Abstract Body: Introduction
Venous thromboembolism (VTE) comprised of deep vein thrombosis (DVT) and pulmonary embolism (PE) incurs significant morbidity and mortality. We hypothesize that Von Willebrand Factor (VWF) inhibition by BB-031 may be an effective thrombolytic in VTE as it has shown thrombolytic efficacy in arterial occlusion models.
Objective
Translation of thrombolytic efficacy and degree of recanalization by aptamer BB-031 and BB-025 reversal in murine VTE models.
Methods
Two murine VTE models were performed by jugular vein occlusion (JVO) and inferior vena cava (IVC) stasis in C57/BL6 wild type (WT) and diet-induced obese (DIO) mice. Thrombosis was induced with 5% FeCl₃ application to the JV for 30 sec x 2, or occlusion of the IVC for 30 min by bulldog clip. Bolus treatment with saline (vehicle control), 5.0 mg/kg BB-031, 6 mg/kg ADAMTS13, 400 mg/kg N-acetyl cysteine (NAC), 400U heparin, 5.0 mg/kg BB-025 5 min after 5.0 mg/kg BB-031 bolus or intravenous infusion of 10 mg/kg recombinant tissue plasminogen activator (rTPA) was administered 20 min after clot stabilization. Percent reperfusion was extracted from Transonic Doppler flow probe data. All data was analyzed in GraphPad Prism.
Results
In all WT JVO-induced mice, although rtPA, heparin, and BB-031 all significantly resulted in recanalization beginning 10 minutes after treatment initiation, only females sustained reperfusion beyond 25 minutes (Figure 1). In DIO mice, only BB-031 treatment resulted in significant reperfusion >50% of initial baseline and had returned the JV to 100% recanalization by 30 minutes after treatment. In all WT IVC venous stasis-induced mice, only 5.0 mg/kg BB-031 had significantly higher recanalization compared with all treatment groups beginning 5 minutes after treatment initiation and was sustained in both sexes. 5.0 mg/kg BB-031 had significantly higher recanalization in DIO mice, but reperfusion start was delayed until ~ 15-20 minutes after treatment. Echocardiography showed an average of a 40% decrease in cardiac output after IVC occlusion which returned to baseline within 8 minutes after bolus injection in the 5.0 mg/kg BB-031 group.
Conclusion
BB-031 translated thrombolytic efficacy from arterial thrombosis to venous may provide an alternative pathway forward for large animal VTE studies followed by clinical trials.