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Clinical presentation and diagnosis of heparin-induced thrombocytopenia

Steven Coutre, MD
Section Editor
Lawrence LK Leung, MD
Deputy Editor
Jennifer S Tirnauer, MD


Heparin-induced thrombocytopenia (HIT) is a life-threatening complication of exposure to heparin (ie, unfractionated heparin, low molecular weight [LMW] heparin) that occurs in up to 5 percent of patients exposed, regardless of the dose, schedule, or route of administration.

HIT results from an autoantibody directed against endogenous platelet factor 4 (PF4) in complex with heparin. This antibody activates platelets and can cause catastrophic arterial and venous thrombosis with a mortality rate as high as 20 percent; although, more recently with improved recognition and early intervention, these rates have been reported as below 2 percent. In those suspected of having HIT based on clinical grounds, all exposure to heparin should be eliminated immediately and a non-heparin anticoagulant should be administered until a complete diagnosis can be made.

The clinical presentation and diagnosis of HIT will be discussed here. The management of HIT and the use of heparin and alternative anticoagulants are discussed separately.

(See "Management of heparin-induced thrombocytopenia".)

(See "Heparin and LMW heparin: Dosing and adverse effects".)


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  1. Visentin GP, Ford SE, Scott JP, Aster RH. 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.
  2. Rauova L, Zhai L, Kowalska MA, et al. Role of platelet surface PF4 antigenic complexes in heparin-induced thrombocytopenia pathogenesis: diagnostic and therapeutic implications. Blood 2006; 107:2346.
  3. Kelton JG, Smith JW, Warkentin TE, et al. Immunoglobulin G from patients with heparin-induced thrombocytopenia binds to a complex of heparin and platelet factor 4. Blood 1994; 83:3232.
  4. Rauova L, Poncz M, McKenzie SE, et al. Ultralarge complexes of PF4 and heparin are central to the pathogenesis of heparin-induced thrombocytopenia. Blood 2005; 105:131.
  5. Khandelwal S, Arepally GM. Immune pathogenesis of heparin-induced thrombocytopenia. Thromb Haemost 2016; 116:792.
  6. Visentin GP, Moghaddam M, Beery SE, et al. Heparin is not required for detection of antibodies associated with heparin-induced thrombocytopenia/thrombosis. J Lab Clin Med 2001; 138:22.
  7. Newman PM, Chong BH. Further characterization of antibody and antigen in heparin-induced thrombocytopenia. Br J Haematol 1999; 107:303.
  8. Sachais BS, Litvinov RI, Yarovoi SV, et al. Dynamic antibody-binding properties in the pathogenesis of HIT. Blood 2012; 120:1137.
  9. Warkentin TE, Makris M, Jay RM, Kelton JG. A spontaneous prothrombotic disorder resembling heparin-induced thrombocytopenia. Am J Med 2008; 121:632.
  10. Warkentin TE, Basciano PA, Knopman J, Bernstein RA. Spontaneous heparin-induced thrombocytopenia syndrome: 2 new cases and a proposal for defining this disorder. Blood 2014; 123:3651.
  11. Lee GM, Arepally GM. Diagnosis and management of heparin-induced thrombocytopenia. Hematol Oncol Clin North Am 2013; 27:541.
  12. Greinacher A, Pötzsch B, Amiral J, et al. Heparin-associated thrombocytopenia: isolation of the antibody and characterization of a multimolecular PF4-heparin complex as the major antigen. Thromb Haemost 1994; 71:247.
  13. Rollin J, Pouplard C, Gruel Y. Risk factors for heparin-induced thrombocytopenia: Focus on Fcγ receptors. Thromb Haemost 2016; 116:799.
  14. Newman PM, Chong BH. 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.
  15. Krauel K, Pötschke C, Weber C, et al. Platelet factor 4 binds to bacteria, [corrected] inducing antibodies cross-reacting with the major antigen in heparin-induced thrombocytopenia. Blood 2011; 117:1370.
  16. Greinacher A, Holtfreter B, Krauel K, et al. Association of natural anti-platelet factor 4/heparin antibodies with periodontal disease. Blood 2011; 118:1395.
  17. Brandt E, Ludwig A, Petersen F, Flad HD. Platelet-derived CXC chemokines: old players in new games. Immunol Rev 2000; 177:204.
  18. Pervushina O, Scheuerer B, Reiling N, et al. Platelet factor 4/CXCL4 induces phagocytosis and the generation of reactive oxygen metabolites in mononuclear phagocytes independently of Gi protein activation or intracellular calcium transients. J Immunol 2004; 173:2060.
  19. Sachais BS, Higazi AA, Cines DB, et al. Interactions of platelet factor 4 with the vessel wall. Semin Thromb Hemost 2004; 30:351.
  20. Rollin J, Pouplard C, Sung HC, et al. Increased risk of thrombosis in FcγRIIA 131RR patients with HIT due to defective control of platelet activation by plasma IgG2. Blood 2015; 125:2397.
  21. Hughes M, Hayward CP, Warkentin TE, et al. Morphological analysis of microparticle generation in heparin-induced thrombocytopenia. Blood 2000; 96:188.
  22. Warkentin TE, Hayward CP, Boshkov LK, 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.
  23. 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.
  24. Cines DB, Tomaski A, Tannenbaum S. Immune endothelial-cell injury in heparin-associated thrombocytopenia. N Engl J Med 1987; 316:581.
  25. Chilver-Stainer L, Lämmle B, Alberio L. Titre of anti-heparin/PF4-antibodies and extent of in vivo activation of the coagulation and fibrinolytic systems. Thromb Haemost 2004; 91:276.
  26. 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.
  27. Kasthuri RS, Glover SL, Jonas W, et al. PF4/heparin-antibody complex induces monocyte tissue factor expression and release of tissue factor positive microparticles by activation of FcγRI. Blood 2012; 119:5285.
  28. Kowalska MA, Krishnaswamy S, Rauova L, et al. Antibodies associated with heparin-induced thrombocytopenia (HIT) inhibit activated protein C generation: new insights into the prothrombotic nature of HIT. Blood 2011; 118:2882.
  29. Suvarna S, Espinasse B, Qi R, et al. Determinants of PF4/heparin immunogenicity. Blood 2007; 110:4253.
  30. Reilly MP, Taylor SM, Franklin C, et al. Prothrombotic factors enhance heparin-induced thrombocytopenia and thrombosis in vivo in a mouse model. J Thromb Haemost 2006; 4:2687.
  31. Carlsson LE, Lubenow N, Blumentritt C, et al. Platelet receptor and clotting factor polymorphisms as genetic risk factors for thromboembolic complications in heparin-induced thrombocytopenia. Pharmacogenetics 2003; 13:253.
  32. 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.
  33. Arepally G, McKenzie SE, Jiang XM, et al. Fc gamma RIIA H/R 131 polymorphism, subclass-specific IgG anti-heparin/platelet factor 4 antibodies and clinical course in patients with heparin-induced thrombocytopenia and thrombosis. Blood 1997; 89:370.
  34. Gruel Y, Pouplard C, Lasne D, et al. The homozygous FcgammaRIIIa-158V genotype is a risk factor for heparin-induced thrombocytopenia in patients with antibodies to heparin-platelet factor 4 complexes. Blood 2004; 104:2791.
  35. 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; 115:1797.
  36. Linkins LA, Dans AL, Moores LK, et al. Treatment and prevention of heparin-induced thrombocytopenia: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e495S.
  37. Cines DB, Rauova L, Arepally G, et al. Heparin-induced thrombocytopenia: an autoimmune disorder regulated through dynamic autoantigen assembly/disassembly. J Clin Apher 2007; 22:31.
  38. 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.
  39. Warkentin TE, Levine MN, Hirsh J, et al. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med 1995; 332:1330.
  40. Harbrecht U, Bastians B, Kredteck A, et al. Heparin-induced thrombocytopenia in neurologic disease treated with unfractionated heparin. Neurology 2004; 62:657.
  41. Girolami B, Prandoni P, Stefani PM, et al. The incidence of heparin-induced thrombocytopenia in hospitalized medical patients treated with subcutaneous unfractionated heparin: a prospective cohort study. Blood 2003; 101:2955.
  42. Morris TA, Castrejon S, Devendra G, Gamst AC. No difference in risk for thrombocytopenia during treatment of pulmonary embolism and deep venous thrombosis with either low-molecular-weight heparin or unfractionated heparin: a metaanalysis. Chest 2007; 132:1131.
  43. Warkentin TE, Sheppard JA, Sigouin CS, et al. Gender imbalance and risk factor interactions in heparin-induced thrombocytopenia. Blood 2006; 108:2937.
  44. Stein PD, Hull RD, Matta F, et al. Incidence of thrombocytopenia in hospitalized patients with venous thromboembolism. Am J Med 2009; 122:919.
  45. Pohl C, Kredteck A, Bastians B, et al. Heparin-induced thrombocytopenia in neurologic patients treated with low-molecular-weight heparin. Neurology 2005; 64:1285.
  46. Prandoni P, Siragusa S, Girolami B, et al. The incidence of heparin-induced thrombocytopenia in medical patients treated with low-molecular-weight heparin: a prospective cohort study. Blood 2005; 106:3049.
  47. Smythe MA, Koerber JM, Mattson JC. The incidence of recognized heparin-induced thrombocytopenia in a large, tertiary care teaching hospital. Chest 2007; 131:1644.
  48. Heeger PS, Backstrom JT. Heparin flushes and thrombocytopenia. Ann Intern Med 1986; 105:143.
  49. Laster J, Silver D. Heparin-coated catheters and heparin-induced thrombocytopenia. J Vasc Surg 1988; 7:667.
  50. Muslimani AA, Ricaurte B, Daw HA. Immune heparin-induced thrombocytopenia resulting from preceding exposure to heparin catheter flushes. Am J Hematol 2007; 82:652.
  51. Avila ML, Shah V, Brandão LR. Systematic review on heparin-induced thrombocytopenia in children: a call to action. J Thromb Haemost 2013; 11:660.
  52. Obeng EA, Harney KM, Moniz T, et al. Pediatric heparin-induced thrombocytopenia: prevalence, thrombotic risk, and application of the 4Ts scoring system. J Pediatr 2015; 166:144.
  53. Warkentin TE. Heparin-induced thrombocytopenia: a clinicopathologic syndrome. Thromb Haemost 1999; 82:439.
  54. Warkentin TE, Kelton JG. Interaction of heparin with platelets, including heparin-induced thrombocytopenia. In: Low-Molecular Weight Heparins in Prophylaxis and Therapy of Thromboembolic Diseases. Fundamental and Clinical Cardiology, Bounameaux H (Ed), Marcel Decker, New York 1994. p.75.
  55. Warkentin TE. Clinical presentation of heparin-induced thrombocytopenia. Semin Hematol 1998; 35:9.
  56. Gelisse E, Gratia E, Just B, Mateu P. Catastrophic antiphospholipid syndrome and heparin-induced thrombocytopenia presenting with adrenal insufficiency caused by bilateral hemorrhagic adrenal infarction during sepsis. Ann Fr Anesth Reanim 2014; 33:e83.
  57. Thota R, Porter J, Ganti AK, Peters E. Hemodynamic collapse following bilateral knee arthroplasty: a mysterious case. J Thromb Thrombolysis 2012; 33:3.
  58. Rosenberger LH, Smith PW, Sawyer RG, et al. Bilateral adrenal hemorrhage: the unrecognized cause of hemodynamic collapse associated with heparin-induced thrombocytopenia. Crit Care Med 2011; 39:833.
  59. Kurtz LE, Yang S. Bilateral adrenal hemorrhage associated with heparin induced thrombocytopenia. Am J Hematol 2007; 82:493.
  60. Goel R, Ness PM, Takemoto CM, et al. Platelet transfusions in platelet consumptive disorders are associated with arterial thrombosis and in-hospital mortality. Blood 2015; 125:1470.
  61. Warkentin TE, Safyan EL, Linkins LA. Heparin-induced thrombocytopenia presenting as bilateral adrenal hemorrhages. N Engl J Med 2015; 372:492.
  62. Warkentin TE, Greinacher A, Koster A, et al. Treatment and prevention of heparin-induced thrombocytopenia: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133:340S.
  63. Warkentin TE, Kelton JG. Temporal aspects of heparin-induced thrombocytopenia. N Engl J Med 2001; 344:1286.
  64. Lubenow N, Kempf R, Eichner A, et al. Heparin-induced thrombocytopenia: temporal pattern of thrombocytopenia in relation to initial use or reexposure to heparin. Chest 2002; 122:37.
  65. Greinacher A, Kohlmann T, Strobel U, et al. The temporal profile of the anti-PF4/heparin immune response. Blood 2009; 113:4970.
  66. Alving BM. How I treat heparin-induced thrombocytopenia and thrombosis. Blood 2003; 101:31.
  67. Warkentin TE, Kelton JG. Delayed-onset heparin-induced thrombocytopenia and thrombosis. Ann Intern Med 2001; 135:502.
  68. Rice L, Attisha WK, Drexler A, Francis JL. Delayed-onset heparin-induced thrombocytopenia. Ann Intern Med 2002; 136:210.
  69. Warkentin TE, Kelton JG. A 14-year study of heparin-induced thrombocytopenia. Am J Med 1996; 101:502.
  70. Hong AP, Cook DJ, Sigouin CS, Warkentin TE. Central venous catheters and upper-extremity deep-vein thrombosis complicating immune heparin-induced thrombocytopenia. Blood 2003; 101:3049.
  71. LaMonte MP, Brown PM, Hursting MJ. Stroke in patients with heparin-induced thrombocytopenia and the effect of argatroban therapy. Crit Care Med 2004; 32:976.
  72. Giossi A, Del Zotto E, Volonghi I, et al. Thromboembolic complications of heparin-induced thrombocytopenia. Blood Coagul Fibrinolysis 2012; 23:559.
  73. White PW, Sadd JR, Nensel RE. Thrombotic complications of heparin therapy: including six cases of heparin--induced skin necrosis. Ann Surg 1979; 190:595.
  74. Sallah S, Thomas DP, Roberts HR. Warfarin and heparin-induced skin necrosis and the purple toe syndrome: infrequent complications of anticoagulant treatment. Thromb Haemost 1997; 78:785.
  75. Warkentin TE. Heparin-induced skin lesions. Br J Haematol 1996; 92:494.
  76. Moore A, Lau E, Yang C, et al. Dalteparin-induced skin necrosis in a patient with metastatic lung adenocarcinoma. Am J Clin Oncol 2007; 30:329.
  77. Tietge UJ, Schmidt HH, Jäckel E, et al. Low molecular weight heparin-induced skin necrosis occurring distant from injection sites and without thrombocytopenia. J Intern Med 1998; 243:313.
  78. Warkentin TE, Roberts RS, Hirsh J, Kelton JG. Heparin-induced skin lesions and other unusual sequelae of the heparin-induced thrombocytopenia syndrome: a nested cohort study. Chest 2005; 127:1857.
  79. Tassava T, Warkentin TE. Non-injection-site necrotic skin lesions complicating postoperative heparin thromboprophylaxis. Am J Hematol 2015; 90:747.
  80. Warkentin TE, Elavathil LJ, Hayward CP, et al. The pathogenesis of venous limb gangrene associated with heparin-induced thrombocytopenia. Ann Intern Med 1997; 127:804.
  81. Comp PC, Elrod JP, Karzenski S. Warfarin-induced skin necrosis. Semin Thromb Hemost 1990; 16:293.
  82. Stanton PE Jr, Evans JR, Lefemine AA, et al. White clot syndrome. South Med J 1988; 81:616.
  83. Arthur CK, Grant SJ, Murray WK, et al. Heparin-associated acute adrenal insufficiency. Aust N Z J Med 1985; 15:454.
  84. Warkentin TE, Hirte HW, Anderson DR, et al. Transient global amnesia associated with acute heparin-induced thrombocytopenia. Am J Med 1994; 97:489.
  85. Singla A, Amini MR, Alpert MA, Gornik HL. Fatal anaphylactoid reaction associated with heparin-induced thrombocytopenia. Vasc Med 2013; 18:136.
  86. Hewitt RL, Akers DL, Leissinger CA, et al. Concurrence of anaphylaxis and acute heparin-induced thrombocytopenia in a patient with heparin-induced antibodies. J Vasc Surg 1998; 28:561.
  87. Tholl U, Greinacher A, Overdick K, Anlauf M. Life-threatening anaphylactic reaction following parathyroidectomy in a dialysis patient with heparin-induced thrombocytopenia. Nephrol Dial Transplant 1997; 12:2750.
  88. Warkentin TE, Greinacher A. Heparin-induced anaphylactic and anaphylactoid reactions: two distinct but overlapping syndromes. Expert Opin Drug Saf 2009; 8:129.
  89. Gruel Y, Pouplard C, Nguyen P, et al. Biological and clinical features of low-molecular-weight heparin-induced thrombocytopenia. Br J Haematol 2003; 121:786.
  90. Spectre G, Kalish Y, Schliamser L, Varon D. Heparin-induced thrombocytopenia in myeloproliferative disorders: a rare or under-diagnosed complication? Am J Hematol 2008; 83:420.
  91. Warkentin TE, Roberts RS, Hirsh J, Kelton JG. An improved definition of immune heparin-induced thrombocytopenia in postoperative orthopedic patients. Arch Intern Med 2003; 163:2518.
  92. Linkins LA. Heparin induced thrombocytopenia. BMJ 2015; 350:g7566.
  93. Greinacher A. CLINICAL PRACTICE. Heparin-Induced Thrombocytopenia. N Engl J Med 2015; 373:252.
  94. Warkentin TE. Clinical picture of heparin-induced thrombocytopenia (HIT) and its differentiation from non-HIT thrombocytopenia. Thromb Haemost 2016; 116:813.
  95. www.hematology.org/Practice/Guidelines/11747.aspx (Accessed on January 07, 2014).
  96. Maiti A, Short NJ, Kroll MH. Indiscriminate Testing for Heparin-Induced Thrombocytopenia: A Teachable Moment. JAMA Intern Med 2016; 176:592.
  97. Lo GK, Juhl D, Warkentin TE, et al. 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.
  98. Hicks LK, Bering H, Carson KR, et al. Five hematologic tests and treatments to question. Blood 2014; 124:3524.
  99. Cuker A, Gimotty PA, Crowther MA, Warkentin TE. Predictive value of the 4Ts scoring system for heparin-induced thrombocytopenia: a systematic review and meta-analysis. Blood 2012; 120:4160.
  100. Napolitano LM, Warkentin TE, Almahameed A, Nasraway SA. Heparin-induced thrombocytopenia in the critical care setting: diagnosis and management. Crit Care Med 2006; 34:2898.
  101. Bakchoul T, Giptner A, Najaoui A, et al. Prospective evaluation of PF4/heparin immunoassays for the diagnosis of heparin-induced thrombocytopenia. J Thromb Haemost 2009; 7:1260.
  102. Bryant A, Low J, Austin S, Joseph JE. Timely diagnosis and management of heparin-induced thrombocytopenia in a frequent request, low incidence single centre using clinical 4T's score and particle gel immunoassay. Br J Haematol 2008; 143:721.
  103. Linkins LA, Bates SM, Lee AY, et al. Combination of 4Ts score and PF4/H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia: prospective cohort study. Blood 2015; 126:597.
  104. Lillo-Le Louët A, Boutouyrie P, Alhenc-Gelas M, et al. Diagnostic score for heparin-induced thrombocytopenia after cardiopulmonary bypass. J Thromb Haemost 2004; 2:1882.
  105. Cuker A, Arepally G, Crowther MA, et al. The HIT Expert Probability (HEP) Score: a novel pre-test probability model for heparin-induced thrombocytopenia based on broad expert opinion. J Thromb Haemost 2010; 8:2642.
  106. Joseph L, Gomes MP, Al Solaiman F, et al. External validation of the HIT Expert Probability (HEP) score. Thromb Haemost 2015; 113:633.
  107. Nagler M, Bachmann LM, ten Cate H, ten Cate-Hoek A. Diagnostic value of immunoassays for heparin-induced thrombocytopenia: a systematic review and meta-analysis. Blood 2016; 127:546.
  108. Cuker A. Does my patient have HIT? There should be an app for that. Blood 2016; 127:522.
  109. Nagler M, Bakchoul T. Clinical and laboratory tests for the diagnosis of heparin-induced thrombocytopenia. Thromb Haemost 2016; 116:823.
  110. Chan M, Malynn E, Shaz B, Uhl L. Utility of consecutive repeat HIT ELISA testing for heparin-induced thrombocytopenia. Am J Hematol 2008; 83:212.
  111. Keeling D, Davidson S, Watson H, Haemostasis and Thrombosis Task Force of the British Committee for Standards in Haematology. The management of heparin-induced thrombocytopenia. Br J Haematol 2006; 133:259.
  112. Warkentin TE, Sheppard JI, Moore JC, et al. Quantitative interpretation of optical density measurements using PF4-dependent enzyme-immunoassays. J Thromb Haemost 2008; 6:1304.
  113. Whitlatch NL, Perry SL, Ortel TL. Anti-heparin/platelet factor 4 antibody optical density values and the confirmatory procedure in the diagnosis of heparin-induced thrombocytopenia. Thromb Haemost 2008; 100:678.
  114. 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.
  115. Baroletti S, Hurwitz S, Conti NA, et al. Thrombosis in suspected heparin-induced thrombocytopenia occurs more often with high antibody levels. Am J Med 2012; 125:44.
  116. Arepally GM, Ortel TL. Clinical practice. Heparin-induced thrombocytopenia. N Engl J Med 2006; 355:809.
  117. 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 heparin-induced thrombocytopenia. Am J Clin Pathol 1999; 111:700.
  118. Verma AK, Levine M, Shalansky SJ, et al. Frequency of heparin-induced thrombocytopenia in critical care patients. Pharmacotherapy 2003; 23:745.
  119. Leroux D, Hezard N, Lebreton A, et al. Prospective evaluation of a rapid nanoparticle-based lateral flow immunoassay (STic Expert(®) HIT) for the diagnosis of heparin-induced thrombocytopenia. Br J Haematol 2014; 166:774.
  120. Sun L, Gimotty PA, Lakshmanan S, Cuker A. Diagnostic accuracy of rapid immunoassays for heparin-induced thrombocytopenia. A systematic review and meta-analysis. Thromb Haemost 2016; 115:1044.
  121. Schenk S, El-Banayosy A, Morshuis M, et al. IgG classification of anti-PF4/heparin antibodies to identify patients with heparin-induced thrombocytopenia during mechanical circulatory support. J Thromb Haemost 2007; 5:235.
  122. Lindhoff-Last E, Gerdsen F, Ackermann H, Bauersachs R. Determination of heparin-platelet factor 4-IgG antibodies improves diagnosis of heparin-induced thrombocytopenia. Br J Haematol 2001; 113:886.
  123. Warkentin TE, Sheppard JA, Moore JC, et al. Laboratory testing for the antibodies that cause heparin-induced thrombocytopenia: how much class do we need? J Lab Clin Med 2005; 146:341.
  124. Juhl D, Eichler P, Lubenow N, et al. Incidence and clinical significance of anti-PF4/heparin antibodies of the IgG, IgM, and IgA class in 755 consecutive patient samples referred for diagnostic testing for heparin-induced thrombocytopenia. Eur J Haematol 2006; 76:420.
  125. 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.
  126. Sheridan D, Carter C, Kelton JG. A diagnostic test for heparin-induced thrombocytopenia. Blood 1986; 67:27.
  127. Warkentin TE. Platelet count monitoring and laboratory testing for heparin-induced thrombocytopenia. Arch Pathol Lab Med 2002; 126:1415.
  128. Harenberg J, Huhle G, Giese C, et al. Determination of serotonin release from platelets by enzyme immunoassay in the diagnosis of heparin-induced thrombocytopenia. Br J Haematol 2000; 109:182.
  129. Chong BH, Burgess J, Ismail F. The clinical usefulness of the platelet aggregation test for the diagnosis of heparin-induced thrombocytopenia. Thromb Haemost 1993; 69:344.
  130. Greinacher A, Amiral J, Dummel V, et al. Laboratory diagnosis of heparin-associated thrombocytopenia and comparison of platelet aggregation test, heparin-induced platelet activation test, and platelet factor 4/heparin enzyme-linked immunosorbent assay. Transfusion 1994; 34:381.
  131. Leo A, Winteroll S. Laboratory diagnosis of heparin-induced thrombocytopenia and monitoring of alternative anticoagulants. Clin Diagn Lab Immunol 2003; 10:731.
  132. Padmanabhan A, Jones CG, Curtis BR, et al. A Novel PF4-Dependent Platelet Activation Assay Identifies Patients Likely to Have Heparin-Induced Thrombocytopenia/Thrombosis. Chest 2016; 150:506.
  133. Warkentin TE. Platelet Activation Testing for Heparin-Induced Thrombocytopenia Antibodies: A Problem That Needs Fixing? Chest 2016; 150:478.
  134. Asmis LM, Segal JB, Plantinga LC, et al. Heparin-induced antibodies and cardiovascular risk in patients on dialysis. Thromb Haemost 2008; 100:498.
  135. Nader ND, Khadra WZ, Reich NT, et al. Blood product use in cardiac revascularization: comparison of on- and off-pump techniques. Ann Thorac Surg 1999; 68:1640.
  136. Selleng S, Malowsky B, Strobel U, et al. Early-onset and persisting thrombocytopenia in post-cardiac surgery patients is rarely due to heparin-induced thrombocytopenia, even when antibody tests are positive. J Thromb Haemost 2010; 8:30.
  137. Gruel Y, Pouplard C. Post-operative platelet count profile: the most reliable tool for identifying patients with true heparin-induced thrombocypenia after cardiac surgery. J Thromb Haemost 2010; 8:27.
  138. Warkentin TE, Sheppard JA, Horsewood P, et al. Impact of the patient population on the risk for heparin-induced thrombocytopenia. Blood 2000; 96:1703.
  139. 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.
  140. Visentin GP, Malik M, Cyganiak KA, Aster RH. Patients treated with unfractionated heparin during open heart surgery are at high risk to form antibodies reactive with heparin:platelet factor 4 complexes. J Lab Clin Med 1996; 128:376.
  141. Schallmoser K, Drexler C, Rohde E, et al. The particle gel immunoassay as a rapid test to rule out heparin-induced thrombocytopenia? J Thorac Cardiovasc Surg 2009; 137:781.
  142. Yusuf AM, Warkentin TE, Arsenault KA, et al. Prognostic importance of preoperative anti-PF4/heparin antibodies in patients undergoing cardiac surgery. A systematic review. Thromb Haemost 2012; 107:8.
  143. Pouplard C, May MA, Regina S, et al. Changes in platelet count after cardiac surgery can effectively predict the development of pathogenic heparin-dependent antibodies. Br J Haematol 2005; 128:837.
  144. Pruthi RK, Daniels PR, Nambudiri GS, Warkentin TE. Heparin-induced thrombocytopenia (HIT) during postoperative warfarin thromboprophylaxis: a second example of postorthopedic surgery 'spontaneous' HIT. J Thromb Haemost 2009; 7:499.
  145. Mallik A, Carlson KB, DeSancho MT. A patient with 'spontaneous' heparin-induced thrombocytopenia and thrombosis after undergoing knee replacement. Blood Coagul Fibrinolysis 2011; 22:73.
  146. Ketha S, Smithedajkul P, Vella A, et al. Adrenal haemorrhage due to heparin-induced thrombocytopenia. Thromb Haemost 2013; 109:669.
  147. Pongas G, Dasgupta SK, Thiagarajan P. Antiplatelet factor 4/heparin antibodies in patients with gram negative bacteremia. Thromb Res 2013; 132:217.