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

Abstract

In summary, in a rabbit model of acute bleeding, treatment with 4F-PCC reduced bleeding to control levels following rivaroxaban 150 μg/kg and 300 μg/kg administration.

Reversal of Rivaroxaban Anticoagulation By Nonactivated Prothrombin Complex Concentrate in Urgent Surgery

“…Although a specific antidote for this drug is not currently available, Phase II studies have demonstrated that andexanet alpha effectively reverses the anticoagulant activity of rivaroxaban [12]. On the other hand, several in vitro studies as well as preclinical studies have shown that PCC has the potential to reverse the anticoagulant activity of rivaroxaban [13][14][15][16][17]. In addition, these data have been confirmed in studies performed in healthy volunteers [18,19].…”

The Reversal of Direct Oral Anticoagulants in Animal Models

“…Valuable insights have also been gained from studies using other standardized injuries in small animals, including kidney incision, hepatosplenic bleeding, and mesenteric bleeding (57, 58, 61, 62, 64). Results from these models are broadly consistent, though it is important to be aware of the distinctions between individual studies.…”

“…The action of 4F-PCC as a rivaroxaban reversal agent has also been demonstrated in rabbits (57, 58). While 4F-PCC (Kaskadil 40 U/mL or Beriplex 25 U/kg, 50 U/kg, or 100 U/kg) did not reduce the increase in bleeding seen with administration of rivaroxaban 5 mg/kg or 450 μg/kg in hepatosplenic and kidney incision bleeding models, Beriplex dose-dependently reduced blood loss and bleeding time at lower rivaroxaban doses in the kidney incision model.…”

“…Interestingly, rFVIIa reduced bleeding time but not blood loss in the hepatosplenic bleeding model. While Godier et al (57) observed correction of rivaroxaban effects on aPTT and ROTEM measurements with 4F-PCC, Herzog et al (58) did not see effects on aPTT. Both groups noted partial effects of 4F-PCC on rivaroxaban-mediated PT prolongation.…”

Reversal of Target-Specific Oral Anticoagulants

“…FVIIa effectively reduced rivaroxabaninduced bleeding time but not blood loss in a rabbit model [ 15 ]. Four-factor PCC has been shown to be effective in reducing bleeding following liver laceration in dabigatran-treated animals and following kidney laceration in rivaroxabantreated animals [ 16 ]. Animal studies have also pointed out that stoppage of bleeding following administration of PCC or rFVIIa did not necessarily correlate with a complete reversal of plasma clotting time prolongation.…”