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Background and Aims: The platelet inhibitor aspirin reduces inflammation and atherosclerosis in both apolipoprotein E deficient (apoE -/- ) mice and low-density lipoprotein receptor deficient (Ldlr -/- ) mice. Similarly, the factor Xa inhibitor rivaroxaban reduces atherosclerosis in both apoE -/- and Ldlr -/- mice. We tested the hypothesis that the combination of aspirin and rivaroxaban reduces atherosclerosis in mice to a greater extent than either agent alone., Methods: Male Ldlr -/- mice were fed a western-type diet for 12 weeks to induce atherosclerosis. Cohorts of mice received aspirin in the water and/or rivaroxaban in the diet. Atherosclerosis and lesion composition were measured in the aortic sinus and the aorta. Expression of 55 proteins in the aorta and plasma was determined using multiplex ELISA assays., Results: Aspirin alone, rivaroxaban alone, and the combination of both agents significantly reduced atherosclerosis in the Ldlr -/- mice compared with control Ldlr -/- mice fed a western-type diet. However, there were no significant differences in atherosclerosis in the group receiving aspirin and rivaroxaban compared with the groups that received aspirin or rivaroxaban alone. Aspirin, rivaroxaban and the combination reduced macrophage content and apoptosis in the lesions compared with controls but there was no difference between the three treatment groups. We observed statistically significant changes in the expression of a small number of proteins in the aorta and plasma in mice treated with aspirin and/or rivaroxaban., Conclusions: Contrary to our expectation, the combination of aspirin and rivaroxaban did not further reduce atherosclerosis in Ldlr -/- mice beyond the level observed with each agent alone., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Atherosclerosis is a chronic inflammatory disease that is characterized by the formation of lipid rich plaques in the wall of medium to large sized arteries. Atherothrombosis represents the terminal manifestation of this pathology in which atherosclerotic plaque rupture or erosion triggers the formation of occlusive thrombi. Occlusion of arteries and resultant tissue ischemia in the heart and brain causes myocardial infarction and stroke, respectively. Tissue factor (TF) is the receptor for the coagulation protease factor VIIa, and formation of the TF:factor VIIa complex triggers blood coagulation. TF is expressed at high levels in atherosclerotic plaques by both macrophage-derived foam cells and vascular smooth muscle cells, as well as extracellular vesicles derived from these cells. Importantly, TF mediated activation of coagulation is critically important for arterial thrombosis in the setting of atherosclerotic disease. The major endogenous inhibitor of the TF:factor VIIa complex is TF pathway inhibitor 1 (TFPI-1), which is also present in atherosclerotic plaques. In mouse models, increased or decreased expression of TFPI-1 has been found to alter atherosclerosis. This review highlights the contribution of TF-dependent activation of coagulation to atherthrombotic disease., (Copyright © 2020 Elsevier B.V. All rights reserved.)