Pleiotropic actions of factor Xa inhibition in cardiovascular prevention: mechanistic insights and implications for anti-thrombotic treatment

Abstract

Atherosclerosis is a chronic inflammatory disease in which atherothrombotic complications lead to cardiovascular morbidity and mortality. At advanced stages, myocardial infarction, ischemic stroke and peripheral artery disease (PAD), including major adverse limb events (MALE), are caused either by acute occlusive atherothrombosis, or by thromboembolism. Endothelial dysfunction, vascular smooth muscle cell activation and vascular inflammation are essential in the development of acute cardiovascular events. Effects of the coagulation system on vascular biology extend beyond thrombosis. Under physiological conditions, coagulation proteases in blood are pivotal in maintaining hemostasis and vascular integrity. Under pathological conditions, including atherosclerosis, the same coagulation proteases (including factor Xa, factor VIIa and thrombin) become drivers of atherothrombosis, working in concert with platelets and vessel wall components. While initially atherothrombosis was attributed primarily to platelets, recent advances indicate the critical role of fibrin clot and plasma coagulation factors. Mechanisms of atherothrombosis and hypercoagulability vary depending on plaque erosion or plaque rupture. In addition to contributing to thrombus formation, factor Xa and thrombin can affect endothelial dysfunction, oxidative stress, vascular smooth muscle cell function as well as immune cell activation and vascular inflammation. By these mechanisms they promote atherosclerosis and contribute to plaque instability. In this review, we first discuss the postulated vasoprotective mechanisms of protease activated receptor (PARs) signaling induced by coagulation enzymes under physiological conditions. Next, we discuss preclinical studies linking coagulation with endothelial cell dysfunction, thromboinflammation and atherogenesis. Understanding these mechanisms is pivotal for the introduction of novel strategies in cardiovascular prevention and therapy. We therefore translate these findings to clinical studies of direct oral anticoagulant (DOAC) drugs and discuss the potential relevance of dual pathway inhibition for atherothrombosis prevention and vascular protection.

Antithrombotic Therapy in Patients with Peripheral Artery Disease: A Focused Review on Oral Anticoagulation

“…The most investigated DOAC for the reduction of cardiovascular outcomes in patients with previous atherosclerosis is rivaroxaban, given its pleiotropic actions in cardiovascular prevention. FXa has a dual-pathway function by decreasing thrombin generation and potentially showing complementary favorable activity, such as anti-inflammatory effects and endothelial protection [54,55]. To date, rivaroxaban is the only DOAC that has successfully undergone phase III evaluation in patients with ACS.…”

Many Good Reasons to Switch from Vitamin K Antagonists to Non-Vitamin K Antagonists in Patients with Non-Valvular Atrial Fibrillation

“…By binding and cleaving these transmembrane G protein-coupled receptors, FXa and thrombin initiate downstream intracellular signaling pathways that, in the cardiovascular (CV) system, are protective or detrimental depending on the context, the local concentrations of coagulation factors, and the extent of PAR engagement. While in physiological conditions coagulation proteases exert vasculoprotective effects through PARs, in pathological conditions they elicit PAR-driven cellular events that promote endothelial dysfunction, vascular muscle cell impairment, and inflammation [40]. Along with thrombomodulin and endothelial protein C receptor, thrombin also participates in the activation of a specific PAR, PAR-1, by activated protein C, which is anticoagulant, anti-inflammatory, and antiapoptotic [41].…”

Thrombosis: Grand Challenges Ahead!

“…A second challenge is to determine whether dampening the coagulation cascade by the above strategies, could pave the way for primary prevention in more subjects, also those at risk of atherothrombosis. This should preferably be done in a tailored manner, i.e., taking into account the patient's ambient level of coagulation activity including knowledge of the relevant determinants of this coagulation profile ( 27 ). For instance, ambient coagulation may be characterized by hyperreactivity of platelets in one person or by changes in the plasmatic system in the other.…”

“…For inflammation, this approach finds strong support in the data from Jupiter (stratifying on CRP), Cantos (blocking Il-1beta), and most recent studies with colchicine ( 30 ). The idea of similarly using (combined) antithrombotic drugs to also diminish the “thrombo” element of thrombo-inflammatory vascular disease by improving vascular “health” is a tempting and major challenge for the years ahead ( 27 ).…”

“…Fifth , we are on the verge of better understanding the ways that selective proteases like thrombin and factor Xa direct processes of thrombo-inflammation and the impact that this crosstalk may have in several complex CVD (such as atherosclerosis, atrial fibrillation, ischemic stroke, etc.) ( 27 , 46 ). The fact that millions of patients are on long term oral anticoagulants with, like with vitamin K antagonists (VKA) potential impact on the vasculature (calcification in case of VKA), cannot be overestimated ( 47 ).…”