The nonpeptide glycoprotein IIb/IIIa platelet receptor antagonist SM-20302 reduces tissue plasminogen activator-induced intracerebral hemorrhage after thromboembolic stroke

Platelet activation and deposition in brain microvessels appear to be key events in the pathogenesis of ischemia-induced neuronal degeneration and behavioral deficits. It has been hypothesized that activated platelets in combination with polymorphonuclear leukocytes and fibrin may play a role in vessel reocclusion leading to the "no-reflow" phenomenon after administration of the thrombolytic tissue plasminogen activator (tPA). We studied the effects of the novel glycoprotein IIb/IIIa platelet receptor antagonist SM-20302 when administered in combination with tPA on infarct and hemorrhage rate and volume to determine whether activated platelets are involved in either infarct or hemorrhage generation after a thromboembolic stroke. One hundred thirty-two male New Zealand White rabbits were included in the present study. Rabbits were embolized by injecting a blood clot into the middle cerebral artery via a catheter. Five or 65 minutes after embolization, SM-20302 (5 mg/kg) was infused intravenously. In drug combination studies, tPA was infused intravenously for 30 minutes starting 60 minutes after embolization, and SM-20302 was administered 5 or 65 minutes after embolization. Postmortem analysis included assessment of hemorrhage, infarct size and location, and clot lysis. In the vehicle control group, the hemorrhage rate after a thromboembolic stroke was 33%. There was a significant increase (109%) in the hemorrhage rate in the group of rabbits treated with the thrombolytic tPA. SM-20302 by itself did not significantly alter the embolism-induced hemorrhage rate when administered either 5 or 65 minutes after embolism. The SM-20302 groups had a 42% and 33% incidence of hemorrhage in the 5- and 65-minute groups, respectively. In groups treated with a combination of drugs, the SM-20302/tPA group had a 31% and 71% incidence of hemorrhage when SM-20302 was administered 5 and 65 minutes after embolization, respectively. SM-20302 in combination with tPA also significantly increased infarct rate, but not hemorrhage or infarct volume. This study suggests that treatment of thromboembolic stroke with the combination of a platelet inhibitor and tPA may have a beneficial outcome on the basis of the following: First, acute administration of SM-20302 did not significantly increase hemorrhage rate. Second, SM-20302 in combination with tPA significantly reduced tPA-induced intracerebral hemorrhage. Third, there appears to be a specific window of opportunity when a platelet inhi