Thromb Haemost 2013; 110(01): 162-172
DOI: 10.1160/TH12-12-0907
Animal Models
Schattauer GmbH

Reversal of rivaroxaban anticoagulation by haemostatic agents in rats and primates

Elisabeth Perzborn
1   Global Drug Discovery, Bayer HealthCare Pharmaceuticals AG, Wuppertal, Germany
,
András Gruber
2   Department of Biomedical Engineering, Oregon Health and Science University, School of Medicine, Portland, Oregon, USA
,
Hanna Tinel
1   Global Drug Discovery, Bayer HealthCare Pharmaceuticals AG, Wuppertal, Germany
,
Ulla M. Marzec
2   Department of Biomedical Engineering, Oregon Health and Science University, School of Medicine, Portland, Oregon, USA
,
Ulf Buetehorn
3   Bioanalytics, Bayer HealthCare Pharmaceuticals AG, Wuppertal, Germany
,
Anja Buchmueller
1   Global Drug Discovery, Bayer HealthCare Pharmaceuticals AG, Wuppertal, Germany
,
Stefan Heitmeier
1   Global Drug Discovery, Bayer HealthCare Pharmaceuticals AG, Wuppertal, Germany
,
Volker Laux
1   Global Drug Discovery, Bayer HealthCare Pharmaceuticals AG, Wuppertal, Germany
› Author Affiliations
Financial support: This study was supported by research funding from Bayer HealthCare Pharmaceuticals and Janssen Research & Development, LLC.
Further Information

Publication History

Received: 07 December 2012

Accepted after major revision: 16 April 2013

Publication Date:
30 November 2017 (online)

Summary

Rivaroxaban is an oral, direct factor Xa inhibitor for the management of thromboembolic disorders. Despite its short half-life, the ability to reverse rivaroxaban anticoagulation could be beneficial in life-threatening emergencies. The potential of prothrombin complex concentrate (PCC; Beriplex®), activated PCC (aPCC; FEIBA®) or recombinant activated factor VII (rFVIIa; NovoSeven®) to reverse rivaroxaban in rats and baboons was investigated. Anaesthetised rats pre-treated with intravenous rivaroxaban (2 mg/kg) received intravenous rFVIIa (100/400 μg/kg), PCC (25/50 U/kg) or aPCC (50/100 U/kg) after initiation of bleeding. Clotting times and bleeding times (BTs) were recorded. Rivaroxaban was administered as an intravenous 0.6 mg/kg bolus followed by continuous 0.6 mg/kg/hour infusion in baboons. Animals received intravenous aPCC 50 U/kg (2 U/kg/minute) or rFVIIa 210 μg/kg. BT and clotting parameters were measured. In rats pre-treated with high-dose rivaroxaban, PCC 50 U/kg, aPCC 100 U/kg and rFVIIa 400 μg/kg significantly reduced BT vs rivaroxaban alone (5.4 ± 1.4-fold to 1.5 ± 0.4-fold [p<0.05]; 3.0 ± 0.4-fold to 1.4 ± 0.1-fold [p<0.001]; and 3.5 ± 0.7-fold to 1.7 ± 0.2-fold [p<0.01] vs baseline, respectively). In baboons pre-infused with rivaroxaban and then given aPCC, BT increased by 2.0 ± 0.2-fold and aPCC returned BT to baseline for the duration of its infusion. rFVIIa reduced BT from 2.5 ± 0.3-fold over baseline to 1.7 ± 0.3-fold over baseline. Prolongation of prothrombin time was reduced by PCC, aPCC and rFVIIa in both species. Rivaroxaban reduced thrombin-antithrombin levels; application of PCC and aPCC, but not rFVIIa, increased these levels. In conclusion, PCC, aPCC or rFVIIa have the potential to reverse the anticoagulant and anti-haemostatic effects of rivaroxaban.

 
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