Abstract
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.
Highlights
Tissue plasminogen activator is the only approved thrombolytic therapy for acute ischemic stroke, yet many patients do not recanalize
To determine which Tissue plasminogen activator (tPA) dose best reflects clinical recanalization rates in this model, we aimed to investigate sustained recanalization rates of varying doses of tPA ranging from the clinical dose to the traditional rat dose
We found that the traditional rat dose of tPA (10 mg/kg) was highly effective for carotid artery recanalization (71% recanalization rate)
Summary
Tissue plasminogen activator (tPA) is the only approved thrombolytic therapy for acute ischemic stroke, yet many patients do not recanalize. 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. For any new or adjuvant thrombolytic therapy, rigorous preclinical testing should occur and aim to mimic the clinical conditions of ischemic stroke and tPA efficacy. A dose of 10 mg/kg tPA has been used for rodents This “rat dose” was based on an in vitro study from the early 1980’s that demonstrated that the fibrinolytic system of rats is 10-fold less sensitive than humans[5]. This conversion does not take in to account additional factors that may affect the fibrinolytic process other than body size, and is not generally used when converting doses of tPA for stroke research
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