The fibrinolytic system provides a mechanism for removal of physiologically deposited fibrin. Clot lysis is brought about by the action of plasmin on fibrin. Fibrinolytic events are shown in Figure 11-3. Plasminogen from circulating plasma is laid down with fibrin during the formation of thrombin. Plasminogen is primarily synthesized in the liver and circulates in two forms, one with an NH2-terminal glutamic acid residue (glu-plasminogen) and a second form with an NH2-terminal lysine, valine, or methionine residue (lys-plasminogen). Glu-plasminogen can be converted to lys-plasminogen by limited proteolytic degradation. Lys-plasminogen has a higher affinity for fibrin and cellular receptors and is also more readily activated to plasmin than glu-plasminogen. Both forms of plasminogen bind to fibrin through specific lysine-binding sites. These lysine binding sites also mediate the interaction of plasminogen with its inhibitor, a2-antiplasmin (a2AP). Thrombin activated fibrinolysis inhibitor-mediated removal of C-terminal lysine and arginine residues will prevent high-affinity plasminogen binding and will attenuate fibrinolysis. Plasminogen is converted to its enzymatically active form, plasmin, by several activators. These activators are widely distributed in body tissues and fluids. Tissue plasminogen activator (t-PA) is the principal intravascular activator of plasminogen. t-PA is a serine protease that binds to fibrin through lysine-binding sites. When t-PA is bound to fibrin, its plasmin generation efficiency increases markedly. Urokinase-type plasminogen activator (u-PA), a second physiologic activator of plasminogen, is present in urine and activates plasminogen to plasmin equally well in the absence and in the presence of fibrin. Plasmin splits fibrin and fibrinogen into fibrindegradation products:
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