title: Plasma glutathione peroxidase deficiency and platelet insensitivity to nitric oxide in children with familial stroke.
abstract: In a previous report by Freedman et al (J Clin Invest. 1996;97:979-987), plasma from 2 brothers with stroke or transient ischemic attack inactivated the 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 deficiency by studying NO-mediated antiplatelet effects in 7 families with familial childhood stroke. Seven families with familial childhood stroke that consecutively 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 GFP in patients' PPP was analyzed by flow cytometry after incubation with a P-selectin-specific monoclonal antibody in the 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 platelet aggregation in PPP from the affected family members and some of their relatives. Of 4 families studied, 3 probands and their corresponding affected parent had 50% decrease in plasma GSH-Px activity. In some patients with childhood stroke, impaired metabolism of reactive oxygen species as a result of reduced GSH-Px activity results in NO insufficiency that affects normal platelet inhibitory mechanisms and predisposes to arterial thrombosis.
authors.affiliation: Department of Hematology, Institute of Thrombosis, Pediatric Neurology Unit, Sheba Medical Center, Tel-Hashomer, 52621, Israel.
authors.forename: G
authors.initials: G
authors.lastname: Kenet
authors.forename: J
authors.initials: J
authors.lastname: Freedman
authors.forename: B
authors.initials: B
authors.lastname: Shenkman
authors.forename: E
authors.initials: E
authors.lastname: Regina
authors.forename: F
authors.initials: F
authors.lastname: Brok-Simoni
authors.forename: F
authors.initials: F
authors.lastname: Holzman
authors.forename: F
authors.initials: F
authors.lastname: Vavva
authors.forename: N
authors.initials: N
authors.lastname: Brand
authors.forename: A
authors.initials: A
authors.lastname: Michelson
authors.forename: M
authors.initials: M
authors.lastname: Trolliet
authors.forename: J
authors.initials: J
authors.lastname: Loscalzo
authors.forename: A
authors.initials: A
authors.lastname: Inbal
mesh_terms: D000293:Adolescent; D000328:Adult; D001792:Blood Platelets / Q000187:drug effects*; D002561:Cerebrovascular Disorders / Q000235:genetics*; D002648:Child; D005192:Family Health; D005260:Female; D005979:Glutathione Peroxidase / Q000097:blood / Q000172:deficiency*; D006801:Humans; D008297:Male; D009569:Nitric Oxide / Q000502:physiology*; D010375:Pedigree
chemical_list: D009569:Nitric Oxide; D005979:Glutathione Peroxidase