[Thrombin and its pharmacologic regulation]

Thrombin plays a crucial role in thrombus formation. It transforms fibrinogen into fibrin and activates platelets. Thrombin has both stimulating and inhibiting effects controlling the feedback regulation of thrombus formation. Thrombin also stimulates circulating cells other than platelets and vascular cells and thus participates in inflammation and wound repair accompanying hemostasis and thrombosis. Thrombin's interaction with cells is mediated by proteolysis activated receptors (PAR), mainly PAR-1 and probably by the recently cloned PAR-3.

Thrombin is an ellipsoid-shaped serine protease whose active site is located at the bottom of a deep groove. One end of the groove bearing the active site carries exosite 1 which links with the C-terminal end of hirudine, PAR-1 and PAR-3, fibrinogen and fibrin, thrombomoduline and platelet GPIb. Exosite 2 is carried on the top side of the molecule opposite the active site. It binds to certain glycoaminoglycanes such as heparin. Thrombin's high substrate specificity results from multiple interactions which occur between different functional domains and complementary domains on the substrate. ACTION OF HEPARIN: The antithrombotic effect of heparin results from its catalytic effect on antithrombin III (AT) inhibition of thrombin. This effect is however limited because heparin is dependent on the concentration of AT and on the of inactivating proteins such as platelet factor 4. In addition, the inhibitory effect of the AT-heparin complex is limited for thrombin bound to the thrombus. Finally, heparin can produce a rare but severe complication, heparin-induced thrombocytopenia. Because of these different drawbacks, research has been focused on other thrombin inhibitors. DIRECT THROMBIN INHIBITORS: The target of these inhibitors is the active site of thrombin. Many compounds are under study, including several which can be administrated orally. The most advanced clinical trials have been conducted with hirudin. Hirudin binds to thrombin at several sites, blocking all the known functions of thrombin. The problem of choosing an agent to maintain antithombotic therapy in patients with heparin-induced thrombocytopenia remains unresolved. Hirudin would be a likely choice as it has no cross reactivity with heparin or heparinoids. Promising early results have been reported.