Abstract Body: 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 and its reversal agent, BB-025, may translate to VTE.
Methods
Jugular vein occlusion (JVO) and inferior vena cava occlusion (IVCO) 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. 10.0 mg/kg rtPA was administered with 10% bolus and remaining 90% over 60 minutes, 400 U heparin IP, and 5.0 mg/kg BB-031, 6.0 mg/kg ADAMTS13, 400 mg/kg N-acetylcysteine (NAC), 5 mg/kg BB-031+10 mg/kg BB-025, 5.0 mg/kg BB-031, and vehicle intravenously. Doppler vein flow velocity was recorded from baseline to determine patency 35 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 79.70% recanalization 35 minutes after occlusion compared to rtPA (18.05%, p=0.1123), heparin (44.44%, p=0.3857), ADAMTS13 (22.16%, p=0.1001), NAC (4.37%, p=0.0298), BB-031+BB-025 (7.13%, p=0.0512), and vehicle (6.79%, p=0.0120), (n=5/group). Male DIO mice significantly reperfused with BB-031 (65.00%) vs rtPA (38.50%, p=0.1611), heparin (4.00%, p=0.0555), ADAMTS13 (-10.12%, p=0.0047), NAC (17.71%, p=0.2979), BB-031+BB-025 (3.25%, p=0.0035), and vehicle (5.12%, p=0.0006), (n=4-6/group). BB-031 treatment after IVCO in both males and females resulted in 124.42% recanalization 35 minutes after occlusion compared to vehicle (10.82%, p=0.0077), and BB-031+BB-025 (-0.16%, p=0.0564), (n=3-10/group). Interestingly, BB-031 treated DIO IVCO mice did not achieve significant reperfusion until 20 min after treatment start compared to 5 min after treatment start in normal IVCO mice.
Conclusion
VWF inhibition by BB-031 maintains patency and effectively thrombolysis in VTE murine models offering future therapeutic alternatives.