Advertisement

International Journal of Hematology

, Volume 103, Issue 6, pp 665–672 | Cite as

Comparison of prothrombin time tests used in the monitoring of edoxaban and their evaluation as indicators of the reversal effect

  • Toshiaki Iba
  • Mari Emmi
  • Makoto Hiki
  • Masataka Nagayama
  • Koichiro Aihara
  • Yoko Tabe
  • Maiko Yuri
  • Akimichi Ohsaka
Original Article

Abstract

Clinical demand for the prompt assessment of the activity of direct-acting factor Xa inhibitors in the emergency care setting is increasing. In the present study, we examined whether prothrombin time (PT) tests can serve as a clinically useful indicator of anti-factor Xa activity. In the first series, the in vitro effect of edoxaban on PT was evaluated by spiking human plasma with edoxaban and measuring PT using three different commercial PT tests. In the second series, the reversal effect of prothrombin complex concentrates (PCC) and activated PCC (aPCC) in edoxaban-spiked plasma was evaluated. In the third series, PT of plasma samples from patients administered either 15 or 30 mg/day of edoxaban was assessed, and the results were compared with edoxaban concentrations determined by a calibrated anti-factor Xa activity assay. The spike test revealed that all PT reagents positively correlated with edoxaban. The sensitivity to edoxaban varied among the three reagents and Triniclot® Excel S showed the best performance. Prolonged PT by edoxaban was reversed by PCC and aPCC in a dose-dependent manner; however, complete reversal was not achieved. Positive correlation between anti-factor Xa activity and PT was shown in the clinical samples at the edoxaban range from 0 to >300 ng/mL.

Keywords

Prothrombin time Anti-factor Xa activity Edoxaban Prothrombin complex concentrates, activated prothrombin complex concentrates 

Notes

Compliance with ethical standard

Conflict of interest

Emmi M. works for Kyowa Medex Co. Ltd. The other authors state that they have no conflict of interests.

References

  1. 1.
    Lip GY, Lane DA. Stroke prevention in atrial fibrillation: a systematic review. JAMA. 2015;313:1950–62.CrossRefPubMedGoogle Scholar
  2. 2.
    Ghanny S, Crowther M. Treatment with novel oral anticoagulants: indications, efficacy and risks. Curr Opin Hematol. 2013;20:430–6.CrossRefPubMedGoogle Scholar
  3. 3.
    Pengo V, Crippa L, Falanga A, Finazzi G, Marongiu F, Palareti G, et al. Questions and answers on the use of dabigatran and perspectives on the use of other new oral anticoagulants in patients with atrial fibrillation. A consensus document of the Italian Federation of Thrombosis Centers (FCSA). Thromb Haemost. 2011;106:868–76.CrossRefPubMedGoogle Scholar
  4. 4.
    Rohde G. Determination of rivaroxaban–a novel, oral, direct Factor Xa inhibitor–in human plasma by high-performance liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2008;872:43–50.CrossRefPubMedGoogle Scholar
  5. 5.
    Tripodi A. Which test to use to measure the anticoagulant effect of rivaroxaban: the prothrombin time test. J Thromb Haemost. 2013;11:576–8.CrossRefPubMedGoogle Scholar
  6. 6.
    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;32:267–71.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Samama MM, Amiral J, Guinet C, Le Flem L, Seghatchian J. Monitoring plasma levels of factor Xa inhibitors: how, why and when? Expert Rev Hematol. 2013;6:155–64.CrossRefPubMedGoogle Scholar
  8. 8.
    Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369:2093–104.CrossRefPubMedGoogle Scholar
  9. 9.
    Büller HR, Décousus H, Grosso MA, Mercuri M, Middeldorp S, Prins MH, et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369:1406–15.CrossRefPubMedGoogle Scholar
  10. 10.
    Ruff CT, Giugliano RP, Braunwald E, Morrow DA, Murphy SA, Kuder JF, et al. Association between edoxaban dose, concentration, anti-Factor Xa activity, and outcomes: an analysis of data from the randomised, double-blind ENGAGE AF-TIMI 48 trial. Lancet. 2015;385:2288–95.CrossRefPubMedGoogle Scholar
  11. 11.
    Yin OQ, Miller R. Population pharmacokinetics and dose-exposure proportionality of edoxaban in healthy volunteers. Clin Drug Investig. 2014;34:743–52.CrossRefPubMedGoogle Scholar
  12. 12.
    Bauer KA. Targeted anti-anticoagulants. N Engl J Med. 2015;373:569–71.CrossRefPubMedGoogle Scholar
  13. 13.
    Pernod G, Albaladejo P, Godier A, Samama CM, Susen S, Gruel Y, et al. Management of major bleeding complications and emergency surgery in patients on long-term treatment with direct oral anticoagulants, thrombin or factor-Xa inhibitors: proposals of the working group on perioperative haemostasis (GIHP)—March 2013. Arch Cardiovasc Dis. 2013;106:382–93.CrossRefPubMedGoogle Scholar
  14. 14.
    Turecek PL, Va´radi K, Gritsch H, Schwarz HP. FEIBA: mode of action. Haemophilia. 2004;10(Suppl 2):3–9.CrossRefPubMedGoogle Scholar
  15. 15.
    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;32:267–71.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Crowther M, Crowther MA. Antidotes for novel oral anticoagulants: current status and future potential. Arterioscler Thromb Vasc Biol. 2015;35:1736–45.CrossRefPubMedGoogle Scholar
  17. 17.
    Siegal DM, Curnutte JT, Connolly SJ, Lu G, Conley PB, Wiens BL, et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med. 2015;373:2413–24.CrossRefPubMedGoogle Scholar
  18. 18.
    Ansell JE, Bakhru SH, Laulicht BE, Steiner SS, Grosso M, Brown K, et al. Use of PER977 to reverse the anticoagulant effect of edoxaban. N Engl J Med. 2014;371:2141–2.CrossRefPubMedGoogle Scholar
  19. 19.
    Cuker A, Husseinzadeh H. Laboratory measurement of the anticoagulant activity of edoxaban: a systematic review. J Thromb Thrombolysis. 2015;39:288–94.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Morishima Y, Kamisato C. Laboratory measurements of the oral direct factor Xa inhibitor edoxaban: comparison of prothrombin time, activated partial thromboplastin time, and thrombin generation assay. Am J Clin Pathol. 2015;143:241–7.CrossRefPubMedGoogle Scholar
  21. 21.
    Samama MM, Mendell J, Guinet C, Le Flem L, Kunitada S. In vitro study of the anticoagulant effects of edoxaban and its effect on thrombin generation in comparison to fondaparinux. Thromb Res. 2012;129:e77–82.CrossRefPubMedGoogle Scholar
  22. 22.
    Becker RC, Yang H, Barrett Y, Mohan P, Wang J, Wallentin L, Alexander JH. Chromogenic laboratory assays to measure the factor Xa-inhibiting properties of apixaban–an oral, direct and selective factor Xa inhibitor. J Thromb Thrombolysis. 2011;32:183–7.CrossRefPubMedGoogle Scholar
  23. 23.
    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;104:1263–71.CrossRefPubMedGoogle Scholar
  24. 24.
    Yuri M, Tabe M, Tsuchiya K, Sadatsuki R, Aoki J, Horii T, et al. Evaluation of factor Xa-specific chromogenic substrate assays and the determination of pharmacokinetics of fondaparinux. Clin Appl Thromb Hemost. 2015;pii:1076029615595878.Google Scholar
  25. 25.
    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;110:283–94.CrossRefPubMedGoogle Scholar
  26. 26.
    Douxfils J, Tamigniau A, Chatelain B, Chatelain C, Wallemacq P, Dogné JM, Mullier F. Comparison of calibrated chromogenic anti-Xa assay and PT tests with LC-MS/MS for the therapeutic monitoring of patients treated with rivaroxaban. Thromb Haemost. 2013;110:723–31.CrossRefPubMedGoogle Scholar
  27. 27.
    Kanemoto M, Kuhara H, Ueda T, Shinohara T, Oda T, Nakao F, et al. Association of apixaban therapy and prothrombin time in patients with atrial fibrillation. Circ J. 2014;78:2651–6.CrossRefPubMedGoogle Scholar
  28. 28.
    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;130:956–66.CrossRefPubMedGoogle Scholar
  29. 29.
    Ogata K, Mendell-Harary J, Tachibana M, Masumoto H, Oguma T, Kojima M, et al. Clinical safety, tolerability, pharmacokinetics, and pharmacodynamics of the novel factor Xa inhibitor edoxaban in healthy volunteers. J Clin Pharmacol. 2010;50:743–53.CrossRefPubMedGoogle Scholar
  30. 30.
    Majeed A, Schulman S. Bleeding and antidotes in new oral anticoagulants. Best Pract Res Clin Haematol. 2013;26:191–202.CrossRefPubMedGoogle Scholar
  31. 31.
    Hemphill JC III, Greenberg SM, Anderson CS, Becker K, Bendok BR, Cushman M, et al. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2015;46:2032–60.CrossRefPubMedGoogle Scholar
  32. 32.
    Fukuda T, Honda Y, Kamisato C, Morishima Y, Shibano T. Reversal of anticoagulant effects of edoxaban, an oral, direct factor Xa inhibitor, with haemostatic agents. Thromb Haemost. 2012;107:253–9.CrossRefPubMedGoogle Scholar
  33. 33.
    Silvain J, Hauguel M, Kerneis M, Collet JP, Montalescot G. Measuring and reversing the effect of non-vitamin K antagonist oral anticoagulants (NOACs). Circ J. 2015;79:289–91.CrossRefPubMedGoogle Scholar
  34. 34.
    Herzog E, Kaspereit F, Krege W, Doerr B, Mueller-Cohrs J, Pragst I, et al. Effective reversal of edoxaban-associated bleeding with four-factor prothrombin complex concentrate in a rabbit model of acute hemorrhage. Anesthesiology. 2015;122:387–98.CrossRefPubMedGoogle Scholar
  35. 35.
    Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369:2093–104.CrossRefPubMedGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2016

Authors and Affiliations

  • Toshiaki Iba
    • 1
  • Mari Emmi
    • 2
  • Makoto Hiki
    • 1
  • Masataka Nagayama
    • 3
  • Koichiro Aihara
    • 1
  • Yoko Tabe
    • 4
  • Maiko Yuri
    • 5
  • Akimichi Ohsaka
    • 5
  1. 1.Department of Emergency and Disaster MedicineJuntendo University School of MedicineTokyoJapan
  2. 2.Scientific and Technical Support DepartmentKyowa Medex Co., Ltd.TokyoJapan
  3. 3.Department of OrthopaedicsJuntendo University School of MedicineTokyoJapan
  4. 4.Department of Clinical Laboratory MedicineJuntendo University School MedicineTokyoJapan
  5. 5.Division of Clinical LaboratoryJuntendo University HospitalTokyoJapan

Personalised recommendations