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(®)/Kcentra(®), 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 μg 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 μg 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.