Abstract Body (Do not enter title and authors here): Introduction
Venous thromboembolism (VTE) manifesting as deep vein thrombosis and pulmonary embolus results in ~300,000 US deaths annually. Risk factors include obesity and current therapy limitations leave ~ 50% of patients with no effective treatment. Circulating von Willebrand Factor (VWF) levels portend poor clinical outcomes. BB-031, an aptamer-based VWF inhibitor with prophylactic and arterial thrombolytic efficacy may translate to VTE.
Methods
Jugular vein occlusion (JVO) was induced by FeCl₃ either before or after intravenous treatment in 14 week old male and female C57/BL6 wild type (WT) or male diet-induced obese (DIO) mice. 5.0 mg/kg BB-031 was administered as a bolus, 10.0 mg/kg rtPA with 10% bolus and remaining 90% over 60 minutes, 400 U heparin as a bolus, or vehicle. Doppler jugular vein flow velocity was recorded from baseline to determine patency 30 minutes after injury. Thrombolytic clots were stabilized for 20 minutes.
Results
Prophylactic mice occluded ~20 minutes after FeCl₃ application with rtPA=18.32 +/- 6.54 min, heparin 17.14 +/- 8.53 min, and vehicle 17.29 +/- 7.26 min. Thrombosis did not occur with BB-031 treatment (n=4-12/group). Treatment after JVO resulted in no difference compared to vehicle in male WT mice, but BB-031-treated WT females resulted in 76.09% recanalization 35 minutes after occlusion compared to rtPA (9.64%, p<0.0001), heparin (30.95%, p=0.7306), or vehicle (22.07%, p<0.0001), (n=5/group). Male DIO mice significantly reperfused with BB-031 (100%) vs rtPA (10.52%), heparin (4.54%), and vehicle (22.50%), p<0.0001, (n=4-6/group).
Conclusion
VWF inhibition by BB-031 maintains patency in a VTE murine model offering future therapeutic alternatives.