75: Evaluation of Selective Factor Xa Inhibition for Artificial Surface Induced Coagulation in an Ovine Venovenous ECMO Model

Introduction: Wearable respiratory support technologies are under development as an alternative therapy for patients with advanced lung disease. Heparin and warfarin are the clinical standard anticoagulants for blood-contacting medical devices, but both require frequent anticoagulation monitoring. Direct oral anticoagulants (DOAC) are currently approved at a fixed dose without any monitoring. The present study evaluates the feasibility of rivaroxaban to inhibit artificial surface-induced coagulation. Methods: 12-hour ovine pharmacokinetics and pharmacodynamics of rivaroxaban were evaluated using activated clotting time (ACT), prothrombin time (PT), and plasma concentration using intravenous bolus doses of 0.25, 0.5, and 1mg/kg. The anticoagulation efficacy of these rivaroxaban doses was compared to heparin with an ACT target of 250-290s using a small-scale VV-ECMO circuit. The primary outcome was device failure, defined as a blood flow resistance increase to 20 times the baseline value. Results: Initial experiments demonstrated dose-dependent pharmacodynamics of rivaroxaban, as measured by ACT and PT (n=2, each). However, sheep expressed a higher volume of distribution (2.2+/-0.4L/kg), shorter half-life (1.8+/-0.3hr), and faster clearance (73+/-21L/hr) than humans. Small-scale ECMO experiments (n=4, each) demonstrated dose-dependent device survival with a mean survival of 58+/-26min (heparin), 31+/-9min (0.25mg/kg), 51+/-17min (0.5mg/kg), and 104+/-33min (1mg/kg) (p<0.01), where heparin and 0.5 mg/kg had comparable survival (p=0.59)(Figure). Conclusion: The results demonstrate that sheep are an appropriate model of rivaroxaban activity in humans, and a 0.5 mg/kg rivaroxaban dose provides artificial surface anticoagulation comparable to heparin. Our next step is to evaluate the long-term efficacy of rivaroxaban in 10-day full-scale VV-ECMO experiments in sheep.