Decreased platelet inhibition by nitric oxide in two brothers with a history of arterial thrombosis.
Highly reactive oxygen species rapidly inactivate nitric oxide (NO), and endothelial product which inhibits platelet activation. We studied platelet inhibition by NO in two brothers with a cerebral thrombotic disorder. Both children had hyperreactive platelets, as determined by whole blood platelet aggregometry and flow cytometric analysis of the platelet surface expression of P-selectin. Mixing experiments showed that the patients'platelets behaved normally in control plasma; however, control platelets suspended in patient plasma were not inhibited by NO. As determined by flow cytometry, in the presence of plasma from either patient there was normal inhibition of the thrombin-induced expression of platelet surface P-selectin by prostacyclin, but not NO. Using a scopoletin assay, we measured a 2.7-fold increase in plasma H2O2 generation in one patient and a 3.4-fold increase in the second patient, both compared woth control plasma. Glutathione peroxidase (GSH-Px) activity was decreased in the patients' plasmas compared with control plasma. The addition of exogenous GSH-Px led to restoration of platelet inhibition by NO. These data show that, in these patients' plasmas, impaired metabolism of reactive oxygen species reduces the bioavailability of NO and impairs normal platelet inhibitory mechanisms. These findings suggest that attenuated NO-mediated platelet inhibition produced by increased reactive oxygen species or impaired antioxidant defense may cause a thrombotic disorder in humans.
Freedman
J E
JE
Whitaker Cardiovascular Institute, Boston University School of Medicine, Massachusetts 02118, USA.
Loscalzo
J
J
Benoit
S E
SE
Valeri
C R
CR
Barnard
M R
MR
Michelson
A D
AD
D006152:Cyclic GMP / Q000097:blood; D011464:Epoprostenol / Q000502:physiology; D005979:Glutathione Peroxidase / Q000097:blood; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007223:Infant; D008297:Male; D009569:Nitric Oxide / Q000502:physiology*; D019007:P-Selectin / Q000097:blood; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D013927:Thrombosis / Q000209:etiology*
D019007:P-Selectin; D010975:Platelet Aggregation Inhibitors; D009569:Nitric Oxide; D006861:Hydrogen Peroxide; D011464:Epoprostenol; D005979:Glutathione Peroxidase; D006152:Cyclic GMP