VPB0570 - Assessment of Impact of Metabolites of Edoxaban and Dabigatran on Fibrin and Thrombin Generation Assays

Background: Edoxaban and dabigatran are factor Xa and direct thrombin inhibitors, respectively and are metabolized in pharmacologically active moiety. These anticoagulants are known to impact coagulation assays, and it is assumed that metabolites could also affect the thrombin and fibrin generation.

Aims: This study aims to compare the pharmacodynamics of DOACs and their metabolites in plasma on thrombin and fibrin generation.

Methods: Edoxaban and its metabolite (M4) were separately spiked in plasma for assessment of their pharmacodynamic properties. Edoxaban and M4 were also spiked together in plasma. The same experiment was performed with dabigatran and its metabolite (glucoronide-dabigatran). Final concentrations in plasma were 30, 50 and 100 ng/mL. The control used is plasma spiked with a PBS solution.
The thrombin generation assay (TGA) was assessed by the calibrated automated thrombogram (CAT) and the fibrin formation was assessed with the FibWave on ACL Top analyzer. A mixture of silica plus phospholipids (PLs) (intrinsic pathway) and tissue factor (±5pM) plus PLs (±4µM) (extrinsic pathway) were used as intermediate reagent. The coagulation process was triggered by the addition of FluCa (TGA) or CaCl2 solution (FibWave).

Results: Edoxaban and M4 impacted more the extrinsic than the intrinsic pathway. Interesting, the M4-metabolite more prolonged clotting time and more reduced the thrombin and fibrin generation than edoxaban.
Dabigatran and glucuronide-dabgiatran impacted acceleration in fibrin assay and time parameters in both assays. Contrary to edoxaban, glucuronide-dabigatran did not seem to have a different pharmadynamic profile than dabigatran.

Conclusion(s): Contrary to edoxaban and M4-metabolite, dabigatran and glucuronide-dabigatran seemed to have similar influence the thrombin and fibrin generation. In the case of an increase in the M4/edoxaban ratio due to hepatic or renal impairments or in case of drug interactions, the impact of M4-metabolite on coagulation could be more important at usual concentrations.