PB1044 - Combined treatment with andexanet alfa and 4F prothrombin complex concentrate in a lethal porcine double trauma model with continuous bleeding

Background: Andexanet alfa (ADA) or prothrombin complex concentrates (4F-PCC) are frequently used to antagonize the anticoagulatory effects of FXa inhibitors. However, certain clinical situations with massive bleeding may require combined therapy with ADA and 4F-PCC.

Aims: To investigate the safety and efficacy of ADA plus 4F-PCC after double trauma in pigs anticoagulated with apixaban.

Methods: 32 male pigs (n=8/group) were orally fed apixaban (20 mg daily/3 days). Standardized blunt liver injuries and bilateral femur fractures were induced in anesthetized animals. The animals received placebo (control), ADA (750mg bolus + 600mg infusion for 2h or only 750 mg bolus) or 4F-PCC (50 IU/kg). 4F-PCC or ADA were administered 15 and 195 minutes after initial liver trauma as repeat (ADA plus ADA) or cross-over treatments (ADA plus 4F-PCC or 4F-PCC plus ADA). At 180 minutes, a second liver injury was undertaken and the second therapy was given. Coagulation parameters were monitored for 430 minutes after trauma or until death.

Results: Mean anti-FXa levels before trauma induction were 229±130 ng/mL and were significantly higher in control and 4F-PCC groups compared to ADA after reversal throughout.
Controls (3478±493 mL) had the highest total blood loss (BL) post-injury, with 100% mortality. Comparable BL was measured with ADA plus 4F-PCC (1965±222 mL) or 4F-PCC plus ADA (1947±267 mL) treated animals with a mortality rate of 50 % and 12.5 % respectively.
Animals treated with ADA plus 4F-PCC or 4F-PCC plus ADA showed a hypercoagulable state with highest levels of activation markers (D-Dimers, TAT) accompanied by multiple thrombi in lung tissue. All animals treated with ADA survived and no thromboembolic events.

Conclusion(s): Combined therapy with ADA and 4F-PCC under apixaban anticoagulation in a model of continuous bleeding is associated with a procoagulant state. Repetitive therapy with ADA was safe with no signs of an overstimulation of coagulation.