Inhibition of thrombin generation 12 hours after intake of direct oral anticoagulants

Abstract

Background The residual antithrombotic activity 12 hours after intake of direct oral anticoagulants (DOACs) is of clinical relevance in the setting of bleeding or urgent surgery. Objective To evaluate the effects of DOACs on thrombin generation 12 hours after DOAC intake in comparison to baseline and a healthy control group. Methods Eighty patients were recruited, 20 patients for each approved DOAC: apixaban, edoxaban, rivaroxaban, and dabigatran. The patients were either to be put on anticoagulation for the first time or had stopped taking oral anticoagulation for at least 48 hours. Blood plasma was sampled before (baseline) and 12 hours after starting DOAC for quantification of drug levels and thrombin generation assayed using an automated system (ST Genesia). Sixty‐one blood donors served as control group. Results The factor Xa inhibitors significantly increased lag time (137%‐219%) and reduced thrombin peak (47%‐76%) and velocity index (17%‐44%) after 12 hours compared to baseline. Dabigatran showed prolongation of lag time to 133% and time to peak to 119%. All patients had residual antithrombotic activity, with reduced thrombin generation parameters 12 hours after DOAC intake compared to baseline and to the healthy control group. This effect remained significant in patients with low residual DOAC plasma levels <50 ng/mL. Conclusion Thrombin generation remains reduced 12 hours after DOAC intake. While thrombin peak is particularly modified by factor Xa inhibitors, all DOACs prolong the lag time and time to thrombin peak. In the setting of bleeding or urgent surgery, the automated thrombin generation assay may assist in decision making and antidote administration.

Study of thrombin generation with St Genesia to evaluate xaban pharmacodynamics: Analytical performances over 18 months

“…In order to compare in vitro the effect of rivaroxaban and apixaban on TG parameters, we chose to use frozen normal plasma (Cryocheck) spiked with increasing concentrations of xabans. Increasing xabans concentrations prolonged TG temporal parameters and decreased values of PH and ETP in a concentration‐dependant manner as previously shown in vitro as well as ex vivo 17,19‐21,26‐28 . These data confirm that measurement of TG parameters with ST Genesia enabled a reliable assessment of the PD response to rivaroxaban and apixaban, PH being more reliable than ETP 19‐21 .…”

2021 Update of the International Council for Standardization in Haematology Recommendations for Laboratory Measurement of Direct Oral Anticoagulants

“…Preliminary observations showed that thrombin generation testing is affected by all anticoagulant drugs, suggesting that this assay could be useful in assessing DOAC activity, but this deserves further confirmation in larger cohorts to validate this approach since to date, the role of TGA for clinical decision-making in DOAC-treated patients is not clear. 68,[70][71][72]…”

“…2). 24,[66][67][68][69][70][71] The ST Genesia (Diagnostica Stago, Asnières sur Seine Cedex, France), an automated analyzer for thrombin generation testing has the potential for a wide implementation in routine laboratories. Preliminary observations showed that thrombin generation testing is affected by all anticoagulant drugs, suggesting that this assay could be useful in assessing DOAC activity, but this deserves further confirmation in larger cohorts to validate this approach since to date, the role of TGA for clinical decision-making in DOAC-treated patients is not clear.…”

Thrombin generation assays are versatile tools in blood coagulation analysis: A review of technical features, and applications from research to laboratory routine

“…TGA has been applied in drug development to explore pharmacological principles and drug related side effects. TGA has for example been recently evaluated in dose finding studies of direct oral anticoagulants and to tailor therapeutic protocols with such substances 45‐48 …”