Correlation of Coagulation Markers and 4F-PCC-Mediated Reversal of Rivaroxaban in a Rabbit Model of Acute Bleeding

Abstract

IntroductionRivaroxaban is an oral, selective direct factor Xa inhibitor approved for several indications in patients at risk of thrombotic events. One limitation of its clinical use is the lack of data pertaining to its reversal in situations where urgent response is critical (e.g. acute bleeding events or emergency surgery). Materials and methodsThis study assessed the effectiveness of a four-factor prothrombin complex concentrate (4F-PCC; Beriplex®/Kcentra®) for the reversal of rivaroxaban-associated bleeding in an in vivo rabbit model, and evaluated the correlations between in vitro coagulation parameters and haemostasis in vivo. ResultsAdministration of single intravenous doses of rivaroxaban (150–450μg/kg) resulted in increased and prolonged bleeding following standardised kidney incision. Pre-incision treatment with 4F-PCC (25–100IU/kg) resulted in a dose-dependent reversal of rivaroxaban (150 and 300μg/kg)-associated increases in time to haemostasis and blood loss; no reversal was seen at the highest rivaroxaban dose (450μg/kg). Of the in vitro biomarkers tested, thrombin generation and whole-blood clotting time correlated well with in vivo measures of 4F-PCC-mediated effects. Thrombin generation was highly reagent-dependent, with the assay initiated using the phospholipid-only reagent being the most predictive of effective haemostasis in vivo. ConclusionsIn summary, in a rabbit model of acute bleeding, treatment with 4F-PCC reduced bleeding to control levels following rivaroxaban 150μg/kg and 300μg/kg administration.