of print]. doi: 10.1378/chest.10-1599. This large serologic study of patients with acute venous thromboembolism demonstrates that fondaparinux, but not UFH or LMWH, is probably safe to give to patients with platelet-activating anti-PF4/heparin antibodies.
61. Warkentin TE, Maurer BT, Aster RH. Heparin-induced thrombocytopenia associated with fondaparinux. N Engl J Med 2007;356:2653-2655.
62. Rota E, Bazzan M, Fantino G. Fondaparinux-related thrombocytopenia in a previous low-molecular-weight heparin (LMWH)-induced heparininduced thrombocytopenia (HIT). Thromb Haemost 2008;99:779-781. (Pubitemid 351694236)
63. Salem M, Elrefai S, Shrit MA, Warkentin TE. Fondaparinux thromboprophylaxis-associated heparin-induced thrombocytopenia syndrome complicated by arterial thrombotic stroke. Thromb Haemost 2010;104:1071-1072.
64. Pistulli R, Oberle V, Figulla HR, et al. Fonadaparinux cross-reacts with heparin antibodies in vitro in a patient with fondaparinux-related thrombocytopenia. Blood Coagul Fibrinolysis 2011;22:76-78.
65. Grubb KJ, Salehi P, Chedrawy EG. Bivalirudin: alternative anticoagulation during cardiopulmonary bypass in patients with heparin-induced thrombocytopenia. Recent Pat Cardiovasc Drug Discov 2010;5:20-24.
66. Kiser TH, Fish DN. Evaluation of bivalirudin treatment for heparin-induced thrombocytopenia in critically ill patients with hepatic and/or renal dysfunction. Pharmacotherapy 2006;26:452-460.
67. Skrupky LP, Smith JR, Deal EN, et al. Comparison of bivalirudin and argatroban for the management of heparin-induced thrombocytopenia. Pharmacotherapy 2010;30:1229-1238. Bivalirudin has never been compared with approved agents for the treatment of HIT in head-to-head fashion. This retrospective cohort study suggests that outcomes with bivalirudin and argatroban are similar.
68. Frame JN, Rice L, Bartholomew JR, Whelton R. Rationale and design of the PREVENT-HIT study: a randomized, open-label pilot study to compare desirudin and argatroban in patients with suspected heparin-induced thrombocytopenia with or without thrombosis. Clin Ther 2010;32:626-636.
69. Boyce SW, Bandyk DF, Bartholomew JR, et al. A randomized, open-label pilot study comparing desirudin and argatroban in patients with suspected heparininduced thrombocytopenia with or without thrombosis. Am J Ther 2010;18:14-22. This is the only randomized controlled comparison of DTIs. Although it was closed prematurely because of poor accrual, the results suggest the potential efficacy, safety, and cost-effectiveness of desirudin in the management of acute HIT.
70. Refaai MA, Chuang C, Menegus M, et al. Outcomes after platelet transfusion in patients with heparin-induced thrombocytopenia. J Thromb Haemost 2010;8:1419-1421. This single-center case series challenges the dogma that platelet transfusion may precipitate thrombosis in patients with acute HIT.
71. Reilly MP, Sinha U, Andre P, et al. PRT-060318, a novel Syk inhibitor, prevents heparin-induced thrombocytopenia and thrombosis in a transgenic mouse model. Blood 2011;117:2241-2246. In this study, treatment with a novel small molecule inhibitor of Syk prevented or mitigated the development of thrombocytopenia and thrombosis in a murine model of HIT.
72. Sachais BS, Rux AH, Hinds JL, Rux JJ. Rational design and characterization of platelet factor 4 antagonists. In: American Society of Hematology Annual Meeting 2010; abstract 724.