Foulon-Pinto Geoffrey, Jourdi Georges, Delrue Maxime, Lafuente-Lafuente Carmelo, Cavalie Candice, Gouin-Thibault Isabelle, Le Guen Julien, Gaussem Pascale, Mirault Tristan, Puymirat Etienne, Lecompte Thomas, Pautas Eric, Curis Emmanuel, Siguret Virginie
INSERM UMR_S1140, Université Paris Cité, Paris, France.
Hématologie Biologique, Hôpital Lariboisière, Assistance Publique-Hôpitaux de Paris, Paris, France.
Res Pract Thromb Haemost. 2025 Jul 15;9(5):102969. doi: 10.1016/j.rpth.2025.102969. eCollection 2025 Jul.
Scarce data are available on pharmacodynamic (PD) variability in very elderly patients receiving direct oral anticoagulants (DOACs) for atrial fibrillation (AF). Thrombodynamics-4D (TD-4D), which simultaneously assesses fibrin clot formation and thrombin generation, has not yet been tested in patients on rivaroxaban, apixaban, or dabigatran.
To (i) evaluate TD-4D's ability to assess DOAC effect added to normal plasma; (ii) assess DOAC PD in very elderly patients with AF along with DOAC concentrations; (iii) identify factors associated with interindividual variability of DOAC PD at peak and trough levels.
Assessment of Direct oral Anticoagulants in Geriatrics (NCT02464488) is a prospective, multicenter study including inpatients aged ≥80 years receiving DOACs for AF for at least 4 days. Fibrinography and thrombography parameters were measured using TD-4D along with plasma DOAC concentrations (antifactor [F]Xa or anti-FIIa activity) and fibrinogen.
We analyzed pooled normal plasma samples spiked with DOACs and 345 samples from 187 Assessment of Direct oral Anticoagulants in Geriatrics patients (mean ± SD, age 87 ± 4 years; 69% females): 69 on rivaroxaban, 70 on apixaban, and 48 on dabigatran. All 3 DOACs prolonged fibrinography lag time and decreased initial rate of clot growth and clot size at 30 minutes in a concentration-dependent manner in spiking experiments and patients. DOACs prolonged temporal thrombography parameters while decreasing thrombin peak height and endogenous thrombin potential. At trough, apixaban and dabigatran concentrations were the only significant predictors of interindividual variability in both thrombin peak height (thrombography) and initial rate of clot growth (fibrinography). In rivaroxaban patients, cardiac failure significantly influenced thrombin peak height variability.
Fibrinography and thrombography, assessed simultaneously with TD-4D, provided consistent results for all 3 DOACs, including dabigatran. Substantial PD variability was observed, partly influenced by DOAC concentrations. The clinical relevance of such variability remains to be demonstrated.
关于接受直接口服抗凝剂（DOACs）治疗心房颤动（AF）的高龄患者的药效学（PD）变异性的数据稀缺。血栓动力学-4D（TD-4D）可同时评估纤维蛋白凝块形成和凝血酶生成，尚未在接受利伐沙班、阿哌沙班或达比加群治疗的患者中进行测试。
（i）评估TD-4D评估添加到正常血浆中的DOAC效果的能力；（ii）评估高龄AF患者的DOAC药效学以及DOAC浓度；（iii）确定在峰浓度和谷浓度时与DOAC药效学个体间变异性相关的因素。
老年患者直接口服抗凝剂评估（NCT02464488）是一项前瞻性、多中心研究，纳入年龄≥80岁、接受DOACs治疗AF至少4天的住院患者。使用TD-4D测量纤维蛋白成像和血栓成像参数，同时测量血浆DOAC浓度（抗因子[F]Xa或抗FIIa活性）和纤维蛋白原。
我们分析了添加DOACs的正常血浆混合样本以及187例老年患者直接口服抗凝剂评估患者（平均±标准差，年龄87±4岁；69%为女性）的345份样本：69例使用利伐沙班，70例使用阿哌沙班，48例使用达比加群。在加样实验和患者中，所有3种DOACs均以浓度依赖性方式延长了纤维蛋白成像滞后时间，并降低了30分钟时凝块生长的初始速率和凝块大小。DOACs延长了血栓成像时间参数，但降低了凝血酶峰值高度和内源性凝血酶潜力。在谷浓度时，阿哌沙班和达比加群浓度是凝血酶峰值高度（血栓成像）和凝块生长初始速率（纤维蛋白成像）个体间变异性的唯一显著预测因素。在利伐沙班治疗的患者中，心力衰竭显著影响凝血酶峰值高度变异性。
与TD-4D同时评估的纤维蛋白成像和血栓成像对所有3种DOACs（包括达比加群）均提供了一致的结果。观察到显著的药效学变异性，部分受DOAC浓度影响。这种变异性的临床相关性仍有待证实。
