Four-factor prothrombin complex concentrate reverses apixaban-associated bleeding in a rabbit model of acute hemorrhage

Background: Apixaban is a direct factor Xa inhibitor approved for the treatment and prevention of thromboembolic disease. There is a lack of data regarding its reversal in cases of acute bleeding or prior to emergency surgery that needs addressing. Objectives: This study assessed whether a four-factor prothrombin complex concentrate (4F-PCC; Beriplex (R)/Kcentra (R), CSL Behring) can effectively reverse apixaban-associated bleeding in an in vivo rabbit model and evaluated the correlations between in vivo hemostasis and in vitro coagulation parameters. Methods: For dose-finding purposes, anesthetized rabbits were treated with a single intravenous dose of apixaban (800-1600 mu g kg(-1)) and, following a standardized kidney incision, volume of blood loss and time to hemostasis were measured. In a subsequent study phase, anesthetized rabbits were treated with apixaban 1200 mu g kg(-1) followed by 4F-PCC (6.25-100 IU kg(-1)), and the effects on the same bleeding parameters were assessed. In parallel, coagulation parameters were monitored. Results: Dose-dependent increases in time to hemostasis and total blood loss were observed post apixaban administration. Preincision treatment with 4F-PCC resulted in a statistically significant reversal in bleeding time (all doses) and volume (doses >= 12.5 IU kg(-1)). Of the coagulation parameters measured, thrombin generation initiated using the RD reagent (phospholipids only) was the most sensitive to in vivo measures of 4F-PCC's hemostatic efficacy, although some correlations were also observed for prothrombin time and whole blood clotting time. Conclusions: In this rabbit model of acute hemorrhage, 4F-PCC showed potential for reversing the bleeding effects of apixaban. Clinical data in apixaban-treated patients are needed to confirm these results.