Thromb Haemost 2018; 118(03): 437-450
DOI: 10.1055/s-0038-1627480
Consensus Document
Schattauer GmbH Stuttgart

International Council for Standardization in Haematology (ICSH) Recommendations for Laboratory Measurement of Direct Oral Anticoagulants

Robert C. Gosselin
,
Dorothy M. Adcock
,
Shannon M. Bates
,
Jonathan Douxfils
,
Emmanuel J. Favaloro
,
Isabelle Gouin-Thibault
,
Cecilia Guillermo
,
Yohko Kawai
,
Edelgard Lindhoff-Last
,
Steve Kitchen
Further Information

Publication History

28 August 2017

21 December 2017

Publication Date:
12 February 2018 (online)

Abstract

This guidance document was prepared on behalf of the International Council for Standardization in Haematology (ICSH) for providing haemostasis-related guidance documents for clinical laboratories. This inaugural coagulation ICSH document was developed by an ad hoc committee, comprised of international clinical and laboratory direct acting oral anticoagulant (DOAC) experts. The committee developed consensus recommendations for laboratory measurement of DOACs (dabigatran, rivaroxaban, apixaban and edoxaban), which would be germane for laboratories assessing DOAC anticoagulation. This guidance document addresses all phases of laboratory DOAC measurements, including pre-analytical (e.g. preferred time sample collection, preferred sample type, sample stability), analytical (gold standard method, screening and quantifying methods) and post analytical (e.g. reporting units, quality assurance). The committee addressed the use and limitations of screening tests such as prothrombin time, activated partial thromboplastin time as well as viscoelastic measurements of clotting blood and point of care methods. Additionally, the committee provided recommendations for the proper validation or verification of performance of laboratory assays prior to implementation for clinical use, and external quality assurance to provide continuous assessment of testing and reporting method.

 
  • References

  • 1 European Medicines Agency - Pradaxa - Procedure EMEA/H/C/829. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-Public_assessment_report/human/000829/WC500041062.pdf . Accessed February 28, 2017
  • 2 Dale BJ, Chan NC, Eikelboom JW. Laboratory measurement of the direct oral anticoagulants. Br J Haematol 2016; 172 (03) 315-336
  • 3 Douxfils J, Gosselin RC. Laboratory assessment of direct oral anticoagulants (DOACs). Semin Thromb Hemost 2017; 43 (03) 277-290
  • 4 Pradaxa [package insert]. Boehringer Ingelheim Pharmaceuticals Inc, Ingelheim am Rhein, Germany. Revised November 2015. Accessed December 31, 2016
  • 5 Blech S, Ebner T, Ludwig-Schwellinger E, Stangier J, Roth W. The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans. Drug Metab Dispos 2008; 36 (02) 386-399
  • 6 Wienen W, Stassen JM, Priepke H, Ries UJ, Hauel N. In-vitro profile and ex-vivo anticoagulant activity of the direct thrombin inhibitor dabigatran and its orally active prodrug, dabigatran etexilate. Thromb Haemost 2007; 98 (01) 155-162
  • 7 Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet 2008; 47 (05) 285-295
  • 8 Stangier J, Rathgen K, Stähle H, Gansser D, Roth W. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol 2007; 64 (03) 292-303
  • 9 Samuelson BT, Cuker A. Measurement and reversal of the direct oral anticoagulants. Blood Rev 2017; 31 (01) 77-84
  • 10 Reilly PA, Lehr T, Haertter S. , et al; RE-LY Investigators. The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy). J Am Coll Cardiol 2014; 63 (04) 321-328
  • 11 Perzborn E, Strassburger J, Wilmen A. , et al. In vitro and in vivo studies of the novel antithrombotic agent BAY 59-7939–an oral, direct Factor Xa inhibitor. J Thromb Haemost 2005; 3 (03) 514-521
  • 12 Depasse F, Busson J, Mnich J, Le Flem L, Gerotziafas GT, Samama MM. Effect of BAY 59–7939—a novel, oral, direct Factor Xa inhibitor - on clot-bound Factor Xa activity in vitro. J Thromb Haemost 2005;3(Suppl 1):Abstract P1104
  • 13 Kubitza D, Perzborn E, Berkowitz SD. The discovery of rivaroxaban: translating preclinical assessments into clinical practice. Front Pharmacol 2013; 4: 145
  • 14 European Medicines Agency. Xarelto - Summary of Product Characteristics. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000944/WC500057108.pdf . Accessed January 15, 2017
  • 15 Mueck W, Stampfuss J, Kubitza D, Becka M. Clinical pharmacokinetic and pharmacodynamic profile of rivaroxaban. Clin Pharmacokinet 2014; 53 (01) 1-16
  • 16 Food and Drug Administration. Xarelto—Prescribing Information. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202439s001lbl.pdf . Accessed January 15, 2017
  • 17 Zhang D, He K, Raghavan N. , et al. Comparative metabolism of 14C-labeled apixaban in mice, rats, rabbits, dogs, and humans. Drug Metab Dispos 2009; 37 (08) 1738-1748
  • 18 Mani H, Lindhoff-Last E. New oral anticoagulants in patients with nonvalvular atrial fibrillation: a review of pharmacokinetics, safety, efficacy, quality of life, and cost effectiveness. Drug Des Devel Ther 2014; 8: 789-798
  • 19 European Medicines Agency. Eliquis - Summary of Product Characteristics. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002148/WC500107728.pdf . Accessed January 15, 2017
  • 20 Furugohri T, Isobe K, Honda Y. , et al. DU-176b, a potent and orally active factor Xa inhibitor: in vitro and in vivo pharmacological profiles. J Thromb Haemost 2008; 6 (09) 1542-1549
  • 21 Ogata K, Mendell-Harary J, Tachibana M. , et al. Clinical safety, tolerability, pharmacokinetics, and pharmacodynamics of the novel factor Xa inhibitor edoxaban in healthy volunteers. J Clin Pharmacol 2010; 50 (07) 743-753
  • 22 Giugliano RP, Ruff CT, Braunwald E. , et al; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013; 369 (22) 2093-2104
  • 23 Büller HR, Décousus H, Grosso MA. , et al; Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 2013; 369 (15) 1406-1415
  • 24 Fuji T, Wang CJ, Fujita S, Kawai Y, Kimura T, Tachibana S. Safety and efficacy of edoxaban, an oral factor Xa inhibitor, for thromboprophylaxis after total hip arthroplasty in Japan and Taiwan. J Arthroplasty 2014; 29 (12) 2439-2446
  • 25 Fuji T, Wang CJ, Fujita S. , et al. Safety and efficacy of edoxaban, an oral factor Xa inhibitor, versus enoxaparin for thromboprophylaxis after total knee arthroplasty: the STARS E-3 trial. Thromb Res 2014; 134 (06) 1198-1204
  • 26 Weitz JI, Connolly SJ, Patel I. , et al. Randomised, parallel-group, multicentre, multinational phase 2 study comparing edoxaban, an oral factor Xa inhibitor, with warfarin for stroke prevention in patients with atrial fibrillation. Thromb Haemost 2010; 104 (03) 633-641
  • 27 Ruff CT, Giugliano RP, Braunwald E. , 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 (9984): 2288-2295
  • 28 Verhamme P, Wells PS, Segers A. , et al. Dose reduction of edoxaban preserves efficacy and safety for the treatment of venous thromboembolism. An analysis of the randomised, double-blind HOKUSAI VTE trial. Thromb Haemost 2016; 116 (04) 747-753
  • 29 Fuji T, Fujita S, Kawai Y. , et al. Safety and efficacy of edoxaban in patients undergoing hip fracture surgery. Thromb Res 2014; 133 (06) 1016-1022
  • 30 Gosselin RC, Adcock DM. The laboratory's 2015 perspective on direct oral anticoagulant testing. J Thromb Haemost 2016; 14 (05) 886-893
  • 31 Adams Jr HP, del Zoppo G, Alberts MJ, Bhatt DL, Brass L, Furlan A, Grubb RL, Higashida RT, Jauch EC, Kidwell C, Lyden PD, Morgenstern LB, Qureshi AI, Rosenwasser RH, Scott PA, Wijdicks EF. ; American Heart Association; American Stroke Association Stroke Council; Clinical Cardiology Council; Cardiovascular Radiology and Intervention Council; Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups. Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: the American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Stroke 2007; 38 (05) 1655-711 . Epub 2007 Apr 12. Erratum in: Stroke. 2007 Jun;38(6)
  • 32 Harenberg J, Krämer S, Du S. , et al. Measurement of rivaroxaban and apixaban in serum samples of patients. Eur J Clin Invest 2014; 44 (08) 743-752
  • 33 McGrail R, Revsholm J, Nissen PH, Grove EL, Hvas AM. Stability of direct oral anticoagulants in whole blood and plasma from patients in steady state treatment. Thromb Res 2016; 148: 107-110
  • 34 Gous T, Couchman L, Patel JP, Paradzai C, Arya R, Flanagan RJ. Measurement of the direct oral anticoagulants apixaban, dabigatran, edoxaban, and rivaroxaban in human plasma using turbulent flow liquid chromatography with high-resolution mass spectrometry. Ther Drug Monit 2014; 36 (05) 597-605
  • 35 Lessire S, Douxfils J, Baudar J. , et al. Is Thrombin Time useful for the assessment of dabigatran concentrations? An in vitro and ex vivo study. Thromb Res 2015; 136 (03) 693-696
  • 36 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
  • 37 Harenberg J, Marx S, Diener H-C. , et al. Comparison of efficacy and safety of dabigatran, rivaroxaban and apixaban in patients with atrial fibrillation using network meta-analysis. Int Angiol 2012; 31 (04) 330-339
  • 38 van Ryn J, Stangier J, Haertter S. , et al. Dabigatran etexilate--a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 2010; 103 (06) 1116-1127
  • 39 Samama MM, Contant G, Spiro TE. , et al; Rivaroxaban Prothrombin Time Field Trial Laboratories. Evaluation of the prothrombin time for measuring rivaroxaban plasma concentrations using calibrators and controls: results of a multicenter field trial. Clin Appl Thromb Hemost 2012; 18 (02) 150-158
  • 40 Douxfils J, Mullier F, Loosen C, Chatelain C, Chatelain B, Dogné J-M. 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
  • 41 Douxfils J, Mullier F, Robert S, Chatelain C, Chatelain B, Dogné J-M. 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
  • 42 Halbmayer W-M, Weigel G, Quehenberger P. , et al. Interference of the new oral anticoagulant dabigatran with frequently used coagulation tests. Clin Chem Lab Med 2012; 50 (09) 1601-1605
  • 43 Hillarp A, Baghaei F, Fagerberg Blixter I. , et al. Effects of the oral, direct factor Xa inhibitor rivaroxaban on commonly used coagulation assays. J Thromb Haemost 2011; 9 (01) 133-139
  • 44 Mani H. Interpretation of coagulation test results under direct oral anticoagulants. Int J Lab Hematol 2014; 36 (03) 261-268
  • 45 Kitchen S, Gray E, Mackie I, Baglin T, Makris M. ; BCSH Committee. Measurement of non-coumarin anticoagulants and their effects on tests of Haemostasis: Guidance from the British Committee for Standards in Haematology. Br J Haematol 2014; 166 (06) 830-841
  • 46 Van Blerk M, Bailleul E, Chatelain B. , et al. Influence of dabigatran and rivaroxaban on routine coagulation assays. A nationwide Belgian survey. Thromb Haemost 2015; 113 (01) 154-164
  • 47 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
  • 48 Hawes EM, Deal AM, Funk-Adcock D. , et al. Performance of coagulation tests in patients on therapeutic doses of dabigatran: a cross-sectional pharmacodynamic study based on peak and trough plasma levels. J Thromb Haemost 2013; 11 (08) 1493-1502
  • 49 Gouin-Thibault I, Flaujac C, Delavenne X. , et al. Assessment of apixaban plasma levels by laboratory tests: suitability of three anti-Xa assays. A multicentre French GEHT study. Thromb Haemost 2014; 111 (02) 240-248
  • 50 Douxfils J, Chatelain C, Chatelain B, Dogné J-M, Mullier F. Impact of apixaban on routine and specific coagulation assays: a practical laboratory guide. Thromb Haemost 2013; 110 (02) 283-294
  • 51 Bonar R, Favaloro EJ, Mohammed S. , et al. The effect of the direct factor Xa inhibitors apixaban and rivaroxaban on haemostasis tests: a comprehensive assessment using in vitro and ex vivo samples. Pathology 2016; 48 (01) 60-71
  • 52 Cuker A, Siegal DM, Crowther MA, Garcia DA. Laboratory measurement of the anticoagulant activity of the non-vitamin K oral anticoagulants. J Am Coll Cardiol 2014; 64 (11) 1128-1139
  • 53 Douxfils J, Chatelain B, Chatelain C, Dogné J-M, Mullier F. Edoxaban: impact on routine and specific coagulation assays. A practical laboratory guide. Thromb Haemost 2016; 115 (02) 368-381
  • 54 Zafar MU, Vorchheimer DA, Gaztanaga J. , et al. Antithrombotic effects of factor Xa inhibition with DU-176b: Phase-I study of an oral, direct factor Xa inhibitor using an ex-vivo flow chamber. Thromb Haemost 2007; 98 (04) 883-888
  • 55 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 (02) 241-247
  • 56 Helin TA, Pakkanen A, Lassila R, Joutsi-Korhonen L. Laboratory assessment of novel oral anticoagulants: method suitability and variability between coagulation laboratories. Clin Chem 2013; 59 (05) 807-814
  • 57 Tripodi A, Chantarangkul V, Guinet C, Samama MM. 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 2011; 9 (01) 226-228
  • 58 Jabet A, Stepanian A, Golmard JL, Flaujac C, Joly BS, Gouin-Thibault I, Siguret V. Are Screening Tests Reliable to Rule Out Direct Oral Anticoagulant Plasma Levels at Various Thresholds (30, 50, or 100 ng/mL) in Emergency Situations?. Chest 2018; 153 (01) 288-290
  • 59 Francart SJ, Hawes EM, Deal AM. , et al. Performance of coagulation tests in patients on therapeutic doses of rivaroxaban. A cross-sectional pharmacodynamic study based on peak and trough plasma levels. Thromb Haemost 2014; 111 (06) 1133-1140
  • 60 Tsutsumi Y, Shimono J, Ohhigashi H, Ito S, Shiratori S, Teshima T. ; Int J Lab. Analysis of the influence of dabigatran on coagulation factors and inhibitors. Int J Lab Hematol 2015; 37 (02) 225-230
  • 61 Gosselin RC, Adcock DM. Comment: analysis of the influence of dabigatran on coagulation factors and inhibitors. Int J Lab Hematol 2016; 38 (01) e4
  • 62 Gosselin R, Grant RP, Adcock DM. Comparison of the effect of the anti-Xa direct oral anticoagulants apixaban, edoxaban, and rivaroxaban on coagulation assays. Int J Lab Hematol 2016; 38 (05) 505-513
  • 63 Dager WE, Gosselin RC, Kitchen S, Dwyre D. Dabigatran effects on the international normalized ratio, activated partial thromboplastin time, thrombin time, and fibrinogen: a multicenter, in vitro study. Ann Pharmacother 2012; 46 (12) 1627-1636
  • 64 Dias JD, Norem K, Doorneweerd DD, Thurer RL, Popovsky MA, Omert LA. Use of thromboelastography (TEG) for detection of new oral anticoagulants. Arch Pathol Lab Med 2015; 139 (05) 665-673
  • 65 Herrmann R, Thom J, Wood A, Phillips M, Muhammad S, Baker R. Thrombin generation using the calibrated automated thrombinoscope to assess reversibility of dabigatran and rivaroxaban. Thromb Haemost 2014; 111 (05) 989-995
  • 66 Adelmann D, Wiegele M, Wohlgemuth RK. , et al. Measuring the activity of apixaban and rivaroxaban with rotational thrombelastometry. Thromb Res 2014; 134 (04) 918-923
  • 67 Chojnowski K, Górski T, Robak M, Treliński J. Effects of rivaroxaban therapy on ROTEM coagulation parameters in patients with venous thromboembolism. Adv Clin Exp Med 2015; 24 (06) 995-1000
  • 68 Körber MK, Langer E, Köhr M, Wernecke KD, Korte W, von Heymann C. In vitro and ex vivo measurement of prophylactic dabigatran concentrations with a new ecarin-based thromboelastometry test. Transfus Med Hemother 2017; 44 (02) 100-105
  • 69 Fontana P, Alberio L, Angelillo-Scherrer A. , et al. Impact of rivaroxaban on point-of-care assays. Thromb Res 2017; 153: 65-70
  • 70 Ebner M, Peter A, Spencer C. , et al. Point-of-care testing of coagulation in patients treated with non-vitamin K antagonist oral anticoagulants. Stroke 2015; 46 (10) 2741-2747
  • 71 Al-Aieshy F, Malmström RE, Antovic J. , et al. Clinical evaluation of laboratory methods to monitor exposure of rivaroxaban at trough and peak in patients with atrial fibrillation. Eur J Clin Pharmacol 2016; 72 (06) 671-679
  • 72 Mani H, Herth N, Kasper A. , et al. Point-of-care coagulation testing for assessment of the pharmacodynamic anticoagulant effect of direct oral anticoagulant. Ther Drug Monit 2014; 36 (05) 624-631
  • 73 Ebner M, Birschmann I, Peter A. , et al. Point-of-care testing for emergency assessment of coagulation in patients treated with direct oral anticoagulants. Crit Care 2017; 21 (01) 32
  • 74 Hemachron Jr Whole Blood Microcoagulation system. Prothrombin time (PT) [package insert]. Edison, NJ: International Technidyne Corporation; Revision March 2007
  • 75 Du S, Weiss C, Christina G. , et al. Determination of dabigatran in plasma, serum, and urine samples: comparison of six methods. Clin Chem Lab Med 2015; 53 (08) 1237-1247
  • 76 DOASENSE GmbH. Heidelberg, Germany. 2017 https://www.doasense.de/Press_Release_of_DOASENSE_GmbH.PDF
  • 77 Vogeser M, Seger C. A decade of HPLC-MS/MS in the routine clinical laboratory--goals for further developments. Clin Biochem 2008; 41 (09) 649-662
  • 78 Adaway JE, Keevil BG. Therapeutic drug monitoring and LC-MS/MS. J Chromatogr B Analyt Technol Biomed Life Sci 2012; 883-884: 33-49
  • 79 Kubitza D, Becka M, Wensing G, Voith B, Zuehlsdorf M. 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 2005; 61 (12) 873-880
  • 80 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 (1-2): 43-50
  • 81 Barrett YC, Wang J, Song Y. , et al. A randomised assessment of the pharmacokinetic, pharmacodynamic and safety interaction between apixaban and enoxaparin in healthy subjects. Thromb Haemost 2012; 107 (05) 916-924
  • 82 Bathala MS, Masumoto H, Oguma T, He L, Lowrie C, Mendell J. Pharmacokinetics, biotransformation, and mass balance of edoxaban, a selective, direct factor Xa inhibitor, in humans. Drug Metab Dispos 2012; 40 (12) 2250-2255
  • 83 Schmitz EM, Boonen K, van den Heuvel DJ. , et al. 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 2014; 12 (10) 1636-1646
  • 84 Douxfils J, Dogné JM, Mullier F. , et al. Comparison of calibrated dilute thrombin time and aPTT tests with LC-MS/MS for the therapeutic monitoring of patients treated with dabigatran etexilate. Thromb Haemost 2013; 110 (03) 543-549
  • 85 Douxfils J, Tamigniau A, Chatelain B. , et al. 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 (04) 723-731
  • 86 Antovic JP, Skeppholm M, Eintrei J. , et al. Evaluation of coagulation assays versus LC-MS/MS for determinations of dabigatran concentrations in plasma. Eur J Clin Pharmacol 2013; 69 (11) 1875-1881
  • 87 Skeppholm M, Hjemdahl P, Antovic JP. , et al. On the monitoring of dabigatran treatment in “real life” patients with atrial fibrillation. Thromb Res 2014; 134 (04) 783-789
  • 88 Skeppholm M, Al-Aieshy F, Berndtsson M. , et al. Clinical evaluation of laboratory methods to monitor apixaban treatment in patients with atrial fibrillation. Thromb Res 2015; 136 (01) 148-153
  • 89 Vogeser M, Seger C. Pitfalls associated with the use of liquid chromatography-tandem mass spectrometry in the clinical laboratory. Clin Chem 2010; 56 (08) 1234-1244
  • 90 Annesley T, Majzoub J, Hsing A, Wu A, Rockwood A, Mason D. Mass spectrometry in the clinical laboratory: how have we done, and where do we need to be?. Clin Chem 2009; 55 (06) 1236-1239
  • 91 Clarke W, Rhea JM, Molinaro R. Challenges in implementing clinical liquid chromatography-tandem mass spectrometry methods--the light at the end of the tunnel. J Mass Spectrom 2013; 48 (07) 755-767
  • 92 Nowak G. The ecarin clotting time, a universal method to quantify direct thrombin inhibitors. Pathophysiol Haemost Thromb 2003; 33 (04) 173-183
  • 93 Pötzsch B, Hund S, Madlener K, Unkrig C, Müller-Berghaus G. Monitoring of recombinant hirudin: assessment of a plasma-based ecarin clotting time assay. Thromb Res 1997; 86 (05) 373-383
  • 94 Lindhoff-Last E, Piechottka GP, Rabe F, Bauersachs R. Hirudin determination in plasma can be strongly influenced by the prothrombin level. Thromb Res 2000; 100 (01) 55-60
  • 95 Gosselin R, Hawes E, Moll S, Adcock D. Performance of various laboratory assays in the measurement of dabigatran in patients receiving therapeutic doses: a prospective study based on peak and trough plasma levels. Am J Clin Pathol 2014; 141 (02) 262-267
  • 96 Lange U, Nowak G, Bucha E. Ecarin chromogenic assay--a new method for quantitative determination of direct thrombin inhibitors like hirudin. Pathophysiol Haemost Thromb 2003; 33 (04) 184-191
  • 97 Douxfils J, Lessire S, Dincq AS. , et al. Estimation of dabigatran plasma concentrations in the perioperative setting. An ex vivo study using dedicated coagulation assays. Thromb Haemost 2015; 113 (04) 862-869
  • 98 Biophen DTI [package insert]. Neuville-sur-Oise, France: Hyphen Biomedical. Revision April 29, 2015
  • 99 Helin TA, Lemponen M, Hjemdahl P, Rönquist-Nii Y, Lassila R, Joutsi-Korhonen L. From laboratory to clinical practice: dabigatran effects on thrombin generation and coagulation in patient samples. Thromb Res 2015; 136 (01) 154-160
  • 100 Love JE, Ferrell C, Chandler WL. Monitoring direct thrombin inhibitors with a plasma diluted thrombin time. Thromb Haemost 2007; 98 (01) 234-242
  • 101 Avecilla ST, Ferrell C, Chandler WL, Reyes M. Plasma-diluted thrombin time to measure dabigatran concentrations during dabigatran etexilate therapy. Am J Clin Pathol 2012; 137 (04) 572-574
  • 102 Stangier J, Feuring M. Using the HEMOCLOT direct thrombin inhibitor assay to determine plasma concentrations of dabigatran. Blood Coagul Fibrinolysis 2012; 23 (02) 138-143
  • 103 Hemoclot Thrombin Inhibitors [package insert]. Neuville-sur-Oise, France: Hyphen Biomedical. Revision March 17, 2015
  • 104 HemosIL Direct Thrombin Inhibitors [package insert]. Bedford, MA: Instrumentation Laboratory. Revision March 2016
  • 105 Douxfils J, Mani H, Minet V. , et al. Non-VKA oral anticoagulants: accurate measurement of plasma drug concentrations. BioMed Res Int 2015; 2015: 345138
  • 106 Douxfils J, Tamigniau A, Chatelain B, Goffinet C, Dogné JM, Mullier F. Measurement of non-VKA oral anticoagulants versus classic ones: the appropriate use of hemostasis assays. Thromb J 2014; 12: 24
  • 107 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
  • 108 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
  • 109 Douxfils J, Chatelain B, Hjemdahl P. , et al. Does the Russell viper venom time test provide a rapid estimation of the intensity of oral anticoagulation? A cohort study. Thromb Res 2015; 135 (05) 852-860
  • 110 Gosselin RC, Adcock Funk DM, Taylor JM. , et al. Comparison of anti-Xa and dilute Russell viper venom time assays in quantifying drug levels in patients on therapeutic doses of rivaroxaban. Arch Pathol Lab Med 2014; 138 (12) 1680-1684
  • 111 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
  • 112 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
  • 113 Lindhoff-Last E, Samama MM, Ortel TL, Weitz JI, Spiro TE. Assays for measuring rivaroxaban: their suitability and limitations. Ther Drug Monit 2010; 32 (06) 673-679
  • 114 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
  • 115 Samama MM, Contant G, Spiro TE. , et al; 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 2012; 107 (02) 379-387
  • 116 Samama MM, Guinet C, Le Flem L, Ninin E, Debue JM. Measurement of dabigatran and rivaroxaban in primary prevention of venous thromboembolism in 106 patients, who have undergone major orthopedic surgery: an observational study. J Thromb Thrombolysis 2013; 35 (02) 140-146
  • 117 Samama MM, Martinoli JL, LeFlem L. , et al. Assessment of laboratory assays to measure rivaroxaban--an oral, direct factor Xa inhibitor. Thromb Haemost 2010; 103 (04) 815-825
  • 118 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 (04) e77-e82
  • 119 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
  • 120 Mani H, Rohde G, Stratmann G. , et al. Accurate determination of rivaroxaban levels requires different calibrator sets but not addition of antithrombin. Thromb Haemost 2012; 108 (01) 191-198
  • 121 Gosselin RC, Francart SJ, Hawes EM, Moll S, Dager WE, Adcock DM. Heparin-calibrated chromogenic anti-Xa activity measurements in patients receiving rivaroxaban: can this test be used to quantify drug level?. Ann Pharmacother 2015; 49 (07) 777-783
  • 122 Yates SG, Smith S, Tharpe W, Shen YM, Sarode R. Can an anti-Xa assay for low-molecular-weight heparin be used to assess the presence of rivaroxaban?. Transfus Apheresis Sci 2016; 55 (02) 212-215
  • 123 Adcock DM, Gosselin R. Direct oral anticoagulants (DOACs) in the laboratory: 2015 review. Thromb Res 2015; 136 (01) 7-12
  • 224 Sabor L, Raphaël M, Dogné JM, Mullier F, Douxfils J. Heparin-calibrated chromogenic anti-Xa assays are not suitable to assess the presence of significant direct factor Xa inhibitors levels. Thromb Res 2017; 156: 36-38
  • 125 Harenberg J, Du S, Krämer S. , et al. Novel methods for assessing oral direct factor Xa and thrombin inhibitors: use of point-of-care testing and urine samples. Semin Thromb Hemost 2013; 39 (01) 66-71
  • 126 Harenberg J, Krämer S, Du S, Weiss C, Krämer R. Concept of a point of care test to detect new oral anticoagulants in urine samples. Thromb J 2013; 11 (01) 15
  • 127 Harenberg J, Du S, Wehling M. , et al. Measurement of dabigatran, rivaroxaban and apixaban in samples of plasma, serum and urine, under real life conditions. An international study. Clin Chem Lab Med 2016; 54 (02) 275-283
  • 128 Harris LF, Rainey P, Castro-López V, O'Donnell JS, Killard AJ. A microfluidic anti-Factor Xa assay device for point of care monitoring of anticoagulation therapy. Analyst (Lond) 2013; 138 (17) 4769-4776
  • 129 Bluecher A, Meyer Dos Santos S, Ferreirós N. , et al. Microfluidic coagulation assay for monitoring anticoagulant therapy in acute stroke patients. Thromb Haemost 2017; 117 (03) 519-528
  • 130 Specific PoC Testing of Coagulation in Patients Treated With NOAC 1 (SPOCT-NOAC 1) [Identifier: NCT02825394]. Available at: www.clinicaltrials.gov . Accessed January 15, 2017
  • 131 FDA. Guidance for Industry Bioanalytical Method Validation. 2001, Revised 2013. Available at: http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm . Accessed January 15, 2017
  • 132 Validation of Analytical Procedures: Text and Methodology Q2(R1). ICH harmonised tripartite guideline. 2005. Available at: www.ich.org . Accessed January 15, 2017
  • 133 Guidance for Industry Q2B Validation of Analytical Procedures: Methodology. 1996. Available at: http://www.fda.gov/cder/guidance/index.htm . Accessed January 15, 2017
  • 134 US Department of Health and Human Services. Clinical laboratory improvement amendments of 1988: final rule. Fed Regist 1992; 57 (40) 7001-7186 . Codified at 42 CFR §1405–494
  • 135 Thompson M, Ellison S, Wood R. Harmonized guidelines for single-laboratory validation of methods of analysis (IUPAC Technical Report). Pure Appl Chem 2002; 74: 835-855
  • 136 Magnussen B, Örnemark U. (eds.). The fitness for purpose of analytical methods. A laboratory guide to method validation and related topics. 2nd edition. Eurachem, 2014. ISBN 978-9187461-59-0) (www.eurachem.org)
  • 137 Guideline on bioanalytical method validation EMEA/CHMP/EWP/192217/2009 Rev. 1 Corr. 2 http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2011/08/WC500109686.pdf
  • 138 Bonar R, Favaloro EJ, Mohammed S, Pasalic L, Sioufi J, Marsden K. The effect of dabigatran on haemostasis tests: a comprehensive assessment using in vitro and ex vivo samples. Pathology 2015; 47 (04) 355-364