Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1993 Sep;92(3):1400–1406. doi: 10.1172/JCI116715

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

G Di Minno 1, G Davì 1, M Margaglione 1, F Cirillo 1, E Grandone 1, G Ciabattoni 1, I Catalano 1, P Strisciuglio 1, G Andria 1, C Patrono 1, et al.
PMCID: PMC288283  PMID: 8376592

Abstract

Homocystinuria due to homozygous cystathionine beta-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.

Full text

PDF
1400

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Akeson A. L., Woods C. W., Mosher L. B., Thomas C. E., Jackson R. L. Inhibition of IL-1 beta expression in THP-1 cells by probucol and tocopherol. Atherosclerosis. 1991 Feb;86(2-3):261–270. doi: 10.1016/0021-9150(91)90222-o. [DOI] [PubMed] [Google Scholar]
  2. Ardlie N. G., Selley M. L., Simons L. A. Platelet activation by oxidatively modified low density lipoproteins. Atherosclerosis. 1989 Apr;76(2-3):117–124. doi: 10.1016/0021-9150(89)90094-4. [DOI] [PubMed] [Google Scholar]
  3. Boers G. H., Smals A. G., Trijbels F. J., Fowler B., Bakkeren J. A., Schoonderwaldt H. C., Kleijer W. J., Kloppenborg P. W. Heterozygosity for homocystinuria in premature peripheral and cerebral occlusive arterial disease. N Engl J Med. 1985 Sep 19;313(12):709–715. doi: 10.1056/NEJM198509193131201. [DOI] [PubMed] [Google Scholar]
  4. Brattstrom L. E., Hardebo J. E., Hultberg B. L. Moderate homocysteinemia--a possible risk factor for arteriosclerotic cerebrovascular disease. Stroke. 1984 Nov-Dec;15(6):1012–1016. doi: 10.1161/01.str.15.6.1012. [DOI] [PubMed] [Google Scholar]
  5. Brattström L., Israelsson B., Tengborn L., Hultberg B. Homocysteine, factor VII and antithrombin III in subjects with different gene dosage for cystathionine beta-synthase. J Inherit Metab Dis. 1989;12(4):475–482. doi: 10.1007/BF01802045. [DOI] [PubMed] [Google Scholar]
  6. Burch J. W., Stanford N., Majerus P. W. Inhibition of platelet prostaglandin synthetase by oral aspirin. J Clin Invest. 1978 Feb;61(2):314–319. doi: 10.1172/JCI108941. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Catella F., FitzGerald G. A. Paired analysis of urinary thromboxane B2 metabolites in humans. Thromb Res. 1987 Sep 15;47(6):647–656. doi: 10.1016/0049-3848(87)90103-4. [DOI] [PubMed] [Google Scholar]
  8. Ciabattoni G., Maclouf J., Catella F., FitzGerald G. A., Patrono C. Radioimmunoassay of 11-dehydrothromboxane B2 in human plasma and urine. Biochim Biophys Acta. 1987 Apr 24;918(3):293–297. doi: 10.1016/0005-2760(87)90233-5. [DOI] [PubMed] [Google Scholar]
  9. Ciabattoni G., Pugliese F., Davi G., Pierucci A., Simonetti B. M., Patrono C. Fractional conversion of thromboxane B2 to urinary 11-dehydrothromboxane B2 in man. Biochim Biophys Acta. 1989 Jul 21;992(1):66–70. doi: 10.1016/0304-4165(89)90051-2. [DOI] [PubMed] [Google Scholar]
  10. Clarke R., Daly L., Robinson K., Naughten E., Cahalane S., Fowler B., Graham I. Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med. 1991 Apr 25;324(17):1149–1155. doi: 10.1056/NEJM199104253241701. [DOI] [PubMed] [Google Scholar]
  11. Davì G., Averna M., Catalano I., Barbagallo C., Ganci A., Notarbartolo A., Ciabattoni G., Patrono C. Increased thromboxane biosynthesis in type IIa hypercholesterolemia. Circulation. 1992 May;85(5):1792–1798. doi: 10.1161/01.cir.85.5.1792. [DOI] [PubMed] [Google Scholar]
  12. Davì G., Catalano I., Averna M., Notarbartolo A., Strano A., Ciabattoni G., Patrono C. Thromboxane biosynthesis and platelet function in type II diabetes mellitus. N Engl J Med. 1990 Jun 21;322(25):1769–1774. doi: 10.1056/NEJM199006213222503. [DOI] [PubMed] [Google Scholar]
  13. Di Minno G., Cerbone A. M., Cirillo F., Postiglione A., Colucci M., Semeraro N., Scarpato N., Gnasso A., Margaglione M., Gallotta G. Hemostatic variables in homozygous familial hypercholesterolemia. Effect of regular plasma cholesterol removal by low density lipoprotein apheresis. Arteriosclerosis. 1990 Nov-Dec;10(6):1119–1126. doi: 10.1161/01.atv.10.6.1119. [DOI] [PubMed] [Google Scholar]
  14. Di Minno G., Mancini M. Measuring plasma fibrinogen to predict stroke and myocardial infarction. Arteriosclerosis. 1990 Jan-Feb;10(1):1–7. doi: 10.1161/01.atv.10.1.1. [DOI] [PubMed] [Google Scholar]
  15. DiMinno G., Coraggio F., Cerbone A. M., Capitanio A. M., Manzo C., Spina M., Scarpato P., Dattoli G. M., Mattioli P. L., Mancini M. A myeloma paraprotein with specificity for platelet glycoprotein IIIa in a patient with a fatal bleeding disorder. J Clin Invest. 1986 Jan;77(1):157–164. doi: 10.1172/JCI112270. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. DiMinno G., Silver M. J., Cerbone A. M., Murphy S. Trial of repeated low-dose aspirin in diabetic angiopathy. Blood. 1986 Oct;68(4):886–891. [PubMed] [Google Scholar]
  17. FitzGerald G. A., Oates J. A., Hawiger J., Maas R. L., Roberts L. J., 2nd, Lawson J. A., Brash A. R. Endogenous biosynthesis of prostacyclin and thromboxane and platelet function during chronic administration of aspirin in man. J Clin Invest. 1983 Mar;71(3):676–688. doi: 10.1172/JCI110814. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Fleisher L. D., Tallan H. H., Beratis N. G., Hirschhorn K., Gaull G. E. Cystathionine synthase deficiency: heterozygote detection using cultured skin fibroblasts. Biochem Biophys Res Commun. 1973 Nov 1;55(1):38–44. doi: 10.1016/s0006-291x(73)80056-7. [DOI] [PubMed] [Google Scholar]
  19. Giannini M. J., Coleman M., Innerfield I. Letter: Antithrombin activity in homocystinuria. Lancet. 1975 May 10;1(7915):1094–1094. doi: 10.1016/s0140-6736(75)91870-x. [DOI] [PubMed] [Google Scholar]
  20. Graeber J. E., Slott J. H., Ulane R. E., Schulman J. D., Stuart M. J. Effect of homocysteine and homocystine on platelet and vascular arachidonic acid metabolism. Pediatr Res. 1982 Jun;16(6):490–493. doi: 10.1203/00006450-198206000-00018. [DOI] [PubMed] [Google Scholar]
  21. Harker L. A., Slichter S. J., Scott C. R., Ross R. Homocystinemia. Vascular injury and arterial thrombosis. N Engl J Med. 1974 Sep 12;291(11):537–543. doi: 10.1056/NEJM197409122911101. [DOI] [PubMed] [Google Scholar]
  22. Heinecke J. W., Rosen H., Suzuki L. A., Chait A. The role of sulfur-containing amino acids in superoxide production and modification of low density lipoprotein by arterial smooth muscle cells. J Biol Chem. 1987 Jul 25;262(21):10098–10103. [PubMed] [Google Scholar]
  23. Hill-Zobel R. L., Pyeritz R. E., Scheffel U., Malpica O., Engin S., Camargo E. E., Abbott M., Guilarte T. R., Hill J., McIntyre P. A. Kinetics and distribution of 111Indium-labeled platelets in patients with homocystinuria. N Engl J Med. 1982 Sep 23;307(13):781–786. doi: 10.1056/NEJM198209233071303. [DOI] [PubMed] [Google Scholar]
  24. Kaplan R., Aynedjian H. S., Schlondorff D., Bank N. Renal vasoconstriction caused by short-term cholesterol feeding is corrected by thromboxane antagonist or probucol. J Clin Invest. 1990 Nov;86(5):1707–1714. doi: 10.1172/JCI114895. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Ku G., Doherty N. S., Schmidt L. F., Jackson R. L., Dinerstein R. J. Ex vivo lipopolysaccharide-induced interleukin-1 secretion from murine peritoneal macrophages inhibited by probucol, a hypocholesterolemic agent with antioxidant properties. FASEB J. 1990 Apr 1;4(6):1645–1653. doi: 10.1096/fasebj.4.6.2318380. [DOI] [PubMed] [Google Scholar]
  26. Mao S. J., Yates M. T., Parker R. A., Chi E. M., Jackson R. L. Attenuation of atherosclerosis in a modified strain of hypercholesterolemic Watanabe rabbits with use of a probucol analogue (MDL 29,311) that does not lower serum cholesterol. Arterioscler Thromb. 1991 Sep-Oct;11(5):1266–1275. doi: 10.1161/01.atv.11.5.1266. [DOI] [PubMed] [Google Scholar]
  27. Maruyama I., Fukuda R., Kazama M., Abe T., Yoshida Y. [A case of homocystinuria with low antithrombin activity (author's transl)]. Nihon Ketsueki Gakkai Zasshi. 1977 Apr;40(2):267–271. [PubMed] [Google Scholar]
  28. Merckx J., Kuntz F. Déficit en facteur VII et homocystinurie. Association fortuite ou syndrome? Nouv Presse Med. 1981 Dec 19;10(46):3796–3796. [PubMed] [Google Scholar]
  29. Mudd S. H., Skovby F., Levy H. L., Pettigrew K. D., Wilcken B., Pyeritz R. E., Andria G., Boers G. H., Bromberg I. L., Cerone R. The natural history of homocystinuria due to cystathionine beta-synthase deficiency. Am J Hum Genet. 1985 Jan;37(1):1–31. [PMC free article] [PubMed] [Google Scholar]
  30. Munnich A., Saudubray J. M., Dautzenberg M. D., Parvy P., Ogier H., Girot R., Manigne P., Frézal J. Diet-responsive proconvertin (factor VII) deficiency in homocystinuria. J Pediatr. 1983 May;102(5):730–734. doi: 10.1016/s0022-3476(83)80247-9. [DOI] [PubMed] [Google Scholar]
  31. Palareti G., Salardi S., Piazzi S., Legnani C., Poggi M., Grauso F., Caniato A., Coccheri S., Cacciari E. Blood coagulation changes in homocystinuria: effects of pyridoxine and other specific therapy. J Pediatr. 1986 Dec;109(6):1001–1006. doi: 10.1016/s0022-3476(86)80284-0. [DOI] [PubMed] [Google Scholar]
  32. Parthasarathy S. Oxidation of low-density lipoprotein by thiol compounds leads to its recognition by the acetyl LDL receptor. Biochim Biophys Acta. 1987 Feb 14;917(2):337–340. doi: 10.1016/0005-2760(87)90139-1. [DOI] [PubMed] [Google Scholar]
  33. Parthasarathy S., Young S. G., Witztum J. L., Pittman R. C., Steinberg D. Probucol inhibits oxidative modification of low density lipoprotein. J Clin Invest. 1986 Feb;77(2):641–644. doi: 10.1172/JCI112349. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Patrignani P., Filabozzi P., Patrono C. Selective cumulative inhibition of platelet thromboxane production by low-dose aspirin in healthy subjects. J Clin Invest. 1982 Jun;69(6):1366–1372. doi: 10.1172/JCI110576. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Patrono C., Ciabattoni G., Remuzzi G., Gotti E., Bombardieri S., Di Munno O., Tartarelli G., Cinotti G. A., Simonetti B. M., Pierucci A. Functional significance of renal prostacyclin and thromboxane A2 production in patients with systemic lupus erythematosus. J Clin Invest. 1985 Sep;76(3):1011–1018. doi: 10.1172/JCI112053. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Roberts L. J., 2nd, Sweetman B. J., Oates J. A. Metabolism of thromboxane B2 in man. Identification of twenty urinary metabolites. J Biol Chem. 1981 Aug 25;256(16):8384–8393. [PubMed] [Google Scholar]
  37. Rubba P., Faccenda F., Pauciullo P., Carbone L., Mancini M., Strisciuglio P., Carrozzo R., Sartorio R., del Giudice E., Andria G. Early signs of vascular disease in homocystinuria: a noninvasive study by ultrasound methods in eight families with cystathionine-beta-synthase deficiency. Metabolism. 1990 Nov;39(11):1191–1195. doi: 10.1016/0026-0495(90)90093-r. [DOI] [PubMed] [Google Scholar]
  38. Salem H. H. The natural anticoagulants. Clin Haematol. 1986 May;15(2):371–391. [PubMed] [Google Scholar]
  39. Uhlemann E. R., TenPas J. H., Lucky A. W., Schulman J. D., Mudd S. H., Shulman N. R. Platelet survival and morphology in homocystinuria due to cystathionine synthase deficiency. N Engl J Med. 1976 Dec 2;295(23):1283–1286. doi: 10.1056/NEJM197612022952303. [DOI] [PubMed] [Google Scholar]
  40. Vesterqvist O., Gréen K. Urinary excretion of 2,3-dinor-thromboxane B2 in man under normal conditions, following drugs and during some pathological conditions. Prostaglandins. 1984 Apr;27(4):627–644. doi: 10.1016/0090-6980(84)90098-4. [DOI] [PubMed] [Google Scholar]
  41. Witztum J. L., Steinberg D. Role of oxidized low density lipoprotein in atherogenesis. J Clin Invest. 1991 Dec;88(6):1785–1792. doi: 10.1172/JCI115499. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES