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Thromb Haemost 1999; 82(02): 439-447
DOI: 10.1055/s-0037-1615864
Research Article
Schattauer GmbH

Heparin-Induced Thrombocytopenia: A Clinicopathologic Syndrome

Theodore E. Warkentin
1   Department of Pathology and Molecular Medicine, and the Department of Medicine, McMaster University; and the Hamilton Regional Laboratory Medicine Program, Hamilton Health Sciences Corporation, Hamilton, Ontario, CANADA
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Publication History

Publication Date:
09 December 2017 (online)

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Introduction

The American vascular surgeons, Weismann and Tobin in 19581 and Roberts and colleagues in 1964,2 were the first to describe unusual thrombi affecting the lower limb arteries in some patients treated with heparin for 7 to 14 days. It was not until the mid-1970s however that Silver and colleagues3,4 identified the key elements of the heparin-induced thrombocytopenia (HIT) syndrome, namely thrombocytopenia associated with thrombosis beginning several days after starting heparin. Further, in vitro studies performed by these investigators suggested the presence of a heparin-dependent, platelet-aggregating factor in serum thought to be immunoglobulin G (IgG).

In 1992, Amiral and colleagues5 identified the antigen target of HIT antibodies. The unusual nature of the HIT antigen, a multimolecular complex of heparin and platelet factor 4 (PF4),5,6 together with the remarkable, perhaps unparalleled, platelet- and endothelium-activating properties of the pathogenic HIT antibodies,7-10 are central to the thrombotic events that occur in these patients. From its obscure beginnings, HIT is now accepted as a common and distinct immunohematologic syndrome with broad implications ranging from public health prevention issues to fundamental questions of pathogenesis, which are leading to new insights into the molecular pathogenesis of thrombosis.

 

  • References

  • 1 Roberts B, Rosato FE, Rosato EF. Heparin–a cause of arterial emboli?. Surgery 1964; 5: 803-808.
    PubMedGoogle Scholar
  • 2 Weismann RE, Tobin RW. Arterial embolism occurring during systemic heparin therapy. Arch Surg 1958; 76: 219-227.
    CrossrefPubMedGoogle Scholar
  • 3 Rhodes GR, Dixon RH, Silver D. Heparin induced thrombocytopenia with thrombotic and hemorrhagic manifestations. Surg Gynecol Obstet 1973; 136: 409-416.
    PubMedGoogle Scholar
  • 4 Rhodes GR, Dixon RH, Silver D. Heparin induced thrombocytopenia: Eight cases with thrombotic-hemorrhagic complications. Ann Surg 1977; 186: 752-758.
    CrossrefPubMedGoogle Scholar
  • 5 Amiral J, Bridey F, Dreyfus M, Vissac AM, Fressinaud E, Wolf M, Meyer D. Platelet factor 4 complexed to heparin is the target for antibodies generated in heparin-induced thrombocytopenia (letter). Thromb Haemost 1992; 68: 95-96.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 6 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: 247-251.
    PubMedGoogle Scholar
  • 7 Kelton JG, Sheridan D, Santos A, Smith J, Steeves K, Smith C, Brown C, Murphy WG. Heparin-induced thrombocytopenia: Laboratory studies. Blood 1988; 72: 925-930.
    PubMedGoogle Scholar
  • 8 Warkentin TE, Hayward CPM, Boshkov LK, Santos AV, Sheppard JI, Bode AP, Kelton JG. Sera from patients with heparin-induced thrombocytopenia generate platelet-derived microparticles with procoagulant activity: An explanation for the thrombotic complications of heparin-induced thrombocytopenia. Blood 1994; 84: 3691-3699.
    PubMedGoogle Scholar
  • 9 Cines DB, Tomaski A, Tannenbaum S. Immune endothelial-cell injury in heparin-associated thrombocytopenia. N Engl J Med 1987; 316: 581-589.
    CrossrefPubMedGoogle Scholar
  • 10 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: 81-88.
    CrossrefPubMedGoogle Scholar
  • 11 Sheridan D, Carter C, Kelton JG. A diagnostic test for heparin-induced thrombocytopenia. Blood 1986; 67: 27-30.
    PubMedGoogle Scholar
  • 12 Warkentin TE, Hayward CPM, Smith CA, Kelly PM, Kelton JG. Determinants of donor platelet variability when testing for heparin-induced thrombocytopenia. J Lab Clin Med 1992; 120: 371-379.
    PubMedGoogle Scholar
  • 13 Greinacher A, Michels I, Kiefel V, Mueller-Eckhardt C. A rapid and sensitive test for diagnosing heparin-associated thrombocytopenia. Thromb Haemost 1991; 66: 734-736.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 14 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: 381-385.
    CrossrefPubMedGoogle Scholar
  • 15 Amiral J, Bridey F, Wolf M, Boyer-Neumann C, Fressinaud E, Vissac AM, Peynaud-Debayle E, Dreyfus M, Meyer D. Antibodies to macromolecular platelet factor 4-heparin complexes in heparin-induced thrombocytopenia: A study of 44 cases. Thromb Haemost 1995; 73: 21-28.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 16 Warkentin TE, Chong BH, Greinacher A. Heparin-induced thrombocytopenia: Towards consensus. Thromb Haemost 1998; 79: 1-7.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 17 Warkentin TE. The clinical picture of heparin-induced thrombocytopenia. In: Warkentin TE, Greinacher A. eds. Heparin-Induced Thrombocytopenia. New York: Marcel Dekker, Inc.; In press.
    Google Scholar
  • 18 Warkentin TE. Pseudo-heparin-induced thrombocytopenia: Insights into the pathogenesis of thrombosis. In: Warkentin TE, Greinacher A. eds. Heparin-Induced Thrombocytopenia. New York: Marcel Dekker, Inc.; In press.
    Google Scholar
  • 19 Salzman EW, Rosenberg RD, Smith MH, Lindon JN, Favreau L. Effect of heparin and heparin fractions on platelet aggregation. J Clin Invest 1980; 65: 64-73.
    CrossrefPubMedGoogle Scholar
  • 20 Warkentin TE, Kelton JG. Interaction of heparin with platelets, including heparin-induced thrombocytopenia. In: Bounameaux H. ed: Low Molecular Weight Heparins in Prophylaxis and Therapy of Thromboembolic Diseases. New York: Marcel Dekker, Inc.; 1994: 75-127.
    Google Scholar
  • 21 Balduini CL, Noris P, Bertolino G, Previtali M. Heparin modifies platelet count and function in patients who have undergone thrombolytic therapy for acute myocardial infraction (letter). Thromb Haemost 1993; 69: 522-523.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 22 Warkentin TE, Kelton JG. A 14-year study of heparin-induced thrombocytopenia. Am J Med 1996; 101: 502-507.
    CrossrefPubMedGoogle Scholar
  • 23 Warkentin TE, Levine MN, Hirsh J, Horsewood P, Roberts RS, Gent M, Kelton JG. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med 1995; 332: 1330-1335.
    CrossrefPubMedGoogle Scholar
  • 24 Warkentin TE, Levine MN, Hirsh J, Klama LN, Kelton JG. Formation of heparin-induced thrombocytopenia IgG without thrombocytopenia: Analysis of a clinical trial (abstract). Blood 1996; 86 (Suppl. 01) 537a.
    PubMedGoogle Scholar
  • 25 Lee DP, Warkentin TE. Frequency of heparin-induced thrombocytopenia. In: Warkentin TE, Greinacher A. eds. Heparin-Induced Thrombocytopenia. New York: Marcel Dekker, Inc.; In press.
    Google Scholar
  • 26 Warkentin TE. Clinical presentation of heparin-induced thrombocytopenia. Semin Hematol 1998; 35 (Suppl. 04) 9-16.
    PubMedGoogle Scholar
  • 27 Ganzer D, Gutezeit A, Mayer G, Greinacher A, Eichler P. Thromboembolieprophylaxe als ausöser thrombembolischer komplicationen. Eine untersuchung zur inzidenz der heparin-induzierten thrombozytopenie (HIT) typ II. Z Orthop Ihre Grenzgeb 1997; 135: 543-549.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 28 Warkentin TE. Heparin-induced skin lesions. Br J Haematol 1996; 92: 494-497.
    CrossrefPubMedGoogle Scholar
  • 29 Hach-Wunderle V, Kainer K, Krug B, Müller-Berghaus G, Pötzsch B. Heparin-associated thrombosis despite normal platelet counts (letter). Lancet 1994; 344: 469-470.
    PubMedGoogle Scholar
  • 30 Klement D, Rammos S, van Kries R, Kirschke W, Kniemeyer HW, Greinacher A. Heparin as a cause of thrombus progression. Heparin-associated thrombocytopenia is an important differential diagnosis in paediatric patients even with normal platelet counts. Eur J Pediatr 1996; 155: 11-14.
    PubMedGoogle Scholar
  • 31 Warkentin TE, Greinacher A. Laboratory testing for HIT antibodies. In: Warkentin TE, Greinacher A. eds. Heparin-Induced thrombocytopenia. New York: Marcel Dekker, Inc.; In press.
    Google Scholar
  • 32 Griffiths E, Dzik WH. Assays for heparin-induced thrombocytopenia. Transfus Med 1997; 7: 1-11.
    CrossrefPubMedGoogle Scholar
  • 33 Warkentin TE, Simpson PJ, Sheppard JI, Moore JC, Horsewood P, Kelton JG. A comparison of activation and antigen assays to diagnose heparin-induced thrombocytopenia (HIT). J Autoimmun 1999; Suppl: 88.
    PubMedGoogle Scholar
  • 34 Eichler P, Budde U, Haas S, Kroll H, Loreth RM, Meyer O, Pachmann U, Pötzsch B, Schabel A, Albrecht D, Greinacher A. First workshop for detection of HIT antibodies: Validation of the heparin-induced platelet-activation test (HIPA) in comparison with a PF4/heparin ELISA. Thromb Haemost. In press.
    PubMedGoogle Scholar
  • 35 Collins JL, Aster RH, Moghaddam M, Piotrowski MA, Strauss TR, McFarland JG. Diagnostic testing for heparin-induced thrombocytopenia (HIT): An enhanced platelet factor 4 complex enzyme linked immunosorbent assay (PF ELISA) (abstract). Blood 1997; 90 (Suppl. 01) 461a.
    PubMedGoogle Scholar
  • 36 Newman PM, Swanson RL, Chong BH. Heparin-induced thrombocytopenia: IgG binding to PF4-heparin complexes in the fluid phase and cross-reactivity with low molecular weight heparin and heparinoid. Thromb Haemost 1998; 80: 292-297.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 37 Favaloro EJ, Bernal-Hoyos E, Exner T, Koutts J. Heparin-induced thrombocytopenia: Laboratory investigation and confirmation of diagnosis. Pathology 1992; 24: 177-183.
    CrossrefPubMedGoogle Scholar
  • 38 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: 344-350.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 39 Arepally G, Reynolds C, Tomaski A, Amiral J, Jawad A, Poncz M, Cines DB. Comparison of the PF4/heparin ELISA assay with the 14C-serotonin assay in the diagnosis of heparin-induced thrombocytopenia. Am J Clin Pathol 1995; 104: 648-654.
    CrossrefPubMedGoogle Scholar
  • 40 Bauer TL, Arepally G, Konkle BA, Mestichelli B, Shapiro SS, Cines DB, Poncz M, McNulty S, Amiral J, Hauck WW, Edie RN, Mannion JD. Prevalence of heparin-associated antibodies without thrombosis in patients undergoing cardiopulmonary bypass surgery. Circulation 1997; 95: 1242-1246.
    CrossrefPubMedGoogle Scholar
  • 41 Look KA, Sahud M, Flaherty S, Zehnder JL. Heparin-induced platelet aggregation vs platelet factor 4 enzyme-linked immunosorbent assay in the diagnosis of heparin-induced thrombocytopenia-thrombosis. Am J Clin Pathol 1997; 108: 78-82.
    CrossrefPubMedGoogle Scholar
  • 42 Amiral J, Wolf M, Fischer A-M, Boyer-Neumann C, Vissac A-M, Meyer D. Pathogenicity of IgA and/or IgM antibodies to heparin-PF4 complexes in patients with heparin-induced thrombocytopenia. Br J Haematol 1996; 92: 954-959.
    CrossrefPubMedGoogle Scholar
  • 43 Amiral J, Marfaing-Koka A, Wolf M, Alessi MC, Tardy B, Boyer-Neumann C, Vissac AM, Fressinaud E, Poncz M, Meyer D. Presence of autoantibodies to interleukin-8 or neutrophil-activating peptide-2 in patients with heparin-induced thrombocytopenia. Blood 1996; 88: 410-416.
    PubMedGoogle Scholar
  • 44 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: 376-383.
    CrossrefPubMedGoogle Scholar
  • 45 Warkentin TE, Kelton JG. Timing of heparin-induced thrombocytopenia (HIT) in relation to previous heparin use: Absence of an anamnestic immune response, and implications for repeat heparin use in patients with a history of HIT (abstract). Blood 1998; 92 (Suppl. 01) 182a.
    PubMedGoogle Scholar
  • 46 King DJ, Kelton JG. Heparin-associated thrombocytopenia. Ann Intern Med 1984; 100: 535-540.
    CrossrefPubMedGoogle Scholar
  • 47 Greinacher A, Warkentin TE. Treatment for heparin-induced thrombocytopenia: an overview. In: Warkentin TE, Greinacher A. eds. Heparin-Induced Thrombocytopenia. New York: Marcel Dekker, Inc.; In press.
    Google Scholar
  • 48 Pötzsch B, Madlener K. Management of cardiopulmonary bypass anticoagulation on patients with heparin-induced thrombocytopenia. In: Warkentin TE, Greinacher A. eds. Heparin-Induced Thrombocytopenia. New York: Marcel Dekker, Inc.; In press.
    Google Scholar
  • 49 Nand S, Wong W, Yuen B, Yetter A, Schmulbach E, Gross Fisher S. Heparin-induced thrombocytopenia with thrombosis: Incidence, analysis of risk factors, and clinical outcomes in 108 consecutive patients treated at a single institution. Am J Hematol 1997; 56: 12-16.
    CrossrefPubMedGoogle Scholar
  • 50 Makhoul RG, Greenberg CS, McCann RL. Heparin-associated thrombocytopenia and thrombosis: A serious clinical problem and potential solution. J Vasc Surg 1986; 4: 522-528.
    CrossrefPubMedGoogle Scholar
  • 51 Warkentin TE, Hong AP. Frequency of upper limb deep venous thrombosis (UL-DVT) in relation to central venous catheter (CVC) use in patients with heparin-induced thrombocytopenia (HIT): Evidence for interaction of systemic (HIT) and local (CVC) prothrombotic risk factors (abstract). Blood 1998; 92 (Suppl. 01) 500a-501a.
    PubMedGoogle Scholar
  • 52 Greinacher A, Völpel H, Janssens U, Hach-Wunderle V, Kemkes-Matthes B, Eichler P, Mueller-Velten HG, Pötzsch B. for the HIT-investigators group. Recombinant hirudin (lepirudin) provides effective and safe anticoagulation in patients with heparin-induced thrombocytopenia type II - a prospective study. Circulation. In press.
    PubMedGoogle Scholar
  • 53 Warkentin TE. Heparin-induced thrombocytopenia: IgG-mediated platelet activation, platelet microparticle generation, and altered procoagulant/anticoagulant balance in the pathogenesis of thrombosis and venous limb gangrene complicating heparin-induced thrombocytopenia. Transfus Med Rev 1996; 10: 249-258.
    CrossrefPubMedGoogle Scholar
  • 54 Warkentin TE, Elavathil LJ, Hayward CPM, Johnston MA, Russett JI, Kelton JG. The pathogenesis of venous limb gangrene associated with heparin-induced thrombocytopenia. Ann Intern Med 1997; 127: 804-812.
    CrossrefPubMedGoogle Scholar
  • 55 Gupta AK, Kovacs MJ, Sauder DN. Heparin-induced thrombocytopenia. Ann Pharmacother 1998; 32: 55-59.
    CrossrefPubMedGoogle Scholar
  • 56 Meyer-Lindenberg A, Quenzel E-M, Bierhoff E, Wolff H, Schindler E, Biniek R. Fatal cerebral venous sinus thrombosis in heparin-induced thrombotic thrombocytopenia. Eur Neurol 1997; 37: 191-192.
    CrossrefPubMedGoogle Scholar
  • 57 Ernest D, Fisher MM. Heparin-induced thrombocytopaenia complicated by bilateral adrenal haemorrhage. Intensive Care Med 1991; 17: 238-240.
    CrossrefPubMedGoogle Scholar
  • 58 Platell CFE, Tan EGC. Hypersensitivity reactions to heparin: Delayed onset thrombocytopenia and necrotizing skin lesions. Aust NZ J Surg 1986; 56: 621-623.
    CrossrefPubMedGoogle Scholar
  • 59 Warkentin TE. Heparin-induced skin lesions. Br J Haematol 92: 494-497 1996; a.
    CrossrefPubMedGoogle Scholar
  • 60 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: 758-790.
    PubMedGoogle Scholar
  • 61 Warkentin TE. Heparin-induced thrombocytopenia, heparin-induced skin lesions, and arterial thrombosis. Thromb Haemost 77 (Suppl.): 562 1997;
    Article in Thieme ConnectPubMedGoogle Scholar
  • 62 Warkentin TE, Sikov WM, Lillicrap DP. Multicentric warfarin-induced skin necrosis complicating heparin-induced thrombocytopenia. Am J Hematol. 1999 in press.
    PubMedGoogle Scholar
  • 63 Popov D, Zarrabi MH, Foda H, Graber M. Pseudopulmonary embolism: acute respiratory distress in the syndrom of heparin-induced thrombocytopenia. Am J Kidney Dis 29: 449-452 1997;
    CrossrefPubMedGoogle Scholar
  • 64 Warkentin TE, Soutar RL, Panju A. Ginsberg JS. Acute systemic reactions to intravenous bolus heparin therapy: Characterization and relationship to heparin-induced thrombocytopenia. Blood 1992; 80 (Suppl. 01) 160a (abstract).
    PubMedGoogle Scholar
  • 65 Ling E, Warkentin TE. Intraoperative heparin flushes and subsequent acute heparin-induced thrombocytopenia. Anesthesiology 1998; 89: 1567-1569.
    CrossrefPubMedGoogle Scholar