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

Michael Metze, Christian Pfrepper, Tristan Klöter, Stephan Stöbe, Roland Siegemund, Thomas Siegemund, Elvira Edel, Ulrich Laufs, Sirak Petros, Michael Metze, Christian Pfrepper, Tristan Klöter, Stephan Stöbe, Roland Siegemund, Thomas Siegemund, Elvira Edel, Ulrich Laufs, Sirak Petros

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.

Keywords: anticoagulants/therapeutic use; blood coagulation; dabigatran/therapeutic use; factor Xa inhibitors/therapeutic use; thrombin/analysis; thrombin/drug effects.

© 2020 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals, Inc on behalf of International Society on Thrombosis and Haemostasis.

Figures

Figure 1
Figure 1
Plasma levels of the different DOACs at baseline (t0 h) and 12 h (t12 h) after intake. DOACs, direct oral anticoagulants
Figure 2
Figure 2
A, Apixaban group: thrombin generation parameters at baseline (t0 h), 12 h after drug intake (t12 h) compared to baseline and controls (numbers represent P values from Mann‐Whitney U‐test). B, Edoxaban group: thrombin generation parameters at baseline (t0 h), 12 h after drug intake (t12 h) compared to baseline and controls (numbers represent P values from Mann‐Whitney U‐test). C, Rivaroxaban group: thrombin generation parameters at baseline (t0 h), 12 h after drug intake (t12 h) compared to baseline and controls (numbers represent P values from Mann‐Whitney U‐test). D, Dabigatran group: thrombin generation parameters at baseline (t0 h), 12 h after drug intake (t12 h) compared to baseline and controls (numbers represent P values from Mann‐Whitney U‐test)

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