Four-Factor Prothrombin Complex Concentrate (4F-PCC) Effectively Reverses Rivaroxaban Induced Bleeding in a Rabbit Model of Acute Bleeding

Rivaroxaban is an oral, selective direct factor Xa inhibitor approved for several indications in patients at risk of thrombotic events. One limitation of this agent is the lack of data pertaining to its reversal in situations where urgent response is critical (e.g. acute bleeding events or emergency surgery).

This study therefore evaluated the effectiveness of a four-factor prothrombin complex concentrate (4F-PCC; Beriplex^® P/N, Kcentra^®, CSL Behring), for the reversal of rivaroxaban-associated bleeding in an in vivo rabbit model of acute bleeding. In addition, the study evaluated the correlation between in vitro coagulation parameters and haemostasis in vivo in order to gain more information on the predictivity of in vitro markers for effective bleeding reversal.

Administration of single intravenous doses of rivaroxaban (150–450 μg/kg) resulted in increased and prolonged bleeding following standardised kidney injury compared to a vehicle treated control group as determined by measurements of total blood loss and time required to achieve full hemostasis. Subsequent treatment with 4F-PCC (25−100 IU/kg) resulted in a dose-dependent reversal of rivaroxaban-associated bleeding signals. Of the in vitro coagulation markers tested, thrombin generation (TGA) and whole blood clotting time (WBCT) correlated well with in vivo measures of PCC-mediated effects. Thrombin generation was highly reagent-dependent, with the assay initiated using tissue factor reagent being most sensitive to the anticoagulant effects induced by Rivaroxaban, while the phospholipid-only reagent being the most predictive of 4F-PCC mediated effective haemostasis in vivo.

In summary, in a rabbit model of acute bleeding, 4F-PCC was able to effectively reduce bleeding to control levels following rivaroxaban 150 μg/kg and 300 μg/kg administrations. The 4F-PCC mediated bleeding reversal correlated best with the in vitro endpoints thrombin generation and whole blood clotting time.