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Semin Thromb Hemost
DOI: 10.1055/s-0044-1782196
Review Article

Pearls and Pitfalls in the Measurement of Direct Oral Anticoagulants

Giuseppe Lippi 
1   Section of Clinical Biochemistry, School of Medicine, University of Verona, Verona, Italy
,
Emmanuel J. Favaloro 
2   Department of Haematology, Institute of Clinical Pathology and Medical Research (ICPMR), Sydney Centres for Thrombosis and Haemostasis, NSW Health Pathology, Westmead Hospital, Westmead, NSW, Australia
3   Faculty of Science and Health, Charles Sturt University, Wagga Wagga, NSW, Australia
4   School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Westmead Hospital, Westmead, New South Wales, Australia
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Abstract

Due to their widespread use, testing for direct oral anticoagulants (DOACs) has become urgent in certain clinical situations. Screening based on widely available, rapid, and simple hemostasis assays such as prothrombin time, activated partial thromboplastin time, or even diluted Russel Viper venom time may provide sufficient evidence of “over-coagulation” and could be used “in small/peripheral/spoke laboratories” as an emergency strategy, but is not thought to be reliable for driving clinical decision making. Given their good correlation with plasma concentration, urine dipsticks may be considered a valuable alternative for emergency screening, although their performance is dependent on renal function, may vary depending on the time since the last urination, and there may be problems of interfacing with the laboratory/hospital information system. Separation methods based on liquid chromatography and mass spectrometry may be clinically questionable, since they measure the concentration rather than the actual inhibitory effect of DOACs, are relatively expensive, cumbersome and time consuming, and therefore seem unsuitable for most conditions requiring urgent clinical decision making. A proposed approach therefore involves establishing a network of routine clinical laboratories, designating a reference center where DOAC tests could be available 24/7, establishing a clear diagnostic care pathway for ordering the tests from the laboratory and standard operating procedures for performing them, the use of the diluted thrombin time for dabigatran and anti-FXa assays (drug-calibrated) for rivaroxaban, apixaban, and edoxaban, as well as providing expert advice throughout the testing process, from ordering to interpretation of results.

Keywords

anticoagulants - direct oral anticoagulants - measurement - assays


Publication History

Article published online:
08 March 2024

© 2024. Thieme. All rights reserved.

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  • References

  • 1 Tsao CW, Aday AW, Almarzooq ZI. et al; American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart Disease and Stroke Statistics-2023 Update: a report from the American Heart Association. Circulation 2023; 147 (08) e93-e621
    Google Scholar
  • 2 Flora GD, Nayak MK. A brief review of cardiovascular diseases, associated risk factors and current treatment regimes. Curr Pharm Des 2019; 25 (38) 4063-4084
    Google Scholar
  • 3 Franchini M, Liumbruno GM, Bonfanti C, Lippi G. The evolution of anticoagulant therapy. Blood Transfus 2016; 14 (02) 175-184
    Google Scholar
  • 4 Lippi G, Mattiuzzi C, Favaloro EJ. Letter to the Editor: 10-year evolution in worldwide usage of anticoagulant drugs. Semin Thromb Hemost 2023; 49 (03) 314-316
    Google Scholar
  • 5 Weitz JI, Bates SM. New anticoagulants. J Thromb Haemost 2005; 3 (08) 1843-1853
    Google Scholar
  • 6 Favaloro EJ, Pasalic L, Curnow J, Lippi G. Laboratory monitoring or measurement of direct oral anticoagulants (DOACs): advantages, limitations and future challenges. Curr Drug Metab 2017; 18 (07) 598-608
    Google Scholar
  • 7 Morrison AS. Screening in Chronic Disease. 2nd ed.. New York, NY: Oxford University Press; 1992
    Google Scholar
  • 8 Tomaselli GF, Mahaffey KW, Cuker A. et al. 2020 ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants: a report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol 2020; 76 (05) 594-622
    Google Scholar
  • 9 Douketis JD, Spyropoulos AC, Duncan J. et al. Perioperative management of patients who are receiving a direct oral anticoagulant. JAMA Intern Med 2019; 179 (11) 1469-1478
    Google Scholar
  • 10 Shaw JR, Li N, Vanassche T. et al. Predictors of preprocedural direct oral anticoagulant levels in patients having an elective surgery or procedure. Blood Adv 2020; 4 (15) 3520-3527
    Google Scholar
  • 11 Lippi G, Favaloro EJ. Recent guidelines and recommendations for laboratory assessment of the direct oral anticoagulants (DOACs): is there consensus?. Clin Chem Lab Med 2015; 53 (02) 185-197
    Google Scholar
  • 12 Adcock DM, Gosselin R. Direct oral anticoagulants (DOACs) in the laboratory: 2015 review. Thromb Res 2015; 136 (01) 7-12
    Google Scholar
  • 13 Patel JP, Chitongo PB, Czuprynska J, Roberts LN, Patel RK, Arya R. Normal prothrombin times in the presence of therapeutic levels of apixaban–in-vivo experience from King's College Hospital. Br J Haematol 2015; 169 (01) 152-153
    Google Scholar
  • 14 Jabet A, Stepanian A, Golmard JL. et al. 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
    Google Scholar
  • 15 Douxfils J, Adcock DM, Bates SM. et al. 2021 Update of the International Council for Standardization in Haematology recommendations for laboratory measurement of direct oral anticoagulants. Thromb Haemost 2021; 121 (08) 1008-1020
    Google Scholar
  • 16 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
    Google Scholar
  • 17 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
    Google Scholar
  • 18 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
    Google Scholar
  • 19 Hillarp A, Strandberg K, Gustafsson KM, Lindahl TL. Unveiling the complex effects of direct oral anticoagulants on dilute Russell's viper venom time assays. J Thromb Haemost 2020; 18 (08) 1866-1873
    Google Scholar
  • 20 Harenberg J, Schreiner R, Hetjens S, Weiss C. Detecting anti-IIa and anti-Xa direct oral anticoagulant (DOAC) agents in urine using a DOAC Dipstick. Semin Thromb Hemost 2019; 45 (03) 275-284
    Google Scholar
  • 21 Harenberg J, Beyer-Westendorf J, Crowther M. et al; Working Group Members. Accuracy of a rapid diagnostic test for the presence of direct oral factor Xa or thrombin inhibitors in urine-a multicenter trial. Thromb Haemost 2020; 120 (01) 132-140
    Google Scholar
  • 22 Harenberg J, Martini A, Du S, Krämer S, Weiss C, Hetjens S. Performance characteristics of DOAC Dipstick in determining direct oral anticoagulants in urine. Clin Appl Thromb Hemost 2021; 27: 1076029621993550
    Google Scholar
  • 23 Martini A, Harenberg J, Bauersachs R. et al. Detection of direct oral anticoagulants in patient urine samples by prototype and commercial test strips for DOACs - a systematic review and meta-analysis. TH Open 2021; 5 (03) e438-e448
    Google Scholar
  • 24 Margetić S, Ćelap I, Huzjan AL. et al. DOAC Dipstick testing can reliably exclude the presence of clinically relevant DOAC concentrations in circulation. Thromb Haemost 2022; 122 (09) 1542-1548
    Google Scholar
  • 25 Harenberg J, Gosselin RC, Cuker A. et al. Algorithm for rapid exclusion of clinically relevant plasma levels of DOACs in patients using the DOAC Dipstick. An expert consensus paper. Thromb Haemost 2024; (e-pub ahead of print) DOI: 10.1055/a-2261-1811.
    Google Scholar
  • 26 Gouveia F, Bicker J, Gonçalves J, Alves G, Falcão A, Fortuna A. Liquid chromatographic methods for the determination of direct oral anticoagulant drugs in biological samples: a critical review. Anal Chim Acta 2019; 1076: 18-31
    Google Scholar
  • 27 Brückner L, Beyer-Westendorf J, Tiebel O, Pietsch J. Development and validation of an analytical method for the determination of direct oral anticoagulants (DOAC) and the direct thrombin-inhibitor argatroban by HPLC-MS/MS. J Thromb Thrombolysis 2022; 53 (04) 777-787
    Google Scholar
  • 28 Douxfils J, Gosselin RC. Laboratory assessment of direct oral anticoagulants. Semin Thromb Hemost 2017; 43 (03) 277-290
    Google Scholar
  • 29 Wiesen MHJ, Blaich C, Streichert T, Michels G, Müller C. Paramagnetic micro-particles as a tool for rapid quantification of apixaban, dabigatran, edoxaban and rivaroxaban in human plasma by UHPLC-MS/MS. Clin Chem Lab Med 2017; 55 (09) 1349-1359
    Google Scholar
  • 30 Gosselin RC, Douxfils J. Measuring direct oral anticoagulants. Methods Mol Biol 2017; 1646: 217-225
    Google Scholar
  • 31 Kuhn J, Gripp T, Flieder T. et al. Measurement of apixaban, dabigatran, edoxaban and rivaroxaban in human plasma using automated online solid-phase extraction combined with ultra-performance liquid chromatography-tandem mass spectrometry and its comparison with coagulation assays. Clin Chim Acta 2018; 486: 347-356
    Google Scholar
  • 32 Favaloro EJ, Gosselin RC. Therapeutic drug monitoring of selected direct oral anticoagulants. In: Therapeutic Drug Monitoring - Newer Drugs and Biomarkers. . 2nd Edition. Editor: Amitava Dasgupta. 2024. Academic Press:
    Google Scholar
  • 33 Favaloro EJ, Lippi G, Koutts J. Laboratory testing of anticoagulants: the present and the future. Pathology 2011; 43 (07) 682-692
    Google Scholar