Chapter 10. Thrombolytic Agents

lntravascular thrombi, leading to myocardial infarction, stroke, pulmonary embolism, or peripheral occlusion are the major cause of mortality and of much morbidity in the economically advanced countries. Administration of thrombolytic agents, that are currently plasminogen activators, is an efficient means to restore blood flow, preserving life and limb. This chapter discusses the new molecular and clinical progress, new activators under study, and problems remaining in thrombolysis. Fibrin-specificity of a plasminogen activator refers to the relative activation of clot-bound versus free plasminogen and depends on many factors. Free plasminogen adopts a compact conformation resistant to activate that clot-bound plasminogen exists in a more open accessible structure, like that of lys-plasminogen. The most specific plasminogen activators in use are tPA and prourokinase (proUK) and the least specific is streptokinase. Fibrin specificity does not lead to greater safety, but enhances efficacy, via the preservation of the circulating plasminogen, needs to sustain the activity of systemically administered plasminogen activators. Partial degradation of fibrinogen, by plasminogen, leads to the accumulation of a clottable truncated fibrinogen known as X-fragment (XF). Plasminogen has higher affinity for polymerized XF than for fibrin, binding to their end-to-end junctions. Resistance to lysis is affected, by the presence of natural inhibitors. Anisoylated plasminogen-SK activator complex is a prodrug form of SK, in which the essential active site serine of complexed SKlys-plasminogen is blocked, via a hydrolytically labile group.