Advertisement

Determination of the cut-off prothrombin time to estimate plasma rivaroxaban overdose status

  • Bohyun Kim
  • Seongsoo JangEmail author
  • Yu-Jin Lee
  • Nuree Park
  • Young-Uk Cho
  • Chan-Jeoung Park
Article
  • 16 Downloads

Abstract

Laboratory monitoring of rivaroxaban (RIV) is required under certain conditions. Mass spectrometry and anti-factor Xa assays are the recommended methods, which may not be readily available. Prothrombin time (PT) is the most widely used and simple coagulation assay. To set the cutoff PT and international normalized ratio (INR) to estimate RIV overdose status. RIV-spiked pooled normal plasma was used. PT test was performed using a CA-7000 coagulometer and Thromborel S reagent. The precise measurement of RIV concentration at the cut-off PT was evaluated according to the Clinical and Laboratory Standard Institute (CLSI) EP12-A2 guideline. The RIV concentration at 275 ng/mL was analyzed using 40 replicates. Receiver operating characteristic (ROC) analysis was performed to determine the cutoff value for the determination of RIV potential overdose status. An imprecision estimation of PT was conducted with 220.00 ng/mL, 247.50 ng/mL, 261.25 ng/mL, 288.75 ng/mL, 302.50 ng/mL and 330.00 ng/mL concentrations of RIV in 60 replicates. According to the ROC analysis, the cutoff clotting times and INR values to determine the overdose status of RIV were 13.45 s and 1.39. With these values, there was a 92.6% probability that plasma samples with RIV concentration ≤ 247.50 ng/mL yielded consistently negative (on-therapy dose) results, and those with ≥ 302.50 ng/mL yield consistent positive (potential overdose) results using our PT assay. PT with a reliable cutoff clotting time and INR can be used to determine the potential overdose status of RIV to facilitate the diagnosis and treatment by controlling the dose.

Keywords

Prothrombin time Rivaroxaban Cutoff Overdose Anticoagulant 

Notes

Author contributions

B. Kim performed research, analyzed and interpreted data, performed statistical analysis, and wrote the manuscript. S. Jang designed research, analyzed and interpreted data. Y.J. Lee and N. Park performed research. Y.U. Cho and C.J. Park analyzed and interpreted data.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest with the contents of this article.

References

  1. 1.
    Adcock DM, Gosselin R (2015) Direct oral anticoagulants (DOACs) in the laboratory: 2015 review. Thromb Res 136:7–12.  https://doi.org/10.1016/j.thromres.2015.05.001 CrossRefGoogle Scholar
  2. 2.
    Levy JH, Spyropoulos AC, Samama CM, Douketis J (2014) Direct oral anticoagulants: new drugs and new concepts. JACC Cardiovasc Interv 7(12):1333–1351.  https://doi.org/10.1016/j.jcin.2014.06.014 CrossRefGoogle Scholar
  3. 3.
    Lippi G, Favaloro EJ (2015) Recent guidelines and recommendations for laboratory assessment of the direct oral anticoagulants (DOACs): is there consensus? Clin Chem Lab Med/FESCC 53(2):185–197.  https://doi.org/10.1515/cclm-2014-0767 Google Scholar
  4. 4.
    Cuker A, Siegal DM, Crowther MA, Garcia DA (2014) Laboratory measurement of the anticoagulant activity of the non-vitamin K oral anticoagulants. J Am Coll Cardiol 64(11):1128–1139.  https://doi.org/10.1016/j.jacc.2014.05.065 CrossRefGoogle Scholar
  5. 5.
    Schmitz EM, Boonen K, van den Heuvel DJ, van Dongen JL, Schellings MW, Emmen JM, van der Graaf F, Brunsveld L, van de Kerkhof D (2014) Determination of dabigatran, rivaroxaban and apixaban by ultra-performance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) and coagulation assays for therapy monitoring of novel direct oral anticoagulants. J Thromb Haemost 12(10):1636–1646.  https://doi.org/10.1111/jth.12702 CrossRefGoogle Scholar
  6. 6.
    Gosselin RC, Adcock DM, Bates SM, Douxfils J, Favaloro EJ, Gouin-Thibault I, Guillermo C, Kawai Y, Lindhoff-Last E, Kitchen S (2018) International Council for Standardization in Haematology (ICSH) recommendations for laboratory measurement of direct oral anticoagulants. Thromb Haemost 118(3):437–450.  https://doi.org/10.1055/s-0038-1627480 CrossRefGoogle Scholar
  7. 7.
    Tripodi A (2013) Which test to use to measure the anticoagulant effect of rivaroxaban: the prothrombin time test. J Thromb Haemost 11(4):576–578.  https://doi.org/10.1111/jth.12166 CrossRefGoogle Scholar
  8. 8.
    Samama MM, Martinoli JL, LeFlem L, Guinet C, Plu-Bureau G, Depasse F, Perzborn E (2010) Assessment of laboratory assays to measure rivaroxaban—an oral, direct factor Xa inhibitor. Thromb Haemost 103(4):815–825.  https://doi.org/10.1160/th09-03-0176 CrossRefGoogle Scholar
  9. 9.
    Samama MM, Contant G, Spiro TE, Perzborn E, Flem LL, Guinet C, Gourmelin Y, Martinoli JL, Rivaroxaban Prothrombin Time Field Trial Laboratories (2012) Evaluation of the prothrombin time for measuring rivaroxaban plasma concentrations using calibrators and controls: results of a multicenter field trial. Clin Appl Thromb/Hemost Off J Int Acad Clin Appl Thromb/Hemost 18(2):150–158.  https://doi.org/10.1177/1076029611426282 CrossRefGoogle Scholar
  10. 10.
    Camici GG, Steffel J, Akhmedov A, Schafer N, Baldinger J, Schulz U, Shojaati K, Matter CM, Yang Z, Luscher TF, Tanner FC (2006) Dimethyl sulfoxide inhibits tissue factor expression, thrombus formation, and vascular smooth muscle cell activation: a potential treatment strategy for drug-eluting stents. Circulation 114(14):1512–1521.  https://doi.org/10.1161/circulationaha.106.638460 CrossRefGoogle Scholar
  11. 11.
    Kubitza D, Becka M, Wensing G, Voith B, Zuehlsdorf M (2005) Safety, pharmacodynamics, and pharmacokinetics of BAY 59-7939—an oral, direct Factor Xa inhibitor—after multiple dosing in healthy male subjects. Eur J Clin Pharmacol 61(12):873–880.  https://doi.org/10.1007/s00228-005-0043-5 CrossRefGoogle Scholar
  12. 12.
    Clinical and Laboratory Standard Institute (2008) User protocol for evaluation of qualitative test performance; Approved Guideline-Second Edition (EP12-A2). CLSI, WayneGoogle Scholar
  13. 13.
    Mueck W, Eriksson BI, Bauer KA, Borris L, Dahl OE, Fisher WD, Gent M, Haas S, Huisman MV, Kakkar AK, Kalebo P, Kwong LM, Misselwitz F, Turpie AG (2008) Population pharmacokinetics and pharmacodynamics of rivaroxaban—an oral, direct factor Xa inhibitor—in patients undergoing major orthopaedic surgery. Clin Pharmacokinet 47(3):203–216.  https://doi.org/10.2165/00003088-200847030-00006 CrossRefGoogle Scholar
  14. 14.
    Kubitza D, Becka M, Zuehlsdorf M, Mueck W (2006) Effect of food, an antacid, and the H2 antagonist ranitidine on the absorption of BAY 59-7939 (rivaroxaban), an oral, direct factor Xa inhibitor, in healthy subjects. J Clin Pharmacol 46(5):549–558.  https://doi.org/10.1177/0091270006286904 CrossRefGoogle Scholar
  15. 15.
    Baglin T, Hillarp A, Tripodi A, Elalamy I, Buller H, Ageno W (2013) Measuring Oral Direct Inhibitors (ODIs) of thrombin and factor Xa: a recommendation from the Subcommittee on Control of Anticoagulation of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. J Thromb Haemost.  https://doi.org/10.1111/jth.12149 Google Scholar
  16. 16.
    Samuelson BT, Cuker A, Siegal DM, Crowther M, Garcia DA (2017) Laboratory assessment of the anticoagulant activity of direct oral anticoagulants: a systematic review. Chest 151(1):127–138.  https://doi.org/10.1016/j.chest.2016.08.1462 CrossRefGoogle Scholar
  17. 17.
    Douxfils J, Gosselin RC (2017) Laboratory assessment of direct oral anticoagulants. Semin Thromb Haemost 43(3):277–290.  https://doi.org/10.1055/s-0036-1597296 CrossRefGoogle Scholar
  18. 18.
    Tripodi A, Ageno W, Ciaccio M, Legnani C, Lippi G, Manotti C, Marcucci R, Moia M, Morelli B, Poli D, Steffan A, Testa S (2018) Position Paper on laboratory testing for patients on direct oral anticoagulants. A Consensus Document from the SISET, FCSA, SIBioC and SIPMeL. Blood Transfus 16(5):462–470.  https://doi.org/10.2450/2017.0124-17 Google Scholar
  19. 19.
    Dale BJ, Chan NC, Eikelboom JW (2015) Laboratory measurement of the direct oral anticoagulants. Br J Haematol.  https://doi.org/10.1111/bjh.13810 Google Scholar
  20. 20.
    Breuer G, Weiss DR, Ringwald J (2014) ‘New’ direct oral anticoagulants in the perioperative setting. Curr Opin Anaesthesiol 27(4):409–419.  https://doi.org/10.1097/aco.0000000000000100 CrossRefGoogle Scholar
  21. 21.
    Kim B, Jang S, Lee YJ, Park N, Cho YU, Park CJ (2019) The rivaroxaban-adjusted normalized ratio: use of the prothrombin time to monitor the therapeutic effect of rivaroxaban. 76(3):122–128.  https://doi.org/10.1080/09674845.2019.1605648
  22. 22.
    Park SH, Seo YH, Park PW, Kim KH, Seo JY, Lee HT (2019) Evaluation of global laboratory methods and establishing on-therapy ranges for monitoring apixaban and rivaroxaban: experience at a single institution. 33(5):e22869.  https://doi.org/10.1002/jcla.22869
  23. 23.
    Tripodi A, Chantarangkul V, Guinet C, Samama MM (2011) The International Normalized Ratio calibrated for rivaroxaban has the potential to normalize prothrombin time results for rivaroxaban-treated patients: results of an in vitro study. J Thromb Haemost 9(1):226–228.  https://doi.org/10.1111/j.1538-7836.2010.04106.x CrossRefGoogle Scholar
  24. 24.
    Harenberg J, Marx S, Kramer R, Giese C, Weiss C (2011) Determination of an international sensitivity index of thromboplastin reagents using a WHO thromboplastin as calibrator for plasma spiked with rivaroxaban. Blood Coagul Fibrinolysis Int J Haemost Thromb 22(8):637–641.  https://doi.org/10.1097/mbc.0b013e328349f1d6 CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Laboratory Medicine, Soonchunhyang University Cheonan HospitalSoonchunhyang University College of MedicineCheonanKorea
  2. 2.Department of Laboratory MedicineUniversity of Ulsan College of Medicine and Asan Medical CenterSeoulKorea
  3. 3.Asan Clinical Research CenterSeoulKorea
  4. 4.Department of Laboratory MedicineUniversity of Ulsan College of Medicine and Asan Medical CenterSeoulKorea

Personalised recommendations