Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
International Journal of Hematology
Published in: International Journal of Hematology 6/2016

01-06-2016 | Original Article

Comparison of prothrombin time tests used in the monitoring of edoxaban and their evaluation as indicators of the reversal effect

Authors: Toshiaki Iba, Mari Emmi, Makoto Hiki, Masataka Nagayama, Koichiro Aihara, Yoko Tabe, Maiko Yuri, Akimichi Ohsaka

Published in: International Journal of Hematology | Issue 6/2016

Login to get access

Abstract

Clinical demand for the prompt assessment of the activity of direct-acting factor Xa inhibitors in the emergency care setting is increasing. In the present study, we examined whether prothrombin time (PT) tests can serve as a clinically useful indicator of anti-factor Xa activity. In the first series, the in vitro effect of edoxaban on PT was evaluated by spiking human plasma with edoxaban and measuring PT using three different commercial PT tests. In the second series, the reversal effect of prothrombin complex concentrates (PCC) and activated PCC (aPCC) in edoxaban-spiked plasma was evaluated. In the third series, PT of plasma samples from patients administered either 15 or 30 mg/day of edoxaban was assessed, and the results were compared with edoxaban concentrations determined by a calibrated anti-factor Xa activity assay. The spike test revealed that all PT reagents positively correlated with edoxaban. The sensitivity to edoxaban varied among the three reagents and Triniclot® Excel S showed the best performance. Prolonged PT by edoxaban was reversed by PCC and aPCC in a dose-dependent manner; however, complete reversal was not achieved. Positive correlation between anti-factor Xa activity and PT was shown in the clinical samples at the edoxaban range from 0 to >300 ng/mL.
Literature
1.
Lip GY, Lane DA. Stroke prevention in atrial fibrillation: a systematic review. JAMA. 2015;313:1950–62.CrossRefPubMed
2.
Ghanny S, Crowther M. Treatment with novel oral anticoagulants: indications, efficacy and risks. Curr Opin Hematol. 2013;20:430–6.CrossRefPubMed
3.
Pengo V, Crippa L, Falanga A, Finazzi G, Marongiu F, Palareti G, et al. Questions and answers on the use of dabigatran and perspectives on the use of other new oral anticoagulants in patients with atrial fibrillation. A consensus document of the Italian Federation of Thrombosis Centers (FCSA). Thromb Haemost. 2011;106:868–76.CrossRefPubMed
4.
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;872:43–50.CrossRefPubMed
5.
Tripodi A. Which test to use to measure the anticoagulant effect of rivaroxaban: the prothrombin time test. J Thromb Haemost. 2013;11:576–8.CrossRefPubMed
6.
Harenberg J, Krämer R, Giese C, Marx S, Weiss C, Wehling M. Determination of rivaroxaban by different factor Xa specific chromogenic substrate assays: reduction of interassay variability. J Thromb Thrombolysis. 2011;32:267–71.CrossRefPubMedPubMedCentral
7.
Samama MM, Amiral J, Guinet C, Le Flem L, Seghatchian J. Monitoring plasma levels of factor Xa inhibitors: how, why and when? Expert Rev Hematol. 2013;6:155–64.CrossRefPubMed
8.
Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369:2093–104.CrossRefPubMed
9.
Büller HR, Décousus H, Grosso MA, Mercuri M, Middeldorp S, Prins MH, et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369:1406–15.CrossRefPubMed
10.
Ruff CT, Giugliano RP, Braunwald E, Morrow DA, Murphy SA, Kuder JF, 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;385:2288–95.CrossRefPubMed
11.
Yin OQ, Miller R. Population pharmacokinetics and dose-exposure proportionality of edoxaban in healthy volunteers. Clin Drug Investig. 2014;34:743–52.CrossRefPubMed
12.
13.
Pernod G, Albaladejo P, Godier A, Samama CM, Susen S, Gruel Y, 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;106:382–93.CrossRefPubMed
14.
Turecek PL, Va´radi K, Gritsch H, Schwarz HP. FEIBA: mode of action. Haemophilia. 2004;10(Suppl 2):3–9.CrossRefPubMed
15.
Harenberg J, Krämer R, Giese C, Marx S, Weiss C, Wehling M. Determination of rivaroxaban by different factor Xa specific chromogenic substrate assays: reduction of interassay variability. J Thromb Thrombolysis. 2011;32:267–71.CrossRefPubMedPubMedCentral
16.
Crowther M, Crowther MA. Antidotes for novel oral anticoagulants: current status and future potential. Arterioscler Thromb Vasc Biol. 2015;35:1736–45.CrossRefPubMed
17.
Siegal DM, Curnutte JT, Connolly SJ, Lu G, Conley PB, Wiens BL, et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med. 2015;373:2413–24.CrossRefPubMed
18.
Ansell JE, Bakhru SH, Laulicht BE, Steiner SS, Grosso M, Brown K, et al. Use of PER977 to reverse the anticoagulant effect of edoxaban. N Engl J Med. 2014;371:2141–2.CrossRefPubMed
19.
Cuker A, Husseinzadeh H. Laboratory measurement of the anticoagulant activity of edoxaban: a systematic review. J Thromb Thrombolysis. 2015;39:288–94.CrossRefPubMedPubMedCentral
20.
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;143:241–7.CrossRefPubMed
21.
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:e77–82.CrossRefPubMed
22.
Becker RC, Yang H, Barrett Y, Mohan P, Wang J, Wallentin L, Alexander JH. Chromogenic laboratory assays to measure the factor Xa-inhibiting properties of apixaban–an oral, direct and selective factor Xa inhibitor. J Thromb Thrombolysis. 2011;32:183–7.CrossRefPubMed
23.
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;104:1263–71.CrossRefPubMed
24.
Yuri M, Tabe M, Tsuchiya K, Sadatsuki R, Aoki J, Horii T, et al. Evaluation of factor Xa-specific chromogenic substrate assays and the determination of pharmacokinetics of fondaparinux. Clin Appl Thromb Hemost. 2015;pii:1076029615595878.
25.
Douxfils J, Chatelain C, Chatelain B, Dogné JM, Mullier F. Impact of apixaban on routine and specific coagulation assays: a practical laboratory guide. Thromb Haemost. 2013;110:283–94.CrossRefPubMed
26.
Douxfils J, Tamigniau A, Chatelain B, Chatelain C, Wallemacq P, Dogné JM, Mullier F. 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;110:723–31.CrossRefPubMed
27.
Kanemoto M, Kuhara H, Ueda T, Shinohara T, Oda T, Nakao F, et al. Association of apixaban therapy and prothrombin time in patients with atrial fibrillation. Circ J. 2014;78:2651–6.CrossRefPubMed
28.
Douxfils J, Mullier F, Loosen C, Chatelain C, Chatelain B, Dogné JM. Assessment of the impact of rivaroxaban on coagulation assays: laboratory recommendations for the monitoring of rivaroxaban and review of the literature. Thromb Res. 2012;130:956–66.CrossRefPubMed
29.
Ogata K, Mendell-Harary J, Tachibana M, Masumoto H, Oguma T, Kojima M, et al. Clinical safety, tolerability, pharmacokinetics, and pharmacodynamics of the novel factor Xa inhibitor edoxaban in healthy volunteers. J Clin Pharmacol. 2010;50:743–53.CrossRefPubMed
30.
Majeed A, Schulman S. Bleeding and antidotes in new oral anticoagulants. Best Pract Res Clin Haematol. 2013;26:191–202.CrossRefPubMed
31.
Hemphill JC III, Greenberg SM, Anderson CS, Becker K, Bendok BR, Cushman M, et al. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2015;46:2032–60.CrossRefPubMed
32.
Fukuda T, Honda Y, Kamisato C, Morishima Y, Shibano T. Reversal of anticoagulant effects of edoxaban, an oral, direct factor Xa inhibitor, with haemostatic agents. Thromb Haemost. 2012;107:253–9.CrossRefPubMed
33.
Silvain J, Hauguel M, Kerneis M, Collet JP, Montalescot G. Measuring and reversing the effect of non-vitamin K antagonist oral anticoagulants (NOACs). Circ J. 2015;79:289–91.CrossRefPubMed
34.
Herzog E, Kaspereit F, Krege W, Doerr B, Mueller-Cohrs J, Pragst I, et al. Effective reversal of edoxaban-associated bleeding with four-factor prothrombin complex concentrate in a rabbit model of acute hemorrhage. Anesthesiology. 2015;122:387–98.CrossRefPubMed
35.
Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369:2093–104.CrossRefPubMed
Metadata
Title
Comparison of prothrombin time tests used in the monitoring of edoxaban and their evaluation as indicators of the reversal effect
Authors
Toshiaki Iba
Mari Emmi
Makoto Hiki
Masataka Nagayama
Koichiro Aihara
Yoko Tabe
Maiko Yuri
Akimichi Ohsaka
Publication date
01-06-2016
Publisher
Springer Japan
Published in
International Journal of Hematology / Issue 6/2016
Print ISSN: 0925-5710
Electronic ISSN: 1865-3774
DOI
https://doi.org/10.1007/s12185-016-1975-5

Other articles of this Issue 6/2016

International Journal of Hematology 6/2016 Go to the issue

Progress in Hematology

Guest editorial: Cooperative networks for stem cell homeostasis in normal and malignant hematopoiesis: from metabolism to epigenetics

Original Article

Iron overload in non-transfusion-dependent thalassemia: association with genotype and clinical risk factors

Original Article

Pregnancy outcomes of patients with paroxysmal nocturnal hemoglobinuria treated with eculizumab: a Japanese experience and updated review

Case Report

A Japanese family with X-linked sideroblastic anemia affecting females and manifesting as macrocytic anemia

Progress in Hematology

DNA methylation in normal and malignant hematopoiesis

Original Article

Miscarriage and recurrent miscarriage in patients with congenital factor V deficiency: a report of six cases in Iran
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits