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Thromb Haemost 2018; 118(07): 1203-1214
DOI: 10.1055/s-0038-1657772
Coagulation and Fibrinolysis
Georg Thieme Verlag KG Stuttgart · New York

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

Romain Siriez
1   University of Namur, Department of Pharmacy, Namur Thrombosis and Hemostasis Center (NTHC), Namur Research Institute for LIfe Sciences (NARILIS), Namur, Belgium
,
Jonathan Evrard
1   University of Namur, Department of Pharmacy, Namur Thrombosis and Hemostasis Center (NTHC), Namur Research Institute for LIfe Sciences (NARILIS), Namur, Belgium
,
Jean-Michel Dogné
1   University of Namur, Department of Pharmacy, Namur Thrombosis and Hemostasis Center (NTHC), Namur Research Institute for LIfe Sciences (NARILIS), Namur, Belgium
,
Lionel Pochet
1   University of Namur, Department of Pharmacy, Namur Thrombosis and Hemostasis Center (NTHC), Namur Research Institute for LIfe Sciences (NARILIS), Namur, Belgium
,
Damien Gheldof
1   University of Namur, Department of Pharmacy, Namur Thrombosis and Hemostasis Center (NTHC), Namur Research Institute for LIfe Sciences (NARILIS), Namur, Belgium
2   Qualiblood s.a., Namur, Belgium
,
Bernard Chatelain
3   Université catholique de Louvain, CHU UCL Namur, Namur Thrombosis and Hemostasis Center (NTHC), Namur Research Institute for Life Sciences (NARILIS), Hematology Laboratory, Yvoir, Belgium
,
François Mullier
3   Université catholique de Louvain, CHU UCL Namur, Namur Thrombosis and Hemostasis Center (NTHC), Namur Research Institute for Life Sciences (NARILIS), Hematology Laboratory, Yvoir, Belgium
,
Jonathan Douxfils
1   University of Namur, Department of Pharmacy, Namur Thrombosis and Hemostasis Center (NTHC), Namur Research Institute for LIfe Sciences (NARILIS), Namur, Belgium
2   Qualiblood s.a., Namur, Belgium
› Author Affiliations
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Publication History

13 February 2018

01 May 2018

Publication Date:
11 June 2018 (online)

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Abstract

Introduction Betrixaban is a novel direct oral factor Xa inhibitor approved by the Food and Drug Administration for prophylaxis of venous thromboembolism in adult patients hospitalized for an acute illness at risk for thromboembolic complications. Assessment of the anti-coagulant effect of betrixaban may be useful in some situations. Also, clinicians need to know how routine coagulation assays are influenced.

Objective The aim of this study is to determine which coagulation assay(s) should be used to assess the impact of betrixaban on haemostasis and provide laboratory guidance for their interpretation.

Materials and Methods Betrixaban was spiked at final concentrations ranging from 0 to 250 ng/mL in platelet-poor plasma. Different reagents from several manufacturers were tested and the impact of betrixaban on pro-thrombin time (PT), activated partial thromboplastin time (aPTT), dilute Russel viper venom time (dRVV-T), chromogenic anti-Xa assays, thrombin generation assay (TGA), and a large panel of haemostasis diagnostic tests has been assessed.

Results A concentration-dependent prolongation of aPTT, PT and dRVV-T is observed. The sensitivity mainly depends on the reagent. Chromogenic anti-Xa assays show high sensitivity depending on the reagent and/or the methodology. These assays applicable for other direct factor Xa inhibitors have to be adapted to obtain a relevant range of measurement. TGA may also be attractive to assess the anti-coagulant activity of betrixaban.

Conclusion 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.

Keywords

betrixaban - drug measurement - coagulation tests - guidance - factor Xa inhibitors

Supplementary Material

 

  • References

  • 1 Palladino M, Merli G, Thomson L. Evaluation of the oral direct factor Xa inhibitor - betrixaban. Expert Opin Investig Drugs 2013; 22 (11) 1465-1472
    CrossrefPubMedSearch in Google Scholar
  • 2 Food and Drug Administration. FDA approved betrixaban (BEVYXXA, Portola) for the prophylaxis of venous thromboembolism (VTE) in adult patients. 2017–06–23. Available at: https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm564422.htm . Accessed July 3, 2017
    PubMed
  • 3 Connolly SJ, Eikelboom J, Dorian P. , et al. Betrixaban compared with warfarin in patients with atrial fibrillation: results of a phase 2, randomized, dose-ranging study (Explore-Xa). Eur Heart J 2013; 34 (20) 1498-1505
    CrossrefPubMedSearch in Google Scholar
  • 4 Thoenes M, Minguet J, Bramlage K, Bramlage P, Ferrero C. Betrixaban - the next direct factor Xa inhibitor?. Expert Rev Hematol 2016; 9 (12) 1111-1117
    CrossrefPubMedSearch in Google Scholar
  • 5 Cohen AT, Harrington R, Goldhaber SZ. , et al. The design and rationale for the Acute Medically Ill Venous Thromboembolism Prevention with Extended Duration Betrixaban (APEX) study. Am Heart J 2014; 167 (03) 335-341
    CrossrefPubMedSearch in Google Scholar
  • 6 Cohen AT, Harrington RA, Goldhaber SZ. , et al; APEX Investigators. Extended thromboprophylaxis with betrixaban in acutely Ill medical patients. N Engl J Med 2016; 375 (06) 534-544
    CrossrefPubMedSearch in Google Scholar
  • 7 Chan NC, Bhagirath V, Eikelboom JW. Profile of betrixaban and its potential in the prevention and treatment of venous thromboembolism. Vasc Health Risk Manag 2015; 11: 343-351
    PubMedSearch in Google Scholar
  • 8 Douxfils J, Ageno W, Samama CM. , et al. Laboratory testing in patients treated with direct oral anticoagulants: a practical guide for clinicians. J Thromb Haemost 2018; 16 (02) 209-219
    CrossrefPubMedSearch in Google Scholar
  • 9 Douxfils J, Chatelain B, Chatelain C, Dogné JM, Mullier F. Edoxaban: impact on routine and specific coagulation assays. A practical laboratory guide. Thromb Haemost 2016; 115 (02) 368-381
    Thieme ConnectPubMedSearch in Google Scholar
  • 10 Douxfils J, Chatelain C, Chatelain B, Dogné JM, Mullier F. Impact of apixaban on routine and specific coagulation assays: a practical laboratory guide. Thromb Haemost 2013; 110 (02) 283-294
    Thieme ConnectPubMedSearch in Google Scholar
  • 11 Douxfils J, Mullier F, Loosen C, Chatelain C, Chatelain B, Dogné JM. Assessment of the impact of rivaroxaban on coagulation assays: laboratory recommendations for the monitoring of rivaroxaban and review of the literature. Thromb Res 2012; 130 (06) 956-966
    CrossrefPubMedSearch in Google Scholar
  • 12 Douxfils J, Mullier F, Robert S, Chatelain C, Chatelain B, Dogné JM. Impact of dabigatran on a large panel of routine or specific coagulation assays. Laboratory recommendations for monitoring of dabigatran etexilate. Thromb Haemost 2012; 107 (05) 985-997
    Thieme ConnectPubMedSearch in Google Scholar
  • 13 Mani H, Hesse C, Stratmann G, Lindhoff-Last E. Ex vivo effects of low-dose rivaroxaban on specific coagulation assays and coagulation factor activities in patients under real life conditions. Thromb Haemost 2013; 109 (01) 127-136
    Thieme ConnectPubMedSearch in Google Scholar
  • 14 Mani H, Hesse C, Stratmann G, Lindhoff-Last E. Rivaroxaban differentially influences ex vivo global coagulation assays based on the administration time. Thromb Haemost 2011; 106 (01) 156-164
    Thieme ConnectPubMedSearch in Google Scholar
  • 15 Freyburger G, Macouillard G, Labrouche S, Sztark F. Coagulation parameters in patients receiving dabigatran etexilate or rivaroxaban: two observational studies in patients undergoing total hip or total knee replacement. Thromb Res 2011; 127 (05) 457-465
    CrossrefPubMedSearch in Google Scholar
  • 16 Food and Drug Administration. Clinical Pharmacology and Biopharmaceutics review(s); 2016–10–23. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208383Orig1s000ClinPharmR.pdf . Accessed July 3, 2017
    PubMed
  • 17 Camici GG, Steffel J, Akhmedov A. , et al. Dimethyl sulfoxide inhibits tissue factor expression, thrombus formation, and vascular smooth muscle cell activation: a potential treatment strategy for drug-eluting stents. Circulation 2006; 114 (14) 1512-1521
    CrossrefPubMedSearch in Google Scholar
  • 18 Practical-Haemostasis.com - A Practical Guide to Laboratory Haemostasis, Dilute Russell's Viper Venom Time [DRVVT]. Available at: http://www.practical-haemostasis.com/Thrombophilia%20Tests/APS/drvvt.html . Accessed August 7, 2017
    PubMed
  • 19 Douxfils J, Gosselin RC. Laboratory assessment of direct oral anticoagulants. Semin Thromb Hemost 2017; 43 (03) 277-290
    Thieme ConnectPubMedSearch in Google Scholar
  • 20 Kitchens CS. To bleed or not to bleed? Is that the question for the PTT?. J Thromb Haemost 2005; 3 (12) 2607-2611
    CrossrefPubMedSearch in Google Scholar
  • 21 Gosselin RC, Adcock D, Hawes EM, Francart SJ, Grant RP, Moll S. Evaluating the use of commercial drug-specific calibrators for determining PT and APTT reagent sensitivity to dabigatran and rivaroxaban. Thromb Haemost 2015; 113 (01) 77-84
    Thieme ConnectPubMedSearch in Google Scholar
  • 22 Barrett YC, Wang Z, Frost C, Shenker A. Clinical laboratory measurement of direct factor Xa inhibitors: anti-Xa assay is preferable to prothrombin time assay. Thromb Haemost 2010; 104 (06) 1263-1271
    Thieme ConnectPubMedSearch in Google Scholar
  • 23 Hillarp A, Gustafsson KM, Faxälv L. , et al. Effects of the oral, direct factor Xa inhibitor apixaban on routine coagulation assays and anti-FXa assays. J Thromb Haemost 2014; 12 (09) 1545-1553
    CrossrefPubMedSearch in Google Scholar
  • 24 Moore GW. Recent guidelines and recommendations for laboratory detection of lupus anticoagulants. Semin Thromb Hemost 2014; 40 (02) 163-171
    Thieme ConnectPubMedSearch in Google Scholar
  • 25 Exner T, Ellwood L, Rubie J, Barancewicz A. Testing for new oral anticoagulants with LA-resistant Russells viper venom reagents. An in vitro study. Thromb Haemost 2013; 109 (04) 762-765
    Thieme ConnectPubMedSearch in Google Scholar
  • 26 Altman R, Gonzalez CD. Simple and rapid assay for effect of the new oral anticoagulant (NOAC) rivaroxaban: preliminary results support further tests with all NOACs. Thromb J 2014; 12 (01) 7
    CrossrefPubMedSearch in Google Scholar
  • 27 Altman R, Gonzalez CD. Supporting the use of a coagulometric method for rivaroxaban control: a hypothesis-generating study to define the safety cut-offs. Thromb J 2015; 13: 26
    CrossrefPubMedSearch in Google Scholar
  • 28 Testa S, Legnani C, Tripodi A. , et al. Poor comparability of coagulation screening test with specific measurement in patients receiving direct oral anticoagulants: results from a multicenter/multiplatform study. J Thromb Haemost 2016; 14 (11) 2194-2201
    CrossrefPubMedSearch in Google Scholar
  • 29 Smith SA, Comp PC, Morrissey JH. Phospholipid composition controls thromboplastin sensitivity to individual clotting factors. J Thromb Haemost 2006; 4 (04) 820-827
    CrossrefPubMedSearch in Google Scholar
  • 30 Smith SA, Comp PC, Morrissey JH. Traces of factor VIIa modulate thromboplastin sensitivity to factors V, VII, X, and prothrombin. J Thromb Haemost 2006; 4 (07) 1553-1558
    CrossrefPubMedSearch in Google Scholar
  • 31 Becker RC, Yang H, Barrett Y. , et al. Chromogenic laboratory assays to measure the factor Xa-inhibiting properties of apixaban–an oral, direct and selective factor Xa inhibitor. J Thromb Thrombolysis 2011; 32 (02) 183-187
    CrossrefPubMedSearch in Google Scholar
  • 32 Becker RC, Alexander JH, Newby LK. , et al. Effect of apixaban, an oral and direct factor Xa inhibitor, on coagulation activity biomarkers following acute coronary syndrome. Thromb Haemost 2010; 104 (05) 976-983
    Thieme ConnectPubMedSearch in Google Scholar
  • 33 Jensen KOF, Hansen SH, Goetze JP, Jesting A, Stensballe J, Hansen H. Preliminary report: measurement of apixaban and rivaroxaban in plasma from bleeding patients. Eur J Haematol 2017; 99 (05) 431-436
    CrossrefPubMedSearch in Google Scholar
  • 34 Samama MM, Amiral J, Guinet C, Perzborn E, Depasse F. An optimised, rapid chromogenic assay, specific for measuring direct factor Xa inhibitors (rivaroxaban) in plasma. Thromb Haemost 2010; 104 (05) 1078-1079
    Thieme ConnectPubMedSearch in Google Scholar
  • 35 Lessire S, Douxfils J, Pochet L. , et al. Estimation of rivaroxaban plasma concentrations in the perioperative setting in patients with or without heparin bridging. Clin Appl Thromb Hemost 2018; 24 (01) 129-138
    CrossrefPubMedSearch in Google Scholar
  • 36 Harenberg J, Krämer R, Giese C, Marx S, Weiss C, Wehling M. Determination of rivaroxaban by different factor Xa specific chromogenic substrate assays: reduction of interassay variability. J Thromb Thrombolysis 2011; 32 (03) 267-271
    CrossrefPubMedSearch in Google Scholar
  • 37 Jourdi G, Siguret V, Martin AC. , et al. Association rate constants rationalise the pharmacodynamics of apixaban and rivaroxaban. Thromb Haemost 2015; 114 (01) 78-86
    Thieme ConnectPubMedSearch in Google Scholar
  • 38 Robert S, Ghiotto J, Pirotte B. , et al. Is thrombin generation the new rapid, reliable and relevant pharmacological tool for the development of anticoagulant drugs?. Pharmacol Res 2009; 59 (03) 160-166
    CrossrefPubMedSearch in Google Scholar
  • 39 Gerotziafas GT, Baccouche H, Sassi M. , et al. Optimisation of the assays for the measurement of clotting factor activity in the presence of rivaroxaban. Thromb Res 2012; 129 (01) 101-103
    CrossrefPubMedSearch in Google Scholar
  • 40 Ratzinger F, Lang M, Belik S. , et al. Lupus-anticoagulant testing at NOAC trough levels. Thromb Haemost 2016; 116 (02) 235-240
    Thieme ConnectPubMedSearch in Google Scholar
  • 41 Exner T, Michalopoulos N, Pearce J, Xavier R, Ahuja M. Simple method for removing DOACs from plasma samples. Thromb Res 2018; 163: 117-122
    CrossrefPubMedSearch in Google Scholar