Abstract-Reactive oxygen species play an important role at the site of vascular injuries and arterial thromboses. We studied the mechanism mediating platelet aggregation induced by H 2 O 2 , a major cellular oxidant. Exposure to H 2 O 2 triggered platelet aggregation, but only when the platelets were stirred. Strong platelet aggregation induced by H 2 O 2 required the presence of the tyrosine phosphatase inhibitor sodium orthovanadate (NaVO 4 ) and was dependent on the participation of integrin ␣ IIb  3 (glycoprotein IIb-IIIa 2 Leukocytes and platelets have been found adjacent during acute coronary syndromes and even circulate as clusters in the blood of patients with unstable angina.3-5 Leukocytes and, in particular, neutrophils produce large amounts of reactive oxygen species (ROS), which could influence platelet function in a paracrine fashion. 6 Moreover, superoxide and hydroxyl radicals have been shown to be produced by anoxic and subsequently reoxygenated platelets.7 Previous studies on the effects of ROS and, in particular, hydrogen peroxide (H 2 O 2 ) on platelets indicated that ROS might exert a dual effect on platelets. In the presence of nitric oxide (NO), H 2 O 2 seems to potentiate the inhibitory effect of NO on agonist-mediated platelet activation. 8 In contrast, in the presence of arachidonate, H 2 O 2 enhances aggregation induced by phospholipid-derived arachidonate.9,10 To further characterize the effect of H 2 O 2 on platelet reactivity, we sought to characterize the effect of ROS and, in particular, of H 2 O 2 on platelet signaling pathways.Integrin ␣ IIb  3 , the classic platelet fibrinogen receptor, can exist in resting or activated states, and the latter can occur with or without ligand engagement. Activation corresponds to a structural change, whereby the affinity of ␣ IIb  3 for fibrinogen and other adhesive molecules in solution is markedly increased.11 Moreover, integrin ␣ IIb  3 can be found in 2 different compartments relative to extracellular ligands: exposed (to extracellular ligands) or cryptic (not accessible to extracellular ligands).12 Receptor molecules can be recruited from cryptic storage to the platelet surface or removed from the surface through a process of endocytosis.12-14 The molecular reactions that lead to receptor activation have been studied:  3 seems to play the role of a regulatory subunit of the receptor, whereas ␣ IIb appears to mediate receptor specificity. 15,16 There is good evidence that the activation process utilizes ATP 15 and involves interaction of the short cytoplasmic domain of  3 with a regulatory factor. 15,17,18 H 2 O 2 can induce a strong tyrosine kinase response in smooth muscle cells, especially in cells whose tyrosine phosphatases are concurrently inhibited with orthovanadate.