Published Online
on May 19, 2003

A more recent version of this article appeared on June 10, 2003

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Submitted on December 31, 2002
Revised on February 27, 2003
Accepted on March 1, 2003

Adjuvant Treatment With a Glycoprotein IIb/IIIa Receptor Inhibitor Increases the Therapeutic Window for Low-Dose Tissue Plasminogen Activator Administration in a Rat Model of Embolic Stroke

Li Zhang MD, Zheng Gang Zhang MD, PhD, Ruilan Zhang MD, Daniel Morris MD, Mei Lu PhD, Barry S. Coller MD, and Michael Chopp PhD^*

From the Departments of Neurology (L.Z., Z.G.Z., R.Z., M.C.), Emergency Medicine (D.M.), and Biostatistics and Research Epidemiology (M.L.), Henry Ford Health Sciences Center, Detroit, Mich; the Laboratory of Blood and Vascular Biology, The Rockefeller University, New York, NY (B.S.C.); and the Department of Physics, Oakland University, Rochester, Mich (M.C.).

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

Background--Platelet aggregation and fibrin deposition are key events leading to microvascular thrombosis and progressive impairment of downstream microvascular perfusion after stroke. We tested the hypothesis that inhibition of platelet function with a GP IIb/IIIa receptor antagonist would increase the efficacy and safety and increase the time window for thrombolytic therapy for stroke with full- and half-dose tissue plasminogen activator (tPA).

Methods and Results--Rats were subjected to embolic middle cerebral artery occlusion. Four hours after ischemia, rats were treated with 7E3 F(ab`)<sub>2</sub> (6 mg/kg) in combination with tPA at doses of 10 and 5 mg/kg, tPA alone at a dose of 10 or 5 mg/kg, 7E3 F(ab`)₂ (6 mg/kg) alone, or saline. Combination treatment with 7E3 F(ab`)<sub>2</sub> and tPA (full- or half-dose) significantly (P<0.05) reduced infarct volume and neurological deficits compared with saline-treated rats. However, treatment with 7E3 F(ab`)₂ or tPA (full- or half-dose) alone did not reduce infarct volume. Quantitative measurements of cerebral microvessels perfused by FITC-dextran revealed that combination treatment with 7E3 F(ab`)<sub>2</sub> and full-dose tPA significantly (P<0.05) increased the percentage of FITC-dextran-perfused vessels compared with saline and full-dose tPA-treated rats. In addition, treatment with 7E3 F(ab`)₂ in combination with full-dose tPA significantly (P<0.05) decreased microvascular platelet accumulation and matrix metalloproteinase 9 immunoreactivity and protected against loss of collagen IV immunoreactivity.

Conclusions--Combination treatment with 7E3 F(ab`)₂ with full- and half-dose tPA at 4 hours after ischemia significantly reduces infarct volume and improves neurological outcome. Enhancement of patency and integrity of cerebral microvessels most likely contributes to the benefits observed with this combination therapy.

Key words: cerebral ischemia • plasminogen activators • platelets • microcirculation

Related Article:

Adding to the Effectiveness of Intravenous Tissue Plasminogen Activator for Treating Acute Stroke

James C. Grotta
Circulation 2003 107: 2769-2770. [Extract] [Full Text]

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