Abstract WMP44: Functional Recovery Following a Combination of Thrombin Inhibitor Argatroban and Tissue Plasminogen Activator (tPA) in Thromboembolic Stroke in Nonhuman Primates

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Abstract

Introduction: Early treatment following an acute stroke with the thrombolytic tissue plasminogen activator (tPA) increases functional recovery. Complications of tPA treatment include hemorrhaging and narrow therapeutic time window. Thus, better treatments for acute stroke are needed. While a number of novel treatments for acute ischemic stroke have been derived from preclinical rodent stroke models, to date, none have succeeded in clinical studies. Nonhuman primates are phylogenetically closer to humans than rodents, which could narrow the current translational shortfall between preclinical and clinical findings. The goal of the current study was to test the effect of a combination of argatroban, a thrombin inhibitor, and tPA on functional recovery and brain infarction size following thromboembolic ischemia in nonhuman primates.

Methods: Autologous blood clots were injected into the internal carotid artery of cynomolgus macaques to induced a thromboembolic stroke. Either tPA (0.9 mg/kg; n = 8) or vehicle (n = 8) was intravenously infused for one hour an hour following the induction of ischemia. In a third group, after completion of tPA infusion, argatroban (0.6 mg/kg; n= 7) was intravenously infused for 22 hours. Doppler ultrasound recorded middle cerebral artery (MCA) blood flow for six hours following induction of stroke. In addition, brain infarct volume (TTC staining) and functional assessment (Neurologic Deficit Score; NDS) were determined 24 hours after ischemia.

Results: Compared to vehicle treatment, tPA treatment significantly decreased MCA occlusion time, brain infarct volume and NDS. Treatment with the combination of argatroban and tPA decreased occlusion time, brain infarct volume and NDS similar to tPA treatment alone.

Conclusion: The current study suggests that the addition of argatroban could enhance recanalization rates observed with tPA treatment alone. However, in contrast to previous findings in rats, the combination of argatroban and tPA does not appear to further enhance tissue or functional recovery from a thromboembolic stroke compared to tPA treatment alone.

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