HEMOSTASIS/BLOOD CLOTTING MECHANISM (part 1)--Natural Anticoagulants

HEMOSTASIS/BLOOD CLOTTING MECHANISM (part 1)--Natural Anticoagulants Endothelial NO• strongly inhibits platelet aggregation and adhesion to the vessel wall. Endothelial cells metabolize ADP, a strong promoter of thrombogenesis, to antithrombogenic metabolites. The lumi- nal surface of the endothelium is coated with heparan sulfate, which binds a number of clotting factors, including the antiprotease 2-macroglobulin. Endothelial heparan sulfate activates antithrombin, which binds to several coagulation factors, IIa, IXa, Xa, Xia and XIIa, which are free and not bound in complexes or in the clot. Endothelial cells may also lyse some clots as they form through the plasminogen/ plasminogen activator/plasmin system. Endothelial cells have several other anticoagulant activi- ties. A cofactor on the endothelial cell surface inactivates thrombin by forming a complex with thrombin and antithrom- bin III (a plasma antiprotease). Thrombin itself activates pro- tein C by binding its receptor, thrombomodulin, at endothelial cell surfaces. Both protein C and thrombomodulin are synthesized by endothelial cells. Activated protein C destroys coagulation factors V and VIII. TFPI generated dur- ing coagulation is bound to endothelium, where it inhibits the TF–VIIa complex. TF and TFPI are synthesized and secreted by endothelial cells as well as other vascular cells. The endothelium is also intimately involved in initiating and propagating thrombosis. The event that triggers most thrombosis is endothelial injury, which imparts a prothrom- botic property to endothelium. Endothelial cells synthesize von Willebrand factor, which promotes platelet adherence and activates clotting factor V. Endothelial cells also bind factors IX and X, a process that favors coagulation at the endothelial surface. Finally, inflammatory agents, including cytokines released from monocytes, activate proco- agulants on the surface of intact endothelium. Interleukin-1 and tumor necrosis factor cause endothelial cells to present thromboplastin to the plasma, thus potentially triggering the extrinsic coagulation pathway. Thus, thrombi may form when endothelial function is altered, when endothelial continuity is lost or when blood flow in a vessel becomes abnormal, such as turbulent or static. Simple loss of endothelial cells or injury to a vessel with good flow produces platelet pavementing but not thrombosis