Clinical pearls: Laboratory assessments of direct oral anticoagulants (DOACS)

Robert C. Gosselin; Jonathan Douxfils; Dorothy Adcock

doi:10.1055/s-0038-1667872

Phlebologie, Inhaltsverzeichnis

Hamostaseologie 2018; 47(04): 215-221
DOI: 10.1055/s-0038-1667872

Übersichtsarbeit – Review

Schattauer GmbH

Clinical pearls: Laboratory assessments of direct oral anticoagulants (DOACS)

Laborbeurteilung von direkten oralen Antikoagulanzien (DOAKs)

Authors

Robert C. Gosselin

¹University of California, Davis Health System, Hemophilia Treatment Center, Sacramento, California, United States
Jonathan Douxfils

²University of Namur, Department of Pharmacy, Namur Thrombosis and Hemostasis Centre (NTHC), Namur Research Institute for Life Sciences (NARILIS), Namur, Belgium
Dorothy Adcock

³Qualiblood s.a., Namur, Belgium. Laboratory Corporation of America® Holdings – Burlington, North Carolina, United States

Abstract

Summary

Direct oral anticoagulants (DOACS) are used for stroke prevention in patients with atrial fibrillation as well as for prophylaxis and treatment of venous thromboembolism.

Clinicians who treat, or may encounter, patients with DOAC exposure, should be aware of the limitations of coagulation testing in this setting, and seek counsel from their laboratory to understand the effects of DOACS on coagulation results. Generally, assays that employ clot based principles, or methods that require thrombin or Factor Xa activation or substrates may be affected by the presence of DOACS. The clinical laboratory should have an algorithmic testing plan for adequately assessing the presence of all DOACS and readily provide this information to clinicians. We describe Clinical Pearls for DOAC assessment using common and esoteric coagulation testing.

Zusammenfassung

Direkte orale Antikoagulanzien (DOAK) werden zur Schlaganfallprophylaxe bei Patienten mit Vorhofflimmern und zur Prophylaxe sowie Behandlung von venösen Thrombembolien eingesetzt. Ärzte, die Patienten unter DOAK-Therapie behandeln oder mit diesen konfrontiert werden, sollten sich über die Grenzen der Bestimmung der Gerinnungswerte unter diesen Bedingungen im Klaren sein. Sie sollten den Rat ihres Labors einholen, um die Wirkungen der DOAK auf die Gerinnungswerte richtig einzuschätzen. Generell können Assays, die auf funktionellen Clotting-Tests basieren, oder Methoden, die Thrombin oder Faktor Xa als Substrat verwenden bzw. deren Aktivierung erfordern, von DOAK beeinflusst werden. Das klinische Labor sollte über einen algorithmischen Testplan verfügen, um die Präsenz aller DOAK in geeigneter Weise zu beurteilen und den Ärzten diese Informationen umgehend zur Verfügung stellen zu können. Wir beschreiben klinische Perlen für die DOAK-Untersuchung anhand der üblichen Gerinnungstests wie auch selteneren Verfahren.

Nachdruck aus und zu zitieren als: Hämostaseologie 2017; 37: 295–301

10.5482/HAMO-17-01-0002

Keywords

Dabigatran - rivaroxaban - apixaban - edoxaban - direct oral anticoagulants

Schlüsselwörter

Dabigatran - Rivaroxaban - Apixaban - Edoxaban - direkte orale Antikoagulanzien

Volltext

Referenzen

References
1 Kearon C, Akl EA, Comerota AJ. et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians EvidenceBased Clinical Practice Guidelines. Chest 2012; 141: e419S-94S.
2 You JJ, Singer DE, Howard PA. et al. Antithrombotic therapy for atrial fibrillation: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians EvidenceBased Clinical Practice Guidelines. Chest 2012; 141: e531S-75S.
3 Barnes GD, Ageno W, Ansell J. et al. Recommendation on the Nomenclature for Oral Anticoagulants: communication from the SSC of the ISTH. J Thromb Haemost 2015; 13 (06) 1154-1156.
4 Nutescu EA, Burnett A, Fanikos J. et al. Pharmacology of anticoagulants used in the treatment of venous thromboembolism. J Thromb Thrombolys 2016; 41: 15-31.
5 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: 1128-1139.
6 Giugliano RP, Ruff CT, Braunwald E. et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013; 369: 2093-2104.
7 Ageno W, Gallus AS, Wittkowsky A. et al. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141: e44S-88S.
8 Gosselin RC, Adcock DM. The laboratory’s 2015 perspective on direct oral anticoagulant testing. J Thromb Haemost 2016; 14: 886-893.
9 Masotti L, Campanini M. Pharmacology of new oral anticoagulants: mechanism of action, pharmacokinetics, pharmacodynamics. Ital J Med 2013; 07: 1.
10 Bauer KA. Targeted Anti-Anticoagulants. N Engl J Med 2015; 373: 569-571.
11 Ieko M, Naitoh S, Yoshida M, Takahashi N. Profiles of direct oral anticoagulants and clinical usage-dosage and dose regimen differences. J Intens Care 2016; 04: 19.
12 Salem JE, Sabouret P, Funck-Brentano C, Hulot JS. Pharmacology and mechanisms of action of new oral anticoagulants. Fundam Clin Pharmacol 2015; 29: 10-20.
13 Baglin T, Hillarp A, Tripodi A. et al. 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 2013; 11: 756-760.
14 Baglin T, Keeling D, Kitchen S. Committee for Standards in H. Effects on routine coagulation screens and assessment of anticoagulant intensity in patients taking oral dabigatran or rivaroxaban: guidance from the British Committee for Standards in Haematology. Brit J Haematol 2012; 159: 427-429.
15 Harenberg J, Du S, Weiss C. et al. Methods to determine apixaban of the Subcommittee on Control of Anticoagulation of the International Society of T and Haemostasis. Report of the Subcommittee on Control of Anticoagulation on the determination of the anticoagulant effects of apixaban: communication from the SSC of the ISTH. J Thromb Haemost 2014; 12: 801-804.
16 Tran H, Joseph J, Young L. et al. New oral anticoagulants: a practical guide on prescription, laboratory testing and peri-procedural/bleeding management. Australasian Society of Thrombosis and Haemostasis. Intern Med J 2014; 44: 525-536.
17 Benzon HT, Avram MJ, Green D, Bonow RO. New oral anticoagulants and regional anaesthesia. Brit J Anaest 2013; 111 (Suppl. 01) 196-113.
18 Koscielny J, Rutkauskaite E. Rivaroxaban and hemostasis in emergency care. Emerg Med Internat 2014; 2014: 935474.
19 Pernod G, Albaladejo P, Godier A. 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: 382-393.
20 Hapgood G, Butler J, Malan E. et al. The effect of dabigatran on the activated partial thromboplastin time and thrombin time as determined by the Hemoclot thrombin inhibitor assay in patient plasma samples. Thromb Haemost 2013; 110: 308-315.
21 Nowak G. The ecarin clotting time, a universal method to quantify direct thrombin inhibitors. Pathophysiol Haemost Thromb 2003; 33: 173-183.
22 Gosselin RC, Dwyre DM, Dager WE. Measuring dabigatran concentrations using a chromogenic ecarin clotting time assay. Ann Pharmacother 2013; 47: 1635-1640.
23 Harenberg J, Erdle S, Marx S, Kramer R. Determination of rivaroxaban in human plasma samples. Sem Thromb Hemost 2012; 38: 178-184.
24 Hillarp A, Gustafsson KM, Faxalv 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: 1545-1553.
25 Douxfils J, Chatelain B, Chatelain C. et al. Edoxaban: Impact on routine and specific coagulation assays. A practical laboratory guide. Thromb Haemost 2016; 115: 368-381.
26 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. Thrombos Res 2015; 135: 852-860.
27 McGlasson DL, Fritsma GA. Measuring dabigatran with the dilute Russell viper venom confirm assay in an anticoagulation clinic population. Blood Coagul Fibrinolysis 2016; 27: 53-57.
28 Gosselin RC, Adcock DMFunk, 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: 1680-1684.
29 Dias JD, Norem K, Doorneweerd DD. et al. Use of Thromboelastography (TEG) for Detection of New Oral Anticoagulants. Arch Pathol Lab Med 2015; 139: 665-673.
30 Adelmann D, Wiegele M, Wohlgemuth RK. et al. Measuring the activity of apixaban and rivaroxaban with rotational thrombelastometry. Thromb Res 2014; 134: 918-923.
31 Harenberg J, Du S, Kramer S. et al. Patients’ Serum and Urine as Easily Accessible Samples for the Measurement of Non-Vitamin K Antagonist Oral Anticoagulants. Semin Thromb Hemost 2015; 41: 228-3632.
32 Douxfils J, Gosselin RC. Laboratory Assessment of Direct Oral Anticoagulants. Semin Thromb Hemost 2017; 43: 277-290.
33 Douxfils J, Pochet L, Lessire S. et al. Mass spectrometry in the therapeutic drug monitoring of direct oral anticoagulants. Useful or useless?. Trend Anal Chem 2016; 84 (Part B): 41-50.
34 Levy JH, Ageno W, Chan NC. et al. When and how to use antidotes for the reversal of direct oral anticoagulants: guidance from the SSC of the ISTH. J Thromb Haemost 2016; 14: 623-627.
35 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: 1133-1140.
36 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: 1493-1502.
37 Douxfils J, Mullier F, Robert S. et al. Impact of dabigatran on a large panel of routine or specific coagulation assays. Laboratory recommendations for monitoring of dabigatran etexilate. Thromb Haemost 2012; 107: 985-997.
38 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: 723-731.
39 Douxfils J, Chatelain C, Chatelain B. et al. Impact of apixaban on routine and specific coagulation assays: a practical laboratory guide. Thromb Haemost 2013; 110: 283-294.
40 Dale BJ, Ginsberg JS, Johnston M. et al. Comparison of the effects of apixaban and rivaroxaban on prothrombin and activated partial thromboplastin times using various reagents. J Thromb Haemost 2014; 12: 1810-1815.
41 Adcock DM, Gosselin R. Direct Oral Anticoagulants (DOACS) in the Laboratory: 2015 Review. Thromb Res 2015; 136: 7-12.
42 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: 505-513.
43 Gosselin RC, Adcock DM. Assessing nonvitamin K antagonist oral anticoagulants (NOACs) in the laboratory. Int J lab Hematol 2015; 37 (Suppl. 01) 46-51.
44 Lippi G, Favaloro E. 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. Sem Throm Hemost 2015; 41: 208-227.
45 Gosselin RC, Adcock D, Hawes EM. et al. Evaluating the use of commercial drug-specific calibrators for determining PT and APTT reagent sensitivity to dabigatran and rivaroxaban. Thromb Haemost 2015; 113: 77-84.
46 Douxfils J, Dogne 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: 543-549.
47 Adcock DM, Gosselin R, Kitchen S, Dwyre DM. The effect of dabigatran on select specialty coagulation assays. Am J Clin Pathol 2013; 139: 102-109.
48 Bonar R, Favaloro EJ. Mohammed 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. Pathol 2016; 48: 60-71.
49 Prentice CR. Acquired coagulation disorders. Clin Haematol 1985; 14: 413-442.
50 Gosselin R, Dager W, Roberts A. et al. Effect of telavancin (Vibativ) on routine coagulation test results. Am J Clin Pathol 2011; 136: 848-854.
51 Pengo V, Tripodi A, Reber G. et al. Update of the guidelines for lupus anticoagulant detection. Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. J Thromb Haemost 2009; 07: 1737-1740.
52 Lessire S, Douxfils J. Baudar et al. Is Thrombin Time useful for the assessment of dabigatran concentrations? An in vitro and ex vivo study. Thrombos Res 2015; 136: 693-696.
53 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: 1263-1271.
54 Gosselin RC, Francart SJ, Hawes EM. et al. Heparin-Calibrated Chromogenic Anti-Xa Activity Measurements in Patients Receiving Rivaroxaban: Can This Test Be Used to Quantify Drug Level?. Ann Pharmacother 2015; 49: 777-783.
55 Spannagl M, Bichler J, Birg A. et al. Development of a chromogenic substrate assay for the determination of hirudin in plasma. Blood Coagul Fibrinolysis 1991; 02: 121-127.
56 Douxfils J, Mullier F, Loosen C. et al. Assessment of the impact of rivaroxaban on coagulation assays: laboratory recommendations for the monitoring of rivaroxaban and review of the literature. Thrombos Res 2012; 130: 956-966.
57 Schmitz EM, Boonen K, van den Heuvel DJ. et al. Determination of dabigatran, rivaroxaban and apixaban by ultra-performance liquid chromatography – tandem mass spectrometry (UPLCMS/MS) and coagulation assays for therapy monitoring of novel direct oral anticoagulants. J Thromb Haemost 2014; 12: 1636-1646.
58 Douxfils J, Mani H, Minet V. et al. Non-VKA Oral Anticoagulants: Accurate Measurement of Plasma Drug Concentrations. Biomed Res Int 2014; 2014: 345138.
59 Gous T, Couchman L, Patel JP. et al. Measurement of the direct oral anticoagulants apixaban, dabigatran, edoxaban, and rivaroxaban in human plasma using turbulent flow liquid chromatography with high-resolution mass spectrometry. Therap Drug Monit 2014; 36: 597-605.
60 Siriez R, Evrard J, Dogné JM, Pochet L, Gheldof D, Chatelain B, Mullier F, Douxfils J. Betrixaban: Impact on Routine and Specific Coagulation Assays A Practical Laboratory Guide. Thromb Haemost. 2018 Jun 11. doi: 10.1055/s-0038–1657772. [Epub ahead of print].