Endothelial function and hemostasis

The vascular endothelium influences not only the three classically interact ing components of hemostasis: the vessel, the blood platelets and the clott ing and fibrinolytic systems of plasma, but also the natural sequelae: infl ammation and tissue repair. Two principal modes of endothelial behaviour ma y be differentiated, best defined as an anti- and a prothrombotic state. Un der physiological conditions endothelium mediates vascular dilatation (form ation of NO, PGI(2), adenosine, hyperpolarising factor), prevents platelet adhesion and activation (production of adenosine, NO and PGI(2), removal of ADP), blocks thrombin formation (tissue factor pathway inhibitor, activati on of protein C via thrombomodulin, activation of antithrombin III) and mit igates fibrin deposition (t- and scu-plasminogen activator production). Adh esion and transmigration of inflammatory leukocytes are attenuated, e.g. by NO and IL-10, and oxygen radicals are efficiently scavenged (urate, NO, gl utathione, SOD). When the endothelium is physically disrupted or functional ly perturbed by postischemic reperfusion, acute and chronic inflammation, a therosclerosis, diabetes and chronic arterial hypertension, then completely opposing actions pertain. This prothrombotic, proinflammatory state is cha racterised by vaso-constriction, platelet and leukocyte activation and adhe sion (externalisation, expression and upregulation of von Willebrand factor , platelet activating factor, P-selectin, ICAM-1, IL-8, MCP-1, TNF alpha, e tc.), promotion of thrombin formation, coagulation and fibrin deposition at the vascular wall (expression of tissue factor, PAI-1, phosphatidyl serine , etc.) and, in platelet-leukocyte coaggregates, additional inflammatory in teractions via attachment of platelet CD40-ligand to endothelial, monocyte and B-cell CD40. Since thrombin formation and inflammatory stimulation set the stage for later tissue repair, complete abolition of such endothelial r esponses cannot be the goal of clinical interventions aimed at limiting pro coagulatory, prothrombotic actions of a dysfunctional vascular endothelium.