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), 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.
Kenet
G
G
Department of Hematology, Institute of Thrombosis, Pediatric Neurology Unit, Sheba Medical Center, Tel-Hashomer, 52621, Israel.
Freedman
J
J
Shenkman
B
B
Regina
E
E
Brok-Simoni
F
F
Holzman
F
F
Vavva
F
F
Brand
N
N
Michelson
A
A
Trolliet
M
M
Loscalzo
J
J
Inbal
A
A
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
D009569:Nitric Oxide; D005979:Glutathione Peroxidase