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The aim of this article is to highlight the importance of thrombotic processes in the development and complications of atherosclerotic vascular disease.Thrombin generated at sites of vascular inflammation activates major atheroma-associated cells including endothelial cells, platelets, smooth muscle cells, monocytes, and macrophages. Thrombin-activated cells produce a plethora of inflammatory mediators, such as regulated upon activation normal T cell expressed presumed secreted, macrophage migration inhibitory factor, and CD40 ligand, that promote atherosclerotic lesion formation and atherothrombotic complications of vascular disease. Additionally, thrombin-induced inflammatory mediators stimulate tissue factor procoagulant activity within atheroma to initiate a positive feedback loop where thrombin activation launches inflammatory signals that lead to further thrombin activation. Platelets, the main cellular effectors of the thrombotic system, also play a central role in the biology of atherosclerosis by producing inflammatory mediators and directing leukocyte incorporation into plaques through platelet-mediated leukocyte adhesion.New research has identified signaling pathways that intertwine thrombotic and inflammatory pathways with the development and progression of atherosclerosis. These signaling pathways contain positive feedback loops that propagate atherogenesis. Targeting molecular regulators at the interface of thrombosis and inflammation simultaneously may reduce thrombosis and inflammation, thus breaking pathological cycles that promote atherosclerosis and associated thrombotic complications.