Thrombin regulation by physiological inhibitors: the role of vitronectin

The generation of thrombin and its various activities have to be tightly controlled in the circulation as well as at extracellular sites to prevent pathological situations. Both vessel wall-associated thrombomodulin and circulating serine protease inhibitors meet the requirements for regulation of thrombin function. The final products of thrombin inhibition are ternary complexes together with the adhesion protein vitronectin. Due to a conformational switch in the vitronectin molecule, ternary complexes are endowed with heparin-binding properties and become specifically bound to cell surface sites on endothelial and other cells. This interaction appears to be responsible for the clearance and translocation of ternary complexes in the vasculature and at other sites. In addition, ternary complexes may provoke other cellular activities by binding to nonintegrin cell surface receptors. Along the vasculature, extracellular-associated vitronectin serves as a binding and stabilizing cofactor for plasminogen activator inhibitor 1, which thereby becomes a slow-reacting thrombin inhibitor. It is believed that clot-associated vitronectin-PAI-1 complex not only stabilizes initial thrombus formation, but is also responsible for thrombin neutralization and the necessary switch towards fibrinolysis. Vitronectin thereby becomes an integral cofactor for regulation and control of thrombin multifunctional activities.