Abnormally high thromboxane biosynthesis in homozygous homocystinuria evidence for platelet involvement and probucol-sensitive mechanism

Homocystinuria due to homozygous cystathionine β-synthase deficiency is an inborn error of metabolism characterized by a high incidence of thrombosis and premature atherosclerosis. We evaluated TXA₂ biosynthesis in vivo and several in vitro tests of platelet function in 11 homocystinuric patients and 12 healthy controls. In vitro, patients' platelet aggregation was within control values as were TXB₂ formation, fibrinogen binding, and ATP secretion in response to thrombin. In contrast, the urinary excretion of 11-dehydro-TXB₂, a major enzymatic derivative of TXA₂, was > 2 SD of controls in all patients (1,724±828 pg/mg creatinine, mean±SD, in patients vs. 345±136 in controls, P <0.001). The administration to four patients of low-dose aspirin (50 mg/d for 1 wk) reduced metabolite excretion by > 80%. The recovery of 11-dehydro-TXB₂ excretion over the 10 d that followed aspirin cessation occurred with a pattern consistent with the entry into the circulation of platelets with intact cyclooxygenase activity. Prolonged partial reduction in the abnormally high excretion of both 11-dehydro-TXB₂ and 2,3-dinor-TXB₂, was also observed in seven patients who ingested 500 mg daily for 3 wk of the antioxidant drug probucol. These results provide evidence for enhanced thromboxane biosynthesis in homocystinuria and for its partial dependence on probucol-sensitive mechanisms. Furthermore, the elevated TXA₂ formation in homocystinuria is likely to reflect, at least in part, in vivo platelet activation.