TY - JOUR
T1 - Abnormally high thromboxane biosynthesis in homozygous homocystinuria evidence for platelet involvement and probucol-sensitive mechanism
AU - Di Minno, Giovanni
AU - Davi, Giovanni
AU - Margaglione, Maurizio
AU - Cirillo, Ferdinando
AU - Grandone, Elvira
AU - Ciabattoni, Giovanni
AU - Catalano, Isabella
AU - Strisciuglio, Pietro
AU - Andria, Generoso
AU - Patrono, Carlo
AU - Mancini, Mario
PY - 1993/9
Y1 - 1993/9
N2 - 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.
AB - 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.
KW - 11-dehydro-TXB
KW - 2,3-dinor-TXB
KW - Anti-oxidant
KW - Aspirin
KW - Cystathionine β-synthase deficiency
UR - http://www.scopus.com/inward/record.url?scp=0027247803&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0027247803&partnerID=8YFLogxK
M3 - Article
C2 - 8376592
AN - SCOPUS:0027247803
VL - 92
SP - 1400
EP - 1406
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 3
ER -