Skip to main content
SpringerLink
Log in

Drugs for the Prevention and Treatment of Thrombosis in Patients with Heparin-Induced Thrombocytopenia

  • Therapy in Practice
  • Published:
American Journal of Cardiovascular Drugs Aims and scope Submit manuscript

Abstract

Most patients with heparin-induced thrombocytopenia (HIT), a serious adverse effect of heparin mediated by platelet-activating heparin-dependent antibodies, require alternative anticoagulation. This is because HIT is highly prothrombotic and is characterized by markedly increased thrombin generation. Unfractionated heparins seem to induce HIT more often than low molecular weight heparins. There are three anticoagulants for which there is an emerging consensus for their efficacy in management of HIT, and which are currently approved for treatment of HIT in several countries: the recombinant hirudin, lepirudin, a direct thrombin inhibitor; the synthetic direct thrombin inhibitor, argatroban; and the heparinoid, danaparoid sodium, mainly exhibiting antifactor-Xa activity. Rrecommendations for optimal use of these drugs in HIT are given in this review stressing the need for immediate treatment of patients with HIT without awaiting laboratory diagnosis. Hirudin, the drug for which most data from prospective trials exists, can be safely and effectively used in patients with HIT, its dramatically increased elimination half-life in patients with renal failure being the most important drawback. Argatroban, which is mainly eliminated by the liver, could be used preferentially in such patients with renal impairment. Interference with the international normalized ratio makes oral anticoagulation, which is necessary in many patients with HIT, problematic. Activated partial thromboplastin time is sufficient to monitor lepirudin and argatroban treatment in most cases.

Danaparoid sodium, with an antifactor-X activity half-life of about 24 hours seems to be best suited for thrombosis prophylaxis in patients with HIT. In some patients monitoring by determining antifactor-Xa activity is necessary. No antidote is available for any of the drugs discussed, and bleeding complications are the most important adverse effects. In situations such as hemodialysis or cardiopulmonary bypass, not only the characteristics of the drug in use itself, but also availability of monitoring methods play an important role. Adjunctive treatments have not been systematically evaluated and should be used cautiously. Recent data suggest that re-exposure of patients with a history of HIT with heparin, for example during cardiopulmonary bypass, can be well tolerated provided no circulating HIT antibodies are detectable at the time of re-exposure, and heparin is strictly avoided pre- and postoperatively.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Table I
Table II
Table III

Similar content being viewed by others

References

  1. 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: 1330–5

    PubMed  CAS  Google Scholar 

  2. Warkentin TE, Chong BH, Greinacher A. Heparin-induced thrombocytopenia: towards consensus. Thromb Haemost 1998; 79: 1–7

    PubMed  CAS  Google Scholar 

  3. Amiral J, Bridey F, Wolf M, et al. Antibodies to macromolecular platelet factor 4-heparin complexes in heparin-induced thrombocytopenia: a study of 44 cases. Thromb Haemost 1995; 73: 21–82

    PubMed  CAS  Google Scholar 

  4. Amiral J, Marfaing-Koka A, Wolf M, et al. Presence of autoantibodies to interleucin-8 or neutrophil-activating peptide-2 in patients with heparin-associated thrombocytopenia. Blood 1996; 88: 410–6

    PubMed  CAS  Google Scholar 

  5. Greinacher A, Michels I, Mueller-Eckhardt C. Heparin-associated thrombocytopenia: the antibody is not heparin specific. Thromb Haemost 1992; 67: 545–9

    PubMed  CAS  Google Scholar 

  6. Cines DB, Tomaski A, Tannenbaum S. Immune endothelial-cell injury in heparinassociated thrombocytopenia. N Engl J Med 1987; 316: 581–9

    PubMed  CAS  Google Scholar 

  7. Visentin GP, Ford SE, Scott JP, et al. 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: 81–8

    PubMed  CAS  Google Scholar 

  8. Greinacher A, Poetzsch 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: 247–51

    PubMed  CAS  Google Scholar 

  9. Chong BH, Fawaz I, Chestermann CN, et al. Heparin-induced thrombocytopenia: mechanism of interaction of the heparin-dependent antibody with platelets. Br J Haematol 1989; 73: 235–40

    PubMed  CAS  Google Scholar 

  10. Kelton JG, Sheridan D, Santos A, et al. Heparin-induced thrombocytopenia: laboratory studies. Blood 1988; 72: 925–30

    PubMed  CAS  Google Scholar 

  11. Chong BH, Murray B, Berndt MC, et al. Plasma P-selectin is increased in thrombotic consumptive platelet disorders. Blood 1994; 83: 1535–41

    PubMed  CAS  Google Scholar 

  12. 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: 3691–9

    PubMed  CAS  Google Scholar 

  13. Warkentin TE. Limitations of conventional treatment options for heparin-induced thrombocytopenia. Semin Hematol 1998; 35: 17–25

    PubMed  CAS  Google Scholar 

  14. Warkentin TE, Kelton JE. A 14-year study of heparin-induced thrombocytopenia. Am J Med 1996; 101: 502–7

    PubMed  CAS  Google Scholar 

  15. Wallis DE, Workman DL, Lewis BE, et al. Failure of early heparin cessation as treatment for heparin-induced thrombocytopenia. Am J Med 1999; 106: 629–35

    PubMed  CAS  Google Scholar 

  16. Warkentin TE, Elavathil LJ, Hayward CP, et al. The pathogenesis of venous limb gangrene associated with heparin-induced thrombocytopenia. Ann Intern Med 1997; 127: 804–12

    PubMed  CAS  Google Scholar 

  17. 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: 457–61

    PubMed  CAS  Google Scholar 

  18. Alban S, Greinacher A. Role of sulfated polysaccharides in the pathogenesis of heparin-induced thrombocytopenia. In: Warkentin TE, Greinacher A, editors. Heparin-induced thrombocytopenia. 2nd ed. Marcel Dekker 2001: 167-87

  19. Mayo DJ, Cullinane AM, Merryman PK, Horne MK III. Serologic evidence of heparin sensitization in cancer patients receiving heparin flushes of venous access devices. Support Care Cancer 1999; 7: 425–7

    PubMed  CAS  Google Scholar 

  20. Lee DH, Warkentin TE. Frequency of heparin-induced thrombocytopenia. In: Warkentin TE, Greinacher A, editors. Heparin-induced thrombocytopenia, 2nd ed., Marcel Dekker, 2001: 87-121

  21. Greinacher A, Warkentin TE. Treatment of heparin-induced thrombocytopenia: an overview. In: Warkentin TE, Greinacher A, editors. Heparin-induced thrombocytopenia, 2nd edition, Marcel Dekker, 2001: 291-322

  22. Hoechst Marion Roussel. Refludan Lepirudin: Scientific monograph. New Jersey, USA: Hoechst Marion Roussel

  23. Desirudin (Revasc) Product information. Novartis Pharma GmbH, Nürnberg, Germany, 1998

  24. Hirsh J, Warkentin TE, Raschke R, et al. Heparin and low molecular weight heparin. Mechanisms of action, pharmacokinetics, dosing considerations, monitoring, efficacy and safety. Chest 1998; 114: 489S–510S

    PubMed  CAS  Google Scholar 

  25. Markwardt F. The development of hirudin as an antithrombotic drug. Thromb Res 1994; 74: 1–23

    PubMed  CAS  Google Scholar 

  26. Weite JI, Hudoba M, Massel D, et al. Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin III-independent inhibitors. J Clin Invest 1990; 86: 385–91

    Google Scholar 

  27. Weite JI, Leslie B, Hudoba M. Thrombin binds to soluble fibrin degradation products where it is protected from inhibition by heparin-antithrombin but susceptible to inactivation by antithrombin-independent inhibitors. Circulation 1998; 97: 544–52

    Google Scholar 

  28. Hogg PJ, Jackson CM, Labanowski JK, et al. Binding of fibrin monomer and heparin to thrombin in a ternary complex alters the environment of the thrombin catalytic site, reduces affinity for hirudin, and inhibits cleavage of fibrinogen. J Biol Chem 1996; 271: 26088–95

    PubMed  CAS  Google Scholar 

  29. Hogg PJ, Bock PE. Modulation of thrombin and heparin activities by fibrin. Thromb Haemost 1997; 77: 424–33

    PubMed  CAS  Google Scholar 

  30. Markwardt F, Nowak G, Stürzebecher J, et al. Clinicopharmacological studies with recombinant hirudin. Thromb Res 1988; 52: 393–400

    PubMed  CAS  Google Scholar 

  31. Markwardt F, Fink G, Kaiser B, et al. Pharmacological survey of recombinant hirudin. Pharmazie 1988; 43: 202–7

    PubMed  CAS  Google Scholar 

  32. Lepirudin (HBW 023): Investigators brochure. Behringwerke AG, Marburg/Lahn, Germany. Edition no. 6. Jan 31, 1997

    Google Scholar 

  33. Schiele F, Vuillemenot A, Kramarz P, et al. A pilot study of subcutaneous recombinant hirudin (HBW 023) in the treatment of deep vein thrombosis. Thromb Haemost 1994; 71: 558–62

    PubMed  CAS  Google Scholar 

  34. Nowak G, Markwardt F, Fink E. Pharmacokinetic studies with recombinant hirudin in dogs. Folia Haematol 1988; 115: 70–4

    CAS  Google Scholar 

  35. Markwardt F. Development of hirudin as an antithrombotic agent. Semin Thromb Haemost 1989; 15: 269–82

    CAS  Google Scholar 

  36. Nowak G, Bucha E, Gööck T, et al. Pharmacology of r-hirudin in renal impairment. Thromb Res 1992; 66: 707–15

    PubMed  CAS  Google Scholar 

  37. Nowak G, Bucha E, Gööck T, et al. Pharmakokinetik von Hirudin bei gestörter Nierenfunktion. Hämostaseologie 1991; 11: 152–7

    Google Scholar 

  38. Nowak G, Bucha E, Brauns I, et al. Anticoagulation with r-hirudin in regular haemodialysis with heparin-induced thrombocytopenia (HIT II). The first long term application of r-hirudin in ahaemodialysis patient. Wien Klin Wochenschr 1997; 109: 354–8

    PubMed  CAS  Google Scholar 

  39. Vanholder R, Camez A, Veys N, et al. Pharmacokinetics of recombinant hirudin in hemodialyzed end-stage renal failure patients. Thromb Haemost 1997; 77: 650–5

    PubMed  CAS  Google Scholar 

  40. Vanholder R, Camez A, Veys NM, et al. Recombinant Hirudin: A specific thrombin-inhibiting anticoagulant for hemodialysis. Kidney Int 1994; 45: 1754–9

    PubMed  CAS  Google Scholar 

  41. Lange U, Lehr A, Nowak G. Biologically active metabolites of recombinant and PEG-hirudin in rat urine — isolation and biochemical characterization. Ann Hematol 1996; 72 Suppl. I: P233

    Google Scholar 

  42. Greinacher A, Völpel H, Janssens U, et al. Recombinant hirudin (lepirudin) provides safe and effective anticoagulation in patients with the immunologic type of heparin-induced thrombocytopenia: a prospective study. Circulation 1999; 99: 73–80

    PubMed  CAS  Google Scholar 

  43. Greinacher A, Janssens U, Berg G, et al. Lepirudin (recombinant hirudin) for parenteral anticoagulation in patients with heparin-induced thrombocytopenia. Circulation 1999; 100: 587–93

    PubMed  CAS  Google Scholar 

  44. Hempel S, Lubenow N, Greinacher A. Nierenersatztherapie unter r-hirudin (Refludan) bei Heparin-induzierter Thrombozytopenie Typ II [abstract]. Infusionsther Transfusionsmed 1998; 25: (5) 7

    Google Scholar 

  45. van Wyk V, Badenhorst PN, Luus HG, et al. A comparison between the use of recombinant hirudin and heparin during hemodialysis. Kidney Int 1995; 48: 1338–43

    PubMed  Google Scholar 

  46. Fischer KG, van de Loo A, Bohler J. Recombinant hirudin (lepirudin) as anticoagulant in intensive care patients treated with continuous hemodialysis. Kidney Int 19999; 56 Suppl. 72: S46-S50

  47. Bucha E, Nowak G, Czerwinski R, et al. R-hirudin as anticoagulant in regular hemodialysis therapy: Finding of therapeutic r-hirudin blood/plasma concentrations and respective dosages. Clin Appl Thromb Hemost 1999; 5: 164–70

    PubMed  CAS  Google Scholar 

  48. Pötzsch B, Madiener K. Management of cardiopulmonary bypass anticoagulation in patients with heparin-induced thrombocytopenia. In: Warkentin TE, Greinacher A, editors. Heparin-induced thrombocytopenia, 2nd edition, Marcel Dekker 2001: 429-44

  49. Organization to Assess Strategies for Ischemic Syndromes (OASIS-2) Investigators. Effects of recombinant hirudin (lepirudin) compared with heparin on death, myocardial infarction, refractory angina, and revascularization procedures in patients with acute myocardial ischaemia without ST elevation: a randomized trial. Lancet 1999; 353: 429–38

    Google Scholar 

  50. Hafner G, Rupprecht HJ, Luz M, et al. Recombinant hirudin as a periprocedural antithrombotic in coronary angioplasty for unstable angina pectoris [see comments]. Eur Heart J 1996; 17: 1207–15

    PubMed  CAS  Google Scholar 

  51. Rupprecht HJ, Terres W, Ozbek C, et al. Recombinant hirudin (HBW 023) prevents troponin T release after coronary angioplasty in patients with unstable angina. J Am Coll Cardiol 1995; 26: 1637–42

    PubMed  CAS  Google Scholar 

  52. Neuhaus KL, Molhoek GP, Zeymer U, et al. Recombinant hirudin (lepirudin) for the improvement of thrombolysis with streptokinase in patients with acute myocardial infarction: results of the HIT-4 trial. J Am Coll Cardiol 1999; 34: 966–73

    PubMed  CAS  Google Scholar 

  53. Antman EM. Hirudin in acute myocardial infarction. Thrombolysis and Thrombin Inhibition in Myocardial Infarction (TIMI) 9B trial [see comments]. Circulation 1996; 94: 911–21

    PubMed  CAS  Google Scholar 

  54. Schiffmann H, Unterhalt M, Harms K, et al. Successful treatment of heparin-induced thrombocytopenia (HIT) type II in childhood with recombinant hirudin. Monatsschr Kinderheilkd 1997; 145: 606–12

    Google Scholar 

  55. Eriksson BI, Ekman S, Lindbratt S, et al. Prevention of thromboembolism with use of recombinant hirudin. Results of a double-blind, multicenter trial comparing the efficacy of desirudin (Revasc) with that of unfractionated heparin in patients having a total hip replacement. J Bone Joint Surg Am 1997; 79: 326–33

    PubMed  CAS  Google Scholar 

  56. Eriksson BI, Wille-Jörgensen P, Kälebo P, et al. A comparison of recombinant hirudin with a low-molecular weight heparin to prevent thromboembolic complications after total hip replacement. N Engl J Med 1997; 337: 1329–35

    PubMed  CAS  Google Scholar 

  57. Hoet B, Tornai I, Arnout J, et al. Open study of intravenous recombinant hirudin (CGP 39393) on platelet function and coagulation in healthy volunteers. Drug Invest 1994; 7: 127–33

    CAS  Google Scholar 

  58. Breddin HK. Neue Aspekte zu Hirudin. medwelt 1997; 48: 64–6

    Google Scholar 

  59. Zoldhelyi P, Webster MWI, Fuster V, et al. Recombinant hirudin in patients with chronic, stable coronary artery disease. Safety, half-life, and effect on coagulation parameters. Circulation 1993; 88: 2015–22

    PubMed  CAS  Google Scholar 

  60. Nowak G, Bucha E. Quantitative determination of hirudin in blood and body fluids. Semin Thromb Haemost 1996; 22: 197–202

    CAS  Google Scholar 

  61. Verstraete M, Nurmohamed M, Kienast J, et al. Biologic effects of recombinant hirudin (CGP 39393) in human volunteers. J Am Coll Cardiol 1993; 22: 1080–8

    PubMed  CAS  Google Scholar 

  62. Marbet GA, Verstraete M, Kienast J, et al. Clinical pharmacology of intravenously administered recombinant desulfatohirudin (CGP 39393) in healthy volunteers. J Cardiovasc Pharmacol 1993; 22: 364–72

    PubMed  CAS  Google Scholar 

  63. Bridey F, Dreyfus M, Parent F, et al. Recombinant hirudin (HBW 023): biological data of ten patients with severe venous thrombo-embolism. Am J Hematol 1995; 49: 67–72

    PubMed  CAS  Google Scholar 

  64. Zeymer U, von Essen R, Tebbe U, et al. Recombinant hirudin and front-loaded alteplase in acute myocardial infarction: Final results of a pilot study. HIT-I (hirudin for the improvement of thrombolysis). Eur Heart J 1995; 16 Suppl. D: 22–7

    PubMed  CAS  Google Scholar 

  65. Zeymer U, von Essen R, Tebbe U, et al. Frequency of ‘optimal anticoagulation’ for acute myocardial infarction after thrombolysis with front-loaded recombinant tissue-type plasminogen activator and conjunctive therapy with recombinant hirudin (HBW 023). Am J Cardiol 1995; 76: 997–1001

    PubMed  CAS  Google Scholar 

  66. Nurmohamed MT, Berckmans RJ, Morrien-Salomons WM, et al. Monitoring anticoagulant therapy by activated partial thromboplastin time: Hirudin assessment. Thromb Haemost 1994; 72: 685–92

    PubMed  CAS  Google Scholar 

  67. Pötzsch B, Hund S, Madiener K, Unkrig C, Muller-Berghaus G. Monitoring of recombinant hirudin: Assessment of a plasma-based ecarin clotting time assay. Thromb Res 1997; 86: 373–83

    PubMed  Google Scholar 

  68. Pötzsch B, Madiener K, Seelig C, Riess C, Greinacher A, Müller-Berghaus G. Monitoring of r-hirudin anticoagulation during cardiopulmonary bypass — Assessment of the whole blood ecarin clotting time. Thromb Haemost 1997; 77: 920–25

    PubMed  Google Scholar 

  69. Kornalik F, Blombäck B. Prothrombin activation induced by ecarin — a prothrombin converting enzyme from Echis carinatus venom. Thromb Res 1975; 6: 57–63

    PubMed  CAS  Google Scholar 

  70. Nishida S, Fujita T, Kohno N, Atoda H, Morita T, Takeya H, Kido I, Paine MJ, Kawabata S, Iwanaga S. cDNA cloning and deduced amino acid sequence of prothrombin activator (ecarin) from Kenyan Echis carinatus venom. Biochemistry 1995; 34: 1771–1778

    PubMed  CAS  Google Scholar 

  71. Morita T, Iwanaga S, Suzuki T. The mechanism of activation of bovine prothrombin by an activator isolated from Echis carinatus venom and characterization of the new active intermediates. J Biochem 1976; 79: 1089–108

    PubMed  CAS  Google Scholar 

  72. Novoa E, Seegers WH. Mechanisms of alpha-thrombin and beta-thrombin-E formation: use of ecarin for isolation of meizothrombin 1. Thromb Res 1980; 18: 657–68

    PubMed  CAS  Google Scholar 

  73. Greinacher A, Eichler P, Lubenow N, et al. Heparin-induced thrombocytopenia with thromboembolic complications: meta-analysis of two prospective trials to assess the value of parenteral treatment with lepirudin and its therapeutic aPTT range. Blood 2000; 96: 846–51

    PubMed  CAS  Google Scholar 

  74. Lindhoff-Last E, Piechottka GP, Rabe F, et al. Hirudin determination in plasma can be strongly influenced by the prothrombin level. Thromb Res 2000; 100: 55–60

    PubMed  CAS  Google Scholar 

  75. McKeage K, Plosker GL. Argatroban. Drugs 2001; 61: 515–22

    PubMed  CAS  Google Scholar 

  76. Swan SK, St Peter JV, Lambrecht LJ, et al. Comparison of anticoagulant effects and safety of argatroban and heparin in healthy subjects. Pharmacotherapy 2000; 20: 756–70

    PubMed  CAS  Google Scholar 

  77. Swan SK, Hursting MJ. The pharmacokinetics and pharmacodynamics of argatroban: effects of age, gender, and hepatic or renal dysfunction. Pharmacotherapy 2000; 20: 318–29

    PubMed  CAS  Google Scholar 

  78. von Essen R, Zeymer U, Tebbe U, et al. HBW 023 (recombinant hirudin) for the acceleration of thrombolysis and prevention of coronary reocclusion in acute myocardial infarction: results of a dose-finding study (HIT II) by the Arbeitsgemeinschaft Leitender Kardiologischer Krankenhausärzte. Coron Artery Dis 1998; 9: 265–72

    Google Scholar 

  79. Ibbotson SH, Grant PJ, Kerry R, et al. The influence of infusions of 1-desamino-8-D-arginine vasopressin (DDAVP) in vivo on the anticoagulant effect of recombinant hirudin (CGP39393) in vitro. Thromb Haemost 1991; 65: 64–6

    PubMed  CAS  Google Scholar 

  80. Amin DM, Mant TG, Walker SM, et al. Effect of a 15 minute infusion of DDAVP on the pharmacokinetics and pharmacodynamics on Revasc during a four-hour intravenous infusion in healthy volunteers. Thromb Haemost 1997; 77: 127–32

    PubMed  CAS  Google Scholar 

  81. Diehl KH, Romisch J, Hein B, et al. Investigation of activated prothrombin complex concentrate as potential hirudin antidote in animal models. Haemostasis 1995; 25: 182–92

    PubMed  CAS  Google Scholar 

  82. Irami MS, Harvey JW, Sexon RG. Reversal of hirudin-induced bleeding diathesis by prothrombin complex concentrate. Am J Cardiol 1995; 75: 422–3

    Google Scholar 

  83. Frank RD, Farber H, Stefanidis I, et al. Hirudin elimination by hemofiltration: a comparative in vitro study of different membranes. Kidney Int 1999; 56: 41–6

    Google Scholar 

  84. Bucha E, Kreml R, Nowak G. In vitro study of r-hirudin permeability through membranes of different haemodialysers. Nephrol Dial Transplant 1999; 14: 2922–6

    PubMed  CAS  Google Scholar 

  85. Fischer KG. Hemodialysis in heparin-induced thrombocytopenia. In: Warkentin TE, Greinacher A, editors. Heparin-induced thrombocytopenia, 2nd edition, Marcel Dekker 2001: 409-27

  86. Benz K, Nauck M, Beck KH, et al. Filtration characteristics of recombinant hirudin by different hemodialyzers in vitro [abstract]. Ann Hematol 2000; 79: A26

    Google Scholar 

  87. Eichler P, Friesen HJ, Lubenow N, et al. Antihirudin antibodies in patients with heparin-induced thrombocytopenia treated with lepirudin: incidence, effects on aPTT, and clinical relevance. Blood 2000; 96: 2373–8

    PubMed  CAS  Google Scholar 

  88. Huhle G, Song X, Wang LC, et al. Generation and disappearance of antihirudin antibodies during treatment with r-hirudin. Fibrinol Proteol 1998; 12 Suppl. 2: 91–113

    Google Scholar 

  89. Huhle G, Hoffmann U, Song XH, et al. Immunantwort auf rekombinantes Hirudin: Eine Übersicht (Immune Response to Recombinant Hirudin: an Overview). Haemostaseologie 1999; 19: 50–4

    CAS  Google Scholar 

  90. Huhle, G, Hoffmann U, Song X, et al. Immunologic response to recombinant hirudin in HIT type II patients during long-term treatment. Br J Haematol 1999; 106: 195–201

    PubMed  CAS  Google Scholar 

  91. Close P, Bichler J, Kerry R, et al. Weak allergenicity of recombinant hirudin CGP 39393 (REVASC) in immunocompetent volunteers. The European Hirudin in Thrombosis Group (HIT Group). Coron Artery Dis 1994; 5: 943–9

    PubMed  CAS  Google Scholar 

  92. Eichler P, Eriksson BI, Pötzsch B, et al. Anti-hirudin antibodies following low dose subcutaneous application of desirudin for thrombosis prophylaxis after hipreplacement surgery. Incidence and clinical relevance [abstract]. Thromb Haemost 1999; Suppl.: 855

  93. Schiele F, Vuillemenot A, Kramarz P, et al. Use of recombinant hirudin as antithrombotic treatment in patients with heparin-induced thrombocytopenia. Am J Hematol 1995; 50: 20–5

    PubMed  CAS  Google Scholar 

  94. Madei W, Klieser HP, Hoerauf K. Heparin-induced thrombocytopenia as a cause of persistent bleeding after cardiac pacemaker implantation. Dtsch Med Wochenschr 1999; 124: 487–90

    PubMed  CAS  Google Scholar 

  95. Wagner AD, Kleber G, Lindner A, et al. 19jähriger Patient mit generalisiertem Krampfanfall und rezidivierenden Thrombosen unter Heparintherapie. Internist 1998; 39: 766–9

    Google Scholar 

  96. Schmidt OH, Lang W Heparin-induced thrombocytopenia with thromboembolic arterial occlusion treated with recombinant hirudin. N Engl J Med 1997; 337: 1389

    PubMed  CAS  Google Scholar 

  97. Harenberg J, Huhle G, Piazolo L, et al. Anticoagulation in patients with heparininduced thrombocytopenia type II. Semin Thromb Hemost 1997; 189-96

  98. Olbrich K, Wiersbitzky M, Wacke W, et al. Atypical heparin-induced thrombocytopenia complicated by intracardiac thrombus, effectively treated with ultra-lowdose rt-PA lysis and recombinant hirudin (Lepirudin). Blood Coagul Fibrinolysis 1998; 9: 273–7

    PubMed  CAS  Google Scholar 

  99. Janssens U, Breithardt OA, Greinacher A. Successful thrombolysis of right atrial and ventricle thrombi encircling a temporary pacemaker lead in a patient with heparin-induced thrombocytopenia type II. Pacing Clin Electrophysiol 1999; 22: 678–81

    PubMed  CAS  Google Scholar 

  100. Hursting MJ, Alford KL, Becker JC, et al. Novastan (brand of argatroban): a smallmolecule, direct thrombin inhibitor. Semin Thromb Hemost 1997; 23: 503–16

    PubMed  CAS  Google Scholar 

  101. Lewis BE, Hursting MJ. Argatroban therapy in heparin-induced thrombocytopenia. In: Warkentin TE, Greinacher A, editors Heparin-induced thrombocytopenia, 2nd edition, Marcel Dekker 2001: 291-322

  102. Sheth SB, DiCicco RA, Hursting MJ, et al. Interpreting the international normalized ratio (INR) in individuals receiving argatroban and warfarin. Thromb Haemost 2001; 85:(3) 435–40

    PubMed  CAS  Google Scholar 

  103. Lewis BE, Wallis DE, Berkowitz SD, et al. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation 2001; 103: 1838–43

    PubMed  CAS  Google Scholar 

  104. Lewis BE, Wallis DE, Zehnder JL, et al. Argatroban reexposure in patients with heparin-induced thrombocytopenia [abstract]. Blood 2000; 96: 52a

    Google Scholar 

  105. Walenga JM, Ahmad S, Hoppensteadt DA, et al. Prolonged argatroban treatment does not result in the generation of neutralizing antibodies [abstract]. Thromb Haemost 1999; 82 Suppl.: 390

    Google Scholar 

  106. Greinacher A. Treatment of heparin-induced thrombocytopenia. Thromb Haemost 1999; 82: 457–67

    PubMed  CAS  Google Scholar 

  107. Magnani HN. Heparin-induced thrombocytopenia (HIT): an overview of 230 patients treated with Orgaran (Org 10172). Thromb Haemost 1993; 70: 554–61

    PubMed  CAS  Google Scholar 

  108. Magnani HN. Orgaran (Danaparoid sodium) use in the syndrome of heparin-induced-thrombocytopenia. Proceedings of a workshop held in London 1996, Nov 1. Platelets 1997; 8: 74–81

    Google Scholar 

  109. Ortel TL, Chong BH. New treatment options for heparin-induced thrombocytopenia. Semin Hematol 1998; 35 (4 Suppl. 5): 26–34; discussion 35-6

    PubMed  CAS  Google Scholar 

  110. Meulemann DG. Orgaran (Org 10172): 1st pharmacological profile in experimental models. Haemostasis 1992; 22: 58–65

    Google Scholar 

  111. Wilde MI, Markham A. Danaparoid: a review of its pharmacology and clinical use the management of heparin-induced thrombocytopenia. Drugs 1997; 54: 903–24

    PubMed  CAS  Google Scholar 

  112. Skoutakis VA. Danaparoid in the prevention of thromboembolic complications. Ann Pharmacother 1997; 31: 876–87

    PubMed  CAS  Google Scholar 

  113. Chong BH, Magnani HN. Danaparoid for the treatment of heparin-induced thrombocytopenia. In: Warkentin TE, Greinacher A, editors. Heparin-induced thrombocytopenia, 2nd edition, Marcel Dekker 2001: 323-47

  114. Laposata M, Green D, Van Cott EM, et al. College of American Pathologists Conference Therapy The clinical use and laboratory monitoring of low-molecular-weight heparin, danaparoid, hirudin and related compounds, and argatroban. Arch Pathol Lab Med 1998; 122: 799–807

    PubMed  CAS  Google Scholar 

  115. Chong BH. Low molecular weight heparinoid and heparin-induced thrombocytopenia [abstract]. Aust NZ J Med 1996; 26: 331

    Google Scholar 

  116. Farner B, Eichler P, Kroll H, et al. A comparison of danaparoid and lepirudin in heparin-induced thrombocytopenia. Thromb Haemost 2001; 85: 950–7

    PubMed  CAS  Google Scholar 

  117. Newman PM, Swanson RL, Chong BH. IgG binding to PF4-heparin complexes in the fluid phase and cross-reactivity with low molecular weight heparin and heparinoid. Thromb Haemost 1998; 80: 292–7

    PubMed  CAS  Google Scholar 

  118. Insler SR, Kraenzler EJ, Barholomew JR, et al. Thrombosis during the use of the heparinoid Organon 10172 in a patient with heparin-induced thrombocytopenia. Anesthesiology 1997; 86: 495–8

    PubMed  CAS  Google Scholar 

  119. Warkentin TE. Danaparoid (Orgaran) for the treatment of heparin-induced thrombocytopenia (HIT) and thrombosis: effects on in vivo thrombin and crosslinked fibrin generation, and evaluation of the clinical significance of in vitro cross-reactivity of danaparoid for HIT-IgG. Blood 1996; 88: 626a

    Google Scholar 

  120. van Wyk V, Badenhorst PN, Kotzé HF. The effect of r-hirudin vs heparin on bloodmembrane interactions during haemodialysis. Clin Nephrol 1997; 8: 381–7

    Google Scholar 

  121. Kern H, Ziemer S, Kox WJ. Bleeding after intermittent or continuous r-hirudin during CVVH. Intensive Care Med 1999; 25: 1311–4

    PubMed  CAS  Google Scholar 

  122. Matsuo T, Kario K, Kodama K, et al. Clinical application of the synthetic thrombin inhibitor, argatroban (MD-805). Semin Thromb Hemost 1992; 18: 155–60

    PubMed  CAS  Google Scholar 

  123. Koide M, Yamamoto S, Matsuo M, et al. Anticoagulation for heparin-induced thrombocytopenia with spontaneous platelet aggregation in a patient requiring hemodialysis. Nephrol Dial Transplant 1995; 10: 2137–40

    PubMed  CAS  Google Scholar 

  124. Ireland H, Lane DA, Flynn A, et al. The anticoagulant effect of heparinoid Org 10172 during haemodialysis: an objective assessment. Thromb Haemost 1986; 55: 271–5

    PubMed  CAS  Google Scholar 

  125. Rowlings PA, Mansberg R, Rozenberg MC, et al. The use of a low-molecular weight heparinoid (Org 10172) for extracorporeal procedures in patients with heparin-dependent thrombocytopenia and thrombosis. Aust NZ J Med 1991; 21: 52–4

    CAS  Google Scholar 

  126. Riess FC, Bleese N, Kormann J, et al. Recombinant hirudin is a heparin alternative in cardiac surgery [letter]. Cardiothoracic Vasc Anesthesia 1997; 11: 538–9

    CAS  Google Scholar 

  127. Thannheimer A, Preuner JG, Pötzsch B, et al. Heparin-associated thrombocytopenia in open-heart surgery: heparin or hirudin as anticoagulant: the antibody decides. Ann Hematol 1996; 72 Suppl. I: P222

    Google Scholar 

  128. Koster A, Kuppe H, Hetzer R, et al. Emergent cardiopulmonary bypass in five patients with heparin-induced thrombocytopenia type II employing recombinant hirudin. Anesthesiology 1998; 89: 777–80

    PubMed  CAS  Google Scholar 

  129. Pötzsch B, Iversen S, Riess FC, et al. Recombinant hirudin as an anticoagulant in open-heart surgery: a case report [abstract]. Ann Hematol 1993; 68 Suppl. 2: A46

    Google Scholar 

  130. Pötzsch B, Riess FC, Völpel H, et al. Recombinant hirudin as anticoagulant during open-heart surgery [abstract]. Thromb Haemost 1995; 73: 1456

    Google Scholar 

  131. Pötzsch B, Greinacher A, Riess FC, et al. Recombinant hirudin as anticoagulant in cardiac surgery: experiences with eleven patients [abstract]. Annals Hematol 1996; 72: A4

    Google Scholar 

  132. Riess FC, Löwer C, Seelig C, et al. Recombinant hirudin as a new anticoagulant during cardiac operations instead of heparin: successful for aortic valve replacement in man. J Thorac Cardiovasc Surg 1995; 110: 265–7

    PubMed  CAS  Google Scholar 

  133. Riess FC, Pötzsch B, Bader R, et al. A case report on the use of recombinant hirudin as an anticoagulant for cardiopulmonary bypass in open heart surgery. Eur J Cardiothoracic Surg 1996; 10: 386–388

    CAS  Google Scholar 

  134. Riess FC, Poetzsch B, Mueller-Berghaus G. Recombinant hirudin as an anticoagulant during cardiac surgery. In: Pifarré R, editor. New Anticoagulants for the Cardiovascular Patient. Philadelphia: Hanley & Belfus, Inc. 1997: 197–222

    Google Scholar 

  135. Magnani HN, Beijering RJR, ten Cate JW, et al. Orgaran anticoagulation for cardiopulmonary bypass in patients with heparin-induced thrombocytopenia. In: Pifarré R, editor. New anticoagulants for the cardiovascular patient. Philadelphia: Hanley & Belfus, Inc., 1997

    Google Scholar 

  136. Walenga JM, Koza MJ, Terrell MR, et al. Experimental evaluation of argatroban for cardiopulmonary bypass. In: Pifarré R, editor. New Anticoagulants for the Cardiovascular Patient. Philadelphia: Hanley & Belfus, Inc., 1997: 251–63

    Google Scholar 

  137. Pötzsch B, Klovekorn WP, Madiener K. Use of heparin during cardiopulmonary bypass in patients with a history of heparin-induced thrombocytopenia. N Engl J Med 2000; 343: 515

    PubMed  Google Scholar 

  138. Olinger GN, Hussey CV, Olive JA, et al. Cardiopulmonary bypass for patients with previously documented heparin-induced platelet aggregation. J Thorac Cardiovasc Surg 1984; 87: 673–7

    PubMed  CAS  Google Scholar 

  139. Ranze O, Ranze P, Magnani HN, et al. Heparin-induced thrombocytopenia in paediatric patients — a review of the literature and a new case treated with danaparoid sodium. Eur J Pediatr 1999; 158 Suppl. 3: S130–3

    PubMed  Google Scholar 

  140. Danaparoid Produkt Information, Organon, Akzo-Organon, Oss, The Netherlands, 1999

  141. Huhle G, Geberth M, Hoffmann U, et al. Management of heparin-associated thrombocytopenia in pregnancy with subcutaneous r-hirudin. Gynecol Obstet Invest 2000; 49: 67–9

    PubMed  CAS  Google Scholar 

  142. Lindhoff-Last E, Willeke A, Thalhammer C et al. Hirudin treatment in a breastfeeding woman [Letter]. Lancet 2000; 355: 467–8

    PubMed  CAS  Google Scholar 

  143. Greinacher A, Eckhardt T, Mussmann J, et al. Pregnancy complicated by heparin associated thrombocytopenia: management by a prospectively in vitro selected heparinoid (Org 10172). Thromb Res 1993; 71: 123–6

    PubMed  CAS  Google Scholar 

  144. Iida S, Komatsu T, Sato T, et al. Pharmacokinetic studies of argatroban (MD-805) in rats: excretion into milk and foeto-placental transfer. Jap Pharmacol Ther 1986; 14: 229–35

    Google Scholar 

  145. Warkentin TE, Kelton JG. Temporal aspects of heparin-induced thrombocytopenia. N Engl J Med 2001; 344: 1286–92

    PubMed  CAS  Google Scholar 

  146. Kempf R, Eichner A, Lubenow N, et al. Heparin-induced thrombocytopenia: temporal pattern of platelet counts in patients being firstly exposed or reexposed to heparin. Ann Hematol 2000; 79 Suppl. 1: A92

    Google Scholar 

  147. Selleng S, Lubenow N, Wollert H-G, et al. Emergency cardiopulmonary bypass in a bilaterally nephrectomized patient with a history of heparin-induced thrombocytopenia: successful reexposure to heparin. Ann Thorac Surg 2000; 71: 1041–2

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Immunology and Transfusion Medicine, Ernst-Moritz-Arndt-University Greifswald, Germany

    Norbert Lubenow &  Andreas Greinacher

  2. Institut für Immunologie und Transfusionsmedizin, Ernst-Moritz-Arndt Universität, Klinikum/Sauerbruchstrasse, 17489, Greifswald, Germany

    Andreas Greinacher

Authors
  1. Norbert Lubenow
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andreas Greinacher
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Andreas Greinacher.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lubenow, N., Greinacher, A. Drugs for the Prevention and Treatment of Thrombosis in Patients with Heparin-Induced Thrombocytopenia. Am J Cordiovosc Drugs 1, 429–443 (2001). https://doi.org/10.2165/00129784-200101060-00003

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00129784-200101060-00003

Keywords

Search

Navigation