Glycoprotein IIb/IIIa Antagonist, Murine 7E3 F(ab′)2, and Tissue Plasminogen Activator in Focal Ischemia: Evaluation of Efficacy and Risk of Hemorrhage with Combination Therapy

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Abstract
Tissue hypoperfusion during cerebral ischemia results from occlusion of large and small vessels. Combination treatment strategies using fibrinolytics to thrombolyse an embolic clot and antiplatelet agents to prevent reocclusion and the formation of new platelet thrombi in the microcirculation may offer advantages over single-agent therapy. The authors report on the effects of tissue plasminogen activator (rt-PA), a glycoprotein (GP) IIb/IIIa receptor antagonist, 7E3 F(ab′)2, or a combination of the two agents in a focal embolic model of cerebral ischemia in Wistar rats. Focal ischemia was produced by introducing an autologous thrombus into the right side middle cerebral artery. Forty-six male Wistar rats were randomly divided into 6 groups: control (n = 8), 7E3 F(ab′)2 (n = 9, 6 mg/kg), rt-PA (n = 9, 10 mg/kg), rt-PA (n = 6, 20 mg/kg), and 7E3 F(ab′)2 with either 10 mg/kg (n = 10) (low-dose combination) or 20 mg/kg (n = 6) (high-dose combination) rt-PA. Evaluation of neurobehavioral scores, cerebral angiography, bleeding time, and measurement of brain infarction volume were used to determine efficacy. All actively treated groups showed a significant reduction in the infarct volume. Animals treated with 7E3 F(ab′)2 showed reduced infarction volumes (24.0 ± 5.1%) compared with controls (42.43 ± 5.6%, P < 0.02). Treatment with rt-PA significantly reduced infarction volume (20.7 ± 3.3, = 0.01) at 10 mg/kg and at 20 mg/kg (19.5 ± 8.2%, P < 0.05). Compared with vehicle-treated animals, the low-dose combination (16.4 ± 5.5, P < 0.003) and high-dose combination (23.7 ± 6.2%, P < 0.05) showed significant reduction in infarction volume. Cerebral angiography revealed significantly better recanalization in the combination group (5/6 animals in the high dose and 4/6 in low dose) compared with animals treated with 7E3 F(ab′)2 (3/10) or rt-PA alone (2/6). Bleeding time significantly increased from 11.25 ± 1.9 minutes in the control group to 17 ± 3.1 minutes in the rt-PA group, 24.5 ± 2.6 minutes in the 7E3 F(ab′)2 group, 25.7 ± 3.1 minutes in the low-dose combination group, and 32.5 ± 4.7 minutes in the high-dose combination group. The incidence of intercerebral hemorrhage was highest in the high-dose combination group (6 of 6 animals) and lowest in the single treatment with 7E3 F(ab′)2 alone (1 of 10 animals) ( P < 0.05). Our data show that murine 7E3 F(ab′)2 alone has therapeutic effects when used after cerebral ischemia. Although this study suggests that higher doses of thrombolytic combined with anti-GPIIb/IIIa therapy may increases the risk of intracranial hemorrhage, the data also support the notion that anti-GPIIb/IIIa agents can safely be combined with low doses of thrombolytic agent to produce significant attenuation of neuronal damage with no increase in the incidence of cerebral hemorrhage.