Effects of direct oral anticoagulant treatment on hemostasis in patients with atrial fibrillation

Abstract: The direct oral anticoagulants (DOAC) – dabigatran, rivaroxaban, apixaban and edoxaban – were approved without the need for routine monitoring. However, in parallel with clinical implementation, studies on how to measure the effect of DOACs have become a research area of increasing interest during the last decade. The obvious need to assess the anticoagulant effect of DOACs in emergency situations such as bleeding and before emergency surgery has driven this research. Further characterization of the effects of DOACs on different parts of hemostasis has also been in focus of research. The aims of this thesis were to evaluate and improve the use of point-of-care (POC) tests to rapidly determine DOAC effects, and to further increase knowledge of different DOACs’ effect on hemostasis by analyzing their effect on both global and more specific coagulation assays. In study I, we evaluated two whole blood-based tests, the viscoelastic test rotational thromboelastometry (ROTEM), and the flow-based Total Thrombus-Formation analysis system (T-TAS) in patients with atrial fibrillation (AF) on dabigatran treatment. We found that dabigatran concentration correlated strongly with ROTEM clotting time (CT) when activated with two commercial triggers (r-values 0.92 and 0.93), but CT could still be within normal reference interval at significant dabigatran concentrations. There were weak correlations however, between dabigatran concentration and T-TAS data, both time-related thrombus formation and total thrombus formation (r-values 0.39-0.41). In study II, we used ROTEM-CT to show that a thrombin-based trigger was more sensitive than commercial triggers for detection of dabigatran, both in vitro and in samples from patients with AF. The thrombin-based trigger accurately discriminated between samples with dabigatran concentrations above or below 20 ng/mL (100 % sensitivity and specificity). In study III, we went on to investigate the most commonly used DOAC, i.e apixaban. Using ROTEMCT we showed that a factor Xa (FXa)-based trigger was more sensitive than a snake venom-based or commercial trigger for detection of apixaban, both in vitro and in samples from AF patients. The FXa-based trigger accurately discriminated between samples with apixaban concentration above or below 20 ng/mL (100 % sensitivity and specificity). Results were available within 20 min, considerably faster than emergency analyses of drugconcentrations determined at the chemistry lab of the hospital. In study IV, we investigated the effects of DOACs by analyzing both direct and global methods of hemostasis. For comparison, plasma from warfarin-treated patients were also analyzed. Dabigatran treatment was associated with a more permeable fibrin network, delayed thrombin generation and fibrin formation and a lower fibrin turn-over compared to rivaroxaban and apixaban. Warfarin tended to have stronger effects than the FXa-inhibitors. There were no significant differences between apixaban and rivaroxaban in any of the tests performed. In conclusion, ROTEM with DOAC-specific triggers is a promising method to rapidly detect DOAC effect in emergency situations. In patients treated with OACs according to clinical routine, dabigatran treatment was the drug associated with the broadest anticoagulating effects.

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