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(Circulation. 2001;104:1124.)
© 2001 American Heart Association, Inc.

Clinical Investigation and Reports

Oxidative Stress and Platelet Activation in Homozygous Homocystinuria

G. Davì, MD; G. Di Minno, MD; A. Coppola, MD; G. Andria, MD; A. M. Cerbone, MD; P. Madonna, MD; A. Tufano, MD; A. Falco, MD; P. Marchesani, MD; G. Ciabattoni, MD; C. Patrono, MD

From the Center of Excellence on Aging and the Departments of Biomedical Sciences and Drug Sciences, University of Chieti G. D’Annunzio, Chieti (G. Davì, A.F., P. Marchesani, G.C., C.P.), and the Departments of Clinical and Experimental Medicine and Pediatrics, University of Naples Federico II, Naples (G. Di Minno, A.C., G.A., A.M.C., P. Madonna, A.T.), Italy.

Reprint requests to Giovanni Davì, MD, Department of Medicine and Aging, University of Chieti G. D’Annunzio School of Medicine, via dei Vestini 31, 66013 Chieti, Italy. E-mail gdavi{at}unich.it

Background—— Severe hyperhomocysteinemia due to cystathionine ß-synthase deficiency (CßSD) is associated with early atherothrombotic vascular disease. Homocysteine may exert its effects by promoting oxidative damage. In the present study, we investigated whether in vivo formation of 8-iso-prostaglandin (PG) F₂, a platelet-active product of arachidonic acid peroxidation, is enhanced in CßSD and whether it correlates with in vivo platelet activation, as reflected by thromboxane (TX) metabolite excretion.

Methods and Results—— Urine and blood samples were obtained from patients with homozygous CßSD (n=13) and age-matched healthy subjects. Urinary 8-iso-PGF₂ excretion was significantly higher in CßSD patients than in control subjects (640±384 versus 213±43 pg/mg creatinine; P=0.0015) and correlated with plasma homocysteine (=0.398, P=0.0076). Similarly, urinary 11-dehydro-TXB₂ excretion was enhanced in CßSD (1166±415 versus 324±72 pg/mg creatinine; P=0.0015) and correlated with urinary 8-iso-PGF₂ (=0.362, P=0.0153). Vitamin E supplementation (600 mg/d for 2 weeks) was associated with a statistically significant increase in its plasma levels (from 16.6±4.6 to 40.4±8.7 µmol/L, P=0.0002) and with reductions in 8-iso-PGF₂ (from 790±159 to 559±111 pg/mg creatinine, P=0.018) and 11-dehydro-TXB₂ (from 1273±383 to 913±336 pg/mg creatinine, P=0.028). A statistically significant inverse correlation was found between urinary 8-iso-PGF₂ and plasma vitamin E levels (=-0.745, P=0.0135).

Conclusions—— The results of the present study suggest that enhanced peroxidation of arachidonic acid to form bioactive F₂-isoprostanes may represent an important mechanism linking hyperhomocysteinemia and platelet activation in CßSD patients. Moreover, they provide a rationale for dose-finding studies of vitamin E supplementation in this setting.

Key Words: homocystinuria • platelets • thromboxane • isoprostanes • lipids

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