Plasma glutathione peroxidase deficiency and platelet insensitivity to nitric oxide in children with familial stroke

In a previous report by Freedman et al (J Clin Invest. 1996;97:979-987), pl asma from 2 brothers with stroke or transient ischemic attack inactivated t he antiplatelet effects of nitric oxide (NO), and this effect was found to be a consequence of a deficiency of plasma glutathione peroxidase (GSH-Px). In this study, we attempted to define the generalizability of this deficie ncy by studying NO-mediated antiplatelet effects in 7 families with familia l childhood stroke. Seven families with familial childhood stroke that cons ecutively presented to a large referral center were included in the study. We monitored ADP-induced aggregation of normal gel-filtered platelets (GFP) in platelet-poor plasma (PPP) from normal individuals and from patients in the presence or absence of an NO donor (S-nitroso-glutathione). Surface P- selectin expression of normal CFP in patients' PPP was analyzed by flow cyt ometry after incubation with a P-selectin-specific monoclonal antibody in t he presence or absence of the NO donor. We also measured GSH-Px activity in plasmas from family members and normal controls using standard methods. In 6 of 7 families, NO failed to inhibit platelet P-selectin expression and p latelet aggregation in PPP from the affected family members and some of the ir relatives. Of 4 families studied, 3 probands and their corresponding aff ected parent had 50% decrease in plasma GSH-Px activity. In some patients w ith childhood stroke, impaired metabolism of reactive oxygen species as a r esult of reduced GSH-Px activity results in NO insufficiency that affects n ormal platelet inhibitory mechanisms and predisposes to arterial thrombosis .