title: Four-factor prothrombin complex concentrate reverses apixaban-associated bleeding in a rabbit model of acute hemorrhage.
abstract: BACKGROUND
  Apixaban 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.
  
  
  OBJECTIVE
  This 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.
  
  
  METHODS
  For 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.
  
  
  RESULTS
  Dose-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.
  
  
  CONCLUSIONS
  In 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.
authors.affiliation: Research, CSL Behring GmbH, Marburg, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Herzog
authors.affiliation: Research, CSL Behring GmbH, Marburg, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Kaspereit
authors.affiliation: Research, CSL Behring GmbH, Marburg, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Krege
authors.affiliation: Research, CSL Behring GmbH, Marburg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Mueller-Cohrs
authors.affiliation: Research, CSL Behring GmbH, Marburg, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Doerr
authors.affiliation: Research, CSL Behring GmbH, Marburg, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Niebl
authors.affiliation: Research, CSL Behring GmbH, Marburg, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Dickneite
mesh_terms: D000208:Acute Disease; D000818:Animals; D000931:Antidotes / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects; D001779:Blood Coagulation Factors / Q000494:pharmacology*; D001780:Blood Coagulation Tests; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006470:Hemorrhage / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy*; D006487:Hemostasis / Q000187:drug effects*; D006490:Hemostatics / Q000494:pharmacology*; D011720:Pyrazoles; D011728:Pyridones; D011817:Rabbits; D013997:Time Factors
chemical_list: D000931:Antidotes; D001779:Blood Coagulation Factors; D006490:Hemostatics; D011720:Pyrazoles; D011728:Pyridones; C025667:prothrombin complex concentrates; C522181:apixaban
keywords: anticoagulants; apixaban; drug evaluation; hemorrhage; preclinical study; prothrombin complex concentrates