Tissue Plasminogen Activator for preclinical stroke research: Neither “rat” nor “human” dose mimics clinical recanalization in a carotid occlusion model

Tissue plasminogen activator (tPA) is the only approved thrombolytic therapy for acute ischemic stroke, yet many patients do not recanalize. Enhancing thrombolytic efficacy of tPA is a major focus of stroke research. Traditionally, a "rat dose" of 10 mg/kg has been used in rodent models. Recent studies suggested that the clinical "human" dose (0.9 mg/kg) may better mimic clinical recanalization. These studies only compared the rat and clinical doses, and so we aimed to test recanalization efficacy of multiple tPA doses ranging from 0.9 to 10 mg/kg in a model of endothelial injury and vessel stenosis. The common carotid artery of rats was crushed and stenosed to allow in-situ occlusive thrombus formation (Folt's model of 'physiological' thrombus). Intravenous tPA was administered 60 minutes post-occlusion (n = 6-7/group). Sustained recanalization rates were 0%, 17%, 67% and 71%, for 0.9, 1.8, 4.5, and 10 mg/kg, respectively. Median time to sustained recanalization onset decreased with increasing dosage. We conclude that 10 mg/kg of tPA is too effective, whereas 0.9 mg/kg is ineffective for lysis of occlusive thrombi formed in situ. Neither dose mimics clinical tPA responses. A dose of 2x the clinical dose is a more appropriate mimic of clinical tPA recanalization in this model.