Plasma levels do not predict thrombin generation in patients taking direct oral anticoagulants

Abstract

Background The antithrombotic effect of direct oral anticoagulants (DOAC) in specific clinical scenarios is difficult to assess. Objective This study aimed to evaluate the effect of DOAC on thrombin generation (TG) in relation to their plasma level. Methods Eighty patients newly started on anticoagulation were included, 20 patients for each DOAC—apixaban, edoxaban, rivaroxaban, and dabigatran. Plasma was sampled before DOAC (baseline), at plasma peak time, 6 and 12 hours after starting DOAC for quantification of drug levels and TG. Results The baseline TG before DOAC intake showed inter‐individual variability. All DOACs significantly prolonged lag time (LT) and time to peak (TTP), but did not change endogenous thrombin potential (ETP). Anti‐Xa inhibitors but not dabigatran reduced thrombin peak, but the effect of apixaban at plasma peak was less pronounced (factor 1.6). LT and TTP prolongation of dabigatran was lower compared to anti‐Xa inhibitors. All DOACs showed a nonlinear dose‐response relationship, with the greatest antithrombotic effect at lower DOAC plasma levels. The inhibition of TG parameters between baseline and peak was parallel between individual patients but the coefficient of variation of TG was lower compared to drug levels. Conclusion The antithrombotic effect at DOAC peak plasma level measured by TG depends on the patient‐specific baseline TG level and the drug‐specific inhibition by the particular DOAC. Although peak plasma levels have a high variability, the variation of TG is lower compared to drug levels. Therefore, TG assays may be superior to plasma levels in the assessment of the intensity of anticoagulation.

The influence of direct oral anticoagulants on thrombin generation on Ceveron TGA

“…Normal TG parameters in apixaban treated patients have a slightly higher sensitivity and NPV for the prediction of low plasma levels compared to rivaroxaban but PPV and speci city were much better for rivaroxaban. This observation has been shown for the fully automated ST Genesia system as well 14 and is caused by the higher substance speci c reduction of TG by rivaroxaban 3 . The fact that speci city and PPV are lower in the TGA ceveron compared to the ST Genesia system 14 might be explained by the different activating agents and calibrators, but it could also be because of the different patient cohorts analysed in both studies.…”

“…Calibrated tests have been introduced to measure the concentration of DOACs in patient's plasma 2 . However, this does not necessarily correlate with the global hemostatic status of the patient 3 .…”

“…In those patients, blood was sampled at 3 time points after the intake of the DOAC. It is known that the individual base-line TG level has a high inter-and intraindividual variability 3,21,22 . The same DOAC plasma level in two different patients does not neccessarly translate into the same TG values 3 .…”

Influence of direct oral anticoagulants on thrombin generation on Ceveron TGA

“…It is known that the individual baseline TG level has a high inter and intraindividual variability. 3,21,22 The same DOAC plasma level in two different patients does not neccessarily translate into the same TG values. 3 Therefore, the higher correlation between the drug levels and the TG parameters reported with the CAT and the ST Genesia systems 10,14 may have been caused, at least in part, by the higher amount of blood samples taken from the same patient on the same day.…”

“…2 However, this does not necessarily correlate with the global hemostatic status of the patient. 3 The thrombin generation assay (TGA) is a global hemostatic assay to measure the tendency of a plasma sample to form thrombin after the initiation of the coagulation cascade. 4 It has initially been developed by Hemker and colleagues 5 and reflects the total thrombin kinetic.…”