Betrixaban: Impact on Routine and Specific Coagulation Assays—A Practical Laboratory Guide

Siriez, Romain; Evrard, Jonathan; Dogné, Jean‐Michel; Pochet, Lionel; Gheldof, Damien; Châtelain, Bernard; Mullier, François; Douxfils, Jonathan

doi:10.1055/s-0038-1657772

Cited by 21 publications

(26 citation statements)

References 25 publications

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“…The ionic force and the pH of the buffer solution are parameters that could also impact the sensitivity of a particular assay . From the results of this study and in regard to previous studies, we can suggest that betrixaban does not have a similar inhibitory profile to chromogenic anti‐Xa assays than other direct factor Xa inhibitors. This may be due to differences in Ki between the direct factor Xa inhibitors (ie, betrixaban: 0.12 nmol/L, edoxaban: 0.56 nmol/L, apixaban: 0.74 nmol/L and rivaroxaban: 0.47 nmol/L) .…”

Section: Discussionsupporting

confidence: 42%

“…Chromogenic anti‐Xa assays have already been described as accurate assays for the measurement of plasmatic drug level of direct FXa inhibitors . In our previous article, we pointed out that these tests had to be improved . These modifications decrease the dynamic range of quantification and the upper limit of measurement, but on the other hand, they improve the values of the limits of detection and quantification of the HemosIL ® Liquid Anti‐Xa and Biophen ® DiXaI ® assays.…”

Section: Discussionmentioning

confidence: 99%

“…Betrixaban, a novel direct oral factor Xa inhibitor developed by Portola Pharmaceuticals Inc (South San Francisco, CA, USA), has received its market authorization under the brand name of BevyxXa ® on the 23th of June 2017 in the United States (US) for the prophylaxis of venous thromboembolisms (VTE) in adult patients with acute medical illness who are at risk of VTE . Previous study mentioned that chromogenic anti‐Xa assays seem to be useful to estimate the amount of betrixaban in plasma . Nevertheless, the sensitivity of available tests is limited and improvement is needed to encompass the on‐therapy range .…”

Section: Introductionmentioning

confidence: 99%

“…1 Previous study mentioned that chromogenic anti-Xa assays seem to be useful to estimate the amount of betrixaban in plasma. 2 Nevertheless, the sensitivity of available tests is limited and improvement is needed to encompass the on-therapy range. 3 The on-therapy range of betrixaban is lower than the ones usually reported with other direct factor Xa inhibitors in chronic indications, 4 and thus, the current methodologies are not appropriate for the measurement of betrixaban.…”

Section: Introductionmentioning

confidence: 99%

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Development of new methodologies for the chromogenic estimation of betrixaban concentrations in plasma

Siriez

Evrard

Dogné

et al. 2019

Int J Lab Hematology

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Introduction Chromogenic anti‐Xa assays are the most appropriate tests to estimate the amount of betrixaban in plasma but the sensitivity of available tests is limited and improvements are needed to encompass the on‐therapy range. Methods Betrixaban was spiked at concentrations ranging from 0 to 500 ng/mL in plasma from healthy donors. Three commercial tests were used (Biophen®DiXaI®, STA®Liquid Anti‐Xa, and HemosIL®Liquid Anti‐Xa), and adaptation of their sample dilution scheme was performed. These new methodologies were also tested on plasma spiked with amounts of unfractionated heparin (UFH), low molecular weight heparins (LMWH), or fondaparinux covering the on‐therapy ranges to evaluate their sensitivity to indirect factor Xa inhibitors. Results Results showed concentration‐dependent decreases in OD/min inversely proportional to the dilutions. While modifications improve the sensitivity of these tests to betrixaban (eg, ½*OD/min of 502 ng/mL [95% CI: 495‐508 ng/mL] for Biophen®DiXaI® [1:50] is reduced to 51 ng/mL [95% CI: 50‐52 ng/mL] for improved Biophen®DiXaI® [1:5]), results also showed an increased sensitivity to indirect factor Xa inhibitors, except for Biophen®DiXaI® which remains insensitive to UFH and LMWH. Conclusions Results showed that the improvement of current chromogenic anti‐Xa methodologies enhances the sensitivity of these assays to betrixaban but also to indirect factor Xa inhibitors. This lack of specificity may lead to overestimation of betrixaban concentrations in patients bridged with heparins. To avoid this cross‐interference, the use of the Biophen®DiXaI® may be a solution except for fondaparinux which remains active even in the presence of the Biophen®DiXaI®’s specific buffer. For the other chromogenic assays, the conception and validation of specific buffer is required.

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Section: Discussionsupporting

confidence: 42%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Development of new methodologies for the chromogenic estimation of betrixaban concentrations in plasma

Siriez

Evrard

Dogné

et al. 2019

Int J Lab Hematology

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“…In general, direct thrombin inhibitors (dTI) tend to prolong the APTT more than the PT while direct FXa inhibitors (DXa) drugs prolong the PT to a greater extent than the aPTT. Likewise, one‐stage factor activity and inhibitor (ie, Bethesda) assays that are dependent on either the aPTT or PT are affected by DOAC presence and the degree of interference depends on reagent responsiveness, specific DOAC present, and DOAC concentration . DOAC‐affected one‐stage factor activity results spuriously underestimate factor activity which may or may not demonstrate nonparallelism.…”

Section: Doac Laboratory Interferencementioning

confidence: 99%

An update on laboratory assessment for direct oral anticoagulants (DOACs)

Gosselin

Adcock²,

Douxfils

2019

Int J Lab Hematology

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104

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The first direct oral anticoagulant (DOAC) to be approved for clinical use was dabigatran, a direct thrombin inhibitor, in 2010. Since that time, four additional DOACs, all direct anti‐Xa inhibitors, have been approved, including rivaroxaban, apixaban, edoxaban and betrixaban. Our knowledge about the effect of DOACs on laboratory testing, as well as the use of the laboratory for measuring DOACs has been an evolving process. These drugs are not routinely monitored in the same fashion as coumadin, but there is an increasing demand on the laboratory to have the capacity to adequately assess DOAC anticoagulant effect (pharmacodynamics) or levels (pharmacokinetics) in either emergent or the routine situations. This manuscript provides an update on laboratory guidance and progress of methods for measuring DOACs.

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The edoxaban‐M4 metabolite and measurement of edoxaban by chromogenic assays in human plasma

Siriez

Yıldız

Bouvy³

et al. 2022

Research and Practice in Thrombosis and Haemostasis

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Introduction:Edoxaban is the only anti-Xa inhibitor metabolized in pharmacologically active moiety that could interfere with chromogenic anti-Xa assays, especially in case of drug-drug interactions or physiological disorders. Materials and methods:We evaluated the contribution of the main metabolite of edoxaban, edoxaban-M4 (M4), in 79 plasma samples from patients taking edoxaban.The total anti-Xa activity was evaluated on three different chromogenic factor Xabased assays. Results were compared with a validated ultra-high-performance liquid chromatography coupled with a tandem mass spectrometry measurement. Edoxaban and its active M4 metabolite have also been spiked separately in normal pooled plasma to assess the sensitivity of chromogenic anti-Xa assays to both molecules individually.Results: Spiked edoxaban or M4 provided different slopes of linear regression models between chromogenic and chromatographic measurement (from 0.97 for STA Liquid Anti-Xa to 1.10 for Biophen Heparin LRT Low with edoxaban and from 0.70 for Biophen DiXaI High to 0.83 for Biophen Heparin LRT High, respectively). A positive correlation is observed between the increase of the ratio M4/edoxaban with the difference between chromogenic and chromatographic measurements. Conclusion:Edoxaban and M4 do not similarly impact chromogenic assays, leading to biased chromogenic estimations of ponderal concentrations. In patient samples, this impact is even more important at low concentrations or in the case of an increase in the M4/edoxaban ratio because of hepatic or renal impairments or in case of drug interactions. This study highlights the limitations and risks of error of expressing results in ponderal concentrations instead of global activity anti-Xa.

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Betrixaban: Impact on Routine and Specific Coagulation Assays—A Practical Laboratory Guide

Abstract: Adapted chromogenic anti-Xa assays are the most appropriate assays to estimate the concentration of betrixaban. Betrixaban significantly affects several haemostasis diagnostic tests and this needs to be taken into consideration when requesting and interpreting such tests.

Cited by 21 publications

References 25 publications

Development of new methodologies for the chromogenic estimation of betrixaban concentrations in plasma

Development of new methodologies for the chromogenic estimation of betrixaban concentrations in plasma

An update on laboratory assessment for direct oral anticoagulants (DOACs)

The edoxaban‐M4 metabolite and measurement of edoxaban by chromogenic assays in human plasma

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