Pharmacology of selective thrombin inhibitors

Thrombin plays a key role in thrombosis and haemostasis, and is selectively inhibited by hirudin and synthetic inhibitors. Hirudin, a polypeptide (molecular weight 7,000 daltons) extracted from medicinal leeches, can now be produced by gene technology. Hirudin binds selectively to thrombin with high affinity and inhibits its enzymatic properties. Besides heparin, hirudin is not inhibited by platelet factor 4; it prolongs in vitro and ex vivo routine blood coagulation assays and prevents thrombosis in a number of animal models without increasing haemorrhagic risk. In humans, hirudin disappears from the blood with a half-life of 1 h, is devoid of undesirable side effects and has been shown to be efficient in the treatment of chronic disseminated intravascular coagulation (DIC). A number of synthetic direct thrombin inhibitors have been described, including benzamidine derivatives which share identical pharmacological properties with hirudin; however their biological half-life after i.v. injection is shorter. Other derivatives (amidino-phenyl-pyruvic acid) have longer half-lives and have been used to treat chronic DIC in man.