Physiologic regulation and pathologic disorders of fibrinolysis

Physiologic fibrinolysis is a reparative process that occurs in response to hemostatic plug or thrombus formation. The final enzymatic step, fibrin proteolysis, results from a coordinated interaction of enzymes and inhibitors, which produces effective action at the site of the disease and spares the proteins of the blood or uninvolved parts of the vascular system. The agent of fibrinolysis, the enzyme plasmin, is derived from its zymogen (plasminogen) through limited proteolysis effected by plasminogen activators. They can be grouped according to functional and immunologic properties into the tissue type and urokinase-like plasminogen activators. The ability of alpha 2 antiplasmin to neutralize efficiently free (nonfibrin-bound) plasmin prevents inappropriate systemic activation of fibrinolysis. This control is superseded in certain conditions, such as with the therapeutic administration of plasminogen activators to lyse pathologic thrombi, when plasmin degrades plasma fibrinogen into degradation fragments (X, Y, D, and E). Degradation of cross-linked fibrin results in distinctive products that are characterized by cross-linked (factor XIIIa-induced) derivatives such as D dimer. Disease states resulting from abnormalities in the fibrinolytic system include both hemorrhagic disorders, resulting from excessive fibrinolysis, and thrombosis, as the result of deficient fibrinolysis. Hyperfibrinolysis can result from pharmacologic administration of activators or from defective inhibition produced by alpha 2 antiplasmin deficiency. Hypofibrinolytic thrombosis can result from hereditary defects, for instance of plasminogen or fibrinogen, or from pharmacologic inhibition of fibrinolysis such as with epsilon aminocaproic acid. Laboratory evaluation of fibrinolysis is useful for monitoring fibrinolytic therapy and assessing thrombotic disorders and bleeding; it also includes the specific measurements of plasminogen activator, plasminogen, plasmin, inhibitors and circulating fibrinogen, and cross-linked fibrin degradation products.