title: Correlation of coagulation markers and 4F-PCC-mediated reversal of rivaroxaban in a rabbit model of acute bleeding.
abstract: BACKGROUND
  Rivaroxaban is an oral, selective direct factor Xa inhibitor approved for several indications in patients at risk of thrombotic events. One limitation of its clinical use is the lack of data pertaining to its reversal in situations where urgent response is critical (e.g. acute bleeding events or emergency surgery).
  
  
  METHODS
  This study assessed the effectiveness of a four-factor prothrombin complex concentrate (4F-PCC; Beriplex(®)/Kcentra(®)) for the reversal of rivaroxaban-associated bleeding in an in vivo rabbit model, and evaluated the correlations between in vitro coagulation parameters and haemostasis in vivo.
  
  
  RESULTS
  Administration of single intravenous doses of rivaroxaban (150-450 μg/kg) resulted in increased and prolonged bleeding following standardised kidney incision. Pre-incision treatment with 4F-PCC (25-100 IU/kg) resulted in a dose-dependent reversal of rivaroxaban (150 and 300 μg/kg)-associated increases in time to haemostasis and blood loss; no reversal was seen at the highest rivaroxaban dose (450 μg/kg). Of the in vitro biomarkers tested, thrombin generation and whole-blood clotting time correlated well with in vivo measures of 4F-PCC-mediated effects. Thrombin generation was highly reagent-dependent, with the assay initiated using the phospholipid-only reagent being the most predictive of effective haemostasis in vivo.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Preclinical Research & Development, CSL Behring GmbH, PO Box 1230, 35002 Marburg, Germany. Electronic address: eva.herzog@cslbehring.com.
authors.forename: Eva
authors.initials: E
authors.lastname: Herzog
authors.affiliation: Preclinical Research & Development, CSL Behring GmbH, PO Box 1230, 35002 Marburg, Germany. Electronic address: franz.kaspereit@cslbehring.com.
authors.forename: Franz
authors.initials: F
authors.lastname: Kaspereit
authors.affiliation: Preclinical Research & Development, CSL Behring GmbH, PO Box 1230, 35002 Marburg, Germany. Electronic address: wilfried.krege@cslbehring.com.
authors.forename: Wilfried
authors.initials: W
authors.lastname: Krege
authors.affiliation: Preclinical Research & Development, CSL Behring GmbH, PO Box 1230, 35002 Marburg, Germany. Electronic address: jochen.mueller-cohrs@cslbehring.com.
authors.forename: Jochen
authors.initials: J
authors.lastname: Mueller-Cohrs
authors.affiliation: Preclinical Research & Development, CSL Behring GmbH, PO Box 1230, 35002 Marburg, Germany. Electronic address: baerbel.doerr@cslbehring.com.
authors.forename: Baerbel
authors.initials: B
authors.lastname: Doerr
authors.affiliation: Preclinical Research & Development, CSL Behring GmbH, PO Box 1230, 35002 Marburg, Germany. Electronic address: peter.niebl@cslbehring.com.
authors.forename: Peter
authors.initials: P
authors.lastname: Niebl
authors.affiliation: Preclinical Research & Development, CSL Behring GmbH, PO Box 1230, 35002 Marburg, Germany. Electronic address: gerhard.dickneite@cslbehring.com.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Dickneite
mesh_terms: D000208:Acute Disease; D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects*; D001779:Blood Coagulation Factors / Q000627:therapeutic use*; D004195:Disease Models, Animal; D065427:Factor Xa Inhibitors / Q000009:adverse effects* / Q000097:blood; D006470:Hemorrhage / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D011817:Rabbits; D000069552:Rivaroxaban / Q000009:adverse effects* / Q000097:blood; D013917:Thrombin / Q000378:metabolism
chemical_list: D001779:Blood Coagulation Factors; D065427:Factor Xa Inhibitors; C025667:prothrombin complex concentrates; D000069552:Rivaroxaban; D013917:Thrombin
keywords: Animal study; Anticoagulation reversal; Haemorrhage; Prothrombin complex concentrates; Rivaroxaban