LOOD CONTAINS an enzymatic system called the B fibrinolytic system, one of the main functions of which is the dissolution of fibrin clots in the blood vessels. The fibrinolytic system comprises a proenzyme, plasminogen, which can be converted to the active enzyme plasmin by different plasminogen activators (PAS). Two physiologic PAS have been identified, initially based on their immunologic relationship with the PA found in tissues (tissue-type PA [t-PA]) or with the PA found in urine (urokinase-type PA [u-PA]). Inhibition of fibrinolysis occurs at the level of the activators (by PA-inhibitors [PAIS]) or at the level of plasmin (mainly by a,-antiplasmin). Physiologic fibrinolysis is highly fibrin-specific as a result of specific molecular interactions between PA, plasminogen, fibrin, plasmin, and a,-antiplasmin.'

Cardiovascular diseases, mainly comprising coronary artery disease leading to myocardial infarction, cerebrovascular disease causing strokes, and venous thrombosis predisposing to pulmonary embolism and the post-phlebitic syndrome, are a major cause of death and disability. The triggering event in the clinical expression of the acute ischemic event is not the underlying atherosclerotic lesion, but a thrombotic obstruction of the artery. Thus, the common cardiovascular diseases have, as their immediate underlying etiology, thrombosis of critically situated blood vessels with loss of blood flow to vital organs. One approach to the treatment of thrombosis consists of the pharmacologic dissolution of the blood clot via the intravenous infusion of PAS. Currently, five thrombolytic agents are either approved for clinical use or under clinical investigation in patients with acute myocardial infarction. These agents are streptokinase (SK), two-chain u-PA (tcu-PA; urokinase), anisoylated plasminogen streptokinase activator complex (APSAC), recombinant t-PA (rt-PA), and recombinant single-chain u-PA (rscu-PA; prourokinase).]