Evaluation of Recombinant Tissue Plasminogen Activator in Embolic Stroke

Abstract

In an effort to determine the value of tissue-type plasminogen activator (TPA) in the treatment of embolic stroke, 17 rabbits were subjected to a model of embolic stroke in which 2-hour-old, tin-impregnated, autologous clots were embolized to the bifurcation of the internal carotid artery at the circle of Willis via retrograde injection into the cannulated external carotid artery. High-resolution digital subtraction radiography was used to localize clots intracranially at the carotid bifurcation. Circulation through the internal carotid artery and intracranial vessels was monitored with serial digital subtraction angiography before and after embolization and during treatment. Disappearance of the tin marker on the digital subtraction radiograph indicated dissolution of clot and was associated with reestablishment of circulation on the digital subtration angiogram. Experimental animals were treated with human-specific recombinant TPA 30 minutes, 2 hours, or 4 hours after clot embolization. TPA was administered as an intravenous bolus of 0.5 mg/kg followed by an infusion of 1 mg/kg/h for 2 hours. Digital subtraction angiograms were performed every 30 minutes. All clots dissolved, and cerebral circulation was reestablished within 120 minutes of treatment. In control animals treated with saline, embolized clots were stable, and the internal carotid artery remained occluded. At the completion of each study, the animal was perfused with freshly prepared, buffered 2,3,5-triphenyltetrazolium chloride (TTC) for demarcation of cerebral infarction. Control animals demonstrated infarction of 50 ± 3.6% of the ipsilateral cerebral hemisphere, with an infarct weight of 2.1 ± 0.2 g. The weight of cerebral infarction, as defined by the failure of tissue to stain with TTC, was reduced significantly in TPA-treated animals (P < 0.01). Treatment begun 30 minutes after clot embolization resulted in the most pronounced reduction in cerebral infarction. No intracerebral bleeding was observed. Results indicate that treatment with TPA is effective in dissolving embolic clots and reestablishing intracranial circulation. For best protection against cerebral infarction, however, treatment should be started as soon as possible.