Semin Thromb Hemost 2006; 32(8): 803-809
DOI: 10.1055/s-2006-955463
Copyright © 2006 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Heparin-Induced Thrombocytopenia: A Review

Bruno Girolami1 , Antonio Girolami2
  • 1Department of Medicine, Azienda Ospedaliera di Padova, Padova, Italy
  • 2University of Padua Medical School, Department of Medical and Surgical Sciences, Padua, Italy
Further Information

Publication History

Publication Date:
15 December 2006 (online)

ABSTRACT

Immune heparin-induced thrombocytopenia (HIT) is a relevant adverse drug reaction consisting in a hypercoagulable state caused by an anticoagulant agent. The incidence is ~6.5% in patients receiving unfractionated heparin after orthopedic surgery, and is equal to or lower than 1% in other settings. HIT occurrence is a function of heparin type, duration of heparin administration, patient population, and gender. The pathogenesis is due to an antibody response to the complex heparin/platelet factor 4 in most cases, with secondary activation of platelets and coagulation, and finally increased thrombin generation. Thrombocytopenia, venous or arterial thrombosis, heparin-induced skin necrosis, adrenal hemorrhage, and transient amnesia can characterize the clinical course of HIT. Platelet monitoring in patients receiving heparin is indicated to early detect HIT. A thrombotic event can be the first manifestation of HIT. Laboratory demonstration of heparin-dependent platelet activation confirms the clinical diagnosis; antigenic or functional assays are available. Once HIT is highly likely or confirmed serologically, immediate heparin cessation is mandatory and an alternative therapeutic anticoagulant is needed due to the high risk (or the presence) of thrombotic events. The available nonheparin anticoagulants aim to reduce thrombin generation. Lepirudin, argatroban, and bivalirudin (direct thrombin inhibitors) and danaparoid and fondaparinux (factor Xa inhibitors) represent the current treatment options for HIT. Vitamin K antagonists can be used safely only after a stable platelet count has been obtained.

REFERENCES

  • 1 Warkentin T E, Greinacher A. Heparin-induced thrombocytopenia: recognition, treatment, and prevention: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.  Chest. 2004;  126 311S-337S
  • 2 Warkentin T E. Heparin-induced thrombocytopenia: pathogenesis and management.  Br J Haematol. 2003;  121 535-555
  • 3 Warkentin T E, Roberts R S, Hirsh J, Kelton J G. An improved definition of immune heparin-induced thrombocytopenia in postoperative orthopedic patients.  Arch Intern Med. 2003;  163 2518-2524
  • 4 Sheridan D, Carter C, Kelton J G. A diagnostic test for heparin-induced thrombocytopenia.  Blood. 1986;  67 27-30
  • 5 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;  34 381-385
  • 6 Chong B H. Heparin induced thrombocytopenia.  Aust NZ J Med. 1992;  22 145-152
  • 6a Schmitt B P, Adelman B. Heparin-associated thrombocytopenia: a critical review and pooled analysis.  Am J Med. 1993;  305 221-225
  • 7 Ganzer D, Gutezeit A, Mayer G, Greinecher A, Eichler P. Prevention of thromboembolism as a cause of thromboembolic complications. A study of the incidence of heparin-induced thrombocytopenia type II.  Z Orthop Ihre Grenzgeb. 1997;  135 543-549
  • 8 Mahlfeld K, Franke J, Schaeper O, Kayser R, Grasshoff H. Heparin-induced thrombocytopenia as a complication of postoperative prevention of thromboembolism with unfractionated heparin/low molecular weight heparin after hip and knee prosthesis implantation.  Unfallchirurg. 2002;  105 327-331
  • 9 Ganzer D, Gutezeit A, Mayer G. Potentials risks in drug prevention of thrombosis-low-molecular-weight heparin versus standard heparin.  Z Orthop Ihre Grenzgeb. 1999;  137 457-461
  • 10 Marx A, Huhle G, Hoffmann U et al.. Heparin-induced thrombocytopenia after elective hip joint replacement with postoperative prevention of thromboembolism with low-molecular-weight heparin.  Z Orthop Ihre Grenzgeb. 1999;  137 536-539
  • 11 Warkentin T E, Sheppard J A, Horsewood P et al.. Impact of the patient population on the risk for heparin-induced thrombocytopenia.  Blood. 2000;  96 1703-1708
  • 12 Calaitges J G, Liem T K, Spadone D, Nichols W K, Silver D. The role of heparin-associated antiplatelet antibodies in the outcome of arterial reconstruction.  J Vasc Surg. 1999;  29 779-785
  • 13 Lindhoff-Last E, Eichler P, Stein M et al.. A prospective study on the incidence and clinical relevance of heparin-induced antibodies in patients after vascular surgery.  Thromb Res. 2000;  97 387-393
  • 14 Kappers-Klunne M C, Boon D M, Hop W C et al.. Heparin-induced thrombocytopenia and thrombosis: a prospective analysis of the incidence in patients with heart and cerebrovascular diseases.  Br J Haematol. 1997;  96 442-446
  • 15 Lozano M, Perez S, Cid J et al.. Is the incidence of heparin induced thrombocytopenia the same everywhere? The case of Spain.  Thromb Haemost. 2001;  , (suppl); XVIII Congress ISTH (abst P2718)
  • 16 Lindhoff-Last E, Nakov R, Misselwitz F, Breddin H K, Bauersachs R. Incidence and clinical relevance of heparin-induced antibodies in patients with deep vein thrombosis treated with unfractionated or low-molecular-weight heparin.  Br J Haematol. 2002;  118 1137-1142
  • 17 Girolami B, Prandoni P, Stefani P M et al.. The incidence of heparin-induced thrombocytopenia in hospitalized medical patients treated with subcutaneous unfractionated heparin: a prospective cohort study.  Blood. 2003;  101 2955-2959
  • 18 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 3049-3054
  • 19 Visentin G P, Ford S E, Scott J P, Aster L H. 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
  • 20 Amiral J, Bridey F, Dreyfus M et al.. Platelet factor 4 complexed to heparin is the target for antibodies generated in heparin-induced thrombocytopenia.  Thromb Haemost. 1992;  68 95-96
  • 21 Kelton J G, Smith J W, Warkentin T E et al.. Immunoglobulin G from patients with heparin-induced thrombocytopenia binds to a complex of heparin and platelet factor 4.  Blood. 1994;  83 3232-3239
  • 22 Rauova L, Poncz M, McKenzie S E et al.. Ultralarge complexes of PF4 and heparin are central to the pathogenesis of heparin-induced thrombocytopenia.  Blood. 2005;  105 131-138
  • 23 Greinacher A, Alban S, Kummel V et al.. 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;  74 886-892
  • 24 Amiral J, Meyer D. Heparin-dependent antigens in heparin-induced antibodies. In: Warketin TE, Greinecher A Heparin-Induced Thrombocytopenia. 3rd ed. New York, NY; Marcel Dekker 2004: 165-178
  • 25 Ziporen L, Li Z Q, Park K S et al.. Defining an antigenic epitope on platelet factor 4 associated with heparin-induced thrombocytopenia.  Blood. 1998;  92 3250-3259
  • 26 Li Z Q, Liu W, Park K S et al.. Defining a second epitome for heparin-induced thrombocytopenia/thrombosis antibodies using KKO, a murine HIT-like monoclonal antibody.  Blood. 2002;  99 1230-1236
  • 27 Suh J S, Malik M I, Aster R H et al.. Characterization of the humoral immune response in heparin-induced thrombocytopenia.  Am J Hematol. 1997;  54 196-201
  • 28 Greinacher A, Potzsch 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;  71 247-251
  • 29 Newman P M, Chong B H. Heparin-induced thrombocytopenia: new evidence for the dynamic binding of purified anti-PF4-heparin antibodies to platelets and the resultant platelet activation.  Blood. 2000;  96 182-187
  • 30 Warkentin T E, Kelton J G. Temporal aspects of heparin-induced thrombocytopenia.  N Engl J Med. 2001;  344 1286-1292
  • 31 Warkentin T E, Kelton J G. Delayed-onset heparin-induced thrombocytopenia and thrombosis.  Ann Intern Med. 2001;  135 502-506
  • 32 Warkentin T E. Clinical presentation of heparin-induced thrombocytopenia.  Semin Hematol. 1998;  35 9-16
  • 33 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;  14 121-129
  • 34 Warkentin T E, Kelton J G. A 14-year study of heparin-induced thrombocytopenia.  Am J Med. 1996;  101 502-507
  • 35 Arthur C K, Grant SJB, Murray W K et al.. Heparin-associated acute adrenal insufficiency.  Aust NZ J Med. 1985;  15 454-455
  • 36 Warkentin T E, Hirte H W, Anderson D R et al.. Transient global amnesia associated with acute heparin-induced thrombocytopenia.  Am J Med. 1994;  97 489-491
  • 37 Warkentin T E, Levine M N, Hirsh J et al.. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin.  N Engl J Med. 1995;  332 1330-1335
  • 38 Greinacher A, Völpel H, Janssens U for the HIT Investigators Group et al.. Recombinant hirudin (lepirudin) provides safe and effective anticoagulation in patients with heparin-induced thrombocytopenia: a prospective study.  Circulation. 1999;  99 73-80
  • 39 Greinacher A, Janssens U, Berg G for the Heparin associated Thrombocytopenia Study (HAT) Investigators et al.. Lepirudin (recombinant hirudin) for parenteral anticoagulation in patients with heparin-induced thrombocytopenia.  Circulation. 1999;  100 587-593
  • 40 Eichler P, Lubenow N, Greinacher A. Results of the third prospective study of treatment with lepirudin in patients with heparin-induced thrombocytopenia (HAT).  Blood. 2002;  100(suppl 1) 704a , (abst)
  • 41 Lewis B E, Wallis D E, Berkowitz S D et al.. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia.  Circulation. 2001;  103 1838-1843
  • 42 Lewis B E, Wallis D E, Leya F et al.. Argatroban anticoagulation in patients with heparin-induced thrombocytopenia.  Arch Intern Med. 2003;  163 1849-1856
  • 43 Eichler P, Kroll H, Greinacher A. A comparison of danaparoid and lepirudin in heparin-induced thrombocytopenia.  Thromb Haemost. 2001;  85 950-957
  • 44 Warkentin T E. Danaparoid (Orgaran®) for the treatment of heparin-induced thrombocytopenia (HIT) and thrombosis: effects on in vivo thrombin and cross-linked fibrin generation, and evaluation of the clinical significance of in vitro cross-reactivity (XR) of danaparoid for HIT-IgG.  Blood. 1996;  88(suppl 1) 626a , (abst)
  • 45 Magnani H N. Heparin-induced thrombocytopenia (HIT): an overview of 230 patients treated with Orgaran (Org 10172).  Thromb Haemost. 1993;  70 554-561
  • 46 Magnani H N. Orgaran (danaparoid sodium) use in the syndrome of heparin-induced thrombocytopenia.  Platelets. 1997;  8 74-81
  • 47 Lubenow N, Eichler P, Lietz T, Farner B, Greinacher A. Lepirudin for prophylaxis of thrombosis in patients with acute isolated heparin-induced thrombocytopenia: an analysis of 3 prospective studies.  Blood. 2004;  104 3072-3077
  • 48 Greinacher A, Volpel H, Janssens V et al.. Recombinant hirudin (lepirudin) provides safe and effective anticoagulation in patients with heparin-induced thrombocytopenia: A prospective study.  Circulation. 1999;  99 73-80
  • 49 Lewis B E, Wallis D E, Leya F et al.. Argatroban anticoagulation in patients with heparin-induced thrombocytopenia.  Arch Intern Med. 2003;  163 1849-1856
  • 50 Lewis B E. Argatroban in heparin-induced thrombocytopenia type II: clinical experience-trials and practice. Paper presented at: Symposium XIX ISTH Congress July 12-18, 2003 Birmingham, UK;
  • 51 Gillis S, Merin G, Zahger D et al.. Danaparoid for cardiopulmonary bypass in patients with previous heparin-induced thrombocytopenia.  Br J Haematol. 1997;  98 657-659
  • 52 Farner B, Eichler P, Kroll H, Greinacher A. A comparison of danaparoid and lepirudin in heparin-induced thrombocytopenia.  Thromb Haemost. 2001;  85 950-957

Bruno GirolamiM.D. Ph.D. 

Azienda Ospedaliera di Padova Via Giustiniani 2 35100 Padova

Italy

Email: bruno.girolami@sanita.padova.it

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