Automated Thrombin Generation Assay for Rivaroxaban, Apixaban, and Edoxaban Measurements

Tamana Meihandoest; Jan-Dirk Studt; Adriana Mendez; Lorenzo Alberio; Pierre Fontana; Walter A Wuillemin; Adrian Schmidt; Lukas Graf; Bernhard Gerber; Gabriela Monika Maeder; Cédric Bovet; Thomas C Sauter; Michael Nagler

doi:10.3389/fcvm.2021.717939

Automated Thrombin Generation Assay for Rivaroxaban, Apixaban, and Edoxaban Measurements

Front Cardiovasc Med. 2021 Sep 9:8:717939. doi: 10.3389/fcvm.2021.717939. eCollection 2021.

Authors

Tamana Meihandoest^{1

2}, Jan-Dirk Studt³, Adriana Mendez⁴, Lorenzo Alberio⁵, Pierre Fontana⁶, Walter A Wuillemin⁷, Adrian Schmidt⁸, Lukas Graf⁹, Bernhard Gerber^{10

11}, Gabriela Monika Maeder², Cédric Bovet², Thomas C Sauter¹², Michael Nagler^{2

13}

Affiliations

¹ Department of Epidemiology, Maastricht University, Maastricht, Netherlands.
² Department of Clinical Chemistry, Inselspital, Bern University Hospital, and University of Bern, Bern, Switzerland.
³ Division of Medical Oncology and Hematology, University and University Hospital Zurich, Zurich, Switzerland.
⁴ Department of Laboratory Medicine, Cantonal Hospital Aarau, Aarau, Switzerland.
⁵ Service and Central Laboratory of Hematology, CHUV, Lausanne University Hospital, Lausanne, Switzerland.
⁶ Division of Angiology and Hemostasis, Geneva University Hospital, Geneva, Switzerland.
⁷ Division of Hematology and Central Hematology Laboratory, Cantonal Hospital of Lucerne and University of Bern, Bern, Switzerland.
⁸ Clinic of Medical Oncology and Hematology and Institute of Laboratory Medicine, City Hospital Waid and Triemli, Zurich, Switzerland.
⁹ Centre for Laboratory Medicine St. Gallen, St. Gallen, Switzerland.
¹⁰ Clinic of Hematology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
¹¹ University of Zurich, Zurich, Switzerland.
¹² Department of Emergency Medicine, Inselspital, Bern University Hospital, Bern, Switzerland.
¹³ Department of Hematology, Inselspital, Bern University Hospital, Bern, Switzerland.

Abstract

Background: The thrombin generation assay (TG) is a promising approach to measure the degree of anticoagulation in patients treated with direct oral anticoagulants (DOAC). A strong association with plasma drug concentrations would be a meaningful argument for the potential use to monitor DOAC. Objectives: We aimed to study the correlation of TG with rivaroxaban, apixaban, and edoxaban drug concentrations in a large, prospective multicenter cross-sectional study. Methods: Five-hundred and fifty-nine patients were included in nine tertiary hospitals. The Technothrombin® TG was conducted in addition to an anti-Xa assay; LC-MS/MS was performed as the reference standard. Results: Correlation (r_s) between thrombin generation measurements and drug concentrations was -0.72 for peak thrombin generation (95% confidence interval, CI, -0.77, -0.66), -0.55 for area under the curve (AUC; 95% CI -0.61, -0.48), and 0.80 for lag time (95% CI 0.75, 0.84). In contrast, r_s was 0.96 with results of the anti-Xa activity (95% CI 0.95-0.97). Sensitivity with regard to the clinically relevant cut-off value of 50 μgL^-1 was 49% in case of peak thrombin generation (95% CI, 44, 55), 29% in case of AUC (95% CI, 24, 34), and 64% in case of lag time (95% CI, 58, 69). Sensitivity of the anti-Xa assay was 95% (95% CI, 92, 97). Conclusions: The correlation of thrombin generation measurements with DOAC drug concentrations was weak, and clinically relevant drug levels were not predicted correctly. Our results do not support an application of TG in the monitoring of DOAC.

Keywords: anti-Xa assay; apixaban; diagnostic accuracy; direct oral anticoagulants; edoxaban; laboratory monitoring; rivaroxaban; thrombin generation assay.