Overcoming issues in plasmatic evaluation of direct Factor Xa inhibitors

: Recent advances in DOAC measurement

Abstract

After several decades of dominance of vitamin K antagonists (VKAs) and indirect coagulation inhibitors in the field of anticoagulant agents, pharmaceutical companies developed a new class of anti-thrombotic - anticoagulants: Direct Oral Anticoagulants (DOACs). Among them are the direct thrombin inhibitors, of which the only representative is dabigatran etexilate (Pradaxa®) and the direct factor Xa (FXa) inhibitors. These currently include rivaroxaban (Xarelto®), apixaban (Eliquis®) and edoxaban (Lixiana®). The arrival on the market of these new molecules required the adaptation and development of new dosing methods for evaluating their concentration and effect in the coagulation. In parallel, it was necessary to evaluate the impact of these molecules on diagnostic tests used for the identification of coagulation abnormalities in patients. It is at this stage that my thesis subject brings answers and opens new perspectives for the future. The objectives of this thesis were numerous. Firstly, following the arrival of betrixaban (BevyxXa®) in the USA, it was necessary to determine its impact on standard hemostasis and diagnostic tests and to assess the accuracy of chromogenic methods for its monitoring. As chromogenic methods are not considered as gold standard methods for measuring the concentration of these agents in blood samples, we decided to develop in-house UHPLC-MS/MS methods for all DOACs on the European market considering their key, pharmacologically active, metabolites (apixaban, edoxaban and edoxaban-M4, rivaroxaban and dabigatran and acyl-glucuronide). We particularly evaluated the case of edoxaban which is the only anti-Xa drug with active metabolites. Finally, we investigated the overall impact of anti-Xa and dabigatran on the diagnostic tests used for assessment of thrombophilia status. In conclusion, the presence of an anticoagulant or one of its active metabolites can bias or falsify standard or diagnostic, making chromogenic tests difficult to interpret and forcing UHPLC-MS/MS methods to consider active metabolites.

Date of Award	6 Jul 2022
Original language	English
Awarding Institution	University of Namur
Sponsors	University of Namur
Supervisor	Jonathan Douxfils (Supervisor), Jean-Michel Dogne (Co-Supervisor), Julie Laloy (Co-Supervisor), Bernard Masereel (President), Aurélien Lebreton (Jury), Francois Mullier (Jury) & Philippe Hainaut (Jury)