Thrombolytic agents cause the breakdown or dissolution of thrombi. Many of these agents work by converting inactive plasminogen into plasmin, a serine protease, which then cleaves fibrin within the thrombus (Fig. 3.1). Agents that have been studied in acute ischemic stroke include human rt-PA, urokinase, streptokinase, and desmoteplase. Systemic administration of these agents may also cause systemic fibrinogen degradation, reduction in circulating plasminogen and a2-antiplasmin, inactivation of factors V and VIII, platelet disaggregation, and possibly platelet
dysfunction.22'23 This may lead to systemic hypofibrinogenemia, prolongation of the activated partial thromboplastin time (aPTT), and coagulopathy.
This section will review the phase III clinical trials of IV thrombolytic agents for acute ischemic stroke, organized by the type of agent and the time window from stroke onset to study drug delivery (Table 3.1). The 1995 National Institute of Neurological Disorders and Stroke (NINDS) rt-PA trial is presented first because it showed that IV rt-PA, given within 3 hours of stroke onset, reduced stroke-related disability. This trial was the basis for the United States Food and Drug Administration (FDA) approval for rt-PA for use in acute ischemic stroke.
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