Oxidative stress and platelet activation in homozygous homocystinuria

Background-Severe hyperhomocysteinemia due to cystathionine beta -synthase deficiency (C beta SD) 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) F-2 alpha, a platelet-active product of arachidonic acid peroxidation, is enhanced in C beta SD 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 C beta SD (n=13) and age-matched healthy subjects. Urinary 8-iso-PGF(2 alpha) excretion was significantly higher in C beta SD patients than in control subjects (640 +/- 384 versus 213 +/- 43 pg/mg creatinine; P=0.0015) and correlated with plasma homocysteine (rho =0.398, P=0.0076). Similarly, urinary 11-dehydro-TXB2 excretion was enhanced in C beta SD (1166 +/- 415 versus 324 +/- 72 pg/mg creatinine; P=0.0015) and correlated with urinary 8-iso-PGF(2 alpha) (p=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 mu mol/L, P=0.0002) and with reductions in 8-iso-PGF(2 alpha) (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-PGF(2 alpha) and plasma vitamin E levels (rho=-0.745, P=0.0135). Conclusions-The results of the present study suggest that enhanced peroxidation of arachidonic acid to form bioactive F-2-isoprostanes may represent an important mechanism linking hyperhomocysteinemia and platelet activation in C beta SD patients. Moreover, they provide a rationale for dose-finding studies of vitamin E supplementation in this setting.