New insights into modulation of thrombin formation.

Thrombin is a pleiotropic enzyme that regulates hemostasis and nonhemostatic functions, including an array of actions within and on the vasculature. Physiologically, thrombin generation serves mainly to protect against thrombosis, but also to maintain vascular endothelial integrity. This protective effect is mediated in part through generation of anticoagulant enzymes, including activated protein C, formed on the action of thrombin on the endothelial receptor thrombomodulin. Partly, thrombin's vascular effects are effectuated through interaction with protease-activated receptors on various cell types. Pathophysiologically, downregulation and shedding of anticoagulant-acting receptors such as thrombomodulin and endothelial protein C receptor may contribute to a shift in activities of thrombin towards thrombogenic and proinflammatory actions. This shift may typically occur in the process of atherosclerosis, leading to a proatherogenic direction of the effects of thrombin. Therapeutically, the long-term inhibition of thrombin may create new ways of reducing atherosclerosis burden, altering the plaque phenotype.