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Semin Thromb Hemost 2014; 40(01): 106-114
DOI: 10.1055/s-0033-1363461
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Clinical and Laboratory Diagnosis of Heparin-Induced Thrombocytopenia: An Integrated Approach

Adam Cuker
1   Department of Medicine and Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
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Publication History

Publication Date:
21 December 2013 (online)

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Abstract

Heparin-induced thrombocytopenia (HIT) is a clinicopathologic disorder that predisposes to thrombosis. Diagnosis rests on a compatible clinical picture and laboratory evidence of antiplatelet factor 4 (PF4)/heparin antibodies that activate platelets in a heparin-dependent manner. Rapid and accurate diagnosis is paramount to avoid the perils of misdiagnosis. Clinical evaluation may be guided by scoring systems such as the 4Ts and HIT Expert Probability (HEP) score. Laboratory tests include immunoassays, such as the PF4/heparin enzyme–linked immunosorbent assay (ELISA) and functional tests such as the 14C-serotonin release assay and heparin-induced platelet activation assay. Clinical scoring systems and commercially available immunoassays have high sensitivity but modest specificity. Functional assays are more specific, but they are technically demanding. Novel laboratory assays with faster turnaround times, greater specificity, and lesser technical complexity are in development. A Bayesian approach that combines the 4T score and the PF4/heparin ELISA result may be used to estimate the probability of HIT and guide clinical decision making.

Keywords

heparin-induced thrombocytopenia - HIT - diagnosis
 

  • 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
    Article in Thieme ConnectPubMedGoogle Scholar
  • 2 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 (1) 131-138
    CrossrefPubMedGoogle Scholar
  • 3 Cines DB, Tomaski A, Tannenbaum S. Immune endothelial-cell injury in heparin-associated thrombocytopenia. N Engl J Med 1987; 316 (10) 581-589
    CrossrefPubMedGoogle Scholar
  • 4 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 (22) 5285-5293
    CrossrefPubMedGoogle Scholar
  • 5 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-e530S
    CrossrefPubMedGoogle Scholar
  • 6 Cuker A, Cines DB. How I treat heparin-induced thrombocytopenia. Blood 2012; 119 (10) 2209-2218
    CrossrefPubMedGoogle Scholar
  • 7 Cuker A. Current and emerging therapeutics for heparin-induced thrombocytopenia. Semin Thromb Hemost 2012; 38 (1) 31-37
    Article in Thieme ConnectPubMedGoogle Scholar
  • 8 Greinacher A, Eichler P, Lubenow N, Kwasny H, Luz M. Heparin-induced thrombocytopenia with thromboembolic complications: meta-analysis of 2 prospective trials to assess the value of parenteral treatment with lepirudin and its therapeutic aPTT range. Blood 2000; 96 (3) 846-851
    CrossrefPubMedGoogle Scholar
  • 9 Warkentin TE, Kelton JG. A 14-year study of heparin-induced thrombocytopenia. Am J Med 1996; 101 (5) 502-507
    CrossrefPubMedGoogle Scholar
  • 10 Wallis DE, Workman DL, Lewis BE, Steen L, Pifarre R, Moran JF. Failure of early heparin cessation as treatment for heparin-induced thrombocytopenia. Am J Med 1999; 106 (6) 629-635
    CrossrefPubMedGoogle Scholar
  • 11 Cuker A. Heparin-induced thrombocytopenia (HIT) in 2011: an epidemic of overdiagnosis. Thromb Haemost 2011; 106 (6) 993-994
    Article in Thieme ConnectPubMedGoogle Scholar
  • 12 Lewis BE, Wallis DE, Hursting MJ, Levine RL, Leya F. Effects of argatroban therapy, demographic variables, and platelet count on thrombotic risks in heparin-induced thrombocytopenia. Chest 2006; 129 (6) 1407-1416
    CrossrefPubMedGoogle Scholar
  • 13 Lubenow N, Eichler P, Lietz T, Greinacher A ; Hit Investigators Group. Lepirudin in patients with heparin-induced thrombocytopenia - results of the third prospective study (HAT-3) and a combined analysis of HAT-1, HAT-2, and HAT-3. J Thromb Haemost 2005; 3 (11) 2428-2436
    CrossrefPubMedGoogle Scholar
  • 14 Magnani HN, 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 (6) 967-981
    Article in Thieme ConnectPubMedGoogle Scholar
  • 15 Warkentin TE, Greinacher A, Gruel Y, Aster RH, Chong BH ; Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Laboratory testing for heparin-induced thrombocytopenia: A conceptual framework and. implications for diagnosis. J Thromb Haemost 2011; 9: 2498-2500
    CrossrefPubMedGoogle Scholar
  • 16 Oliveira GB, Crespo EM, Becker RC , et al; Complications After Thrombocytopenia Caused by Heparin (CATCH) Registry Investigators. Incidence and prognostic significance of thrombocytopenia in patients treated with prolonged heparin therapy. Arch Intern Med 2008; 168 (1) 94-102
    CrossrefPubMedGoogle Scholar
  • 17 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 (8) 2955-2959
    CrossrefPubMedGoogle Scholar
  • 18 Büller HR, Davidson BL, Decousus H , et al; Matisse Investigators. Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism. N Engl J Med 2003; 349 (18) 1695-1702
    CrossrefPubMedGoogle Scholar
  • 19 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 (4) 1131-1139
    CrossrefPubMedGoogle Scholar
  • 20 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
    CrossrefPubMedGoogle Scholar
  • 21 Hui P, Cook DJ, Lim W, Fraser GA, Arnold DM. The frequency and clinical significance of thrombocytopenia complicating critical illness: a systematic review. Chest 2011; 139 (2) 271-278
    CrossrefPubMedGoogle Scholar
  • 22 Crowther MA, Cook DJ, Meade MO , et al. Thrombocytopenia in medical-surgical critically ill patients: prevalence, incidence, and risk factors. J Crit Care 2005; 20 (4) 348-353
    CrossrefPubMedGoogle Scholar
  • 23 Cook D, Meade M, Guyatt G , et al; PROTECT Investigators for the Canadian Critical Care Trials Group and the Australian and New Zealand Intensive Care Society Clinical Trials Group. Dalteparin versus unfractionated heparin in critically ill patients. N Engl J Med 2011; 364 (14) 1305-1314
    CrossrefPubMedGoogle Scholar
  • 24 Crowther MA, Cook DJ, Albert M , et al; Canadian Critical Care Trials Group. The 4Ts scoring system for heparin-induced thrombocytopenia in medical-surgical intensive care unit patients. J Crit Care 2010; 25 (2) 287-293
    CrossrefPubMedGoogle Scholar
  • 25 Verma AK, Levine M, Shalansky SJ, Carter CJ, Kelton JG. Frequency of heparin-induced thrombocytopenia in critical care patients. Pharmacotherapy 2003; 23 (6) 745-753
    CrossrefPubMedGoogle Scholar
  • 26 Cuker A. Heparin-induced thrombocytopenia: present and future. J Thromb Thrombolysis 2011; 31 (3) 353-366
    CrossrefPubMedGoogle Scholar
  • 27 Warkentin TE, Heddle NM. Laboratory diagnosis of immune heparin-induced thrombocytopenia. Curr Hematol Rep 2003; 2 (2) 148-157
    PubMedGoogle Scholar
  • 28 Lo GK, Juhl D, Warkentin TE, Sigouin CS, 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 (4) 759-765
    CrossrefPubMedGoogle Scholar
  • 29 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 (20) 4160-4167
    CrossrefPubMedGoogle Scholar
  • 30 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 (12) 2642-2650
    CrossrefPubMedGoogle Scholar
  • 31 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 (2) 138-145
    CrossrefPubMedGoogle Scholar
  • 32 Nagler M, Fabbro T, Wuillemin WA. Prospective evaluation of the interobserver reliability of the 4Ts score in patients with suspected heparin-induced thrombocytopenia. J Thromb Haemost 2012; 10 (1) 151-152
    CrossrefPubMedGoogle Scholar
  • 33 Uaprasert N, Chanswangphuwana C, Akkawat B, Rojnuckarin P. Comparison of diagnostic performance of the heparin-induced thrombocytopenia expert probability and the 4Ts score in screening for heparin-induced thrombocytopenia. Blood Coagul Fibrinolysis 2013; 24 (3) 261-268
    CrossrefPubMedGoogle Scholar
  • 34 Farahani N, Kitahara S, Tcherniantchouk O. Prospective comparison of the HIT expert probability (HEP) score versus the Warkentin 4T's score in a quaternary care center. [abstract] J Thromb Haemost 2013; 11 (s2): 936
    PubMedGoogle Scholar
  • 35 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 (11) 1882-1888
    CrossrefPubMedGoogle Scholar
  • 36 Messmore HL, Fabbrini N, Bird ML , et al. Simple scoring system for early management of heparin-induced thrombocytopenia. Clin Appl Thromb Hemost 2011; 17 (2) 197-201
    CrossrefPubMedGoogle Scholar
  • 37 Piednoir P, Allou N, Provenchère S , et al. Heparin-induced thrombocytopenia after cardiac surgery: an observational study of 1,722 patients. J Cardiothorac Vasc Anesth 2012; 26 (4) 585-590
    CrossrefPubMedGoogle Scholar
  • 38 Bakchoul T, Giptner A, Najaoui A, Bein G, Santoso S, Sachs UJ. Prospective evaluation of PF4/heparin immunoassays for the diagnosis of heparin-induced thrombocytopenia. J Thromb Haemost 2009; 7 (8) 1260-1265
    CrossrefPubMedGoogle Scholar
  • 39 Lo GK, Sigouin CS, Warkentin TE. What is the potential for overdiagnosis of heparin-induced thrombocytopenia?. Am J Hematol 2007; 82 (12) 1037-1043
    CrossrefPubMedGoogle Scholar
  • 40 Greinacher A, Juhl D, Strobel U , et al. Heparin-induced thrombocytopenia: a prospective study on the incidence, platelet-activating capacity and clinical significance of antiplatelet factor 4/heparin antibodies of the IgG, IgM, and IgA classes. J Thromb Haemost 2007; 5 (8) 1666-1673
    CrossrefPubMedGoogle Scholar
  • 41 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 patient samples referred for diagnostic testing for heparin-induced thrombocytopenia. Eur J Haematol 2006; 76 (5) 420-426
    CrossrefPubMedGoogle Scholar
  • 42 Zwicker JI, Uhl L, Huang WY, Shaz BH, Bauer KA. Thrombosis and ELISA optical density values in hospitalized patients with heparin-induced thrombocytopenia. J Thromb Haemost 2004; 2 (12) 2133-2137
    CrossrefPubMedGoogle Scholar
  • 43 Warkentin TE, Sheppard JI, Moore JC, Sigouin CS, Kelton JG. Quantitative interpretation of optical density measurements using PF4-dependent enzyme-immunoassays. J Thromb Haemost 2008; 6 (8) 1304-1312
    CrossrefPubMedGoogle Scholar
  • 44 Raschke RA, Curry SC, Warkentin TE, Gerkin RD. Improving clinical interpretation of the anti-platelet factor 4/heparin enzyme-linked immunosorbent assay for the diagnosis of heparin-induced thrombocytopenia through the use of receiver operating characteristic analysis, stratum-specific likelihood ratios, and bayes theorem. Chest 2013; 144 (4) 1269-1275
    CrossrefPubMedGoogle Scholar
  • 45 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; •••: 250-252
    PubMedGoogle Scholar
  • 46 Whitlatch NL, Kong DF, Metjian AD, Arepally GM, Ortel TL. Validation of the high-dose heparin confirmatory step for the diagnosis of heparin-induced thrombocytopenia. Blood 2010; 116 (10) 1761-1766
    CrossrefPubMedGoogle Scholar
  • 47 Warkentin TE, Sheppard JI. No significant improvement in diagnostic specificity of an anti-PF4/polyanion immunoassay with use of high heparin confirmatory procedure. J Thromb Haemost 2006; 4 (1) 281-282
    CrossrefPubMedGoogle Scholar
  • 48 Selleng S, Schreier N, Wollert HG, Greinacher A. The diagnostic value of the anti-PF4/heparin immunoassay high-dose heparin confirmatory test in cardiac surgery patients. Anesth Analg 2011; 112 (4) 774-776
    CrossrefPubMedGoogle Scholar
  • 49 Sachais BS, Litvinov RI, Yarovoi SV , et al. Dynamic antibody-binding properties in the pathogenesis of HIT. Blood 2012; 120 (5) 1137-1142
    CrossrefPubMedGoogle Scholar
  • 50 Cuker A, Rux AH, Hinds JL , et al. Novel diagnostic assays for heparin-induced thrombocytopenia. Blood 2013; 121 (18) 3727-3732
    CrossrefPubMedGoogle Scholar
  • 51 Sachs UJ, von Hesberg J, Santoso S, Bein G, Bakchoul T. Evaluation of a new nanoparticle-based lateral-flow immunoassay for the exclusion of heparin-induced thrombocytopenia (HIT). Thromb Haemost 2011; 106 (6) 1197-1202
    Article in Thieme ConnectPubMedGoogle Scholar
  • 52 Meyer O, Salama A, Pittet N, Schwind P. Rapid detection of heparin-induced platelet antibodies with particle gel immunoassay (ID-HPF4). Lancet 1999; 354 (9189) 1525-1526
    CrossrefPubMedGoogle Scholar
  • 53 Bakchoul T, Giptner A, Najaoui A, Bein G, Santoso S, Sachs UJH. Prospective evaluation of PF4/heparin immunoassays for the diagnosis of heparin-induced thrombocytopenia. J Thromb Haemost 2009; 7 (8) 1260-1265
    CrossrefPubMedGoogle Scholar
  • 54 Davidson SJ, Ortel TL, Smith LJ. Performance of a new, rapid, automated immunoassay for the detection of anti-platelet factor 4/heparin complex antibodies. Blood Coagul Fibrinolysis 2011; 22 (4) 340-344
    CrossrefPubMedGoogle Scholar
  • 55 Althaus K, Hron G, Strobel U , et al. Evaluation of automated immunoassays in the diagnosis of heparin induced thrombocytopenia. Thromb Res 2013; 131 (3) e85-e90
    CrossrefPubMedGoogle Scholar
  • 56 Legnani C, Cini M, Pili C, Boggian O, Frascaro M, Palareti G. 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 (2) 402-409
    Article in Thieme ConnectPubMedGoogle Scholar
  • 57 Van Hoecke F, Devreese K. Evaluation of two new automated chemiluminescent assays (HemosIL® AcuStar HIT-IgG and HemosIL® AcuStar HIT-Ab) for the detection of heparin-induced antibodies in the diagnosis of heparin-induced thrombocytopenia. Int J Lab Hematol 2012; 34 (4) 410-416
    CrossrefPubMedGoogle Scholar
  • 58 Warkentin TE, Greinacher A. Laboratory testing for heparin-induced thrombocytopenia. In: Warkentin TE, Greinacher A, , eds. Heparin-Induced Thrombocytopenia. Boca Raton Informa; 2013: 272-314
    Google Scholar
  • 59 Warkentin TE, Sheppard JI, Raschke RA, Greinacher A. Performance characteristics of a rapid assay for anti-PF4/heparin antibodies: the particle immunofiltration assay. J Thromb Haemost 2007; 5 (11) 2308-2310
    CrossrefPubMedGoogle Scholar
  • 60 Sheridan D, Carter C, Kelton JG. A diagnostic test for heparin-induced thrombocytopenia. Blood 1986; 67 (1) 27-30
    CrossrefPubMedGoogle Scholar
  • 61 Greinacher A, Michels I, Kiefel V, Mueller-Eckhardt C. A rapid and sensitive test for diagnosing heparin-associated thrombocytopenia. Thromb Haemost 1991; 66 (6) 734-736
    Article in Thieme ConnectPubMedGoogle Scholar
  • 62 Stewart MW, Etches WS, Boshkov LK, Gordon PA. Heparin-induced thrombocytopenia: an improved method of detection based on lumi-aggregometry. Br J Haematol 1995; 91 (1) 173-177
    CrossrefPubMedGoogle Scholar
  • 63 Lee DH, Warkentin TE, Denomme GA, Hayward CPM, Kelton JG. A diagnostic test for heparin-induced thrombocytopenia: detection of platelet microparticles using flow cytometry. Br J Haematol 1996; 95 (4) 724-731
    CrossrefPubMedGoogle Scholar
  • 64 Nazi I, Arnold DM, Smith JW , et al. FcγRIIa proteolysis as a diagnostic biomarker for heparin-induced thrombocytopenia. J Thromb Haemost 2013; 11 (6) 1146-1153
    CrossrefPubMedGoogle Scholar
  • 65 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 (4) 344-350
    Article in Thieme ConnectPubMedGoogle Scholar
  • 66 Cines DB, Kaywin P, Bina M, Tomaski A, Schreiber AD. Heparin-associated thrombocytopenia. N Engl J Med 1980; 303 (14) 788-795
    CrossrefPubMedGoogle Scholar
  • 67 Tomer A. A sensitive and specific functional flow cytometric assay for the diagnosis of heparin-induced thrombocytopenia. Br J Haematol 1997; 98 (3) 648-656
    CrossrefPubMedGoogle Scholar
  • 68 Gobbi G, Mirandola P, Tazzari PL , et al. Flow cytometry detection of serotonin content and release in resting and activated platelets. Br J Haematol 2003; 121 (6) 892-896
    CrossrefPubMedGoogle Scholar
  • 69 Vitale M, Tazzari P, Ricci F , et al. Comparison between different laboratory tests for the detection and prevention of heparin-induced thrombocytopenia. Cytometry 2001; 46 (5) 290-295
    CrossrefPubMedGoogle Scholar
  • 70 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 (6) 1277-1281
    Article in Thieme ConnectPubMedGoogle Scholar
  • 71 Favaloro EJ, Bernal-Hoyos E, Exner T, Koutts J. Heparin-induced thrombocytopenia: laboratory investigation and confirmation of diagnosis. Pathology 1992; 24 (3) 177-183
    CrossrefPubMedGoogle Scholar
  • 72 Greinacher A, Amiral J, Dummel V, Vissac A, Kiefel V, Mueller-Eckhardt C. 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 (5) 381-385
    CrossrefPubMedGoogle Scholar
  • 73 Morel-Kopp MC, Tan CW, Brighton TA , et al; ASTH Clinical Trials Group. Validation of whole blood impedance aggregometry as a new diagnostic tool for HIT: results of a large Australian study. Thromb Haemost 2012; 107 (3) 575-583
    Article in Thieme ConnectPubMedGoogle Scholar
  • 74 Prechel M, Walenga JM. Heparin-induced thrombocytopenia: an update. Semin Thromb Hemost 2012; 38 (5) 483-496
    Article in Thieme ConnectPubMedGoogle Scholar
  • 75 Price EA, Hayward CP, Moffat KA, Moore JC, Warkentin TE, Zehnder JL. Laboratory testing for heparin-induced thrombocytopenia is inconsistent in North America: a survey of North American specialized coagulation laboratories. Thromb Haemost 2007; 98 (6) 1357-1361
    Article in Thieme ConnectPubMedGoogle Scholar
  • 76 Sachais BS, Rux AH, Cines DB , et al. Rational design and characterization of platelet factor 4 antagonists for the study of heparin-induced thrombocytopenia. Blood 2012; 119 (25) 5955-5962
    CrossrefPubMedGoogle Scholar
  • 77 Tan CW, Ward CM, Morel-Kopp MC. Evaluating heparin-induced thrombocytopenia: the old and the new. Semin Thromb Hemost 2012; 38 (2) 135-143
    Article in Thieme ConnectPubMedGoogle Scholar