Publisher Summary This chapter discusses the plasminogen and the plasminogen activators. The central step in the fibrinolytic system is conversion of the proenzyme plasminogen to the active enzyme plasmin, a relatively nonspecific serine protease with trypsin-like specificity. Plasminogen is normally included in thrombi as they are formed and the plasmin dissolves the fibrin without systemic fibrinogen breakdown. Plasminogen is made up of two functional domains: a protease domain and a fibrin binding domain. The fibrin binding domain is made up of five homologous triple loop structures known as “kringles;” kringles are also observed in other blood serum proteases, such as prothrombin, urokinase, and tissue-type plasminogen activator. Activated plasmin is generated by two proteolytic events. Once the active moiety, plasmin, has been generated it becomes a relatively nonspecific enzyme with high catalytic activity. The main inhibitor of plasmin in blood is alpha-2 anti-plasmin that is known to compete for the fibrin binding sites of plasmin. Fibrinolysis may be surface mediated in a manner analogous to the surface mediated intrinsic pathway of coagulation. Exogenous activation of plasminogen is accomplished by two basic mechanisms, the proteolytic processing of plasminogen to plasmin by urokinase and the conformationally based activation of the zymogen plasminogen by nonenzyme proteins, such as streptokinase. Streptokinase activates the fibrinolytic system indirectly by initially forming a one-to-one stoichiometric complex with plasminogen. Streptokinase is the most widely used thrombolytic agent and has been shown to be effective in the lysis of venous thrombi in the leg, pulmonary emboli, and coronary thrombi in acute myocardial infarctions. Urokinase has been successfully used for thrombolytic therapy in venous thrombosis, pulmonary embolism, and coronary thrombosis. Human studies with melanoma t-PA have been limited because of scarce supply, but pilot studies in venous thrombosis and coronary thrombosis demonstrated the feasibility of clot-specific fibrinolysis in humans.