Assessment of the effect of direct oral anticoagulants dabigatran, rivaroxaban, and apixaban in healthy male volunteers using a thrombin generation assay

Artang, Ramin; Anderson, Maren; Riley, Paul; Nielsen, Jørn Dalsgaard

doi:10.1002/rth2.12044

Cited by 31 publications

(41 citation statements)

References 21 publications

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“…Of note, although the ETP is the thrombin generation parameter most frequently analyzed and reported, velocity index and peak height are probably more sensitive biomarkers of hypercoagulability than ETP itself in the presence of both combined oral contraceptives and factor V Leiden mutation (Table S1). A similar observation has been already made by our group and others in other populations . It is therefore important to analyze the whole thrombin generation profile and not to focus only on ETP.…”

Section: Discussionsupporting

confidence: 84%

Thrombin generation in a woman with heterozygous factor V Leiden and combined oral contraceptives: A case report

Zermatten

Calderara

Aliotta

et al. 2020

Research and Practice in Thrombosis and Haemostasis

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Combined oral contraceptives and factor V Leiden mutation are multiplicative risk factors for venous thromboembolism. However, it remains unknown whether this multiplicative effect is reflected in thrombin generation assays. We report here the evolution of the thrombin generation profile while taking combined oral contraceptives and after their discontinuation in a woman with heterozygous factor V Leiden mutation. The proband exhibited a distinctly prothrombotic thrombin generation profile including markedly decreased thrombomodulin (TM) sensitivity, compared to the control population. This profile possibly reflected a high thrombotic risk. After discontinuation of combined oral contraceptives, thrombin generation and TM sensitivity improved greatly, leaving only a slightly prothrombotic profile. Therefore, the multiplied thrombotic risk occurring with simultaneous combined oral contraceptives and factor V Leiden mutation is reflected by a thrombin generation assay performed without and with TM. This could be a promising tool to identify women taking combined oral contraceptives at high risk for venous thromboembolism. Further studies are needed to verify this hypothesis.

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Section: Discussionsupporting

confidence: 84%

Thrombin generation in a woman with heterozygous factor V Leiden and combined oral contraceptives: A case report

Zermatten

Calderara

Aliotta

et al. 2020

Research and Practice in Thrombosis and Haemostasis

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“…This persistently inhibitory effect had been previously shown in subjects analyzed in the absence of TM, but never in the presence. The involvement of the inhibitory dynamic system of activated protein C, formed in the presence of TM by thrombin, contrasts with what occurs in subjects under vitamin K antagonist therapy, whose hypo‐gamma‐carboxylated protein C and protein S are altered .…”

Section: Discussionsupporting

confidence: 65%

“…While numerous studies on rivaroxaban PK variability have been published, 5–14 few focused on TG parameter time profiles . The originality of the present study lies in two main features: (a) We analyzed ex vivo rivaroxaban PD in a substantial number of healthy volunteers ( n = 59) with TG determined using an automated system under different TF conditions, including one in the presence of TM; (b) relevant PD models were constructed, enabling estimation of interindividual PD variability …”

Section: Discussionmentioning

confidence: 99%

“…13 A more-limited number of studies investigated ex vivo interindividual rivaroxaban PD variability. 9,11,12,[15][16][17][18][19][20][21][22] Among assays measuring clot formation, prothrombin time was the most commonly used in prior published studies, showing a poor suitability to assess rivaroxaban PD, especially at low concentrations. Moreover, prothrombin time sensitivity varies widely across reagents.…”

Section: Introductionmentioning

confidence: 99%

“…18,23,25 Thrombin generation (TG) has been proposed as an attractive assay to assess in vitro or ex vivo direct FXa inhibitor effect on coagulation based on studies with small series of healthy volunteers or patients, after single or repeated direct Xa inhibitors dose exposure (rivaroxaban, apixaban, edoxaban, or otamixaban). [15][16][17][18][19][20][21][22][26][27][28][29][30][31] However, some persistent issues remain regarding the most appropriate experimental conditions among different methods, including TF concentrations. 32 Moreover, data regarding the magnitude of TG parameter interindividual variability in subjects receiving direct Xa inhibitors are scarce.…”

Section: Introductionmentioning

confidence: 99%

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Rivaroxaban pharmacodynamics in healthy volunteers evaluated with thrombin generation and the active protein C system: Modeling and assessing interindividual variability

Siguret

Abdoul

Delavenne

et al. 2019

Journal of Thrombosis and Haemostasis

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Background Rivaroxaban is a direct factor Xa inhibitor with substantial inter‐individual pharmacokinetic (PK) variability. Pharmacodynamic (PD) variability, especially assessed with thrombin generation (TG), has been less documented. Objectives (i) To assess TG parameter time profiles in healthy volunteers, with TG being studied under different conditions and (ii) to model the relationship between rivaroxaban concentrations and TG parameters and subsequently estimate interindividual variability. Methods Sixty healthy male volunteers (DRIVING‐NCT01627665) received a single 40‐mg rivaroxaban dose. Blood sampling was performed at baseline and 10 predefined time points over 24 h. The TG was investigated with the fully automated ST‐Genesia system (Stago), using two tissue‐factor (TF) concentrations, in the absence (−), or presence (+) of thrombomodulin (TM) for the lowest one. The PD models were built to characterize the relationships between plasma rivaroxaban concentrations and endogenous thrombin potential (ETP) or peak height induced by the lowest TF concentration. Results Thrombin generation parameter time profiles with the lowest TF concentration showed a good sensitivity to rivaroxaban, especially +TM (active protein C negative feedback). The relationship between rivaroxaban concentrations and TG parameters was modeled with a sigmoidal relation. Mean rivaroxaban concentrations halving the baseline value of ETP and peak height (−TM) (C50) were of 284 and 33.2 ng/mL, respectively: +TM, C50 declined to 19.4 and 13.8 ng/mL, reflecting a powerful inhibitory effect. The estimated C50 population coefficients of variation were of 12.2% (−TM) and 31.3% (+TM) with the peak height models, 34.8% (+TM) with the ETP model. Conclusions This low‐rivaroxaban to moderate‐rivaroxaban PD variability in healthy volunteers contrasts with the substantial PK variability and deserves to be studied in different patient settings.

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Fully automated thromboelastograph TEG 6s to measure anticoagulant effects of direct oral anticoagulants in healthy male volunteers

Artang

Anderson

Nielsen

2019

Research and Practice in Thrombosis and Haemostasis

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Background The ability to assess the hemostatic effect of the direct oral anticoagulant (DOACs) may be valuable in clinical situations such as bleeding or thrombosis, before urgent surgery, or reversal of anticoagulation. We sought to assess the anticoagulant effect of DOACs with the new‐generation fully automated thrombelastograph TEG 6s using resonance‐frequency viscoelasticity measurements and disposable multichannel microfluidic cartridges. Methods A single dose of oral dabigatran 150 mg, rivaroxaban 20 mg, or apixaban 5 mg was given to 9 healthy males. Phlebotomy was performed at 0, 1, and 3 hours after administration of DOAC. TEG parameters were measured using TEG_6s. Concentrations of DOACs were measured using chromogenic assays. The TEG parameters were correlated to the DOAC concentrations. Results The reaction time (R) demonstrated the strongest response to DOAC intake. There were no correlations between other TEG parameters and DOAC concentrations. Using the direct thrombin inhibitor (DTI) channel, R was significantly correlated with dabigatran levels (r = 0.94, P < 0.0001). Using the anti–factor Xa (AFXa) channel, R was significantly correlated with rivaroxaban and apixaban levels (r = 0.93 and r = 0.83, respectively; P < 0.0001 for both). R >2.5 minutes for dabigatran (DTI channel), >2.5 minutes for apixaban, and >1.8 minutes for rivaroxaban (AFXa channel) were associated with 100% sensitivity and ≥ 90% specificity to detect DOAC levels of ≥ 50 ng/mL. Conclusion We have demonstrated that TEG_6s R has significant correlation with DOAC blood concentrations and has potential for monitoring the DOAC's effect on hemostasis with reasonable sensitivity in the small sample analyzed. This novel technology is easy to use on a small volume of whole blood without requiring a specialized laboratory. Further study is warranted to correlate R with clinical outcomes.

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Assessment of the effect of direct oral anticoagulants dabigatran, rivaroxaban, and apixaban in healthy male volunteers using a thrombin generation assay

Cited by 31 publications

References 21 publications

Thrombin generation in a woman with heterozygous factor V Leiden and combined oral contraceptives: A case report

Thrombin generation in a woman with heterozygous factor V Leiden and combined oral contraceptives: A case report

Rivaroxaban pharmacodynamics in healthy volunteers evaluated with thrombin generation and the active protein C system: Modeling and assessing interindividual variability

Fully automated thromboelastograph TEG 6s to measure anticoagulant effects of direct oral anticoagulants in healthy male volunteers

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