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The Search for the Ideal Thrombolytic Agent: Maximize the Benefit and Minimize the RiskDepartment of Biological Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486 Streptokinase, acylated plasminogen streptokinase complex, and tissue-type plasminogen activator (tPA) are widely used for the treatment of acute myocardial infarction. These thrombolytic agents restore blood flow in occluded coronary arteries, salvage myocardial function, and decrease mortality. The success of thrombolytic therapy depends on the prompt and stable recanalization of the occluded blood vessel. Hemorrhagic events undermine the safety of fibrinolytic agents. Most bleeding complications occur at vascular puncture sites and can be avoided by limiting invasive procedures; however, an increased incidence of devastating intracranial bleeds is also encountered. The cause of thrombolytic-induced intracranial hemorrhage is unknown but may be due to lysis of protective hemostatic plugs. Another potential contributor to bleeding is activation of circulating plasminogen by the exogenous plasminogen activator to yield fluid-phase plasmin. Plasmin is a promiscuous proteinase that degrades many proteins that play pivotal roles in hemostasis and the integrity of the microvasculature. Tissue-type plasminogen activator activity is depressed in the absence of fibrin; hence, its use as a thrombolytic agent was anticipated to avoid the untoward consequences of plasminemia. However, the administration of pharmacologic doses of tPA can result in the activation of appreciable quantities of circulating plasminogen. In contrast to currently available thrombolytic agents, the activity of the vampire bat salivary plasminogen activator (BatPA) displays a strict requirement for the presence of fibrin. Assessment of BatPA using animal models of arterial thrombosis has demonstrated efficacy but without activation of systemic plasminogen. The avoidance of plasminemia when using BatPA as a fibrinolytic agent may circumvent bleeding complications that can compromise the safety of thrombolytic therapy.
Key Words: Thrombolysis • plasminogen activator • fibrinolytic therapy • acute myocardial infarction
Toxicologic Pathology, Vol. 21, No. 2,
190-198 (1993) |
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