Thromb Haemost 2008; 99(05): 819-829
DOI: 10.1160/TH07-11-0693
Theme Issue Article
Schattauer GmbH

The direct thrombin inhibitor hirudin

Andreas Greinacher
1   Institut für Immunologie und Transfusionsmedizin, Ernst-Moritz-Arndt Universität Greifswald, Greifswald, Germany
,
Theodore E. Warkentin
2   Department of Pathology and Molecular Medicine, and Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada
› Author Affiliations
Further Information

Publication History

Received 20 November 2007

Accepted after minor revision 08 January 2008

Publication Date:
30 November 2017 (online)

Summary

This review discusses the pharmacology and clinical applications of hirudin, a bivalent direct thrombin inhibitor (DTI). Besides the current major indication for hirudin – anticoagulation of patients with heparin-induced thrombocytopenia (HIT) – the experience with hirudin in other indications, especially acute coronary syndromes, are briefly presented. Hirudins have been formally studied prior to their regulatory approval; however, important information on their side effects and relevant preventative measures only became available later. Therefore, current recommendations and dosing schedules for hirudin differ considerably from the information given in the package inserts. Drawbacks of hirudin and important precautions for avoiding potential adverse effects are discussed in detail in the third part of this review.

 
  • References

  • 1 Clore GM, Sukumaran DK, Nilges M. et al. The conformations of hirudin in solution: a study using nuclear magnetic resonance, distance geometry and restrained molecular dynamics. EMBO J 1987; 6: 529-537.
  • 2 Stone SR, Hofsteenge J. Kinetics of the inhibition of thrombin by hirudin. Biochemistry 1986; 25: 4622-4628.
  • 3 Markwardt F, Kaiser B, Richter M. Haemostyptic effects of batroxobin with regard to hirudin treatment. Thromb Res 1992; 68: 475-482.
  • 4 Hogg PJ, Jackson CM. Fibrin monomer protects thrombin from inactivation by heparin-antithrombin III: implications for heparin efficacy. Proc Natl Acad Sci USA 1989; 86: 3619-3623.
  • 5 Weitz 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: 385-391.
  • 6 Weitz 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: 544-552.
  • 7 Meyer BJ, Badimon JJ, Chesebro JH. et al. Dissolution of mural thrombus by specific thrombin inhibition with r-hirudin: comparison with heparin and aspirin. Circulation 1998; 97: 681-685.
  • 8 Glusa E, Markwardt F. Platelet functions in recombinant hirudin-anticoagulated blood. Haemostasis 1990; 20: 112-118.
  • 9 Markwardt F. Development of hirudin as an antithrombotic agent. Semin Thromb Haemost 1989; 15: 269-282.
  • 10 Nowak G. Pharmacokinetics of hirudin. Semin Thromb Haemost 1991; 17: 145-149.
  • 11 Nowak G, Bucha E, Goock T. et al. Pharmacology of r-hirudin in renal impairment. Thromb Res 1992; 66: 707-715.
  • 12 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 a haemodialysis patient. Wien Klin Wochenschr 1997; 109: 354-358.
  • 13 Vanholder R, Camez A, Veys N. et al. Pharmacokinetics of recombinant hirudin in haemodialyzed end-stage renal failure patients. Thromb Haemost 1997; 77: 650-655.
  • 14 Vanholder RC, Camez AA, Veys NM. et al. Recombinant hirudin: a specific thrombin inhibiting anticoagulant for haemodialysis. Kidney Int 1994; 45: 1754-1759.
  • 15 Dager WE, White RH. Use of lepirudin in patients with heparin-induced thrombocytopenia and renal failure requiring haemodialysis. Ann Pharmacother 2001; 35: 885-890.
  • 16 Fischer KG. Hirudin in renal insufficiency. Semin Thromb Haemost 2002; 28: 467-482.
  • 17 Shepherd MF. Dosage of lepirudin in renal failure. Am J Health Syst Pharm 2002; 59: 77-78.
  • 18 Wittkowsky AK, Kondo LM. Lepirudin dosing in dialysis-dependent renal failure. Pharmacotherapy 2000; 20: 1123-1128.
  • 19 Huhle G, Hoffmann U, Hoffmann I. et al. 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.
  • 20 Nowak G. Clinical monitoring of hirudin and direct thrombin inhibitors. Semin Thromb Haemost 2001; 27: 537-541.
  • 21 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: 558-562.
  • 22 Hafner G, Roser M, Nauck M. Methods for the monitoring of direct thrombin inhibitors. Semin Thromb Haemost 2002; 28: 425-430.
  • 23 Lange U, Nowak G, Bucha E. Ecarin chromogenic assay–a new method for quantitative determination of direct thrombin inhibitors like hirudin. Pathophysiol Haemost Thromb 2003; 33: 184-191.
  • 24 Lange U, Olschewski A, Nowak G. et al. Ecarin chromogenic assay: an innovative test for quantitative determination of direct thrombin inhibitors in plasma. Hamostaseologie 2005; 25: 293-300.
  • 25 Gosselin RC, King JH, Janatpour KA. et al. Comparing direct thrombin inhibitors using aPTT, ecarin clotting times, and thrombin inhibitor management testing. Ann Pharmacother 2004; 38: 1383-1388.
  • 26 Callas D, Hoppensteadt D, Iqbal O. et al. Ecarin clotting time (ECT) is a reliable method for the monitoring of hirudins, argatroban, efegatran and related drugs in therapeutic and cardiovascular indications. Blood 1995; 86 (Suppl. 01) 866a (Abstract).
  • 27 Nowak G, Bucha E. Quantitative determination of hirudin in blood and body fluids. Semin Thromb Haemost 1996; 22: 197-202.
  • 28 Potzsch B, Hund S, Madlener K. et al. Monitoring of recombinant hirudin: assessment of a plasma-based ecarin clotting time assay. Thromb Res 1997; 86: 373-383.
  • 29 Potzsch B, Madlener K, Seelig C. et al. Monitoring of r-hirudin anticoagulation during cardiopulmonary bypass– assessment of the whole blood ecarin clotting time. Thromb Haemost 1997; 77: 920-925.
  • 30 Koster A, Hansen R, Grauhan O. et al. Hirudin monitoring using the TAS ecarin clotting time in patients with heparin-induced thrombocytopenia type II. J Cardiothorac Vasc Anesth 2000; 14: 249-252.
  • 31 Fabrizio MC. Use of ecarin clotting time (ECT) with lepirudin therapy in heparin-induced thrombocytopenia and cardiopulmonary bypass. J Extra Corpor Technol 2001; 33: 117-125.
  • 32 De Denus S, Spinler SA. Clinical monitoring of direct thrombin inhibitors using the ecarin clotting time. Pharmacotherapy 2002; 22: 433-435.
  • 33 Liu H, Fleming NW, Moore PG. Anticoagulation for patients with heparin-induced thrombocytopenia using recombinant hirudin during cardiopulmonary bypass. J Clin Anesth 2002; 14: 452-455.
  • 34 Gray E, Harenberg J. Collaborative study on monitoring methods to determine direct thrombin inhibitors lepirudin and argatroban. J Thromb Haemost 2005; 3: 2096-2097.
  • 35 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.
  • 36 Warkentin TE, Greinacher A, Craven S. et al. Differences in the clinically effective molar concentrations of four direct thrombin inhibitors explain their variable prothrombin time prolongation. Thromb Haemost 2005; 94: 958-964.
  • 37 Antman EM. Hirudin in acute myocardial infarction. Safety report from the Thrombolysis and Thrombin Inhibition in Myocardial Infarction (TIMI) 9A Trial. Circulation 1994; 90: 1624-1630.
  • 38 Neuhaus KL, von Essen R, Tebbe U. et al. Safety observations from the pilot phase of the randomized r-Hirudin for Improvement of Thrombolysis (HIT-III) study. A study of the Arbeitsgemeinschaft Leitender Kardiologischer Krankenhausarzte (ALKK). Circulation 1994; 90: 1638-1642.
  • 39 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: 1637-1642.
  • 40 Effects of recombinant hirudin (lepirudin) compared with heparin on death, myocardial infarction, refractory angina, and revascularisation procedures in patients with acute myocardial ischaemia without ST elevation: a randomised trial. Organisation to Assess Strategies for Ischemic Syndromes (OASIS-2) Investigators. Lancet 1999; 353: 429-438.
  • 41 Parent F, Bridey F, Dreyfus M. et al. Treatment of severe venous thrombo-embolism with intravenous Hirudin (HBW 023): an open pilot study. Thromb Haemost 1993; 70: 386-388.
  • 42 Schiele F, Lindgaerde F, Eriksson H. et al. Subcutaneous recombinant hirudin (HBW 023) versus intravenous sodium heparin in treatment of established acute deep vein thrombosis of the legs: a multicentre prospective dose-ranging randomized trial. International Multicentre Hirudin Study Group. Thromb Haemost 1997; 77: 834-838.
  • 43 Eriksson BI, Ekman S, Kalebo P. et al. Prevention of deep-vein thrombosis after total hip replacement: direct thrombin inhibition with recombinant hirudin, CGP 39393. Lancet 1996; 347: 635-639.
  • 44 Eriksson BI, Wille-Jorgensen P, Kalebo 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: 1329-1335.
  • 45 Lubenow N, Greinacher A. Hirudin in heparin-induced thrombocytopenia. Semin Thromb Haemost 2002; 28: 431-438.
  • 46 Greinacher A, Lubenow N, Eichler P. Anaphylactic and anaphylactoid reactions associated with lepirudin in patients with heparin-induced thrombocytopenia. Circulation 2003; 108: 2062-2065.
  • 47 Greinacher A, Eichler P, Albrecht D. et al. Antihirudin antibodies following low-dose subcutaneous treatment with desirudin for thrombosis prophylaxis after hip-replacement surgery: incidence and clinical relevance. Blood 2003; 101: 2617-2619.
  • 48 Lubenow N, Eichler P, Lietz T. et al. 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: 2428-2436.
  • 49 Riess FC, Potzsch 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 Cardiothorac Surg 1996; 10: 386-388.
  • 50 Lubenow N, Eichler P, Lietz T. et al. Lepirudin for prophylaxis of thrombosis in patients with acute isolated heparin-induced thrombocytopenia: an analysis of three prospective studies. Blood 2004; 104: 3072-3077.
  • 51 Comparison of the effects of two doses of recombinant hirudin compared with heparin in patients with acute myocardial ischemia without ST elevation: a pilot study. Organization to Assess Strategies for Ischemic Syndromes (OASIS) Investigators. Circulation 1997; 96: 769-777.
  • 52 Direct thrombin inhibitors in acute coronary syndromes: principal results of a meta-analysis based on individual patients’ data. Lancet 2002; 359: 294-302.
  • 53 Mehta SR, Yusuf S, Peters RJG. et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001; 358: 527-533.
  • 54 Riess FC, Lower 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: 265-267.
  • 55 Warkentin TE, Greinacher A. Heparin-induced thrombocytopenia and cardiac surgery. Ann Thorac Surg 2003; 76: 2121-2131.
  • 56 Riess FC, Poetzsch B, Madlener K. et al. Recombinant hirudin for cardiopulmonary bypass anticoagulation: a randomized, prospective, and heparin-controlled pilot study. Thorac Cardiovasc Surg 2007; 55: 233-238.
  • 57 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: 777-780.
  • 58 Koster A, Hansen R, Kuppe H. et al. Recombinant hirudin as an alternative for anticoagulation during cardiopulmonary bypass in patients with heparin-induced thrombocytopenia type II: a 1-year experience in 57 patients. J Cardiothorac Vasc Anesth 2000; 14: 243-248.
  • 59 Follis F, Schmidt CA. Cardiopulmonary bypass in patients with heparin-induced thrombocytopenia and thrombosis. Ann Thorac Surg 2000; 70: 2173-2181.
  • 60 Johnston N, Jessen ME, DiMaio M. et al. The emergency use of recombinant hirudin in cardiopulmonary bypass. J Extra Corpor Technol 1999; 31: 211-215.
  • 61 Latham P, Revelis AF, Joshi GP. et al. Use of recombinant hirudin in patients with heparin-induced thrombocytopenia with thrombosis requiring cardiopulmonary bypass. Anesthesiology 2000; 92: 263-266.
  • 62 Longrois D, de Maistre E, Bischoff N. et al. Recombinant hirudin anticoagulation for aortic valve replacement in heparin-induced thrombocytopenia. Can J Anaesth 2000; 47: 255-260.
  • 63 Hach-Wunderle V. Hirudin in der Gefäßchirurgie. Hirudin in der vaskulaeren Medizin.. Bremen: Uni- Med-Verlag; 2001: 76-77.
  • 64 Fischer KG, van de LA, Bohler J. Recombinant hirudin (lepirudin) as anticoagulant in intensive care patients treated with continuous haemodialysis. Kidney Int Suppl 1999: S46-S50.
  • 65 Kern H, Ziemer S, Kox WJ. Bleeding after intermittent or continuous r-hirudin during CVVH. Intensive Care Med 1999; 25: 1311-1314.
  • 66 Tardy B, Lecompte T, Boelhen F. et al. Predictive factors for thrombosis and major bleeding in an observational study in 181 patients with heparin-induced thrombocytopenia treated with lepirudin. Blood 2006; 108: 1492-1496.
  • 67 Frank RD, Farber H, Stefanidis I. et al. Hirudin elimination by haemofiltration: a comparative in vitro study of different membranes. Kidney Int Suppl 1999: S41-S45.
  • 68 Bucha E, Nowak G, Czerwinski R. et al. R-hirudin as anticoagulant in regular haemodialysis therapy: finding of therapeutic R-hirudin blood/plasma concentrations and respective dosages. Clin Appl Thromb Haemost 1999; 5: 164-170.
  • 69 Huhle G, Song X, Wang LC. et al. Generation and disappearance of antihirudin antibodies during treatment with r-hirudin. Fibrinol Proteol 1998; 12: 91-113.
  • 70 Song X, Huhle G, Wang L. et al. Generation of antihirudin antibodies in heparin-induced thrombocytopenic patients treated with r-hirudin. Circulation 1999; 100: 1528-1532.
  • 71 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: 2373-2378.
  • 72 Liebe V, Bruckmann M, Fischer KG. et al. Biological relevance of anti-recombinant hirudin antibodies– results from in vitro and in vivo studies. Semin Thromb Haemost 2002; 28: 483-490.
  • 73 Huhle G, Liebe V, Hudek R. et al. Anti-r-hirudin antibodies reveal clinical relevance through direct functional inactivation of r-hirudin or prolongation of r-hirudin’s plasma half-life. Thromb Haemost 2001; 85: 936-938.
  • 74 Fischer KG, Liebe V, Hudek R. et al. Anti-hirudin antibodies alter pharmacokinetics and pharmacodynamics of recombinant hirudin. Thromb Haemost 2003; 89: 973-982.
  • 75 Badger NO, Butler K, Hallman LC. Excessive anticoagulation and anaphylactic reaction after rechallenge with lepirudin in a patient with heparin-induced thrombocytopenia. Pharmacotherapy 2004; 24: 1800-1803.
  • 76 Bircher AJ, Czendlik CH, Messmer SL. et al. Acute urticaria caused by subcutaneous recombinant hirudin: evidence for an IgG-mediated hypersensitivity reaction. J Allergy Clin Immunol 1996; 98: 994-996.
  • 77 Zollner TM, Gall H, Volpel H. et al. Type IV allergy to natural hirudin confirmed by in vitro stimulation with recombinant hirudin. Contact Dermatitis 1996; 35: 59-60.
  • 78 Smith KJ, Rosario-Collazo J, Skelton H. Delayed cutaneous hypersensitivity reactions to hirudin. Arch Pathol Lab Med 2001; 125: 1585-1587.
  • 79 Jappe U, Reinhold D, Bonnekoh B. Arthus reaction to lepirudin, a new recombinant hirudin, and delayed-type hypersensitivity to several heparins and heparinoids, with tolerance to its intravenous administration. Contact Dermatitis 2002; 46: 29-32.
  • 80 Bircher AJ, Harr T, Hohenstein L. et al. Hypersensitivity reactions to anticoagulant drugs: diagnosis and management options. Allergy 2006; 61: 1432-1440.
  • 81 Warkentin TE, Kelton JG. A 14-year study of heparin- induced thrombocytopenia. Am J Med 1996; 101: 502-507.
  • 82 Wallis DE, Lewis BE, Walenga JM. Failure of current strategies in the prevention of thrombosis in patients with heparin-induced thrombocytopenia: a clinician’s perspective. Semin Thromb Haemost 1999; 25 (Suppl. 01) 3-7.
  • 83 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: 183-188.
  • 84 Lubenow N, Warkentin TE, Greinacher A. et al. Results of a systematic evaluation of treatment outcomes for heparin-induced thrombocytopenia in patients receiving danaparoid, ancrod, and/or coumarin explain the rapid shift in clinical practice during the 1990s. Thromb Res 2006; 117: 507-515.
  • 85 Hacquard M, de Maistre E, Lecompte T. Lepirudin: is the approved dosing schedule too high?. J Thromb Haemost 2005; 3: 2593-2596.
  • 86 Warkentin TE, Greinacher A. Heparin-induced thrombocytopenia: recognition, treatment, and prevention: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2008 in press.
  • 87 Warkentin TE. Should vitamin K be administered when HIT is diagnosed after administration of coumarin?. J Thromb Haemost 2006; 4: 894-896.
  • 88 Warkentin TE, Greinacher A. Heparin-induced thrombocytopenia: recognition, treatment, and prevention: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126: 311S-337S.
  • 89 Hermann JP, Kutryk MJ, Serruys PW. Clinical trials of direct thrombin inhibitors during invasive procedures. Thromb Haemost 1997; 78: 367-376.
  • 90 Farner B, Eichler P, Kroll H. et al. A comparison of danaparoid and lepirudin in heparin-induced thrombocytopenia. Thromb Haemost 2001; 85: 950-957.