Comparing Hemostatic Efficacy of Four-factor Prothrombin Complex Concentrate with Andexanet Alfa in an Apixaban-treated Polytrauma Male Porcine Model

BACKGROUND: This study directly compared the hemostatic efficacy of two first-line treatments for reversing the effects of direct oral anticoagulants in patients with massive bleeding, andexanet alfa and four-factor prothrombin complex concentrate (4F-PCC), in an apixaban anticoagulated male porcine polytrauma model. METHODS: Male pigs (N = 32) received 20 mg/day apixaban for 3 days. Trauma was simulated by inducing standard liver injuries and bilateral femur fractures. After resuscitation, the animals received control, 4F-PCC (25 or 50 U/kg), or andexanet alfa (1,000-mg bolus followed by 1,200-mg infusion over 2 h); n = 8 animals per group. Blood loss, survival, and coagulation parameters were evaluated. RESULTS: Both 50 U/kg 4F-PCC and andexanet alfa treatment achieved 100% survival. Blood loss was significantly reduced compared with the control group (mean ± SD 3,843 ± 406 ml), with the largest effects observed for andexanet alfa (1,123 ± 197 ml) followed by 50 U/kg 4F-PCC (1,855 ± 372 ml) and then 25 U/kg 4F-PCC. Consistent with the mechanism of action, andexanet alfa led to significantly lower apixaban anti-factor Xa activity (15.6 ± 6.2 ng/ml) compared with control or 4F-PCC treatment until 180 min after trauma. However, 4F-PCC treatment was able to dose-dependently overcome the trauma-induced reduction in coagulation factors II, VII, IX, and X in contrast to andexanet alfa. While andexanet alfa shortened lag time and increased peak thrombin generation, 4F-PCC dose-dependently improved peak height and endogenous thrombin potential. No thromboembolic complications were observed. CONCLUSIONS: In a male polytrauma porcine model of apixaban anticoagulation, both high-dose 4F-PCC and andexanet alfa were fully effective in achieving survival and hemostatic control. Andexanet alfa achieved hemostasis more rapidly, while 4F-PCC showed sustained restoration of factors II, VII, IX, and X levels, as well as thrombin generation.