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.

In a rabbit model of hemostasis, four-factor prothrombin complex concentrate administration significantly decreased edoxaban-associated hemorrhage.

SummaryBackgroundApixaban is a direct factor Xa inhibitor approved for the treatment and prevention of thromboembolic disease. There is a lack of data regarding its reversal in cases of acute bleeding or prior to emergency surgery that needs addressing.ObjectivesThis study assessed whether a four‐factor prothrombin complex concentrate (4F‐PCC; Beriplex®/Kcentra®, CSL Behring) can effectively reverse apixaban‐associated bleeding in an in vivo rabbit model and evaluated the correlations between in vivo hemostasis and in vitro coagulation parameters.MethodsFor dose‐finding purposes, anesthetized rabbits were treated with a single intravenous dose of apixaban (800–1600 μg kg−1) and, following a standardized kidney incision, volume of blood loss and time to hemostasis were measured. In a subsequent study phase, anesthetized rabbits were treated with apixaban 1200 μg kg−1 followed by 4F‐PCC (6.25–100 IU kg−1), and the effects on the same bleeding parameters were assessed. In parallel, coagulation parameters were monitored.ResultsDose‐dependent increases in time to hemostasis and total blood loss were observed post apixaban administration. Preincision treatment with 4F‐PCC resulted in a statistically significant reversal in bleeding time (all doses) and volume (doses ≥ 12.5 IU kg−1). Of the coagulation parameters measured, thrombin generation initiated using the RD reagent (phospholipids only) was the most sensitive to in vivo measures of 4F‐PCC's hemostatic efficacy, although some correlations were also observed for prothrombin time and whole blood clotting time.ConclusionsIn this rabbit model of acute hemorrhage, 4F‐PCC showed potential for reversing the bleeding effects of apixaban. Clinical data in apixaban‐treated patients are needed to confirm these results.

Summary.  Background:  Prophylaxis of hemophilia B, at present, requires multiple infusions of human factor (F)IX concentrates per week. A FIX molecule with a prolonged half‐life has the potential to greatly improve the convenience of, and adherence to, prophylaxis. Objectives:  The aim of our studies was to investigate the pharmacokinetic (PK) and pharmacodynamic (PD) profile of a recombinant fusion protein linking coagulation FIX with albumin (rIX‐FP). Methods:  Cynomolgus monkeys and hemophilia B dogs received single intravenous doses of rIX‐FP (50–500 IU kg−1). rIX‐FP plasma levels were determined by an activity‐based assay (dogs only) and anti‐FIX ELISA methods. Additionally, activated partial thromboplastin time (APTT) was determined in hemophilia B dogs. Data were compared with a direct study comparator (recombinant FIX [rFIX]) or previously published data. Results:  The terminal half‐life of rIX‐FP was prolonged in both species compared with FIX reference data. In hemophilia B dogs, human FIX antigen levels remained above 0.05 IU mL−1 more than three times longer after rIX‐FP (7.3 days) compared with rFIX (2.3 days), whereas respective calculations based on activity levels confirmed the observed superior profile. Prolonged PDs of rIX‐FP were demonstrated with APTT < 60 s sustained around four times longer with rIX‐FP (5.9 days) than rFIX (1.5 days). Conclusions:  These studies indicate that the recombinant albumin fusion technology successfully improves the PK profile of FIX. Clinical studies will test whether the improved kinetics result in a significant half‐life extension in patients with hemophilia B.