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

Abstract

IntroductionHomocystinuria due to homozygous cystathionine tl-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 1 1-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 1i-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. (J. Clin. Invest.

Hydrogen sulphide pathway contributes to the enhanced human platelet aggregation in hyperhomocysteinemia

“…In HHcy patients, increased platelet activation has been associated with elevated production of tromboxane A 2 (28)(29)(30). In line with these findings, in MTHFR++ carriers, we found that urine thromboxane metabolites were significantly higher than in healthy individuals.…”

Impaired Homocysteine Metabolism and Atherothrombotic Disease

“…Methionine-loading experiments in control and folate-deficient animals indicated that homocysteine plasma concentration correlates with platelet aggregation and the biosynthesis of the powerful proaggregant thromboxane A 2 (Durand et al, 1997a). In agreement with this latter finding, an increase in thromboxane synthesis was described in homocystinuric patients (Di Minno et al, 1993). Along with a possible reduction of the antiplatelet effects of NO, this increase in thromboxane biosynthesis might contribute to platelet activation in moderate hyperhomocysteinemia (Durand et al, 1997a).…”

Flow-Induced Constriction in Arterioles of Hyperhomocysteinemic Rats Is Due to Impaired Nitric Oxide and Enhanced Thromboxane A 2 Mediation

“…Thus, it is likely that the flow-induced arteriolar release of TXA 2 together with that released from platelets 11 contributes to the development of increased vascular tone and urinary excretion of TXB 2 , the stable end metabolite of TXA 2 shown to be present in patients with genetic HHcy. 29,30 The underlying mechanism for the simultaneous impaired NO release and enhanced TXA 2 production in the endothelium of arterioles of HHcy rats 10,11 is not known. Several previous studies in endothelial cells in culture 31,32 suggest a role for an increased level of reactive oxygen species (ROS).…”