Bivalent direct thrombin inhibitors: hirudin and bivalirudin.
Hirudin derivatives (e.g. lepirudin, desirudin) and hirudin analogues (e.g. bivalirudin) are bivalent direct thrombin inhibitors; that is, they bind to two distinct sites on thrombin-its active (catalytic) site and its fibrinogen-binding site (exosite 1). These bivalent binding properties contribute to their high affinity and high specificity for thrombin. This review compares the pharmacological properties of these agents, and describes studies of their efficacy and safety in diverse clinical settings such as immune heparin-induced thrombocytopenia, postoperative antithrombotic prophylaxis, and treatment of acute coronary syndrome. Certain disadvantages of hirudin, such as its predominant renal excretion and immunogenicity, have been overcome through development of the hirudin analogue, bivalirudin. Compared with hirudin derivatives, bivalirudin exhibits a shorter half-life (25 vs 80 minutes), predominant non-renal (enzymic) metabolism, and low immunogenicity. Further work is required to define the scope of clinical thrombosis problems that could benefit from these novel agents.
Warkentin
Theodore E
TE
Department of Pathology and Molecular Medicine, McMaster University, and Hamilton Regional Laboratory Medicine Program, Hamilton General Site, Hamilton Health Sciences, Ont., Canada L8L 2X2. twarken@mcmaster.ca
D000991:Antithrombins / Q000276:immunology / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001665:Binding Sites; D024764:Hirudin Therapy / Q000009:adverse effects / Q000379:methods; D006629:Hirudins / Q000031:analogs & derivatives* / Q000276:immunology / Q000378:metabolism / Q000493:pharmacokinetics; D006801:Humans; D010446:Peptide Fragments; D011994:Recombinant Proteins; D016896:Treatment Outcome
D000991:Antithrombins; D006629:Hirudins; D010446:Peptide Fragments; D011994:Recombinant Proteins; C074619:bivalirudin