CLOPIDOGREL ENHANCEMENT OF RT-PA THROMBOLYSIS IN A THROMBOEMBOLIC MODEL OF CEREBRAL-ISCHEMIA IN RATS

Objective: The effects of postembolic treatment with clopidogrel-a thi enopyridine derivative and inhibitor of platelet aggregation-alone and in combination with rt-PA were investigated in a thromboembolic model of monofocal cerebral ischemia in rats. Methods: After injection of a single in vitro prefabricated fibrin-rich autologous macroclot (400 m u m x 4 mm) into the internal carotid artery of Sprague Dawley rats, t he animals were assigned to one of four intravenous treatment groups: (1) continuous saline infusion over 45 min starting 60 min after embol ization (control); (2) rt-PA as a continuous infusion at 6 mg/kg for 4 5 min starting 60 min after embolization; (3) clopidogrel at 20 mg/kg immediately after embolization followed by a continuous saline infusio n for 45 min starting 60 min after injection; (4) rt-PA as in group 2 plus clopidogrel as in group 3. Results: Embolization produced occlusi ons of the ipsilateral middle cerebral artery or the internal carotid artery at the origin of the middle cerebral artery. Occlusions were st able in the control group. Administration of rt-PA at a thrombolytic t hreshold dose together with clopidogrel resulted in a recanalization o f the middle cerebral artery as demonstrated by angiographic control i mmediately after treatment. Recanalization was associated with a decre ase in the neurological deficit (30% vs control) and in the subcortica l and total infarct volumes (18 and 25%) at 24 h albeit the difference s did not attain significance. No gross intracranial hemorrhages were observed following clopidogrel/rt-PA coadministration. Postembolic tre atment with clopidogrel alone tended to reduce infarct volume and to i mprove neurological outcome. Tail transection bleeding time was prolon ged in the clopidogrel group (4.7-fold) and in both rt-PA-treated grou ps (> g-fold). Ex vivo platelet aggregation was inhibited by clopidogr el treatment but not by rt-PA infusion. Conclusion: These data provide evidence for the first time that rt-PA thrombolysis after ischemic st roke can be enhanced by adjunctive postembolic antiplatelet therapy. T his effect was not accompanied by gross intracranial hemorrhages.