title: Effective reversal of edoxaban-associated bleeding with four-factor prothrombin complex concentrate in a rabbit model of acute hemorrhage.
abstract: BACKGROUND
  Edoxaban is an oral, selective direct factor Xa inhibitor approved in Japan for venous thromboembolism prevention after orthopedic surgery. Data are lacking regarding reversal strategies for edoxaban; this study assessed whether four-factor prothrombin complex concentrate (Beriplex/Kcentra; CSL Behring GmbH, Marburg, Germany) can effectively reverse its effects on hemostasis using a previously described rabbit model.
  
  
  METHODS
  The study comprised assessments of thrombin generation in vitro, pharmacokinetic parameters, and edoxaban reversal in vivo. In a blinded in vivo stage, a standardized kidney incision was performed in animals (n = 11 per group) randomized to receive vehicle + saline, edoxaban (1,200 μg/kg) + saline, or edoxaban (1,200 μg/kg) + four-factor prothrombin complex concentrate (50 IU/kg). Animals were monitored for treatment impact on hemostasis and coagulation parameters. Data are median (range). Statistical tests were adjusted for multiple testing.
  
  
  RESULTS
  Edoxaban administration increased blood loss (30 [2 to 44] ml) and time to hemostasis (23 [8.5 to 30.0] min) compared with the control group (3 [1 to 8] ml and 3 [2.0 to 5.0] min, respectively). Biomarkers of coagulation (prothrombin time, activated partial thromboplastin time, whole blood clotting time) and thrombin generation parameters (e.g., peak thrombin, endogenous thrombin potential, lag time) were also affected by edoxaban. Administration of four-factor prothrombin complex concentrate significantly reduced time to hemostasis (to 8 [6.5 to 14.0] min, observed P < 0.0001) and total blood loss (to 9 [4 to 22] ml, observed P = 0.0050) compared with the edoxaban + saline group. Of the biomarkers tested, prothrombin time, whole blood clotting time, and endogenous thrombin potential correlated best with clinical parameters.
  
  
  CONCLUSIONS
  In a rabbit model of hemostasis, four-factor prothrombin complex concentrate administration significantly decreased edoxaban-associated hemorrhage.
authors.affiliation: From Preclinical Research and Development, CSL Behring GmbH, Marburg, Germany (E.H., F.K., W.K., B.D., J.M-C., I.P., G.D.); and Biological Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd., Tokyo, Japan (Y.M.).
authors.forename: Eva
authors.initials: E
authors.lastname: Herzog
authors.forename: Franz
authors.initials: F
authors.lastname: Kaspereit
authors.forename: Wilfried
authors.initials: W
authors.lastname: Krege
authors.forename: Baerbel
authors.initials: B
authors.lastname: Doerr
authors.forename: Jochen
authors.initials: J
authors.lastname: Mueller-Cohrs
authors.forename: Ingo
authors.initials: I
authors.lastname: Pragst
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Morishima
authors.forename: Gerhard
authors.initials: G
authors.lastname: Dickneite
mesh_terms: D000208:Acute Disease; D000818:Animals; D001779:Blood Coagulation Factors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001780:Blood Coagulation Tests; D002682:Chinchilla; D023381:Endpoint Determination; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced* / Q000517:prevention & control*; D006474:Hemorrhagic Disorders / Q000517:prevention & control; D006490:Hemostatics / Q000493:pharmacokinetics / Q000627:therapeutic use*; D066298:In Vitro Techniques; D011725:Pyridines / Q000037:antagonists & inhibitors* / Q000493:pharmacokinetics / Q000633:toxicity*; D011817:Rabbits; D013844:Thiazoles / Q000037:antagonists & inhibitors* / Q000493:pharmacokinetics / Q000633:toxicity*; D013917:Thrombin / Q000378:metabolism
chemical_list: D001779:Blood Coagulation Factors; D006490:Hemostatics; D011725:Pyridines; D013844:Thiazoles; C025667:prothrombin complex concentrates; D013917:Thrombin; C552171:edoxaban