Distinct pleiotropic effects of direct oral anticoagulants on cultured endothelial cells: a comprehensive review

Abstract

Direct Oral Anticoagulants (DOACs) have simplified the treatment of thromboembolic disease. In addition to their established anticoagulant effects, there are indications from clinical and preclinical studies that DOACs exhibit also non-anticoagulant actions, such as anti-inflammatory and anti-oxidant actions, advocating overall cardiovascular protection. In the present study, we provide a comprehensive overview of the existing knowledge on the pleiotropic effects of DOACs on endothelial cells (ECs) in vitro and their underlying mechanisms, while also identifying potential differences among DOACs. DOACs exhibit pleiotropic actions on ECs, such as anti-inflammatory, anti-atherosclerotic, and anti-fibrotic effects, as well as preservation of endothelial integrity. These effects appear to be mediated through inhibition of the proteinase-activated receptor signaling pathway. Furthermore, we discuss the potential differences among the four drugs in this class. Further research is needed to fully understand the pleiotropic effects of DOACs on ECs, their underlying mechanisms, as well as the heterogeneity between various DOACs. Such studies can pave the way for identifying biomarkers that can help personalize pharmacotherapy with this valuable class of drugs.

Pleiotropic Effects of Direct Oral Anticoagulants in Chronic Heart Failure and Atrial Fibrillation: Machine Learning Analysis

“…As mentioned above, preclinical studies showed anti-inflammatory, antioxidant and anti-fibrotic effects on endothelial cells. Importantly, several studies highlighted DOAC-mediated effects on endothelial cells in terms of improvement in endothelial function and integrity and the inhibition of neo-angiogenesis [ 22 , 39 , 40 ]. Although peculiar effects of a single molecule have not yet been determined, it is generally accepted that factor Xa inhibitors produce anti-angiogenic and anti-fibrotic effects beyond the anti-inflammatory action and stabilization of endothelial cells.…”

“…The ability of DOACs to regulate PAR responses provides new insights into their actions beyond anticoagulation. Indeed, several preclinical studies demonstrated that DOACs exhibit pleiotropic actions on endothelial cells such as anti-inflammatory, anti-atherosclerotic and anti-fibrotic effects, as well as the preservation of endothelial integrity [ 19 , 20 , 21 , 22 ]. It has been established that DOACs block some pro-inflammatory processes, regulating the expression of some key cytokines in a plethora of in vitro cell systems [ 22 ] as well as in animal models of atherosclerotic lesions [ 23 , 24 ].…”

“…Indeed, several preclinical studies demonstrated that DOACs exhibit pleiotropic actions on endothelial cells such as anti-inflammatory, anti-atherosclerotic and anti-fibrotic effects, as well as the preservation of endothelial integrity [ 19 , 20 , 21 , 22 ]. It has been established that DOACs block some pro-inflammatory processes, regulating the expression of some key cytokines in a plethora of in vitro cell systems [ 22 ] as well as in animal models of atherosclerotic lesions [ 23 , 24 ]. Furthermore, the decrease in endothelial permeability and reduction in ROS generation have been reported as the main mechanisms underlying the capability of DOACs to enhance endothelial barrier integrity [ 25 , 26 ].…”

Circulating microRNAs and DNA Methylation as Regulators of Direct Oral Anticoagulant Response in Atrial Fibrillation and Key Elements for the Identification of the Mechanism of Action (miR-CRAFT): Study Design and Patient Enrolment

“…Notably, there is evidence that the activation of PAR signaling in the heart plays a pivotal role in cardiac inflammation, fibrotic response, and repair processes [ 31 ]. DOACs, by inhibiting factor Xa and thrombin, are recognized for preventing PAR signaling activation, thereby extending their effects beyond thromboembolism [ 2 ] []. Recent findings also propose that DOACs may deter atrial remodeling in rats through PAR signaling inhibition [ 32 ] and ameliorate cardiac fibrosis in AF mice [ 33 ].…”

“…Thus, the anticoagulant effect of DOACs is exerted via the inhibition of blood clotting. Since thrombin is well known to activate protease-activated receptor (PAR) signaling, DOACs potentially exert effects beyond anticoagulation [ 2 ].…”