Anti-Inhibitor Coagulant Complex, Prothrombin Complex Concentrate, and Recombinant Factor VIIa Reverse Prothrombin Time Prolonged by Edoxaban In Human Plasma

Hemorrhage is an unwanted effect of any anticoagulant. In animal studies, edoxaban, a novel direct factor Xa (FXa) inhibitor, does not cause significant bleeding at therapeutic doses; however at higher than 10-times the doses the compound prolongs bleeding time. In clinical studies, edoxaban causes bleeding complications comparable to standard anticoagulants, warfarin and enoxaparin in patients with atrial fibrillation and patients undergoing orthopedic surgery. In case of emergency, antidotes to reverse the anticoagulant effect of edoxaban would be helpful.

To determine the effects of three hemostatic agents: anti-inhibitor coagulant complex, prothrombin complex concentrate, and recombinant factor VIIa (rFVIIa) on prothrombin time (PT) prolonged by edoxaban using pooled human plasma in vitro.

Anti-inhibitor coagulant complex (Feiba), prothrombin complex concentrate (PPSB-HT), and rFVIIa were purchased from Baxter, Nihon Pharmaceutical, and Novo Nordisk Pharma. Pooled human normal plasma was obtained from George King Bio-Medical. PT was measured with a microcoagulometer (Amelung KC-10A micro) as follows. Five μL of anti-inhibitor coagulant complex, prothrombin complex concentrate, and rFVIIa solutions or vehicle (saline) and 45 μL of plasma spiked with edoxaban or 5% DMSO-saline solution were added to a cuvette and pre-incubated at 37°C for 1 min. Coagulation was started by the addition of 100 μL of HemosIL PT-fibrinogen HS PLUS (Instrumentation Laboratory) to the mixture. The clotting time was measured.

Mean PT of the control plasma in three experiments was 17.8 − 18.4 sec. Edoxaban at concentrations of 150 and 300 ng/mL significantly prolonged PT. Addition of anti-inhibitor coagulant complex (0.15, 0.5 and 1.5 U/mL) significantly and concentration-dependently shortened the prolonged PT caused by edoxaban. At the maximum concentration (1.5 U/mL), anti-inhibitor coagulant complex reversed PT to 19.5 and 25.0 sec from 31.5 and 43.7 sec in the presence of 150 and 300 ng/mL edoxaban, respectively. Prothrombin complex concentrate (0.15, 0.5 and 1.5 U/mL) and rFVIIa (100, 300 and 1000 ng/mL) also significantly and concentration-dependently reversed anticoagulant effect of edoxaban. At the maximum concentration of prothrombin complex concentrate (1.5 U/mL), PT was shortened to 23.7 and 31.6 sec from 30.7 and 42.5 sec in the presence of 150 and 300 ng/mL edoxaban. rFVIIa at the maximum concentration (1000 ng/mL) reversed PT to 17.3 and 24.2 sec from 30.7 and 43.1 sec in the presence of 150 and 300 ng/mL edoxaban. Anti-inhibitor coagulant complex, prothrombin complex concentrate and rFVIIa each alone significantly shortened PT in a concentration-dependent manner. In the presence of anti-inhibitor coagulant complex (1.5 U/mL), prothrombin complex concentrate (1.5 U/mL), and rFVIIa (1000 ng/mL), PT was 13.1, 15.1, and 11.6 sec, respectively.

The present study demonstrates that anti-inhibitor coagulant complex, prothrombin complex concentrate, and rFVIIa effectively reversed the anticoagulant effect of edoxaban in pooled human plasma in vitro. Therefore, it is suggested that these hemostatic agents have the potential to be antidotes to edoxaban in cases of hemorrhage.

Morishima:Daiichi Sankyo Co., Ltd.: Employment. Off Label Use: Drugs: anti-inhibitor coagulant complex, prothrombin complex concentrate, and recombinant factor VIIa Purpose: Reversal of the anticoagulant effect of edoxaban, a factor Xa inhibitor. Honda:Daiichi Sankyo Co., Ltd.: Employment. Shibano:Daiichi Sankyo Co., Ltd.: Employment.