1257. VWF Inhibition by RNA Aptamer Prevents Occlusion in a Canine Vascular Injury Model
Authors: Kendyl Carlisle; Debra Wheeler; David Dornbos III; Camille Bratton; Jenna Wilson; Cole Anderson; Caitlin Hatten; Gabe Shimmin; Vamsi Chodisetty; Shahid Nimjee (Columbus, OH)
Introduction: Occlusive arterial thrombosis leading to stroke and myocardial infarction contribute to ~13 million global deaths annually. The glycoprotein von Willebrand Factor (VWF) is a critical player in the cascade resulting in platelet activation, aggregation, and adhesion to the blood vessel wall. In this study, we investigate the ability of DTRI-031, an RNA aptamer which binds to and inhibits VWF, to maintain patency in a canine ferric chloride-induced carotid artery injury model. Methods: Adult beagles were infused intravenously with either DTRI-031 (n=4) or vehicle (n=4) followed by 50% FeCl 3 -induced injury. Blood velocity (Transonic flow probe), heart rate, ECG, and blood pressure were measured continuously. Blood was drawn to measure platelet closing times (PFA-100 Siemens) before injury and 5, 15, 60 min after injury, in addition to immediately before sacrifice. Angiograms were performed and carotids were H&E stained to verify patency and extent of occlusion. Results: All vehicle treated canines resulted in occlusion within 41.4 minutes after injury and remained occluded through time of sacrifice. Only one DTRI-031 canine injury resulted in occlusion (64.2 min after injury), whereas three of the four canines maintained 100% patency throughout the experimental time line (34.25 ± 8.01 vs 72.25 ± 6.27) 2 hours after injury, (p<0.05). Platelet reactivity to ADP/Collagen (PFA-100) revealed significantly increased platelet closing time in all DTRI-031 canines through 60 min after injury. Conclusion: DTRI-031 VWF inhibition resulted in significant prophylactic efficacy compared to vehicle treatment in canine FeCl 3 -induced vascular injury and may offer a new target for anti-thrombotic therapeutics.