Abstract 16899: Neutralization of Bleeding Induced by Direct Factor Xa and Thrombin Inhibitors by Prothrombin Complex Concentrates Alone and in Combination with Antifibrinolytic Agents

Abstract

Introduction: Concerns remain over bleeding with direct factor Xa and thrombin inhibitors in cases of overdose or medical emergency. This study tested the ability of PCCs to reverse bleeding induced by apixaban, rivaroxaban or dabigatran in a standardized rat tail resection model. Methods: Individual groups of anesthetized rats (8-10) were anticoagulated with apixaban, rivaroxaban or dabigatran and subsequently treated with vehicle, 3-factor (Profilnine), 4-factor (Beriplex) or activated 4-factor PCC (FEIBA). Five minutes post-PCC administration, a tail snip was performed and bleeding time was measured. Upon cessation of bleeding, a blood samples were collected for ex vivo analysis and the rat was humanely euthanized. Results: In comparison to saline control (6.8 + 1.1 sec) apixaban (300μg/kg) prolonged bleeding time (17.1±5.6; p=0.024). Beriplex at doses ≤10U/kg did not shorten bleeding time while 10U/kg Profilnine did. FEIBA prolonged bleeding beyond that seen with apixaban alone (22.6±11.4 and 37.5±5.2 min for 5 and 10U/kg doses; p<0.001 apixaban + 10U/kg FEIBA vs. apixaban). 100 and 300μg/kg rivaroxaban prolonged bleeding time (20.8±2.5, p=0.002 vs. saline; 25.0±10.0 min, p<0.001 vs. saline). Profilnine was more effective than Beriplex or FEIBA in reversing rivaroxaban-induced bleeding. Dabigatran-induced bleeding was prevented by Beriplex or Profilnine but enhanced by FEIBA (50.3±8.3 vs. 15.9±1.2 min; p<0.001). Treatment of apixaban or rivaroxaban anticoagulated rats with FEIBA + 10mg/kg epsilon aminocaproic acid, produced bleeding times comparable to those of non-anticoagulated rats (apixaban: 6.7±5.0 min; rivaroxaban: 7.7±6.4 min). Ex vivo analysis of blood samples did not show any relevance with the observed bleeding or its modulation. Discussion: PCCs appear useful for neutralizing bleeding induced by direct factor Xa and thrombin inhibitors, but each PCC exhibits a distinct neutralization profile. Co-administration of a fibrinolytic inhibitor may enhance effectiveness of hemorrhage reversal by PCCs.