Illustration of platelet CD36 redox signaling in arterial thrombosis. Oxidized lipids are recognized by scavenger receptor CD36 on the platelet surface. CD36 signal transduction leads to H₂O₂ generation from NADPH oxidase. H₂O₂ promotes oxidative cysteine modification of cellular regulators of platelet activation, including SFK. Specifically, SFK cysteines undergo sulfenylation, which is a potential mechanism for activation of redox-sensitive MAPK ERK5. ERK5 links platelet CD36 signaling to 2 functional phenotypes: (1) platelet aggregation mediated by integrin αIIbβ3; and (2) procoagulant PSer externalization required for assembly of the prothrombinase complex to form fibrin from activated thrombin. The CD36 signaling pathway also cross talks with the collagen receptor GPVI pathway to augment PSer externalization. This redox-regulated CD36 signaling pathway promotes pathophysiologic thrombosis in dyslipidemia. In the absence of CD36 signaling, collagen-mediated GPVI activation promotes platelet integrin αIIbβ3 activation and procoagulant PSer externalization during thrombosis.