Published Online
on October 28, 2004

A more recent version of this article appeared on December 1, 2004

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Submitted on August 26, 2004
Accepted on September 17, 2004

Intravenous Administration of a GPIIb/IIIa Receptor Antagonist Extends the Therapeutic Window of Intra-Arterial Tenecteplase-Tissue Plasminogen Activator in a Rat Stroke Model

Li Zhang MD; Zheng Gang Zhang MD, PhD; Chunling Zhang BS; Rui Lan Zhang MD; and Michael Chopp PhD^*

From the Department of Neurology (L.Z., Z.G.Z., C.Z., R.Z., M.C.), Henry Ford Health Sciences Center, Detroit, Mich; and the Department of Physics (M.C.), Oakland University, Rochester, Mich.

^* To whom correspondence should be addressed. E-mail: chopp{at}neuro.hfh.edu.

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.

Key words: cerebral hemorrhage • cerebral ischemia, transient • thrombolysis • thrombosis

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