Download PDF
Semin Thromb Hemost 2012; 38(05): 483-496
DOI: 10.1055/s-0032-1306432
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Heparin-Induced Thrombocytopenia: An Update

Margaret Prechel
1   Department of Pathology, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois
,
Jeanine M. Walenga
2   Departments of Thoracic & Cardiovascular Surgery and Pathology, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois
› Author Affiliations
Further Information

Publication History

Publication Date:
07 March 2012 (online)

    Permissions and Reprints

Abstract

Heparin-induced thrombocytopenia (HIT) is an immune response to heparin that can progress to severe thrombosis, amputation, and in some cases death. The diagnosis and treatment of HIT is complex, but needs to be considered in the clinical management of patients exposed to heparin due to its serious outcomes. Early diagnosis based on a comprehensive interpretation of clinical and laboratory information improves clinical outcomes. This begins with careful monitoring for thrombocytopenia and thrombosis during and for at least 5 to 10 days after heparin treatment of any dose and duration. Appropriate use and knowledgeable interpretation of laboratory tests for HIT are important, as these vary in sensitivity and specificity, with each type providing unique information. 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. Important drug-specific limitations, dosing, and monitoring guidelines must be respected for patient safety. There continues to be new developments in the field of HIT: laboratory testing, clinical scoring systems, and available new anticoagulants. Research and clinical studies will continue to address the unresolved issues and unmet clinical needs associated with HIT. This review summarizes the clinical management of HIT.

Keywords

heparin-induced thrombocytopenia - antibody assays - anticoagulants - thrombin inhibitor
 

  • References

  • 1 Kelton JG, Sheridan D, Santos A , et al. Heparin-induced thrombocytopenia: laboratory studies. Blood 1988; 72 (3) 925-930
    PubMedGoogle Scholar
  • 2 Warkentin TE. Heparin-induced thrombocytopenia: pathogenesis and management. Br J Haematol 2003; 121 (4) 535-555
    CrossrefPubMedGoogle Scholar
  • 3 Greinacher A, Pötzsch 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 (2) 247-251
    CrossrefPubMedGoogle Scholar
  • 4 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
  • 5 Miller MD, Krangel MS. Biology and biochemistry of the chemokines: a family of chemotactic and inflammatory cytokines. Crit Rev Immunol 1992; 12 (1–2) 17-46
    PubMedGoogle Scholar
  • 6 Greinacher A, Gopinadhan M, Günther JU , 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
    CrossrefPubMedGoogle Scholar
  • 7 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
  • 8 Greinacher A, Alban S, Omer-Adam MA, Weitschies W, Warkentin TE. 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
    CrossrefPubMedGoogle Scholar
  • 9 Warkentin TE, Cook RJ, Marder VJ, Greinacher A. Anti-PF4/heparin antibody formation postorthopedic surgery thromboprophylaxis: the role of non-drug risk factors and evidence for a stoichiometry-based model of immunization. J Thromb Haemost 2010; 8 (3) 504-512
    CrossrefPubMedGoogle Scholar
  • 10 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 (11) 3691-3699
    CrossrefPubMedGoogle Scholar
  • 11 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 (1) 81-88
    CrossrefPubMedGoogle Scholar
  • 12 Rauova L, Hirsch JD, Greene TK , et al. Monocyte-bound PF4 in the pathogenesis of heparin-induced thrombocytopenia. Blood 2010; 116 (23) 5021-5031
    CrossrefPubMedGoogle Scholar
  • 13 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 (2) 121-129
    CrossrefPubMedGoogle Scholar
  • 14 Arepally GM, Mayer IM. Antibodies from patients with heparin-induced thrombocytopenia stimulate monocytic cells to express tissue factor and secrete interleukin-8. Blood 2001; 98 (4) 1252-1254
    CrossrefPubMedGoogle Scholar
  • 15 Walenga JM, Michal K, Hoppensteadt DA, Wood JJ, Robinson JA, Bick RL. Vascular damage correlates between heparin-induced thrombocytopenia and the antiphospholipid syndrome. Clin Appl Thromb Hemost 1999; 5 (Suppl 1) S76-S84
    CrossrefPubMedGoogle Scholar
  • 16 Fareed J, Walenga JM, Hoppensteadt DA , et al. Selectins in the HIT syndrome: pathophysiologic role and therapeutic modulation. Semin Thromb Hemost 1999; 25 (Suppl 1) 37-42
    Article in Thieme ConnectPubMedGoogle Scholar
  • 17 Walenga JM, Jeske WP, Messmore HL. Mechanisms of venous and arterial thrombosis in heparin-induced thrombocytopenia. J Thromb Thrombolysis 2000; 10 (Suppl 1) 13-20
    CrossrefPubMedGoogle Scholar
  • 18 Walenga JM, Jeske WP, Prechel MM, Bakhos M. Newer insights on the mechanism of heparin-induced thrombocytopenia. Semin Thromb Hemost 2004; 30 (Suppl 1) 57-67
    Article in Thieme ConnectPubMedGoogle Scholar
  • 19 Poncz M. Mechanistic basis of heparin-induced thrombocytopenia. Semin Thorac Cardiovasc Surg 2005; 17 (1) 73-79
    CrossrefPubMedGoogle Scholar
  • 20 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
    CrossrefPubMedGoogle Scholar
  • 21 Opatrny L, Warner MN. Risk of thrombosis in patients with malignancy and heparin-induced thrombocytopenia. Am J Hematol 2004; 76 (3) 240-244
    CrossrefPubMedGoogle Scholar
  • 22 Matsuo T, Tomaru T, Kario K, Hirokawa T ; HIT Research Group of Japan. Incidence of heparin-PF4 complex antibody formation and heparin-induced thrombocytopenia in acute coronary syndrome. Thromb Res 2005; 115 (6) 475-481
    CrossrefPubMedGoogle Scholar
  • 23 Warkentin TE, Sheppard JA, Horsewood P, Simpson PJ, Moore JC, Kelton JG. Impact of the patient population on the risk for heparin-induced thrombocytopenia. Blood 2000; 96 (5) 1703-1708
    CrossrefPubMedGoogle Scholar
  • 24 Francis JL, Palmer III GJ, Moroose R, Drexler A. Comparison of bovine and porcine heparin in heparin antibody formation after cardiac surgery. Ann Thorac Surg 2003; 75 (1) 17-22
    CrossrefPubMedGoogle Scholar
  • 25 Ban-Hoefen M, Francis C. Heparin induced thrombocytopenia and thrombosis in a tertiary care hospital. Thromb Res 2009; 124 (2) 189-192
    CrossrefPubMedGoogle Scholar
  • 26 Kadidal VV, Mayo DJ, Horne MK. Heparin-induced thrombocytopenia (HIT) due to heparin flushes: a report of three cases. J Intern Med 1999; 246 (3) 325-329
    CrossrefPubMedGoogle Scholar
  • 27 Jang IK, Hursting MJ. When heparins promote thrombosis: review of heparin-induced thrombocytopenia. Circulation 2005; 111 (20) 2671-2683
    CrossrefPubMedGoogle Scholar
  • 28 Pouplard C, May MA, 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
    CrossrefPubMedGoogle Scholar
  • 29 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 (20) 2518-2524
    CrossrefPubMedGoogle Scholar
  • 30 Warkentin TE, Crowther MA. When is HIT really HIT?. Ann Thorac Surg 2007; 83 (1) 21-23
    CrossrefPubMedGoogle Scholar
  • 31 Levy JH, Hursting MJ. Heparin-induced thrombocytopenia, a prothrombotic disease. Hematol Oncol Clin North Am 2007; 21 (1) 65-88
    CrossrefPubMedGoogle Scholar
  • 32 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
  • 33 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
  • 34 Pouplard C, Amiral J, Borg JY, 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 (5) 700-706
    PubMedGoogle Scholar
  • 35 Prechel MM, Gerdisch M, Wallis DE , et al. A post-operative platelet count threshold contributes to an earlier diagnosis of heparin-induced thrombocytopenia and improved platelet recovery in cardiac surgery patients. The HITME study. Thromb Haemost 2004; 1 (Suppl 1) 1788 (abstract)
    PubMedGoogle Scholar
  • 36 Selleng S, Selleng K, Wollert HG , et al. Heparin-induced thrombocytopenia in patients requiring prolonged intensive care unit treatment after cardiopulmonary bypass. J Thromb Haemost 2008; 6 (3) 428-435
    CrossrefPubMedGoogle Scholar
  • 37 Selleng K, 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: 30-36
    CrossrefPubMedGoogle Scholar
  • 38 Warkentin TE, Linkins LA. Non-necrotizing heparin-induced skin lesions and the 4T's score. J Thromb Haemost 2010; 8 (7) 1483-1485
    CrossrefPubMedGoogle Scholar
  • 39 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
  • 40 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 (5) 721-726
    CrossrefPubMedGoogle Scholar
  • 41 Pouplard C, Gueret P, Fouassier M , et al. 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 (7) 1373-1379
    CrossrefPubMedGoogle Scholar
  • 42 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
  • 43 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
  • 44 Shaheed G, Malkovska V, Mendoza J , et al. PF4 ENHANCED assay for the diagnosis of heparin-induced thrombocytopenia in complex medical and surgical patients. Crit Care Med 2007; 35 (7) 1691-1695
    CrossrefPubMedGoogle Scholar
  • 45 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
  • 46 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
  • 47 Sheridan D, Carter C, Kelton JG. A diagnostic test for heparin-induced thrombocytopenia. Blood 1986; 67 (1) 27-30
    CrossrefPubMedGoogle Scholar
  • 48 Warkentin TE, Sheppard JI, Raschke R, 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
  • 49 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
  • 50 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
  • 51 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 (4) 625-629
    Article in Thieme ConnectPubMedGoogle Scholar
  • 52 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
  • 53 Elalamy I, Galea V, Hatmi M, Gerotziafas GT. Heparin-induced multiple electrode aggregometry: a potential tool for improvement of heparin-induced thrombocytopenia diagnosis. J Thromb Haemost 2009; 7 (11) 1932-1934
    CrossrefPubMedGoogle Scholar
  • 54 Zwicker JI, Uhl L, Huang W-Y, 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
  • 55 Altuntas F, Matevosyan K, Burner J, Shen YM, Sarode R. Higher optical density of an antigen assay predicts thrombosis in patients with heparin-induced thrombocytopenia. Eur J Haematol 2008; 80 (5) 429-435
    CrossrefPubMedGoogle Scholar
  • 56 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 (2) 235-241
    CrossrefPubMedGoogle Scholar
  • 57 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 (4) 678-684
    PubMedGoogle Scholar
  • 58 Amiral J, Pouplard C, Vissac AM, Walenga JM, Jeske WP, Gruel Y. Affinity purification of heparin-dependent antibodies to platelet factor 4 developed in heparin-induced thrombocytopenia: biological characteristics and effects on platelet activation. Br J Haematol 2000; 109 (2) 336-341
    CrossrefPubMedGoogle Scholar
  • 59 Izban KF, Lietz HW, Hoppensteadt DA , 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
    PubMedGoogle Scholar
  • 60 Bakchoul T, Giptner A, Bein G, Santoso S, Sachs UJ. Performance characteristics of two commercially available IgG-specific immunoassays in the assessment of heparin-induced thrombocytopenia (HIT). Thromb Res 2011; 127 (4) 345-348
    CrossrefPubMedGoogle Scholar
  • 61 Althaus K, Strobel U, Warkentin TE, Greinacher A. Combined use of the high heparin step and optical density to optimize diagnostic sensitivity and specificity of an anti-PF4/heparin enzyme-immunoassay. Thromb Res 2011; 128 (3) 256-260
    CrossrefPubMedGoogle Scholar
  • 62 Althaus K, Strobel U, Warkentin TE, Greinacher A. Combined use of the high heparin step and optical density to optimize diagnostic sensitivity and specificity of an anti-PF4/heparin enzyme-immunoassay. Thromb Res 2011; 128 (3) 256-260
    CrossrefPubMedGoogle Scholar
  • 63 Denys B, Stove V, Philippé J, Devreese K. A clinical-laboratory approach contributing to a rapid and reliable diagnosis of heparin-induced thrombocytopenia. Thromb Res 2008; 123 (1) 137-145
    CrossrefPubMedGoogle Scholar
  • 64 Antovic JP, Morberg E-M, Sten-Linder M. Could rapid particle gel immunoassay (IS-PaGIA) replace standard ELISA for laboratory detection of heparin/PF4 antibodies?. Int Jnl Lab Hem 2010; 32: 454-457
    PubMedGoogle Scholar
  • 65 Schneiter S, Colucci G, Sulzer I, Barizzi G, Lämmle B, Alberio L. Variability of anti-PF4/heparin antibody results obtained by the rapid testing system ID-H/PF4-PaGIA. J Thromb Haemost 2009; 7 (10) 1649-1655
    CrossrefPubMedGoogle Scholar
  • 66 Alberio L, Lämmle B. More on: thrombosis and ELISA optical density values in hospitalized patients with heparin-induced thrombocytopenia. J Thromb Haemost 2005; 3 (7) 1549
    CrossrefPubMedGoogle Scholar
  • 67 Alberio L, Kimmerle S, Baumann A, Taleghani BM, Biasiutti FD, Lämmle B. Rapid determination of anti-heparin/platelet factor 4 antibody titers in the diagnosis of heparin-induced thrombocytopenia. Am J Med 2003; 114 (7) 528-536
    CrossrefPubMedGoogle Scholar
  • 68 Köchli A. Variability of anti-PF4/heparin antibody results obtained by the rapid testing system ID-H/PF4-PaGIA: a rebuttal. J Thromb Haemost 2009; 7 (10) 1753-1755 , author reply 1755–1756
    CrossrefPubMedGoogle Scholar
  • 69 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
  • 70 Warkentin TE, Linkins LA. Immunoassays are not created equal. J Thromb Haemost 2009; 7 (8) 1256-1259
    CrossrefPubMedGoogle Scholar
  • 71 Rosovsky RP, Abdel-Wahad OI, Van Cott EM, Kuter DJ. The incidence of thrombosis in patients with isolated heparin induced thrombocytopenia. Blood 2006; 108: 312a (abstract)
    PubMedGoogle Scholar
  • 72 Greinacher A, Ittermann T, Bagemühl J , et al. Heparin-induced thrombocytopenia: towards standardization of platelet factor 4/heparin antigen tests. J Thromb Haemost 2010; 8 (9) 2025-2031
    CrossrefPubMedGoogle Scholar
  • 73 Tardy B, Presles E, Akrour M, de Maistre E, Lecompte T, Tardy-Poncet B. Experts' opinion or the serotonin release assay as a gold standard for the diagnosis of heparin-induced thrombocytopenia (HIT)?. J Thromb Haemost 2011; 9 (8) 1667-1669
    CrossrefPubMedGoogle Scholar
  • 74 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 (1) 216-218
    CrossrefPubMedGoogle Scholar
  • 75 Warkentin TE, Sheppard JA, Moore JC, Moore KM, Sigouin CS, Kelton JG. Laboratory testing for the antibodies that cause heparin-induced thrombocytopenia: how much class do we need?. J Lab Clin Med 2005; 146 (6) 341-346
    CrossrefPubMedGoogle Scholar
  • 76 Levine RL, Hergenroeder GW, Francis JL, Miller CC, Hursting MJ. Heparin-platelet factor 4 antibodies in intensive care patients: an observational seroprevalence study. J Thromb Thrombolysis 2010; 30 (2) 142-148
    CrossrefPubMedGoogle Scholar
  • 77 Prechel M, McDonald MK, Jeske WP, Drenth AF, Walenga JM. Consideration of antibody isotype in interpretation of the serotonin release assay. J Thromb Haemost 2005; 3 (Suppl 1) 2107 (abstract)
    PubMedGoogle Scholar
  • 78 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
  • 79 Selleng S, Malowsky B, Itterman T , et al. Incidence and clinical relevance of anti-platelet factor 4/heparin antibodies before cardiac surgery. Am Heart J 2010; 160 (2) 362-369
    CrossrefPubMedGoogle Scholar
  • 80 McFarland J, Curtis BR, Lochowicz AJ, Gough PL, Jahn L, Aster RH. Correlation of PF4 ELISA results and clinical likelihood of HIT: can we improve on specificity?. Blood 2008; 112: 1174 (abstract)
    PubMedGoogle Scholar
  • 81 Schenk S, El-Banayosy A, Prohaska W , et al. Heparin-induced thrombocytopenia in patients receiving mechanical circulatory support. J Thorac Cardiovasc Surg 2006; 131 (6) 1373-1381 , e4
    CrossrefPubMedGoogle Scholar
  • 82 Chan M, Malynn E, Shaz B, Uhl L. Utility of consecutive repeat HIT ELISA testing for heparin-induced thrombocytopenia. Am J Hematol 2008; 83 (3) 212-217
    CrossrefPubMedGoogle Scholar
  • 83 Francis JL. A critical evaluation of assays for detecting antibodies to the heparin-PF4 complex. Semin Thromb Hemost 2004; 30 (3) 359-368
    Article in Thieme ConnectPubMedGoogle Scholar
  • 84 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
  • 85 Walenga JM, Jeske WP, Fasanella AR, Wood JJ, Ahmad S, Bakhos M. Laboratory diagnosis of heparin-induced thrombocytopenia. Clin Appl Thromb Hemost 1999; 5 (Suppl 1) S21-S27
    CrossrefPubMedGoogle Scholar
  • 86 Messmore HL, Jeske WP, Wehrmacher WH, Walenga JM. Benefit-risk assessment of treatments for heparin-induced thrombocytopenia. Drug Saf 2003; 26 (9) 625-641
    CrossrefPubMedGoogle Scholar
  • 87 Walenga JM, Prechel MM, Jeske WP, Bakhos M. Unfractionated heparin compared with low-molecular-weight heparin as related to heparin-induced thrombocytopenia. Curr Opin Pulm Med 2005; 11 (5) 385-391
    CrossrefPubMedGoogle Scholar
  • 88 Greinacher A, Alban S, Dummel V, Franz G, Mueller-Eckhardt C. Characterization of the structural requirements for a carbohydrate based anticoagulant with a reduced risk of inducing the immunological type of heparin-associated thrombocytopenia. Thromb Haemost 1995; 74 (3) 886-892
    PubMedGoogle Scholar
  • 89 Walenga JM, Koza MJ, Lewis BE, 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
    PubMedGoogle Scholar
  • 90 Warkentin TE. Heparin-induced thrombocytopenia: a clinicopathologic syndrome. Thromb Haemost 1999; 82 (2) 439-447
    PubMedGoogle Scholar
  • 91 Warkentin TE, Kelton JG. Temporal aspects of heparin-induced thrombocytopenia. N Engl J Med 2001; 344 (17) 1286-1292
    CrossrefPubMedGoogle Scholar
  • 92 Lubenow N, Kempf R, Eichner A, Eichler P, Carlsson LE, Greinacher A. Heparin-induced thrombocytopenia: temporal pattern of thrombocytopenia in relation to initial use or reexposure to heparin. Chest 2002; 122 (1) 37-42
    CrossrefPubMedGoogle Scholar
  • 93 Warkentin TE, Greinacher A, Koster A, Lincoff AM ; 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: 340S-380S
    CrossrefPubMedGoogle Scholar
  • 94 Nuttall GA, Oliver Jr WC, Santrach PJ , et al. Patients with a history of type II heparin-induced thrombocytopenia with thrombosis requiring cardiac surgery with cardiopulmonary bypass: a prospective observational case series. Anesth Analg 2003; 96 (2) 344-350
    PubMedGoogle Scholar
  • 95 Selleng S, Haneya A, Hirt S, Selleng K, Schmid C, Greinacher A. Management of anticoagulation in patients with subacute heparin-induced thrombocytopenia scheduled for heart transplantation. Blood 2008; 112 (10) 4024-4027
    CrossrefPubMedGoogle Scholar
  • 96 Levy JH, Winkler AM. Heparin-induced thrombocytopenia and cardiac surgery. Curr Opin Anaesthesiol 2010; 23 (1) 74-79
    CrossrefPubMedGoogle Scholar
  • 97 Lewis BE, Wallis DE, Berkowitz SD , et al; ARG-911 Study Investigators. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation 2001; 103 (14) 1838-1843
    CrossrefPubMedGoogle Scholar
  • 98 Lewis BE, Wallis DE, Leya F, Hursting MJ, Kelton JG ; Argatroban-915 Investigators. Argatroban anticoagulation in patients with heparin-induced thrombocytopenia. Arch Intern Med 2003; 163 (15) 1849-1856
    CrossrefPubMedGoogle Scholar
  • 99 Greinacher A, Völpel H, Janssens U , et al. Recombinant hirudin (lepirudin) provides safe and effective anticoagulation in patients with heparin-induced thrombocytopenia: a prospective study. Circulation 1999; 99 (1) 73-80
    CrossrefPubMedGoogle Scholar
  • 100 Greinacher A, Janssens U, Berg G , et al. Lepirudin (recombinant hirudin) for parenteral anticoagulation in patients with heparin-induced thrombocytopenia. Heparin-Associated Thrombocytopenia Study (HAT) investigators. Circulation 1999; 100 (6) 587-593
    CrossrefPubMedGoogle Scholar
  • 101 Hirsh J, Heddle N, Kelton JG. Treatment of heparin-induced thrombocytopenia: a critical review. Arch Intern Med 2004; 164 (4) 361-369
    CrossrefPubMedGoogle Scholar
  • 102 Warkentin TE. Management of heparin-induced thrombocytopenia: a critical comparison of lepirudin and argatroban. Thromb Res 2003; 110 (2–3) 73-82
    CrossrefPubMedGoogle Scholar
  • 103 Walenga JM, Fasanella AR, Iqbal O , et al. Coagulation laboratory testing in patients treated with argatroban. Semin Thromb Hemost 1999; 25 (Suppl 1) 61-66
    PubMedGoogle Scholar
  • 104 Walenga JM, Drenth AF, Mayuga M , et al. Transition from argatroban to oral anticoagulation with phenprocoumon or acenocoumarol: effect on coagulation factor testing. Clin Appl Thromb Hemost 2008; 14 (3) 325-331
    CrossrefPubMedGoogle Scholar
  • 105 Swan SK, Hursting MJ. The pharmacokinetics and pharmacodynamics of argatroban: effects of age, gender, and hepatic or renal dysfunction. Pharmacotherapy 2000; 20 (3) 318-329
    CrossrefPubMedGoogle Scholar
  • 106 Swan SK, St Peter JV, Lambrecht LJ, Hursting MJ. Comparison of anticoagulant effects and safety of argatroban and heparin in healthy subjects. Pharmacotherapy 2000; 20 (7) 756-770
    CrossrefPubMedGoogle Scholar
  • 107 Walenga JM, Ahmad S, Hoppensteadt D, Iqbal O, Hursting MJ, Lewis BE. Argatroban therapy does not generate antibodies that alter its anticoagulant activity in patients with heparin-induced thrombocytopenia. Thromb Res 2002; 105 (5) 401-405
    CrossrefPubMedGoogle Scholar
  • 108 Lewis BE, Matthai Jr WH, Cohen M, Moses JW, Hursting MJ, Leya F ; ARG-216/310/311 Study Investigators. Argatroban anticoagulation during percutaneous coronary intervention in patients with heparin-induced thrombocytopenia. Catheter Cardiovasc Interv 2002; 57 (2) 177-184
    CrossrefPubMedGoogle Scholar
  • 109 Cetta F, Graham LC, Wrona LL, Arruda MJ, Walenga JM. Argatroban use during pediatric interventional cardiac catheterization. Catheter Cardiovasc Interv 2004; 61 (1) 147-149
    CrossrefPubMedGoogle Scholar
  • 110 Jang IK, Lewis BE, Matthai Jr WH, Kleiman NS. 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 (1) 31-37
    CrossrefPubMedGoogle Scholar
  • 111 LaMonte MP, Brown PM, Hursting MJ. Stroke in patients with heparin-induced thrombocytopenia and the effect of argatroban therapy. Crit Care Med 2004; 32 (4) 976-980
    CrossrefPubMedGoogle Scholar
  • 112 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
  • 113 Gray A, Wallis DE, Hursting MJ, Katz E, Lewis BE. Argatroban therapy for heparin-induced thrombocytopenia in acutely ill patients. Clin Appl Thromb Hemost 2007; 13 (4) 353-361
    CrossrefPubMedGoogle Scholar
  • 114 Matthai Jr WH, Hursting MJ, Lewis BE, Kelton JG. Argatroban anticoagulation in patients with a history of heparin-induced thrombocytopenia. Thromb Res 2005; 116 (2) 121-126
    CrossrefPubMedGoogle Scholar
  • 115 Hursting MJ, Murray PT. Argatroban anticoagulation in renal dysfunction: a literature analysis. Nephron Clin Pract 2008; 109 (2) c80-c94
    CrossrefPubMedGoogle Scholar
  • 116 Jang IK, Baron SJ, Hursting MJ, Anglade E. Argatroban therapy in women with heparin-induced thrombocytopenia. J Womens Health (Larchmt) 2007; 16 (6) 895-901
    CrossrefPubMedGoogle Scholar
  • 117 Jang IK, Hursting MJ, McCollum D. Argatroban therapy in patients with coronary artery disease and heparin-induced thrombocytopenia. Cardiology 2008; 109 (3) 172-176
    CrossrefPubMedGoogle Scholar
  • 118 Levine RL, Hursting MJ, McCollum D. Argatroban therapy in heparin-induced thrombocytopenia with hepatic dysfunction. Chest 2006; 129 (5) 1167-1175
    CrossrefPubMedGoogle Scholar
  • 119 Hursting MJ, Jang IK. Dosing patterns and outcomes in African American, Asian, and Hispanic patients with heparin-induced thrombocytopenia treated with argatroban. J Thromb Thrombolysis 2009; 28 (1) 10-15
    CrossrefPubMedGoogle Scholar
  • 120 Madabushi R, Cox DS, Hossain M , et al. Pharmacokinetic and pharmacodynamic basis for effective argatroban dosing in pediatrics. J Clin Pharmacol 2011; 51 (1) 19-28
    CrossrefPubMedGoogle Scholar
  • 121 Reddy BV, Grossman EJ, Trevino SA, Hursting MJ, Murray PT. Argatroban anticoagulation in patients with heparin-induced thrombocytopenia requiring renal replacement therapy. Ann Pharmacother 2005; 39 (10) 1601-1605
    CrossrefPubMedGoogle Scholar
  • 122 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
  • 123 Tardy B, Lecompte T, Boelhen F , et al; GEHT-HIT Study Group. Predictive factors for thrombosis and major bleeding in an observational study in 181 patients with heparin-induced thrombocytopenia treated with lepirudin. Blood 2006; 108 (5) 1492-1496
    CrossrefPubMedGoogle Scholar
  • 124 Tschudi M, Lämmle B, Alberio L. Dosing lepirudin in patients with heparin-induced thrombocytopenia and normal or impaired renal function: a single-center experience with 68 patients. Blood 2009; 113 (11) 2402-2409
    CrossrefPubMedGoogle Scholar
  • 125 Eichler P, Friesen HJ, Lubenow N, Jaeger B, Greinacher A. Antihirudin antibodies in patients with heparin-induced thrombocytopenia treated with lepirudin: incidence, effects on aPTT, and clinical relevance. Blood 2000; 96 (7) 2373-2378
    PubMedGoogle Scholar
  • 126 Greinacher A, Eichler P, Albrecht D, Strobel U, Pötzsch B, Eriksson BI. Antihirudin antibodies following low-dose subcutaneous treatment with desirudin for thrombosis prophylaxis after hip-replacement surgery: incidence and clinical relevance. Blood 2003; 101 (7) 2617-2619
    CrossrefPubMedGoogle Scholar
  • 127 Fischer KG, Liebe V, Hudek R , et al. Anti-hirudin antibodies alter pharmacokinetics and pharmacodynamics of recombinant hirudin. Thromb Haemost 2003; 89 (6) 973-982
    PubMedGoogle Scholar
  • 128 Greinacher A, Lubenow N, Eichler P. Anaphylactic and anaphylactoid reactions associated with lepirudin in patients with heparin-induced thrombocytopenia. Circulation 2003; 108 (17) 2062-2065
    CrossrefPubMedGoogle Scholar
  • 129 Mahaffey KW, Lewis BE, Wildermann NM , et al; ATBAT Investigators. 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
    PubMedGoogle Scholar
  • 130 Kiser TH, Burch JC, Klem PM, Hassell KL. Safety, efficacy, and dosing requirements of bivalirudin in patients with heparin-induced thrombocytopenia. Pharmacotherapy 2008; 28 (9) 1115-1124
    CrossrefPubMedGoogle Scholar
  • 131 Koster A, Dyke CM, Aldea G , et al. Bivalirudin during cardiopulmonary bypass in patients with previous or acute heparin-induced thrombocytopenia and heparin antibodies: results of the CHOOSE-ON trial. Ann Thorac Surg 2007; 83 (2) 572-577
    CrossrefPubMedGoogle Scholar
  • 132 Dyke CM, Aldea G, Koster A , et al. Off-pump coronary artery bypass with bivalirudin for patients with heparin-induced thrombocytopenia or antiplatelet factor four/heparin antibodies. Ann Thorac Surg 2007; 84 (3) 836-839
    CrossrefPubMedGoogle Scholar
  • 133 Boyce SW, Bandyk DF, Bartholomew JR, Frame JN, Rice L. A randomized, open-label pilot study comparing desirudin and argatroban in patients with suspected heparin-induced thrombocytopenia with or without thrombosis: PREVENT-HIT Study. Am J Ther 2010; 18: 14-22
    PubMedGoogle Scholar
  • 134 Levy JH, Tapson VF, Walenga JM. Desirudin: a summary of recent data in patients with or without risk for heparin-induced thrombocytopenia. Chest Phys 2011; 6 (Suppl) 3-8
    PubMedGoogle Scholar
  • 135 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
  • 136 Lindhoff-Last E, Kreutzenbeck H-J, Magnani HN. Treatment of 51 pregnancies with danaparoid because of heparin intolerance. Thromb Haemost 2005; 93 (1) 63-69
    PubMedGoogle Scholar
  • 137 Chong BH, Gallus AS, Cade JF , et al; Australian HIT Study Group. Prospective randomised open-label comparison of danaparoid with dextran 70 in the treatment of heparin-induced thrombocytopaenia with thrombosis: a clinical outcome study. Thromb Haemost 2001; 86 (5) 1170-1175 Thromb Haemost 2001;86:1170–1175
    PubMedGoogle Scholar
  • 138 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
    Article in Thieme ConnectPubMedGoogle Scholar
  • 139 Kodityal S, Manhas AH, Udden M, Rice L. Danaparoid for heparin-induced thrombocytopenia: an analysis of treatment failures. Eur J Haematol 2003; 71 (2) 109-113
    CrossrefPubMedGoogle Scholar
  • 140 Haas S, Walenga JM, Jeske WP, Fareed J. Heparin-induced thrombocytopenia: clinical considerations of alternative anticoagulation with various glycosaminoglycans and thrombin inhibitors. Clin Appl Thromb Hemost 1999; 5 (1) 52-59
    PubMedGoogle Scholar
  • 141 Tardy B, Tardy-Poncet B, Viallon A, Piot M, Mazet E. Fatal danaparoid-sodium induced thrombocytopenia and arterial thromboses. Thromb Haemost 1998; 80 (3) 530
    PubMedGoogle Scholar
  • 142 Elalamy I, Lecrubier C, Horellou MH, Conard J, Samama MM. Heparin-induced thrombocytopenia: laboratory diagnosis and management. Ann Med 2000; 32 (Suppl 1) 60-67
    PubMedGoogle Scholar
  • 143 Magnani HN. A review of 122 published outcomes of danaparoid anticoagulation for intermittent haemodialysis. Thromb Res 2010; 125 (4) e171-e176
    CrossrefPubMedGoogle Scholar
  • 144 Badger NO. Fondaparinux (Arixtra(R)), a safe alternative for the treatment of patients with heparin-induced thrombocytopenia?. J Pharm Pract 2010; 23 (3) 235-238
    CrossrefPubMedGoogle Scholar
  • 145 Warkentin TE, Lim W. Can heparin-induced thrombocytopenia be associated with fondaparinux use? Reply to a rebuttal. J Thromb Haemost 2008; 6 (7) 1243-1246
    CrossrefPubMedGoogle Scholar
  • 146 Alsaleh KA, Al-Nasser SM, Bates SM, Patel A, Warkentin TE, Arnold DM. Delayed-onset HIT caused by low-molecular-weight heparin manifesting during fondaparinux prophylaxis. Am J Hematol 2008; 83 (11) 876-878
    CrossrefPubMedGoogle Scholar
  • 147 Ratuapli SK, Bobba B, Zafar H. Heparin-induced thrombocytopenia in a patient treated with fondaparinux. Clin Adv Hematol Oncol 2010; 8 (1) 61-65
    PubMedGoogle Scholar
  • 148 Warkentin TE, Maurer BT, Aster RH. Heparin-induced thrombocytopenia associated with fondaparinux. N Engl J Med 2007; 356 (25) 2653-2655 , discussion 2653–2655
    CrossrefPubMedGoogle Scholar
  • 149 Warkentin TE, Cook RJ, Marder VJ , 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
    CrossrefPubMedGoogle Scholar
  • 150 Pouplard C, Couvret C, Regina S, Gruel Y. Development of antibodies specific to polyanion-modified platelet factor 4 during treatment with fondaparinux. J Thromb Haemost 2005; 3 (12) 2813-2815
    CrossrefPubMedGoogle Scholar
  • 151 Hook KM, Abrams CS. Treatment options in heparin-induced thrombocytopenia. Curr Opin Hematol 2010; 17 (5) 424-431
    CrossrefPubMedGoogle Scholar
  • 152 Elalamy I, Tribout B. Can heparin-induced thrombocytopenia be associated with fondaparinux use? A rebuttal. J Thromb Haemost 2008; 6 (7) 1242-1243 , author reply 1243–1246
    CrossrefPubMedGoogle Scholar
  • 153 Walenga JM, Prechel M, Jeske WP , et al. Rivaroxaban—an oral, direct factor Xa inhibitor—has potential for the management of patients with heparin-induced thrombocytopenia. Br J Haematol 2008; 143 (1) 92-99
    CrossrefPubMedGoogle Scholar
  • 154 Warkentin TE, Elavathil LJ, Hayward CP, Johnston MA, Russett JI, Kelton JG. The pathogenesis of venous limb gangrene associated with heparin-induced thrombocytopenia. Ann Intern Med 1997; 127 (9) 804-812
    CrossrefPubMedGoogle Scholar
  • 155 Srinivasan AF, Rice L, Bartholomew JR , 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
    CrossrefPubMedGoogle Scholar
  • 156 Wallis DE, Quintos R, Wehrmacher W, Messmore HL. Safety of warfarin anticoagulation in patients with heparin-induced thrombocytopenia. Chest 1999; 116 (5) 1333-1338
    CrossrefPubMedGoogle Scholar
  • 157 Gosselin RC, Dager WE, King JH , et al. Effect of direct thrombin inhibitors, bivalirudin, lepirudin, and argatroban, on prothrombin time and INR values. Am J Clin Pathol 2004; 121 (4) 593-599
    CrossrefPubMedGoogle Scholar
  • 158 Hursting MJ, Lewis BE, Macfarlane DE. Transitioning from argatroban to warfarin therapy in patients with heparin-induced thrombocytopenia. Clin Appl Thromb Hemost 2005; 11 (3) 279-287
    CrossrefPubMedGoogle Scholar
  • 159 Bartholomew JR, Hursting MJ. Transitioning from argatroban to warfarin in heparin-induced thrombocytopenia: an analysis of outcomes in patients with elevated international normalized ratio (INR). J Thromb Thrombolysis 2005; 19 (3) 183-188
    CrossrefPubMedGoogle Scholar
  • 160 Walenga JM, Lewis BE, Jeske WP , et al. Combined thrombin and platelet inhibition treatment for HIT patients. Hamostaseologie 1999; 19: 128-133
    PubMedGoogle Scholar