Meihandoest Tamana, Studt Jan-Dirk, Mendez Adriana, Alberio Lorenzo, Fontana Pierre, Wuillemin Walter A, Schmidt Adrian, Graf Lukas, Gerber Bernhard, Maeder Gabriela Monika, Bovet Cédric, Sauter Thomas C, Nagler Michael
Department of Epidemiology, Maastricht University, Maastricht, Netherlands.
Department of Clinical Chemistry, Inselspital, Bern University Hospital, and University of Bern, Bern, Switzerland.
Front Cardiovasc Med. 2021 Sep 9;8:717939. doi: 10.3389/fcvm.2021.717939. eCollection 2021.
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. We aimed to study the correlation of TG with rivaroxaban, apixaban, and edoxaban drug concentrations in a large, prospective multicenter cross-sectional study. 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. Correlation (r) 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 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 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). 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.
凝血酶生成测定法（TG）是一种很有前景的方法，用于测量接受直接口服抗凝剂（DOAC）治疗的患者的抗凝程度。与血浆药物浓度密切相关将是其用于监测DOAC的一个有意义的论据。我们旨在通过一项大型前瞻性多中心横断面研究，研究TG与利伐沙班、阿哌沙班和依度沙班药物浓度之间的相关性。九家三级医院纳入了559名患者。除了抗Xa测定外，还进行了Technothrombin®TG测定；采用液相色谱-串联质谱法（LC-MS/MS）作为参考标准。凝血酶生成测量值与药物浓度之间的相关性：凝血酶生成峰值的相关系数（r）为-0.72（95%置信区间，CI，-0.77，-0.66），曲线下面积（AUC）的相关系数为-0.55（95%CI -0.61，-0.48），滞后时间的相关系数为0.80（95%CI 0.75，0.84）。相比之下，与抗Xa活性结果的r为0.96（95%CI 0.95-0.97）。对于临床相关临界值50μg/L，凝血酶生成峰值的敏感性为49%（95%CI，44，55），AUC的敏感性为29%（95%CI ,24, 34），滞后时间的敏感性为64%（95%CI, 58, 69）。抗Xa测定的敏感性为95%（95%CI, 92, 97）。凝血酶生成测量值与DOAC药物浓度之间的相关性较弱，无法正确预测临床相关药物水平。我们的结果不支持将TG应用于DOAC的监测。
