Noncanonical Effects of Oral Thrombin and Factor Xa Inhibitors in Platelet Activation and Arterial Thrombosis

Abstract

Nonvitamin K oral anticoagulants (NOACs) or direct oral anticoagulants comprise inhibitors of factor Xa (rivaroxaban, apixaban, edoxaban) or factor IIa (dabigatran). Both classes efficiently interfere with the final or penultimate step of the coagulation cascade and showed superior net clinical benefit compared with vitamin K antagonists for prevention of thromboembolic events in patients with AF and for prevention and therapy of deep vein thrombosis and pulmonary embolism. None the less, accumulating data suggested, that there may be differences regarding the frequency of atherothrombotic cardiovascular events between NOACs. Thus, the optimal individualized NOAC for each patient remains a matter of debate. Against this background, some basic and translational analyses emphasized NOAC effects that impact on platelet activity and arterial thrombus formation beyond inhibition of plasmatic coagulation. In this review, we will provide an overview of the available clinical and translational evidence for so-called noncanonical NOAC effects on platelet activation and arterial thrombosis.

Factors Associated with Platelet Activation-Recent Pharmaceutical Approaches

“…Interestingly, cessation of dabigatran may induce a state of platelet activation [ 167 ]. Those antiplatelet effects have also been proposed for the factor Xa inhibitors [ 168 ]. It should be stressed that conflicting results have been reported, with Arantes et al noting no differences in the platelet function of patients with coronary artery disease when treated with dabigatran [ 169 ].…”

Elevated 8-isoprostane concentration is associated with thromboembolic events in patients with atrial fibrillation

“…Polzin et al have reported that NOACs, in particular factor Xa inhibitors, can reduce NOX2-mediated ROS production. 41 Woźniak et al have demonstrated that rivaroxaban induces an indirect repair of DNA by inhibiting ROS production in a model of vascular endothelial damage with 25-hydroxycholesterol. 42 Treatment using apixaban and rivaroxaban that inhibit both direct and thrombin-mediated actions of FXa, in part mediated by activation of cellular proteaseactivated receptors, was associated with lower levels of 8-isoprostane as compared to dabigatran.…”

A Rollercoaster Plunge into 2022

“…In 2020, we introduced optional “Visual Summaries” to convey the main message of the manuscript in a clear and concise graphic manner so that readers can grasp its contents and relevance at a glance. In the past two years, we have received an increasing number of such graphical abstracts which greatly improved the reading quality of the articles published 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 some of which have even been selected for the T&H Issue Cover 4 5 11 15 33 38 ( Fig. 2 ).…”