Advertisement

Global thromboelastometry in patients receiving direct oral anticoagulants: the RO-DOA study

  • Maria Cristina VedovatiEmail author
  • Maria Giulia Mosconi
  • Federico Isidori
  • Giancarlo Agnelli
  • Cecilia Becattini
Article

Abstract

Rapidly available tests might be useful to measure the anticoagulant effect of direct oral anticoagulants (DOAs) in emergency situations as bleedings, surgery, or before thrombolysis. The aim of this study was to assess the effects of DOAs on global thromboelastometry (ROTEM). Coagulation parameters assessed at peak and trough in patients with non-valvular atrial fibrillation receiving apixaban, dabigatran or rivaroxaban at steady-state (patients) were compared to those of healthy volunteers (controls). Citrated blood samples were tested by ROTEM using diluted EXTEM assay, with and without the addition of an anti-FXa catcher, and using ECATEM-B, with and without the addition of an anti-FIIa catcher. Overall 30 patients (10 for each DOA) and 15 controls were included. The mean clotting time (CT) of patients at peak and trough were significantly higher compared to controls. The mean CT was significantly shortened after the addition of the anti-FXa catcher to apixaban (p = 0.005 for peak and p = 0.009 for trough) and to rivaroxaban samples (p = 0.005 for both peak and trough) and after the addition of anti-FIIa cather to dabigatran samples (p = 0.005 for both peak and trough). ROC curve analyses showed a good accuracy for CT and for CT/CT + catcher (CTc) in measuring dabigatran anticoagulant activity (AUC 1.000 and 0.993, respectively); for CT, CT/CTc and clot formation time (CFT)/CFT + catcher (CFTc) in measuring both apixaban activity (0.917, 0.880 and 0.880, respectively) and rivaroxaban activity (0.973, 0.987 and 0.860, respectively). In this study the use of ad-hoc designed reagents and catcher molecules was able to accurately identify DOAs activity at ROTEM.

Keywords

Anticoagulants Apixaban Dabigatran Emergencies Rivaroxaban Thrombelastography 

Notes

Acknowledgement

We thank Tem Innovations GmbH for providing reagents free of charge.

Compliance with ethical standards

Conflict of interest

G.A. reports consulting fees from Bayer, Boehringer Ingelheim, and Daiichi Sankyo, lecture fees from Bristol-Myers Squibb and Sanofi-Aventis. C.B. reports lecture fees from Boehringer Ingelheim, Daiichi Sankyo and Bristol-Myers Squibb. M.C.V., M.G.M. and F.I. have no disclosures.

References

  1. 1.
    Brinkman HJ (2015) Global assays and the management of oral anticoagulation. Thromb J 10(13):9CrossRefGoogle Scholar
  2. 2.
    Brown KS, Zahir H, Grosso MA, Lanz HJ, Mercuri MF, Levy JH (2016) Nonvitamin K antagonist oral anticoagulant activity: challenges in measurement and reversal. Crit Care 20:273CrossRefGoogle Scholar
  3. 3.
    Steffel J, Verhamme P, Potpara TS, Albaladejo P, Antz M, Desteghe L, Haeusler KG, Oldgren J, Reinecke H, Roldan-Schilling V, Rowell N, Sinnaeve P, Collins R, Camm AJ, Heidbüchel H, ESC Scientific Document Group (2018) The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur Heart J 39:1330–1393CrossRefGoogle Scholar
  4. 4.
    Barrett YC, Wang Z, Frost C, Shenker A (2010) Clinical laboratory measurement of direct factor Xa inhibitors: anti-Xa assay is preferable to prothrombin time assay. Thromb Haemost 104:1263–1271CrossRefGoogle Scholar
  5. 5.
    Douxfils J, Mullier F, Loosen C, Chatelain C, Chatelain B, Dogne JM (2012) Assessment of the impact of rivaroxaban on coagulation assays: laboratory recommendations for the monitoring of rivaroxaban and review of the literature. Thromb Res 130:956–966CrossRefGoogle Scholar
  6. 6.
    Morishima Y, Kamisato C (2015) 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 143:241–247CrossRefGoogle Scholar
  7. 7.
    Hillarp A, Baghaei F, Fagerberg Blixter I, Gustafsson KM, Stigendal L, Sten-Linder M et al (2011) Effects of the oral, direct factor Xa inhibitor rivaroxaban on commonly used coagulation assays. J Thromb Haemost 9:133–139CrossRefGoogle Scholar
  8. 8.
    Douxfils J, Chatelain C, Chatelain B, Dogne JM, Mullier F (2013) Impact of apixaban on routine and specific coagulation assays: a practical laboratory guide. Thromb Haemost 110:283–294CrossRefGoogle Scholar
  9. 9.
    Douxfils J, Chatelain B, Chatelain C, Dogne JM, Mullier F (2016) Edoxaban: impact on routine and specific coagulation assays. A practical laboratory guide. Thromb Haemost 115:368–381CrossRefGoogle Scholar
  10. 10.
    Ruff CT, Giugliano RP, Braunwald E, Morrow DA, Murphy SA, Kuder JF et al (2015) 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 385:2288–2295CrossRefGoogle Scholar
  11. 11.
    Samama MM, Contant G, Spiro TE, Perzborn E, Guinet C, Gourmelin Y et al (2012) Rivaroxaban Anti-Factor Xa Chromogenic Assay Field Trial Laboratories: evaluation of the anti-factor Xa chromogenic assay for the measurement of rivaroxaban plasma concentrations using calibrators and controls. Thromb Haemost 107:379–387CrossRefGoogle Scholar
  12. 12.
    Asmis LM, Alberio L, Angelillo-Scherrer A, Korte W, Mendez A, Reber G et al (2012) Rivaroxaban: quantification by anti-FXa assay and influence on coagulation tests: a study in 9 Swiss laboratories. Thromb Res 129(4):492–498CrossRefGoogle Scholar
  13. 13.
    Gouin-Thibault I, Flaujac C, Delavenne X, Quenet S, Horellou MH, Laporte S et al (2014) Assessment of apixaban plasma levels by laboratory tests: suitability of three anti-Xa assays. A multicentre French GEHT study. Thromb Haemost 111:240–248CrossRefGoogle Scholar
  14. 14.
    Lippi G, Ardissino D, Quintavalla R, Cervellin G (2014) Urgent monitoring of direct oral anticoagulants in patients with atrial fibrillation: a tentative approach based on routine laboratory tests. J Thromb Thrombolysis 38:269–274CrossRefGoogle Scholar
  15. 15.
    Spalding GJ, Hartrumpf M, Sierig T, Oesberg N, Kirschke CG, Albes JM (2007) Cost reduction of perioperative coagulation management in cardiac surgery: value of “bedside” thrombelastography (ROTEM). Eur J Cardiothorac Surg 31:1052–1057CrossRefGoogle Scholar
  16. 16.
    Schöchl H, Nienaber U, Hofer G, Voelckel W, Jambor C, Scharbert G et al (2010) Goal-directed coagulation management of major trauma patients using thromboelastometry (ROTEM)-guided administration of fibrinogen concentrate and prothrombin complex concentrate. Crit Care 14(2):R55CrossRefGoogle Scholar
  17. 17.
    Sølbeck S, Meyer MA, Johansson PI, Meyer AS, Cotton BA, Stensballe J et al (2014) Monitoring of dabigatran anticoagulation and its reversal in vitro by thrombelastography. Int J Cardiol 176:794–799CrossRefGoogle Scholar
  18. 18.
    Sølbeck S, Nilsson CU, Engström M, Ostrowski SR, Johansson PI (2014) Dabigatran and its reversal with recombinant factor VIIa and prothrombin complex concentrate: a Sonoclot in vitro study. Scand J Clin Lab Invest 74(7):591–598CrossRefGoogle Scholar
  19. 19.
    Bowry R, Fraser S, Archeval-Lao JM, Parker SA, Cai C, Rahbar MH, Grotta JC (2014) Thrombelastography detects the anticoagulant effect of rivaroxaban in patients with stroke. Stroke 45:880–883CrossRefGoogle Scholar
  20. 20.
    Casutt M, Konrad C, Schuepfer G (2012) Effect of rivaroxaban on blood coagulation using the viscoelastic coagulation test ROTEM™. Anaesthesist 61:948–953CrossRefGoogle Scholar
  21. 21.
    Mahamad S, Chaudhry H, Nisenbaum R, McFarlan A, Rizoli S, Ackery A, Sholzberg M (2019) Exploring the effect of factor Xa inhibitors on rotational thromboelastometry: a case series of bleeding patients. J Thromb Thrombolysis 47:272–279CrossRefGoogle Scholar
  22. 22.
    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 61:873–880CrossRefGoogle Scholar
  23. 23.
    Stangier J, Rathgen K, Stähle H, Gansser D, Roth W (2007) The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol 64:292–303CrossRefGoogle Scholar
  24. 24.
    Frost C, Nepal S, Wang J, Schuster A, Byon W, Boyd RA et al (2013) Safety, pharmacokinetics and pharmacodynamics of multiple oral doses of apixaban, a factor Xa inhibitor, in healthy subjects. Br J Clin Pharmacol 76:776–786CrossRefGoogle Scholar
  25. 25.
    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 53:185–197Google Scholar
  26. 26.
    Favaloro EJ, Lippi G (2015) Laboratory testing in the era of direct or non-vitamin K antagonist oral anticoagulants: a practical guide to measuring their activity and avoiding diagnostic errors. Semin Thromb Hemost 41:208–227CrossRefGoogle Scholar
  27. 27.
    Heidbuchel H, Verhamme P, Alings M, Antz M, Diener HC, Hacke W et al (2015) Updated European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation. Europace 17:1467–1507CrossRefGoogle Scholar
  28. 28.
    Pernod G, Albaladejo P, Godier A, Samama CM, Susen S, Gruel Y et al (2013) Working Group on Perioperative Haemostasis. 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 106:382–393CrossRefGoogle Scholar
  29. 29.
    Iapichino GE, Bianchi P, Ranucci M, Baryshnikova E (2017) Point-of-care coagulation tests monitoring of direct oral anticoagulants and their reversal therapy: state of the art. Semin Thromb Hemost 43:423–432CrossRefGoogle Scholar
  30. 30.
    Dias JD, Norem K, Doorneweerd DD, Thurer RL, Popovsky MA, Omert LA (2015) Use of thromboelastography (TEG) for detection of new oral anticoagulants. Arch Pathol Lab Med 139:665–673CrossRefGoogle Scholar
  31. 31.
    Seyve L, Richarme C, Polack B, Marlu R (2018) Impact of four direct oral anticoagulants on rotational thromboelastometry (ROTEM). Int J Lab Hematol 40:84–93CrossRefGoogle Scholar
  32. 32.
    Honickel M, Maron B, van Ryn J, Braunschweig T, ten Cate H, Spronk HM et al (2016) Therapy with activated prothrombin complex concentrate is effective in reducing dabigatran-associated blood loss in a porcine polytrauma model. Thromb Haemost 115:271–284CrossRefGoogle Scholar
  33. 33.
    Oswald E, Velik-Salchner C, Innerhofer P et al (2015) Results of rotational thromboelastometry, coagulation activation markers and thrombin generation assays in orthopedic patients during thromboprophylaxis with rivaroxaban and enoxaparin: a prospective cohort study. Blood Coagul Fibrinolysis 26:136–144CrossRefGoogle Scholar
  34. 34.
    Crapelli GB, Bianchi P, Isgrò G, Biondi A, De Vincentiis C, Ranucci M (2016) A case of fatal bleeding following emergency surgery of an ascending aorta intramural hematoma in a patient under dabigatran treatment. J Cardiothorac Vasc Anesth 4:1027–1031CrossRefGoogle Scholar
  35. 35.
    Herrmann R, Thom J, Wood A, Phillips M, Muhammad S, Baker R (2014) Thrombin generation using the calibrated automated thrombinoscope to assess reversibility of dabigatran and rivaroxaban. Thromb Haemost 111:989–995CrossRefGoogle Scholar
  36. 36.
    Henskens YMC, Gulpen AJW, van Oerle R, Wetzels R, Verhezen P, Spronk H et al (2018) Detecting clinically relevant rivaroxaban or dabigatran levels by routine coagulation tests or thromboelastography in a cohort of patients with atrial fibrillation. Thromb J 16:3CrossRefGoogle Scholar
  37. 37.
    Bliden KP, Chaudhary R, Mohammed N, Muresan AA, Lopez-Espina CG, Cohen E, Raviv G, Doubleday M, Zaman F, Mathew B, Tantry US, Gurbel PA (2017) Determination of non-Vitamin K oral anticoagulant (NOAC) effects using a new-generation thrombelastography TEG 6s system. J Thromb Thrombolysis 43:437–445CrossRefGoogle Scholar
  38. 38.
    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 151:127–138CrossRefGoogle Scholar
  39. 39.
    Ruiz Ortiz M, Muñiz J, Raña Míguez P, Roldán I, Marín F, Asunción Esteve-Pastor M, Cequier A, Martínez-Sellés M, Bertomeu V, Anguita M, FANTASIIA Study Investigators (2018) Inappropriate doses of direct oral anticoagulants in real-world clinical practice: prevalence and associated factors. A subanalysis of the FANTASIIA Registry. Europace 20:1577–1583CrossRefGoogle Scholar
  40. 40.
    Howard M, Lipshutz A, Roess B, Hawes E, Deyo Z, Burkhart JI, Moll S, Shilliday BB (2017) Identification of risk factors for inappropriate and suboptimal initiation of direct oral anticoagulants. J Thromb Thrombolysis 43:149–156CrossRefGoogle Scholar

Copyright information

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

Authors and Affiliations

  • Maria Cristina Vedovati
    • 1
    Email author
  • Maria Giulia Mosconi
    • 1
  • Federico Isidori
    • 1
  • Giancarlo Agnelli
    • 1
  • Cecilia Becattini
    • 1
  1. 1.Internal Vascular and Emergency Medicine - Stroke UnitUniversity of PerugiaPerugiaItaly

Personalised recommendations