Plasma glutathione peroxidase activity is potentially a key regulator of vascular disease-associated thrombosis.

In the current issue of Circulation, Jin et al1 provide insight into how a deficiency in the activity of the primary plasma peroxide-metabolizing enzyme glutathione peroxidase-3 (GPx-3) creates a prothrombotic state with vascular dysfunction. Mice deficient in GPx-3 are shown to have elevated soluble P-selectin (a marker of platelet and prothrombotic activity) and enhanced responses to experimental conditions promoting pulmonary thromboembolism and plateletdependent cerebral infarctions in a no-flow ischemia–reperfusion stroke model. Initial studies on the properties of platelet aggregation in 2 brothers with a cerebral thrombotic disorder identified a deficiency in plasma glutathione peroxidase activity as a key factor explaining the hyperreactivity of their platelets.2 Subsequent studies examining the consequences of promoter polymorphisms in the human GPx-3 gene associated with decreases in plasma GPx-3 expression provided evidence that it was a risk factor for ischemic stroke in young adults and children.3 A deficiency in GPx-3 has been associated with increases in extracellular peroxide-related oxidants and decreased bioavailable nitric oxide that are thought to contribute to promoting platelet activation.2,4 Thus, plasma glutathione peroxidase activity may be a key factor in determining when disease processes activating platelets result in arterial thrombosis.