Assessment of laboratory assays to measure rivaroxaban – an oral, direct factor Xa inhibitor

Meyer Michel Samama; Jean-Luc Martinoli; Léna LeFlem; Céline Guinet; Geneviève Plu-Bureau; François Depasse; Elisabeth Perzborn

doi:10.1160/TH09-03-0176

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2010; 103(04): 815-825
DOI: 10.1160/TH09-03-0176

New Technologies, Diagnostic Tools and Drugs

Schattauer GmbH

Assessment of laboratory assays to measure rivaroxaban – an oral, direct factor Xa inhibitor

Authors

Meyer Michel Samama

¹Hôtel-Dieu University Hospital, Paris, France

²Biomnis Laboratory, Ivry-sur-Seine, France
Jean-Luc Martinoli

³Stago, Asnières, France
Léna LeFlem

²Biomnis Laboratory, Ivry-sur-Seine, France
Céline Guinet

²Biomnis Laboratory, Ivry-sur-Seine, France
Geneviève Plu-Bureau

¹Hôtel-Dieu University Hospital, Paris, France
François Depasse

²Biomnis Laboratory, Ivry-sur-Seine, France
Elisabeth Perzborn

⁴Bayer Schering Pharma AG, Wuppertal, Germany

Abstract

Summary

Although there is no need for routine coagulation monitoring with rivaroxaban – an oral, direct factor Xa inhibitor – a haemostasis assay might be valuable to measure its pharmacodynamic effects. This study aimed to find assays, among those commercially available, to measure rivaroxaban pharmacodynamics. Several global conventional clotting tests, as well as clotting or chromogenic assays to measure anti-factor Xa activity, were studied. A thrombin generation test using calibrated automated thrombogram was also done. Tests were performed with the indirect factor Xa inhibitor fondaparinux for comparison. A concentration-dependent prolongation of prothrombin time (PT), dilute PT, and activated partial thromboplastin time was observed with rivaroxaban. The results varied depending on the reagents. This variability cannot be standardised with the international normalised ratio system commonly used for vitamin K antagonists. Using a standard calibration curve, PT test results can be expressed in plasma concentrations of rivaroxaban rather than PT seconds or ratio. Standard methods for HepTest and two-step prothrombinase-induced clotting time (PiCT) resulted in a paradoxical response, with low concentrations of rivaroxaban reducing clotting times. This was not observed with shorter incubation times, or when antithrombin-deficient (immunodepleted) plasma was used. The chromogenic tests found a dose-dependent relationship between anti-factor Xa activity and rivaroxaban concentration. Modified specific factor Xa chromogenic assays are being further investigated. One-step PiCT and HepTest with shortened incubation times, as well as the widely available PT assay (using a rivaroxaban calibrator) could be useful to monitor the pharmacodynamic effects of rivaroxaban accurately. Finally, all clotting and chromogenic assays showed a concentration-dependent effect induced by rivaroxaban.

Keywords

Clotting assays - factor Xa inhibitor - fondaparinux - pharmacodynamics - rivaroxaban - venous thromboembolism

Full Text

References

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