[Hirudin: the relative failure of a very promising molecule]

Hirudin is a peptide of 65 aminoacids extracted from the leech which very specifically inhibits the action of thrombin. Molecular engineering techniques have made it available for therapeutic usage. Experimental data would suggest that hirudin was the drug of choice for the prevention of coronary thrombosis and recurrences, an indication where heparin is not always effective. Despite well organised studies of tolerance and dosage, three large scale clinical trials have had to be interrupted because of a high incidence of severe bleeding complications. The therapeutic margin of hirudin is therefore as low as that of heparin. The initial results of trials using lower doses have not shown hirudin to be effective than heparin in the prevention of critical events in the long term. The reasons for this relative failure are two-fold: either hirudin and molecules with similar modes of action such as Hirulog are less active in vivo than in vitro, possibly due to the fact that they block the activation of the C protein, a powerful natural antithrombotic mechanism, or, the target of hirudin: thrombin, does not play the fundamental role attributed to it in arterial thrombosis. The good results observed with molecules which inhibit platelet aggregation would suggest a dominant role of the platelets.