THROMBIN INHIBITORS AS ANTITHROMBOTIC AGENTS - THE IMPORTANCE OF RAPID INHIBITION

For use as an antithrombotic agent, a thrombin inhibitor must be poten t and specific, i.e., it should not significantly inhibit the protease s of the anticoagulation (activated protein C) and fibrinolytic system s (plasminogen activator and plasmin). Previous evaluation of potency and specificity has been based on inhibition constants (K-i values). H owever, consideration of the kinetic parameters for natural plasma ser ine protease inhibitors indicates that a low K-i value with thrombin i s not sufficient; the inhibited complex must also form rapidly. Moreov er, potent inhibition of activated protein C and plasmin could be tole rated providing the inhibited complex only forms slowly. An ideal prof ile of kinetic parameters with thrombin, activated protein C and plasm in is formulated and discussed in relation to various classes of throm bin inhibitors. Examination of kinetic data for thrombin inhibitors cu rrently in clinical trials (hirudin and hirulog) indicates that they p ossess this ideal profile of kinetic parameters.