Semin Thromb Hemost 2002; 28(5): 431-438
DOI: 10.1055/s-2002-35283
Copyright © 2002 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Hirudin in Heparin-Induced Thrombocytopenia

Norbert Lubenow, Andreas Greinacher
  • Ernst-Moritz-Arndt University, Greifswald, Germany
Weitere Informationen

Publikationsverlauf

Publikationsdatum:
06. November 2002 (online)

ABSTRACT

Heparin-induced thrombocytopenia (HIT), a serious side effect of heparin treatment, requires alternative anticoagulation in most affected patients. The recombinant hirudin (r-hirudin) lepirudin has been approved for this purpose after two prospective trials in laboratory-confirmed HIT patients. Other drugs available for this purpose are danaparoid sodium (a heparinoid) and argatroban, a synthetic direct thrombin inhibitor. In this article, recommendations for optimal use of r-hirudin in HIT are given, covering therapy in uncomplicated patients as well as in special situations such as heparin reexposure of HIT patients. Because lepirudin's half-life depends on renal function, it may vary between 1 and 200 hours, which requires individual dose adjustments. Lepirudin compares favorably with danaparoid, based on retrospective data. No direct comparisons of lepirudin with argatroban are available, but argatroban might offer advantages in patients with renal failure, because it is mainly eliminated hepatically. Major hemorrhage, the main risk of lepirudin treatment, occurring in about 15% of patients, makes close monitoring important. New monitoring tools, such as the ecarin clotting time (ECT), might further reduce bleeding risks. Antihirudin antibodies, which can alter the pharmacokinetics as well as the pharmacodynamics of hirudin, can also be countered by close monitoring and appropriate dose adjustments. Whereas hirudins have not yet managed to gain importance in non-HIT indications such as unstable coronary syndromes, they have a major role to play in the treatment of HIT. The choice between the available drugs for HIT, namely lepirudin, danaparoid, and argatroban, has to be made according to the clinical presentation of the patient.

REFERENCES

  • 1 Warkentin T E, Levine M N, Hirsh J. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin.  N Engl J Med . 1995;  332 1330-1335
  • 2 Warkentin T E, Chong B H, Greinacher A. Heparin-induced thrombocytopenia: towards consensus.  Thromb Haemost . 1998;  79 1-7
  • 3 Amiral J, Bridey F, Wolf M. Antibodies to macromolecular platelet factor 4-heparin complexes in heparin-induced thrombocytopenia: a study of 44 cases.  Thromb Haemost . 1995;  73 21-28
  • 4 Amiral J, Marfaing-Koka A, Wolf M. Presence of autoantibodies to interleucin-8 or neutrophil-activating peptide-2 in patients with heparin-associated thrombocytopenia.  Blood . 1996;  88 410-416
  • 5 Greinacher A, Michels I, Mueller-Eckhardt C. Heparin-associated thrombocytopenia: the antibody is not heparin specific.  Thromb Haemost . 1992;  67 545-549
  • 6 Cines D B, Tomaski A, Tannenbaum S. Immune endothelial-cell injury in heparin-associated thrombocytopenia.  N Engl J Med . 1987;  316 581-589
  • 7 Visentin G P, Ford S E, Scott J P, Aster R 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
  • 8 Greinacher A, Poetzsch B, Amiral J. 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
  • 9 Chong B H, Fawaz I, Chestermann C N, Berndt M C. Heparin-induced thrombocytopenia: mechanism of interaction of the heparin-dependent antibody with platelets.  Br J Haematol . 1989;  73 235-240
  • 10 Kelton J G, Sheridan D, Santos A. Heparin-induced thrombocytopenia: laboratory studies.  Blood . 1988;  72 925-930
  • 11 Chong B H, Murray B, Berndt M C. Plasma P-selectin is increased in thrombotic consumptive platelet disorders.  Blood . 1994;  83 1535-1541
  • 12 Warkentin T E, Hayward C P, Boshkov L K. 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
  • 13 Arepally G M, Mayer I M. Antibodies from patients with heparin-induced thrombocytopenia stimulate monocytic cells to express tissue factor and secrete interleukin-8.  Blood . 2001;  98 1252-1254
  • 14 Pouplard C, Iochmann S, Renard B. Induction of monocyte tissue factor expression by antibodies to heparin-platelet factor 4 complexes developed in heparin-induced thrombocytopenia.  Blood . 2001;  97 3300-3302
  • 15 Warkentin T E. Limitations of conventional treatment options for heparin-induced thrombocytopenia.  Semin Hematol . 1998;  35 17-25
  • 16 Warkentin T E, Kelton J E. A 14-year study of heparin-induced thrombocytopenia.  Am J Med . 1996;  101 502-507
  • 17 Wallis D E, Workman D L, Lewis B E. Failure of early heparin cessation as treatment for heparin-induced thrombocytopenia.  Am J Med . 1999;  106 629-635
  • 18 Warkentin T E, Elavathil L J, Hayward C P. The pathogenesis of venous limb gangrene associated with heparin-induced thrombocytopenia.  Ann Intern Med . 1997;  127 804-812
  • 19 Ganzer D, Gutezeit A, Mayer G. Potential risks in drug prevention of thrombosis-low-molecular-weight heparin versus standard heparin.  Z Orthop Ihre Grenzgeb . 1999;  137 457-461
  • 20 Alban S, Greinacher A. Role of sulfated polysaccharides in the pathogenesis of heparin-induced thrombocytopenia. In: Warkentin TE, Greinacher A, eds. Heparin-Induced Thrombocytopenia, 2nd ed New York: Marcel Dekker 2001: 167-187
  • 21 Mayo D J, Cullinane A M, Merryman P K, Horne III K M. Serologic evidence of heparin sensitization in cancer patients receiving heparin flushes of venous access devices.  Support Care Cancer . 1999;  7 425-427
  • 22 Lee D H, Warkentin T E. Frequency of heparin-induced thrombocytopenia. In: Warkentin TE, Greinacher A, eds. Heparin-Induced Thrombocytopenia, 2nd ed New York: Marcel Dekker 2001: 87-121
  • 23 Greinacher A, Warkentin T E. Treatment of heparin-induced thrombocytopenia: an overview. In: Warkentin TE, Greinacher A, eds. Heparin-Induced Thrombocytopenia, 2nd ed New York: Marcel Dekker 2001: 291-322
  • 24 Farner B, Eichler P, Kroll H, Greinacher A. A comparison of danaparoid and lepirudin in heparin-induced thrombocytopenia.  Thromb Haemost . 2001;  85 950-957
  • 25 Greinacher A, Völpel H, Janssens U. 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
  • 26 Greinacher A, Janssens U, Berg G. Lepirudin (recombinant hirudin) for parenteral anticoagulation in patients with heparin-induced thrombocytopenia.  Circulation . 1999;  100 587-593
  • 27 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
  • 28 Eichler P, Budde U, Haas S. 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;  81 625-629
  • 29 Lewis B E, Wallis D E, Berkowitz S D, for the ARG-911 Study investigators. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia.  Circulation . 2001;  103 1838-1843
  • 30 Greinacher A, Eichler P, Lubenow N, Kwasny H, Luz M. 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;  96 846-851
  • 31 Huhle G, Hoffmann U, Hoffmann I. A new therapeutic option by subcutaneous recombinant hirudin in patients with heparin-induced thrombocytopenia type II: a pilot study.  Thromb Res . 2000;  99 325-334
  • 32 Warkentin T E, Kelton J G. Temporal aspects of heparin-induced thrombocytopenia.  N Engl J Med . 2001;  344 1286-1292
  • 33 Lubenow N, Kempf R, Eichner A. Heparin-induced thrombocytopenia: temporal pattern of thrombocytopenia in relation to initial use or exposure to heparin.  Chest . 2002;  122 37-42
  • 34 Pötzsch B, Madlener K. Management of cardiopulmonary bypass anticoagulation in patients with heparin-induced thrombocytopenia. In: Warkentin TE, Greinacher A, eds. Heparin-Induced Thrombocytopenia, 2nd ed New York: Marcel Dekker 2001: 429-444
  • 35 Pötzsch B, Klovekorn W P, Madlener K. Use of heparin during cardiopulmonary bypass in patients with a history of heparin-induced thrombocytopenia (Letter).  N Engl J Med . 2000;  343 515
  • 36 Selleng S, Lubenow N, Wollert H-G, Müllejans B, Greinacher A. Emergency cardiopulmonary bypass in a bilaterally nephrectomized patient with a history of heparin-induced thrombocytopenia: successful reexposure to heparin.  Ann Thorac Surg . 2000;  71 1041-1042
  • 37 van Wyk V, Badenhorst P N, Luus H G, Kotzé H F. A comparison between the use of recombinant hirudin and heparin during hemodialysis.  Kidney Int . 1995;  48 1338-1343
  • 38 Vanholder R, Camez A, Veys N. Pharmacokinetics of recombinant hirudin in hemodialyzed end-stage renal failure patients.  Thromb Haemost . 1997;  77 650-655
  • 39 Hempel S, Lubenow N, Greinacher A. Nierenersatztherapie unter r-Hirudin (Refludan) bei Heparin-induzierter Thrombozytopenie Typ II (Abst).  Infusionsther Transfusionsmed . 1998;  25 5/7
  • 40 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: 429-438
  • 41 Hafner G, Rupprecht H J, Luz M. Recombinant hirudin as a periprocedural antithrombotic in coronary angioplasty for unstable angina pectoris [see comments].  Eur Heart J . 1996;  17 1207-1215
  • 42 Rupprecht H J, Terres W, Ozbek C. Recombinant hirudin (HBW 023) prevents troponin T release after coronary angioplasty in patients with unstable angina.  J Am Coll Cardiol . 1995;  26 1637-1642
  • 43 Neuhaus K L, Molhoek G P, Zeymer U. 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;  34 966-973
  • 44 Antman E M. Hirudin in acute myocardial infarction. Thrombolysis and thrombin Inhibition in Myocardial Infarction (TIMI) 9B trial [see comments].  Circulation . 1996;  94 911-921
  • 45 Schiffmann H, Unterhalt M, Harms K. Successful treatment of heparin-induced thrombocytopenia (HIT) type II in childhood with recombinant hirudin.  Monatsschr Kinderheilkd . 1997;  145 606-612
  • 46 Eriksson B I, Ekman S, Lindbratt S. 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;  79 326-333
  • 47 Eriksson B I, Wille-Jörgensen P, Kälebo P. 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 1329-3135