Intravenous administration of a GPIIb/IIIa receptor antagonist extends the therapeutic window of intra-arterial tenecteplase-tissue plasminogen activator in a rat stroke model

Abstract

Background and Purpose - Occlusion of the middle cerebral artery triggers platelet accumulation at the site of occlusion and in downstream microvessels. The platelet-induced secondary thrombosis promotes the progressive development of ischemic brain damage and contributes to the resistance to thrombolysis and to the tight 3-hour therapeutic window. We tested the hypothesis that combination of intravenous (IV) administration of a GPIIb/IIIa receptor antagonist, 7E3 F(ab′)2, with intra-arterial (IA) administration of tenecteplase-tissue plasminogen activator (TNK-tPA) increases the efficacy of thrombolysis and extends the therapeutic window of stroke. Methods - Rats subjected to embolic stroke were treated with IV 7E3 F(ab′)2 (6 mg/kg) in combination with IA or IV TNK-tPA (5 mg/kg) at 4 and 6 hours after onset of stroke, respectively; IA TNK-tPA (5 mg/kg) alone at 6 hours after onset of stroke; or saline at 6 hours after onset of stroke. Results - The combination of IV 7E3 F(ab′)2 (4 hours) and IA TNK-tPA (6 hours) significantly (P<0.05) reduced infarct volume and improved neurological functional deficits, which was associated with significant (P<0.05) reductions in the size of embolus at the origin of the occluded middle cerebral artery and in down-stream microvascular platelet and fibrin deposition, and enhanced microvascular patency compared with saline-treated rats. However, combination of IV 7E3 F(ab′)2 (4 hours) and IV TNK-tPA (6 hours) or IA TNK-tPA (6 hours) alone failed to reduce infarct volume and improve neurological function compared with the saline-treated rats. No significant differences of the incidence of hemorrhage were detected among groups. Conclusions - These data suggest that the combination of IV 7E3 F(ab′)2 (4 hours) and IA TNK-tPA (6 hours) extends the therapeutic window of thrombolysis to 6 hours after stroke.