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  • Aptamer Inhibition of Von Willebrand Factor Reduces Ischemic Stroke Burden in a Gender-Dependent Manner

    Final Number:
    2

    Authors:
    David L Dornbos III MD; Debra Wheeler; Hallie Harris; Surya PhD Gnyawali; Allyson Huttinger; Camille Bratton; Jenna Wilson; Spencer Talentino; Jay Zweier; Chandan Sen; Cameron Rink; Shahid Mehdi Nimjee MD, PhD

    Study Design:
    Laboratory Investigation

    Subject Category:
    Basic Science

    Meeting: AANS/CNS Cerebrovascular Section 2018 Annual Meeting

    Introduction: A clear gender difference exists in stroke, with increased morbidity and mortality in women. The underlying mechanisms remain unknown, although differences in platelet biology may play a role. Von Willebrand Factor (VWF) inhibition has previously demonstrated efficacy in thrombolysis.

    Methods: Male and female 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 0.9% normal saline and murine thrombin, and was allowed to stabilize at 37┬░C, after which it was injected into the MCA. Laser-doppler flowmetry monitoring measured decreased flow following embolus injection. Treatment with vehicle or VWF aptamer (0.5 mg/kg) was initiated 20 minutes after thrombus injection. An MRI was obtained at 24 hours to assess ischemic stroke volumes. An ELISA assay was used to assess VWF levels in murine whole blood.

    Results: Ischemic stroke volume was significantly decreased in female mice treated with VWF aptamer (n=6, 5.49 ± 5.01 mm3) compared to vehicle (n=6, 35.34 ± 9.57 mm3, p<0.05). No significant difference was observed when comparing male mice treated with VWF aptamer (n=11, 18.73 ± 6.95 mm3) or vehicle (n=7, 13.32 ± 2.67 mm3, p=0.56). ELISA analysis of murine whole blood revealed significantly higher VWF expression in female mice (0.27 ± 0.01 ng/mL) compared to males (0.14 ± 0.02 ng/mL, p<0.001).

    Conclusions: Aptamer inhibition of VWF decreases stroke volume in a murine model of embolic stroke in female mice. At the same dose of VWF aptamer, this did not yield significant stroke reduction in male mice. Given the gender discrepancies in VWF expression and thrombolysis with VWF inhibition, the VWF-GP IB-IX-V axis may play a role in the gender differences observed in stroke outcomes and VWF inhibition may result in improved stroke outcomes in females.

    Patient Care: Developing a novel reversible anti-platelet agent as a thrombolytic in the setting of acute ischemic stroke provides a potential therapeutic adjunct to mechanical thrombectomy with minimal hemorrhagic side effects. In addition to its role in thrombolysis, VWF inhibition would also be expected to prevent re-occlusion following successful recanalization.

    Learning Objectives: By the conclusion of this session, participants should be able to: 1) Describe the gender differences in outcome following ischemic stroke. 2) Discuss the importance of novel medical therapies to augment mechanical thrombectomy in this patient population. 3) Discuss the potential benefits of VWF inhibition in ischemic stroke and the role for novel reversible anti-platelet agents in this setting.

    References:

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