Abstract 519: Inhibition of von Willebrand Factor Activity Does Not Delay Cutaneous Wound Healing

Abstract

Introduction: Physiologically, von Willebrand Factor (VWF) recruits platelets to sites of injury by binding to exposed collagen and platelet GPIbα, particularly at sites of high shear. VWF is critical to hemostasis, since complete deficiency leads to bleeding as severe as hemophilia. Conversely, VWF plays a key role in arterial thrombosis, as in myocardial infarction and stroke. Despite being an attractive therapeutic target, no agents directed against VWF are currently available. Our group is testing an RNA aptamer that blocks VWF binding to GPIbα as an antithrombotic. We have previously shown that leukocyte influx and cutaneous healing are impaired in a mouse model of hemophilia. We have also found that wound healing is delayed in mice given target specific oral anticoagulants. The purpose of the current study was to determine whether inhibiting VWF would similarly impair wound healing. Methods: We used C57BL/6J mice administered vehicle or VWF aptamer. At the dose selected, aptamer prolonged the saphenous vein bleeding time for the expected 10 day healing period. Healing was assessed in a skin punch biopsy model. Wound size was measured daily, and following sacrifice the wound area harvested for histology. Inflammation (in the absence of tissue injury) was induced by topical application of cantharidin for 24 hours, followed by tissue harvesting. Results: The in vivo efficacy of the aptamer was verified, since bleeding remained prolonged to a level slightly less severe than hemophilia at the end of the experiment (10 days after wounding). There was no difference in time to healing between control and aptamer-treated mice, with all wounds healed at 10 days. There was also no statistically significant difference in wound size at any time. Cantharidin induced a similar level of cellular influx in treated and control mice. Aptamer-treated mice exhibited a slight amount of inflammation-induced hemorrhage, though not the gross hemorrhage observed in thrombocytopenic mice. Conclusion: Inhibition of VWF activity does not delay cutaneous wound closure, despite inducing a severe hemostatic defect. Compared to other antithrombotic strategies, an aptamer against VWF could avert some undesirable side effects on host defense and tissue repair.