Pleiotropic effects of NOACs with focus on edoxaban: scientific findings and potential clinical implications

Non-vitamin K antagonist oral anticoagulants (NOACs) are well-established as inhibitors of factor Xa (FXa) and thrombin in the treatment and prevention of thrombosis. However, there is growing evidence that beneficial outcomes might be based on additional pleiotropic effects beyond anticoagulation. FXa and thrombin are also known to activate protease-activated receptors (PARs), which can mediate pro-inflammatory and pro-fibrotic effects. Since PAR‑1 and PAR‑2 play an important role in the development of atherosclerosis, the inhibition of this pathway represents an interesting potential target for preventing the progression of atherosclerosis and fibrosis. This review focuses on potential pleiotropic effects of FXa inhibition with edoxaban seen in a variety of studies in different in vitro and in vivo test systems. As common findings from these experiments, edoxaban was able to attenuate FXa- and thrombin-induced pro-inflammatory and pro-fibrotic effects and decrease pro-inflammatory cytokine expression. In some, but not all experiments edoxaban was also shown to decrease the levels of PAR‑1 and PAR‑2 expression. Further studies are required to clarify the clinical implications of the pleiotropic effects mediated by NOACs.