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

Giovanni Di Minno, Giovanni Davi, Maurizio Margaglione, Ferdinando Cirillo, Elvira Grandone, Giovanni Ciabattoni, Isabella Catalano, Pietro Strisciuglio, Generoso Andria, Carlo Patrono, Mario Mancini

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)1400-1406
Number of pages7
JournalJournal of Clinical Investigation
Volume92
Issue number3
Publication statusPublished - Sep 1993

Keywords

  • 11-dehydro-TXB
  • 2,3-dinor-TXB
  • Anti-oxidant
  • Aspirin
  • Cystathionine β-synthase deficiency

ASJC Scopus subject areas

  • Medicine(all)

Fingerprint Dive into the research topics of 'Abnormally high thromboxane biosynthesis in homozygous homocystinuria evidence for platelet involvement and probucol-sensitive mechanism'. Together they form a unique fingerprint.

  • Cite this

    Di Minno, G., Davi, G., Margaglione, M., Cirillo, F., Grandone, E., Ciabattoni, G., Catalano, I., Strisciuglio, P., Andria, G., Patrono, C., & Mancini, M. (1993). Abnormally high thromboxane biosynthesis in homozygous homocystinuria evidence for platelet involvement and probucol-sensitive mechanism. Journal of Clinical Investigation, 92(3), 1400-1406.