Abstract WP70: Aptamer Inhibition of Von Willebrand Factor Ameliorates Ischemic Stroke Burden in a Murine Model of Thromboembolic Stroke

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Abstract

Introduction: While recombinant tissue plasminogen activator (rTPA) is the mainstay of ischemic stroke treatment, recanalization is only achieved in 25-50% of patients. With a significant risk of intracranial hemorrhage, its use has been limited to within 4.5 hours of symptom onset. Previous work has demonstrated that aptamer inhibition of Von Willebrand Factor (VWF) effectively restores reperfusion following murine carotid artery occlusion.

Hypothesis: We tested the hypothesis that VWF aptamer would promote recanalization following thrombotic middle cerebral artery (MCA) occlusion, ameliorating stroke burden with greater efficacy than rTPA.

Methods: Adult wild-type (C57BL/6J) mice were anesthetized, and the right carotid artery was exposed. A 32-gauge intracranial catheter was advanced within the carotid artery. Murine autologous blood was then mixed with 10 μL 0.9% normal saline and 1 μL murine thrombin and was allowed to stabilize at 37 °C for 15 minutes, after which it was injected through the catheter into the MCA. Laser-doppler flowmetry monitoring measured decreased flow following injection of the embolus. Treatment (vehicle, platelet binding buffer, n=5; VWF aptamer, n=6; rTPA, n=7) was initiated 20 minutes after thrombus injection. An MRI was obtained at 24 hours to assess ischemic stroke volumes.

Results: None of the mice receiving rTPA survived to 24 hours, while all mice treated with VWF aptamer and vehicle survived to 24 hours and received an MRI. Ischemic stroke volume was significantly decreased in mice treated with VWF aptamer (5.49 ± 5.01 mm3) compared to vehicle (35.34 ± 9.57 mm3, p<0.05)(Figure 1). No evidence of intracranial hemorrhage was identified in either cohort.

Conclusions: Treatment with VWF aptamer decreases stroke volume on MRI in a murine model of embolic stroke without the risk of hemorrhagic conversion seen in patients treated rTPA. VWF inhibition represents a promising therapy in stroke treatment.

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