In vivo increase in thrombin generation by four-factor prothrombin complex concentrate in apixaban-treated healthy volunteers

Abstract

Background: Four-factor prothrombin complex concentrate (PCC) (Cofact; Sanquin Blood Supply) 50 IU kg-1 increased thrombin generation beyond baseline values in healthy, rivaroxaban-treated subjects. Objective: To assess whether infusion with doses of 37.5 IU kg-1 and 25 IU kg-1 PCC reverses the anticoagulant effect of high-dose apixaban, another oral direct factor Xa inhibitor. Methods: In a randomized, double-blind, placebo-controlled, crossover study, six healthy subjects received twice-daily apixaban 10 mg for 3.5 days followed by a single bolus of 37.5 IU kg-1 PCC, 25 IU kg-1 PCC, or placebo. The primary outcome was the effect of PCC 15 min after infusion on thrombin generation (endogenous thrombin potential [ETP]); secondary outcomes were the immediate effect of PCC on prothrombin time (PT) and the effect of PCC as compared with placebo over a period of 24 h on ETP and PT. Results: Fifteen minutes after infusion of 37.5 IU kg-1 and 25 IU kg-1 PCC, ETP increased from 41% ± 11% to 56% ± 23% (P = 0.06) and from 44% ± 12% to 51% ± 15% (P = 0.03), respectively. ETP significantly differed over time between 37.5 IU kg-1 PCC and placebo during 24 h after infusion (P < 0.01). Both PCC doses restored apixaban-induced PT prolongation after 15 min (P < 0.01), and this was sustained over a period of 24 h. Conclusion: Both 37.5 IU kg-1 PCC and 25 IU/kg PCC improved coagulation parameters in healthy subjects, suggesting partial reversal of the anticoagulant effect of apixaban. This implies that PCC might be considered in patients with apixaban-associated bleeding. However, ETP was not immediately restored to pre-apixaban levels, suggesting that these doses are too low to instantly and fully restore hemostasis at peak apixaban levels.