Type 2 diabetes mellitus (T2DM) is a major cardiovascular risk factor. Persistent platelet activation plays a key role in
atherothrombosis in T2DM. However, current antiplatelet treatments appear less effective in T2DM patients vs nondiabetics at similar risk. A large body of evidence supports the contention that oxidative stress, which characterizes DM, may be responsible, at least in part, for less-than-expected response to
aspirin, with multiple mechanisms acting at several levels. This review discusses the pathophysiological mechanisms related to oxidative stress and contributing to suboptimal
aspirin action or responsiveness. These include: (1) mechanisms counteracting the antiplatelet effect of
aspirin, such as reduced platelet sensitivity to the antiaggregating effects of NO, due to high-
glucose-mediated oxidative stress; (2) mechanisms interfering with COX acetylation especially at the platelet level, e.g.,
lipid hydroperoxide-dependent impaired acetylating effects of
aspirin; (3) mechanisms favoring platelet priming (
lipid hydroperoxides) or activation (
F2-isoprostanes, acting as partial agonists of
thromboxane receptor), or
aldose-reductase pathway-mediated oxidative stress, leading to enhanced platelet
thromboxane A2 generation or
thromboxane receptor activation; (4) mechanisms favoring platelet recruitment, such as
aspirin-induced platelet
isoprostane formation; (5) modulation of megakaryocyte generation and thrombopoiesis by oxidative HO-1 inhibition; and (6)
aspirin-
iron interactions, eventually resulting in impaired pharmacological activity of
aspirin,
lipoperoxide burden, and enhanced generation of
hydroxyl radicals capable of promoting
protein kinase C activation and platelet aggregation. Acknowledgment of oxidative stress as a major contributor, not only of vascular complications, but also of suboptimal response to
antiplatelet agents in T2DM, may open the way to designing and testing novel antithrombotic strategies, specifically targeting oxidative stress-mediated mechanisms of less-than-expected response to
aspirin.