SummaryThis 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, imporKeywords Thrombin, deep vein thrombosis, hirudin, HIT tant 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.
PharmacologyHirudin, the most potent natural thrombin inhibitor, is a 65-amino-acid polypeptide (molecular mass, ~7 kDa) produced by the parapharyngeal glands of the medicinal leech, Hirudo medicinalis. The molecule is stabilized by three disulfide bridges. Its three-dimensional structure (1) reveals three distinct regions: a central core (residues 3-30, 37-46, 56-57), a "finger" (residues 31-36), and a loop (residues 47-55).Hirudins for therapeutic use are produced by recombinant biotechnology using yeast. Recombinant hirudins (r-hirudin) differ from natural hirudin by lacking the sulfate group at Tyr-63. Although this structural change results in a lower affinity of desulfato-hirudins to thrombin, r-hirudins nevertheless are highly specific inhibitors of thrombin, with an inhibition constant for thrombin in the picomolar range (2).Effective inhibition of thrombin by antithrombin and heparin cofactor II require the catalytic actions of heparins. In contrast, hirudins effectively inhibit thrombin independently of any cofactor (3). They form noncovalent-but irreversible--1:1 complexes with thrombin. r-Hirudins bind to at least two sites on thrombin, and are thus classified as bivalent DTI's (Fig. 1). A further difference from heparin-antithrombin and heparin-heparin cofactor II is that r-hirudin inhibits both free and clot-bound thrombin (4, 5), as well as thrombin bound to fibrin split products (6). In contrast, heparinantithrombin complexes are relatively poor at accessing and inactivating clot-bound thrombin. This could explain why hirudin is more effective than heparin in promoting dissolution of mural thrombi in experimental models (7). Another important difference to heparin is that hirudin shows virtually no interaction with plasma proteins (8), whereas heparin binding to plasma proteins is the major explanation for many limitations of heparin, including its
