© 1999 American Heart Association, Inc.
Thrombosis |
Plasma Glutathione Peroxidase Deficiency and Platelet Insensitivity to Nitric Oxide in Children With Familial Stroke
From the Department of Hematology, Institute of Thrombosis and Hemostasis (G.K., B.S., F.B.-S., F.H., A.I.), Pediatric Neurology Unit (N.B.), Sheba Medical Center, Tel-Hashomer, Sackler Faculty of Medicine, Tel-Aviv University, Israel; and the University of Massachusetts Medical School (A.M.), and Whitaker Cardiovascular Institute and Evans Department of Medicine (J.F., F.V., M.T., J.L.), Boston University School of Medicine, Boston, MA.
Correspondence to Aida Inbal, MD, Institute of Thrombosis & Hemostasis, Sheba Medical Center, Tel-Hashomer 52621, Israel.
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.
Key Words: stroke • glutathione peroxidase • platelets • nitric oxide
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