Skip to main content
SpringerLink
Log in

Hyperhomocysteinemia and thrombosis

  • Published:
Lipids

Abstract

Homocysteine (Hcy) is a sulfhydryl amino acid derived from the metabolic conversion of methionine, which is dependent on vitamins (folic acid, B12, and B6) as cofactors or cosubstrates. In 1969, McCully first reported the presence of severe atherosclerotic lesions in patients with severe hyperhomocysteinemia and hypothesized the existence of a pathogenic link between hyperhomocysteinemia and atherogenesis. Several case-control and cross-sectional studies were consistent with the initial hypothesis of McCully, showing that moderate hyperhomocysteinemia is also associated with heightened risk of occlusive arterial disease. Less consistent results have been reported by prospective cohort studies of subjects who were healthy at the time of their enrollment, whereas prospective cohort studies of patients with overt coronary artery disease or other conditions at risk consistently confirmed the association between moderate hyperhomocysteinemia and cardiovascular morbidity and mortality. More recently, an association between moderate hyperhomocysteinemia and heightened risk of venous thromboembolism has been documented, suggesting that hyperhomocysteinemia might be involved not only in atherogenesis, but also in thrombogenesis. The mechanisms by which hyperhomocysteinemia might contribute to atherogenesis and thrombogenesis are incompletely understood. The mainstay of treatment of hyperhomocysteinemia is folic acid, alone or in combination with vitamin B12 and vitamin B6. Although it is quite clear that vitamins effectively reduce the plasma levels of total homocysteine (tHcy), we do not yet know whether they will decrease the risk of vascular disease. The results of ongoing randomized, placebo-controlled, double-blind trials of the effects of vitamins on the thrombotic risk will help ir, defining whether the relationship between hyperhomocysteinemia and thrombosis is causal, and will potentially have a dramatic effect in the prevention of thromboembolic events.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

CBS:

cystathionine-β-synthase

CI:

confidence interval

Hcy:

homocysteine

HUVEC:

human umbilical vein endothelial cells

MTHFR:

methylenetetrahydrofolate reductase

OR:

odds ratio

PML:

postmethionine loading

RR:

relative risk

SLE:

systemic lupus erythematosus

tHcy:

total homocysteine

References

  1. Finkelstein, J.D. (1990) Methionine Metabolism in Mammals, J. Nutr. Biochem. 1, 228–257.

    Article  PubMed  CAS  Google Scholar 

  2. Storch, K.J., Wagne, D.A., Burke, J.F., and Young, V.R. (1990) (1-13C; Methyl-2H3) Methionine Kinetics in Humans: Methionine Conservation and Cysteine Sparing, Am. J. Physiol. 258, E790-E798.

    PubMed  CAS  Google Scholar 

  3. Andersson, A., Brattsröm, L., Israelsson, B., Isaksson, A., Hamfelt, A., and Hultberg, B. (1992) Plasma Homocysteine Before and After Methionine Loading with Regard to Age, Gender, and Menopausal Status, Eur. J. Clin. Investig. 22, 79–87.

    CAS  Google Scholar 

  4. Wouters, M.G.A.J., Moorrees, M.T.E.C., van der Mooren, M.J., Blom, H.J., Boers, G.H., Schellekens, L.A., Thomas, C.M., and Eskes, T.K. (1995) Plasma Homocysteine and Menopausal Status, Eur. J. Clin. Investig. 25, 801–805.

    CAS  Google Scholar 

  5. Nygård, O., Vollset, S.E., Refsum, E., Stensvold, I., Tverdal, A., Nordrehaug, J.E., Ueland, P.M., and Kvale, G. (1995) Total Plasma Homocysteine and Cardiovascular Risk Profile. The Hordaland Homocysteine Study, J. Am. Med. Assoc. 274, 1526–1533.

    Article  Google Scholar 

  6. Lussier-Cacan, S., Xhignesse, M., Piolot, A., Selhub, J., Davignon, J., and Genest, J., Jr. (1996) Plasma Total Homocysteine in Healthy Subjects: Sex-Specific Relation with Biological Traits, Am. J. Clin. Nutr. 64, 587–593.

    PubMed  CAS  Google Scholar 

  7. Selhub, J., Jaques, P.F., Rosenberg, I.H., Rogers, G., Bowman, B.A., Gunter, E.W., Wright, J.D., and Johnson, C.L. (1999) Serum Total Homocysteine Concentrations in the Third National Health and Nutrition Examination Survey (1991–1994): Population Reference Ranges and Contribution of Vitamin Status to High Serum Concentrations, Ann. Intern. Med. 131, 331–339.

    PubMed  CAS  Google Scholar 

  8. Selhub, J., Jaques, P.F., Wilson, P.W.F., Rush, D., and Rosenberg, J.H. (1993) Vitamin Status and Intake as Primary Determinants of Homocysteinemia in an Elderly Population, J. Am. Med. Assoc. 270, 2693–2698.

    Article  CAS  Google Scholar 

  9. Nygård, O., Refsum, H., Ueland, P.M., Stensvold, I., Nordrehaug, J., Kvale, G., and Vollset, S.E. (1997) Coffee Consumption and Plasma Total Homocysteine: The Hordaland Homocysteine Study, Am. J. Clin. Nutr. 65, 136–143.

    PubMed  Google Scholar 

  10. Cravo, M.L., Gloria, L.M., Selhub, J., Nadeau, M.R., Camilo, M.E., Resende, M.P., Cardoso, J.N., Leitao, C.N., and Mira, F.C. (1996) Hyperhomocysteinemia in Chronic Alcoholism: Correlation with Folate, Vitamin B-12 and Vitamin B-6 Status, Am. J. Clin. Nutr. 63, 220–224.

    PubMed  CAS  Google Scholar 

  11. Nygård, O., Refsum, H., Ueland, P.M., and Vollset, S.E. (1998) Major Lifestyle Determinants of Plasma Total Homocysteine Distribution: The Hordaland Homocysteine Study, Am. J. Clin. Nutr. 67, 263–270.

    PubMed  Google Scholar 

  12. Mezzano, D., Munoz, X., Martinez, C., Cuevas, A., Panes, O., Aranda, E., Guasch, V., Strobel, P., Munoz, B., Rodriguez, S., et al. (1999) Vegetarians and Cardiovascular Risk Factors: Hemostasis, Inflammatory Markers, and Plasma Homocysteine, Thromb. Haemostasis 81, 913–917.

    CAS  Google Scholar 

  13. Mann, N.J., Li, D., Sinclair, A.J., Dudman, N.P.B., Guo, X.W., Elsworth, G.R., Wilson, A.U., and Kelly, F.D. (1999) The Effect of Diet on Plasma Homocysteine Concentrations in Healthy Male Subjects, Eur. J. Clin. Nutr. 53, 895–899.

    Article  PubMed  CAS  Google Scholar 

  14. Carmel, R., Green, R., Jacobsen, D.W., Rasmussen, K., Florea, M., and Azen, C. (1999) Serum Cobalamin, Homocysteine, and Methylmalonic Acid Concentrations in a Multiethnic Elderly Population: Ethnic and Sex Differences in Cobalamin and Metabolite Abnormalities, Am. J. Clin. Nutr. 70, 904–910.

    PubMed  CAS  Google Scholar 

  15. Osganian, S.K., Stampfer, M.J., Spiegelman, D., Rimm, E., Cutler, J.A., Feldman, H.A., Montgomery, D.H., Webber, L.S., Lytle, L.A., Bausserman, L., et al. (1999) Distribution of and Factors Associated with Serum Homocysteine Levels in Children: Child and Adolescent Trial for Cardiovascular Health, J. Am. Med. Assoc. 281, 1189–1196.

    Article  CAS  Google Scholar 

  16. Cattaneo, M. (1999) Hyperhomocysteinemia, Atherosclerosis, and Thrombosis, Thromb. Haemostasis 81, 165–176.

    CAS  Google Scholar 

  17. Naughton, E.R., Yap, S., and Mayne, P.D. (1998) Newborn Screening for Homocystinuria: Irish and World Experience, Eur. J. Pediatr. 157 (Suppl. 2), S84-S87.

    Article  Google Scholar 

  18. Mudd, S.H., Levy, H.L., and Skovby, F. (1995) Disorders of Transulfuration, in The Metabolic and Molecular Bases of Inherited Disease (Scriver, C.R., Beaudet, A.L., Sly, W.S., Valle, D., Stanbury, J.B., Wyngarden, J.B., and Fredrickson, D.S., eds.), pp. 1279–1327, McGraw-Hill, New York.

    Google Scholar 

  19. Rozen, R. (1996) Molecular Genetics of Methylenetertrahydrofolate Reductase Deficiency, J. Inherited Metab. Dis. 19, 589–594.

    Article  PubMed  CAS  Google Scholar 

  20. Rosenblatt, D.S., and Cooper, B.A. (1990) Inherited Disorders of Vitamin-B12 Utilization, BioEssay 12, 331–334.

    Article  CAS  Google Scholar 

  21. Rees, M.W., and Rodgers, G.M. (1993) Homocysteinemia: Association of a Metabolic Disorder with Vascular Disease and Thrombosis, Thromb. Res. 71, 337–359.

    Article  PubMed  CAS  Google Scholar 

  22. Kang, S.-S., Zhou, J., Wong, P.W.K., Kowalisyn, J., and Strokosch, G. (1988) Intermediate Homocysteinemia: A Thermolabile Variant of Methylenetetrahydrofolate Reductase, Am. J. Hum. Genet. 43, 414–421.

    PubMed  CAS  Google Scholar 

  23. Frosst, P., Blom, H.J., Milos, R., Goyette, P., Sheppard, C.A., Matthews, R.G., Boers, G.J.H., den Heijer, M., Kluijtmans, L.A.J., van den Heuvel, L.P., and Rozen, R. (1995) A Candidate Genetic Risk Factor for Vascular Disease: A Common Mutation in Methylenetetrahydrofolate Reductase, Nat. Gen. 10, 111–113.

    Article  CAS  Google Scholar 

  24. Ma, J., Stampfer, M.J., Hennekens, C.H., Frosst, P., Selhub, J., Horsford, J., Malinow, M.R., Willett, W.C., and Rozen, R. (1996) Methylenetetrahydrofolate Reductase Polymorphism, Plasma Folate, Homocysteine, and Risk of Myocardial Infarction in U.S. Physicians, Circulation 94, 2410–2416.

    PubMed  CAS  Google Scholar 

  25. Guttormsen, A.B., Ueland, P.M., Nesthus, I., Nygård, O., Schneede, J., Vollset, S.E., and Refsum, H. (1996) Determinants and Vitamin Responsiveness of Intermediate Hyperhomocysteinemia (>40 μmol/liter). The Hordaland Homocysteine Study, J. Clin. Investig. 98, 2174–2183.

    PubMed  CAS  Google Scholar 

  26. Kang, S.-S. (1995) Critical Points for Determining Moderate Hyperhomocyst(e)inaemia, Eur. J. Clin. Investig. 25, 806–808.

    CAS  Google Scholar 

  27. van der Put, N.M.J., Gabreels, F., Stevens, E.M.B., Smaitink, J.A.M., Trijbels, F.J.M., Eskes, T.K.A.B., van den Heuvel, L.P., and Blom, H.J. (1998) A Second Mutation in the Methylenetetrahydrofolate Reductase Gene: an Additional Risk Factor for Neural-Tube Defects? Am. J. Hum. Genet. 62, 1044–1051.

    Article  PubMed  Google Scholar 

  28. Joosten, E., van den Berg, A., Riezler, R., Naurath, H.J., Lindenbaum, J., Stabler, S.P., and Allen, R.H. (1993) Metabolic Evidence that Deficiencies of Vitamin B-12 (Cobalamin), Folate, and Vitamin B-6 Occur Commonly in Elderly People, Am. J. Clin. Nutr. 58, 468–476.

    PubMed  CAS  Google Scholar 

  29. Selhub, J., Jaques, P.F., Bostom, A.G., D'Agostino, R.B., Wilson, P.W.F., Belanger, A.J., O'Leary, D.H., Wolf, P.A., Schaeffer, E.J., and Rosenberg, I.H. (1995) Association Between Plasma Homocysteine Concentrations and Extracranial Carotid-Artery Stenosis, N. Engl. J. Med. 332, 286–291.

    Article  PubMed  CAS  Google Scholar 

  30. Smulders, Y.M., de Man, A.M.E., Stehouwer, C.D.A., and Slaats, E.H. (1999) Trimethoprim and Fasting Plasma Homocysteine, Lancet 352, 1827–1828.

    Article  Google Scholar 

  31. McCully, K.S. (1996) Homocysteine and Vascular Disease, Nat. Med. 2, 386–389.

    Article  PubMed  CAS  Google Scholar 

  32. Ubbink, J.B., van der Merwe, A., Delport, R., Allen, R.H., Stabler, S.P., Riezler, R., and Vermaak, W.J.H. (1996) The Effect of a Subnormal Vitamin B-6 Status on Homocysteine Metabolism, J. Clin. Investig. 98, 177–184.

    PubMed  CAS  Google Scholar 

  33. De Lorgeril, M., Salen, P., Paillard, F., Lacan, P., and Richard, G. (1999) Lipid-Lowering Drugs and Homocysteine, Lancet 353, 209–210.

    Article  PubMed  Google Scholar 

  34. Landray, M.J., Townend, J.N., Martin, S., Martin, U., and Wheeler, D.C. (1999) Lipid-Lowering Drugs and Homocysteine, Lancet 353, 1974–1975.

    Article  PubMed  CAS  Google Scholar 

  35. Dierkes, J., Westphal, S., and Luley, C. (1999) Serum Homocysteine Increases After Therapy with Fenofibrate or Bezafibrate, Lancet 354, 219–220.

    Article  PubMed  CAS  Google Scholar 

  36. Van der Mooren, M.J., Wouters, M.G., Blom, H.J., Schellekens, L.A., Eskes, T.K., and Rolland, R. (1994) Hormone Replacement Therapy May Reduce High Serum Homocysteine in Postmenopausal Women, Eur. J. Clin. Investig. 24, 733–736.

    Google Scholar 

  37. Giltay, E.J., Hoogeveen, E.K., Elbers, J.M.H., Gooren, L.J.G., Asscheman, H., and Stehouwer, C.D.A. (1998) Effects of Sex Steroids on Plasma Total Homocysteine Levels: A Study in Transsexual Males and Females, J. Clin. Endocrinol. Metab. 83, 550–553.

    Article  PubMed  CAS  Google Scholar 

  38. Anker, G., Lonning, P.E., Ueland, P.M., Refsum, H., and Lien, E.A. (1995) Plasma Levels of the Atherogenic Amino Acid Homocysteine in Post-Menopausal Women with Breast Cancer Treated with Tamoxifen, Int. J. Cancer 60, 365–368.

    Article  PubMed  CAS  Google Scholar 

  39. Cattaneo, M., Baglietto, L., Zighetti, M.L., Bettega, D., Robertson, C., Costa, A., Mannucci, P.M., and Decensi, A. (1998) Tamoxifen Reduces Plasma Homocysteine Levels in Healthy Women, Br. J. Oncol. 77, 2264–2266.

    CAS  Google Scholar 

  40. Kang, S.-S., Wong, P.W.K., Glickman, P.B., MacLeod, C.M., and Jaffe, I.A. (1986) Protein-Bound Homocyst(e)ine in Patients with Rheumatoid Arthritis Undergoing D-Penicillamine Treatment, J. Clin. Pharmacol. 26, 712–715.

    PubMed  CAS  Google Scholar 

  41. Wiklund, O., Fager, G., Andersson, A., Lundstam, U., Masson, P., and Hultberg, B. (1996) N-Acetylcysteine Treatment Lowers Plasma Homocysteine but Not Serum Lipoprotein(a) Levels, Atherosclerosis 119, 99–106.

    Article  PubMed  CAS  Google Scholar 

  42. Guba, S.C., Fink, L.M., and Fonseca, V. (1996) Hyperhomocysteinemia. An Emerging and Important Risk Factor for Thromboembolic and Cardiovascular Disease. Am. J. Clin. Pathol. 105, 709–722.

    Google Scholar 

  43. Frantzen, F., Faaren, A.L., Alfheim, I., and Nordhei, A.K. (1998) Enzyme Conversion Immunoassay for Determining Total Homocysteine in Plasma or Serum, Clin. Chem. 44, 311–316.

    PubMed  CAS  Google Scholar 

  44. Shipchandler, M.T., and Moore, E.G. (1995) Rapid, Fully Automated Measurement of Plasma Homocyst(e)ine with the Abbott Imx Analyzer, Clin. Chem. 41, 991–994.

    PubMed  CAS  Google Scholar 

  45. Tripodi, A., Chantarangkul, V., Lombardi, R., Lecchi, A., Mannucci, P.M., and Cattaneo, M. (2001) Multicenter Study of Homocysteine Measurement. Performance Characteristics of Different Methods, Influence of Standards on Interlaboratory Agreement of Results, Thromb. Haemostasis 85, 291–295.

    CAS  Google Scholar 

  46. Pfeiffer, C.M., Huff, D.L., Smith, S.J., Miller, D.T., and Gunter, E.W. (1999) Comparison of Plasma Total Homocysteine Measurements in 14 Laboratories: An International Study, Clin. Chem. 45, 1261–1268.

    PubMed  CAS  Google Scholar 

  47. Fowler, B., Sardharwalla, I.B., and Robins, A.J. (1971) The Detection of Heterozygotes for Homocystinuria by Oral Loading with L-Methionine, Biochem. J. 122, 23P-24P.

    PubMed  CAS  Google Scholar 

  48. Boers, G.H.J., Fowler, B., Smals, A.G.H., Trijbels, F.J.M., Leermakers, A.I., Kleijer, W.J., and Kloppenborg, P.W.C. (1985) Improved Identification of Heterozygotes for Homocystinuria Due to Cystathionine Synthase Deficiency by the Combination of Methionine Loading and Enzyme Determination in Cultured Fibroblasts, Hum. Genet. 69, 164–169.

    Article  PubMed  CAS  Google Scholar 

  49. Falcon, C.R., Cattaneo, M., Panzeri, D., Martinelli, I., and Mannucci, P.M. (1994) High Prevalence of Hyperhomocyst(e)inemia in Patients with Juvenile Venous Thrombosis, Arterioscler. Thromb. 14, 1080–1083.

    PubMed  CAS  Google Scholar 

  50. Fermo, I., Viganò-D'Angelo, S., Paroni, R., Mazzola, G., Calori, G., and D'Angelo, A. (1995) Prevalence of Moderate Hyperhomocysteinemia in Patients with Early-Onset Venous and Arterial Occlusive Disease, Ann. Intern. Med. 123, 747–753.

    PubMed  CAS  Google Scholar 

  51. Cattaneo, M., Martinelli, I., and Mannucci, P.M. (1996) Hyperhomocysteinemia as a Risk Factor for Deep-Vein Thrombosis, N. Engl. J. Med. 335, 974–975.

    Article  PubMed  CAS  Google Scholar 

  52. Graham, I.M., Daly, L.E., Refsum, H.M., Robinson, K., Brattsröm, L.E., Ueland, P.M., Palma-Reis, R.J., Boers, G.H.J., Sheahan, R.G., Israelsson, B., Uiterwaal, C.S., Meleady, R., McMaster, D., Verhoef, P., Witterman, J., Rubba, P., Bellet, H., Wautrecht, J.C., de Valk, H.W., Sales Luis, A.C., Parrot-Roulaud, F.M., Soon Tan, K., Higgins, I., Garcon, D., Medrano, M.J., Candito, M., Evans, A.E., and Andria, G. (1997) Plasma Homocystine as a Risk Factor for Vascular Disease. The European Concerted Action Project, J. Am. Med. Assoc. 277, 1775–1781.

    Article  CAS  Google Scholar 

  53. Bostom, A.G., Roubenoff, R., Dellaripa, P., Nadeau, M.R., Sutherland, P., Wilson, P.W.F., Jaques, P.F., Selhub, J., and Rosenberg, I.H. (1995) Validation of Abbrevated Oral Methionine-Loading Test, Clin. Chem. 41, 948–949.

    PubMed  CAS  Google Scholar 

  54. Cattaneo, M., Agati, B., Lecchi, A., Lombardi, R., Zighetti, M.L., Taioli, E., Mannucci, P.M. (1998) Comparison Between the 2-Hour and the 4-Hour Methionine Loading Test for the Identification of Subjects with Methionine Intolerance, Neth. J. Med. 52, (Suppl.), S37.

    Google Scholar 

  55. Selhub, J., and Miller, J.W. (1992) The Pathogenesis of Homocysteinemia: Interruption of the Coordinate Regulation by S-Adenosylmethionine of the Remethylation and Transsulfuration of Homocysteine, Am. J. Clin. Nutr. 55, 131–138.

    PubMed  CAS  Google Scholar 

  56. Miller, J.W., Nadeau, M.R., Smith, D., and Selhub, J. (1994) Vitamin B-6 Deficiency vs. Folate Deficiency: Comparison of Responses to Methionine Loading in Rats, Am. J. Clin. Nutr. 59, 1033–1039.

    PubMed  CAS  Google Scholar 

  57. Cattaneo, M., Tsai, M.Y., Bucciarelli, P., Taioli, E., Zighetti, M.L., Bignell, M., and Mannucci, P.M. (1997) A Common Mutation in the Methylene-Tetrahydrofolate Reductase Gene (C677T) Increases the Risk for Deep-Vein Thrombosis in Patients with Mutant Factor V (Factor V:Q506), Arterioscler. Thromb. Vasc Biol. 17, 1662–1666.

    PubMed  CAS  Google Scholar 

  58. Ubbink, J.B., Becker, P.J., Vermaak, W.J., and Delport, R. (1995) Results of B-Vitamin Supplementation Study Used in a Prediction Model to Define a Reference Range for Plasma Homocysteine, Clin. Chem. 41, 1033–1037.

    PubMed  CAS  Google Scholar 

  59. Rasmussen, K., Möller, J., Lyngbak, M., Pedersen, A.M., and Dybkjaer, L. (1996) Age- and Gender-Specific Reference Intervals for Total Homocysteine and Methylmalonic Acid in Plasma Before and After Vitamin Supplementation, Clin. Chem. 42, 630–636.

    PubMed  CAS  Google Scholar 

  60. Cattaneo, M., Lombardi, R., Lecchi, A., and Zighetti, M.L. (1999) Is the Oral Methionine Loading Test Insensitive to the Remethylation Pathway of Homocysteine? Blood 93, 1119–1120.

    Google Scholar 

  61. McCully, K.S. (1969) Vascular Pathology of Homocysteinemia: Implications for the Pathogenesis of Atherosclerosis, Am. J. Pathol. 56, 111–128.

    PubMed  CAS  Google Scholar 

  62. Refsum, H., Ueland, P.M., Nygård, O., and Vollset, S.E. (1998) Homocysteine and Cardiovascular Disease, Annu. Rev. Med. 49, 31–62.

    Article  PubMed  CAS  Google Scholar 

  63. Wilcken, D.E.L., and Wilcken, B. (1976) The Pathogenesis of Coronary Artery Disease. A Possible Role for Methionine Metabolism, J. Clin. Investig. 57, 1079–1082.

    PubMed  CAS  Google Scholar 

  64. Boushey, C.J., Beresford, S.A.A., Omenn, G.S., and Motulsky, A.G. (1995) A Quantitative Assessment of Plasma Homocysteine as a Risk Factor for Vascular Disease. Probable Benefits of Increasing Folic Acid Intakes, J. Am. Med. Assoc. 274, 1049–1057.

    Article  CAS  Google Scholar 

  65. Robinson, K., Arheart, K., Refsum, H., Brattström, L., Boers, G., Ueland, P., Rubba, P., Palma-Reis, R., Meleady, R., Daly, L., Witteman, J., and Graham, I., for the European COMAC Group (1998) Low Circulating Folate and Vitamin B6 Concentrations. Risk Factors for Stroke Peripheral Vascular Disease, and Coronary Artery Disease, Circulation 97, 437–443.

    PubMed  CAS  Google Scholar 

  66. Robinson, K., Mayer, E.L., Miller, D.P., Green, R., van Lente, F., Gupta, A., Kattke-Marchant, K., Savon, S.R., Selhub, J., Nissen, S.E., Kutner, M., Topol, E.J., and Jacobsen, D.W. (1995) Hyperhomocysteinemia and Low Pyridoxal Phosphate. Common and Independent Reversible Risk Factors for Coronary Artery Disease, Circulation 92, 2825–2830.

    PubMed  CAS  Google Scholar 

  67. Folsom, A.R., Nielo, F.J., McGovern, P.G., Tsai, M.Y., Malinow, M.R., Eckfeldt, J.H., Hess, D.L., and Davi, C.E. (1998) Prospective Study of Coronary Heart Disease Incidence in Relation to Fasting Total Homocysteine, Related Genetic Polymorphisms, and B Vitamins. The Atherosclerosis Risk in Communities (ARIC) Study, Circulation 98, 204–210.

    PubMed  CAS  Google Scholar 

  68. Malinow, M.R., Nieto, F.J., Szklo, M., Chambless, L.E., and Bond, G. (1993) Carotid Artery Intimal-Medial Wall Thickening and Plasma Homocyst(e)ine in Asymptomatic Adults. The Atherosclerosis in Communities (ARIC) Study. Circulation 87, 1107–1113.

    PubMed  CAS  Google Scholar 

  69. Bots, M.L., Launer, L.J., Lindemans, J., Hofman, A., and Grobbee, D.E. (1997) Homocysteine, Atherosclerosis and Prevalent Cardiovascular Disease in the Elderly: The Rotterdam Study, J. Intern. Med. 242, 339–347.

    Article  PubMed  CAS  Google Scholar 

  70. Konecki, N., Malinow, R., Tunick, P.A., Freedberg, R.S., Rosenzweig, B.P., Katz, E.S., Hess, D.L., Upson, B., Leung, B., Perez, J., and Kronzon, I. (1997) Correlation Between Plasma Homocyst(e)ine and Aortic Atherosclerosis, Am. Heart J. 133, 534–540.

    Article  Google Scholar 

  71. Verhoef, P., Kok, F.J., Kruyssen, D.A.C.M., Schouten, E.G., Witteman, J.C., Grobbe, D.E., Ueland, P.M., and Refsum, H. (1997) Plasma Total Homocysteine, B Vitamins and Risk of Coronary Atherosclerosis, Arterioscler. Thromb. Vasc. Biol. 17, 989–995.

    PubMed  CAS  Google Scholar 

  72. von Eckardstein, A., Malinow, M.R., Upson, B., Heinrich, T., Schulte, H., Schonfeld, R., Kohler, E., and Assmann, G. (1994) Effects of Age, Lipoproteins, and Hemostatic Parameters on the Role of Homocystinemia as a Cardiovascular Risk Factor in Men, Arterioscler. Thromb. 14, 460–464.

    Google Scholar 

  73. van den Berg, M., Stehouwer, C.D.A., Bierdrager, E., and Rauwerda, J.A. (1996) Plasma Homocysteine and Severity of Atherosclerosis in Young Patients with Lower-Limb Atherosclerotic Disease, Arterioscler. Thromb. Vasc. Biol. 16, 165–171.

    PubMed  Google Scholar 

  74. Taylor, L.M., DeFrang, R.D., Harris, E.J., and Porter, J.M. (1991) The Association of Elevated Plasma Homocyst(e)ine with Progression of Symptomatic Peripheral Arterial Disease, J. Vasc. Surg. 13, 128–136.

    Article  PubMed  Google Scholar 

  75. Alfthan, G., Pekkanen, J., Jauhiainen, M., Pitkaniemi, J., Karvonen, M., Tuomilehto, T., Salonen, J.T., and Ehnholm, C. (1994) Relation of Serum Homocysteine and Lipoprotein (a) Concentrations to Atherosclerotic Disease in a Prospective Finnish Population Based Study, Atherosclerosis 106, 9–19.

    Article  PubMed  CAS  Google Scholar 

  76. Stehouwer, C.D.A., Weijenberg, M.P., and van den Berg, M. (1996) Serum Homocysteine and the Five Year Risk of Cardiovascular Disease, Cancer and Cognitive Impairment in Elderly Men, in Prospective Studies on Coronary Heart Disease in the Elderly: the Role of Classical and New Risk Factors (Weijenberg, M., ed.), pp. 83–99, Grafisch Bedrijf Ponsen & Looijen B.V., Wageningen.

    Google Scholar 

  77. Arnesen, E., Refsum, H., Bonan, K.H., Ueland, P.M., Forde, O.H., and Nordrehaug, J.E. (1995) Serum Total Homocysteine and Coronary Heart Disease, Int. J. Epidemiol. 24, 704–709.

    PubMed  CAS  Google Scholar 

  78. Stampfer, M.J., Malinow, M.R., Willett, W.C., Newcomer, L.M., Upson, D., Tishler, P.V., and Hennekens, C.H. (1992) A Prospective Study of Plasma Homocyst(e)ine and Risk of Myocardial Infarction in U.S. Physicians, J. Am. Med. Assoc. 268, 877–881.

    Article  CAS  Google Scholar 

  79. Chasan-Taber, L., Selhub, J., Rosenberg, I.H., Malinow, M.R., Terry, P., Tishler, P.V., Willett, W., Hennekens, C.H., and Stampfer, M.J. (1996) A Prospective Study of Folate and Vitamin B6 and Risk of Myocardial Infarction in U.S. Physicians, J. Am. Coll. Nutr. 15, 136–143.

    PubMed  CAS  Google Scholar 

  80. Verhoef, P., Hennekens, C.H., Allen, R.H., Stabler, S.P., Willett, W.C., and Stampfer, M.J. (1997) Plasma Total Homocysteine and Risk of Angina Pectoris with Subsequent Coronary Artery Bypass Surgery, Am. J. Cardiol. 79, 799–801.

    Article  PubMed  CAS  Google Scholar 

  81. Verhoef, P., Hennekens, C.H., Malinow, M.R., Kok, F.J., Willert, W.C., and Stampfer, M.J. (1994) A Prospective Study of Plasma Homocyst(e)ine and Risk of Ischemic Stroke, Stroke 25, 1924–1930.

    PubMed  CAS  Google Scholar 

  82. Perry, I.J., Refsum, H., Morris, R.W., Ebrahim, S.B., Ueland, P.M., and Shaper, A.G. (1995) Prospective Study of Serum Total Homocysteine Concentration and Risk of Stroke in Middle-Aged British Men, Lancet 346, 1395–1398.

    Article  PubMed  CAS  Google Scholar 

  83. Evans, R.W., Shaten, B.J., Hempel, J.D., Cutler, J.A., and Kuller, L.H., for the MRFIT Research Group (1997) Homocyst(e)ine and Risk of Cardiovascular Disease in the Multiple Risk Factor Intervention Trial, Arterioscler. Thromb. Vasc. Biol. 17, 1947–1953.

    PubMed  CAS  Google Scholar 

  84. Wald, N.J., Watt, H.C., Law, M.R., Weir, D.G., McPartlin, J., and Scott, J.M. (1998) Homocysteine and Ischemic Heart Disease. Results of a Prospective Study with Implications Regarding Prevention, Arch. Intern. Med. 158, 862–867.

    Article  PubMed  CAS  Google Scholar 

  85. Ubbink, J.B., Fehily, A.M., Pickering, J., Elwood, P.C., and Vermaak, W.J.H. (1998) Homocysteine and Ischaemic Heart Disease in the Caerphilly Cohort, Atherosclerosis 140, 349–356.

    Article  PubMed  CAS  Google Scholar 

  86. Whincup, P.H., Refsum, H., Perry, I.J., Morris, R., Walker, M., Lennen, L., Thomson, A., Ueland, P.M., and Ebrahim, S.B.J. (1999) Serum Total Homocysteine and Coronary Heart Disease: Prospective Study in Middle Aged Men, Heart 82, 448–454.

    PubMed  CAS  Google Scholar 

  87. Stehouwer, C.D.A., Weijenberg, M.P., van den Berg, M., Jakobs, C., Feskens, E.J.M., and Kromhout, D. (1998) Serum Homocysteine and Risk of Coronary Heart Disease and Cerebrovascular Disease in Elderly Men. A 10-Year Follow-Up, Arterioscler. Thromb. Vasc. Biol. 18, 1895–1901.

    PubMed  CAS  Google Scholar 

  88. Bots, M.L., Launer, L.J., Lindemans, J., Hoes, A.W., Hofman, A., Witteman, J.C.M., Koudstaal, P.J., and Grobbee, D.E. (1999) Homocysteine and Short-Term Risk of Myocardial Infarction and Stroke in the Elderly. The Rotterdam Study, Arch. Intern. Med. 159, 38–44.

    Article  PubMed  CAS  Google Scholar 

  89. Bostom, A.G., Rosenberg, I.H., Silbershatz, H., Jaques, P.F., Selhub, J., D'Agostino, R.B., Wilson, P.W.F., and Wolf, P.A. (1999) Nonfasting Plasma Total Homocysteine Levels and Stroke Incidence in Elderly Persons: The Framingham Study, Ann. Intern. Med. 131, 352–355.

    PubMed  CAS  Google Scholar 

  90. Ridker, P.M., Manson, J.E., Buring, J.E., Shih, J., Matias, M., and Hennekens, C.H. (1999) Homocysteine and Risk of Cardiovascular Disease Among Postmenopausal Women, J. Am. Med. Assoc. 281, 1817–1821.

    Article  CAS  Google Scholar 

  91. Bostom, A.G., Silbershatz, H., Rosenberg, I.H., Selhub, J., D'Agostino, R.B., Wolf, P.A., Jaques, P.F., and Wilson, P.W.F. (1999) Nonfasting Plasma Total Homocysteine Levels and All-Cause and Cardiovascular Disease Mortality in Elderly Framingham Men and Women, Arch. Intern. Med. 159, 1077–1080.

    Article  PubMed  CAS  Google Scholar 

  92. Kark, J.D., Selhub, J., Adler, B., Gofin, J., Abramson, J.H., Friedman, G., and Rosenberg, I.H. (1999) Nonfasting Plasma Total Homocysteine Level and Mortality in Middle-Aged and Elderly Men and Women in Jerusalem, Ann. Intern. Med. 131, 321–330.

    PubMed  CAS  Google Scholar 

  93. Nygård, O., Nordrehaug, J.E., Refsum, H., Ueland, P.M., Farstad, M., and Vollset, S.E. (1997) Plasma Homocysteine Levels and Mortality in Patients with Coronary Artery Disease, N. Engl. J. Med. 337, 230–236.

    Article  PubMed  Google Scholar 

  94. Petri, M., Roubenoff, R., Dallal, G.E., Nadeau, M.R., Selhub, J., and Rosenberg, I.H. (1996) Plasma Homocysteine as a Risk Factor for Atherothrombotic Events in Systemic Lupus Erythematosus, Lancet 348, 1120–1124.

    Article  PubMed  CAS  Google Scholar 

  95. Robinson, K., Gupta, A., Dennis, V., Arheart, K., Chaudhary, D., Green, R., Vigo, P., Mayer, E.L., Selhub, J., Kutner, M., and Jacobsen, D.W. (1996) Hyperhomocysteinemia Confers an Independent Increased Risk of Atherosclerosis in End-Stage Renal Disease and Is Closely Linked to Plasma Folate and Pyridoxine Concentrations, Circulation 94, 2743–2748.

    PubMed  CAS  Google Scholar 

  96. Bostom, A.G., and Lathrop, L. (1997) Hyperhomocysteinemia in End-Stage Renal Disease: Prevalence, Etiology, and Potential Relationship to Arteriosclerotic Outcomes, Kidney Int. 52, 10–20.

    PubMed  CAS  Google Scholar 

  97. Bostom, A.G., Shemin, D., Verhoef, P., Nadeau, M.R., Jacques, P.F., Selhub, J., Dworkin, L., and Rosenberg, I.H. (1997) Elevated Fasting Total Plasma Homocysteine Levels and Cardiovascular Disease Outcomes in Maintenance Dialysis Patients. A Prospective Study, Arterioscler. Thromb. Vasc. Biol. 17, 2554–2558.

    PubMed  CAS  Google Scholar 

  98. Moustapha, A., Naso, A., Nahlawi, M., Gupta, A., Arheart, K.L., Jacobsen, D.W., Robinson, K., and Dennis, V.W. (1998) Prospective Study of Hyperhomocysteinemia as an Adverse Cardiovascular Risk Factor in End-Stage Renal Disease, Circulation 20, 138–141.

    Google Scholar 

  99. Stehouwer, C.D.A., Gall, A.-A., Hougaard, P., Jakobs, C., and Parving, H.-H. (1999) Plasma Homocysteine Concentration Predicts Mortality in Non-Insulin-Dependent Diabetic Patients With and Without Albuminuria, Kidney Int. 55, 308–314.

    Article  PubMed  CAS  Google Scholar 

  100. Hoogeveen, E.K., Kostense, P.J., Jakobs, C., Dekker, J.M., Nijpels, G., Heine, R.J., Bouter, L.M., and Stehouwer, C.D.A. (2000) Hyperhomocysteinemia Increase Risk of Death, Especially in Type 2 Diabetes. 5-Year Follow-Up of the Hoorn Study, Circulation 101, 1506–1511.

    PubMed  CAS  Google Scholar 

  101. Gudnason, V., Stansbie, D., Scott, J., Bowron, A., Nicaud, V., and Humphries, S., on Behalf of the EARS Group (1998) C677T (Thermolabile Alanine/Valine) Polymorphism in Methylenete-trahydrofolate Reductase (MTHFR): Its Frequency and Impact on Plasma Homocysteine Concentration in Different European Populations, Atherosclerosis 136, 347–354.

    Article  PubMed  CAS  Google Scholar 

  102. Alfthan, G., Aro, A., and Gey, K.F. (1997) Plasma Homocysteine and Cardiovascular Disease Mortality, Lancet 349, 397.

    Article  PubMed  CAS  Google Scholar 

  103. Kluijtmans, L.A.J., van den Heuvel, L.P.W.J., Boers, G.H.J., Frosst, P., Stevens, E.M.B., van Oost, B.A., den Heijer, M., Trijbels, F.J.M., Rozen, R., and Blom, H.J. (1996) Molecular Genetic Analysis in Mild Hyperhomocysteinemia: A Common Mutation in the Methylenetetrahydrofolate Reductase Gene Is a Genetic Risk Factor for Cardiovascular Disease, Am. J. Hum. Genet. 58, 35–41.

    PubMed  CAS  Google Scholar 

  104. Mudd, S.H., Havlik, R., Levy, H.L., McKusick, V.A., and Feinleib, M. (1981) A Study of Cardiovascular Risk in Heterozygotes for Homocystinuria, Am. J. Hum. Genet. 33, 883–893.

    PubMed  CAS  Google Scholar 

  105. de Valk, H.W., van Eeden, M.K.G., Banga, J.D., van der Griend, R., de Groot, E., Haas, F.J., Meuwissen, O.J., Duran, M., Smeitimk, J.A., Poll-The, B.T., de Klerk, J.B., Wittebol-Post, D., and Rolland, M.O. (1996) Evaluation of the Presence of Premature Atherosclerosis in Adults with Heterozygosity for Cystathionine-Beta-Synthase Deficiency, Stroke 27, 1134–1136.

    PubMed  Google Scholar 

  106. Boers, G.H.J., Smals, A.G.H., Tijbels, F.J.M., Fowler, B., Bakkeren, J.A.J.M., Schoonderwaldt, H.C., Klijer, W.J., and Kloppenborg, P.W.C. (1985) Heterozygosity for Homocystinuria in Premature Peripheral and Cerebral Occlusive Arterial Disease, N. Engl. J. Med. 313, 709–715.

    Article  PubMed  CAS  Google Scholar 

  107. Clarke, R., Daly, L., Robinson, K., Naughten, E., Cahalane, S., Fowler, B., and Graham, I. (1991) Hyperhomocysteinemia: An Independent Risk Factor for Vascular Disease, N. Engl. J. Med. 324, 1149–1155.

    Article  PubMed  CAS  Google Scholar 

  108. Kluijtmans, L.A.J., Kastelein, J.J.P., Lindemans, J., Boers, G.H.J., Heil, S.G., Bruschke, A.V.G., Jukema, J.W., van den Heuvel, L.P.W.J., Trijbels, F.J.M., Boerma, G.J.M., Verheugt, F.W.A., Willems, F., and Blom, H.J. (1997) Thermolabile Methylenetetrahydrofolate Reductase in Coronary Artery Disease, Circulation 96, 2573–2577.

    PubMed  CAS  Google Scholar 

  109. Brattström, L. (1997) Common Mutation in the Methylenete-trahydrofolate Reductase Gene Offers No Support for Mild Hyperhomocysteinemia Being a Causal Risk Factor for Cardiovascular Disease, Circulation 96, 3805–3806.

    PubMed  Google Scholar 

  110. Mager, A., Lalezari, S., Shohat, T., Birnbaum, Y., Adler, Y., Magal, N., and Shohat, M. (1999) Methylenetetrahydrofolate Reductase Genotypes and Early-Onset Coronary Artery Disease, Circulation 100, 2406–2410.

    PubMed  CAS  Google Scholar 

  111. Nowak-Gottl, U., Strater, R., Heinecke, A., Junker, R., Koch, H.-G., Schierer, G., and von, Eckardstein, A., for the Childhood Stroke Study Group (1999) Lipoprotein (a) and Genetic Polymorphisms of Clotting Factor V, Prothrombin, and Methylenetetrahydrofolate Reductase Are Risk Factors for Spontaneous Tschemic Stroke in Childhood, Blood 94, 3678–3682.

    PubMed  CAS  Google Scholar 

  112. Tsai, M.Y., Bignell, M., Schwichtenberg, K., and Hanson, N.Q. (1996) High Prevalence of a Mutation in the Cystathionine β-Synthase Gene, Am. J. Hum. Genet. 59, 1262–1267.

    PubMed  CAS  Google Scholar 

  113. Sperandeo, M.P., De Franchis, R., Andria, G., and Sebastio, G. (1996) A 68-bp Insertion Found in a Homocystinuric Patient Is a Common Variant and Is Skipped by Alternative Splicing of the Cystathionine β-Synthase mRNA, Am. J. Hum. Genet. 59, 1391–1393.

    PubMed  CAS  Google Scholar 

  114. Kluijtmans, L.A.J., Boers, G.H.J., Trijbels, F.J.M., van Lith-Zanders, H.M.A., van den Heuvel, L.P.W.J., and Blom, H.J. (1997) A Common 844ins68 Insertion Variant in the Cystathionine-β-Synthase Gene, Biochem. Mol. Med. 62, 23–25.

    Article  PubMed  CAS  Google Scholar 

  115. McQuillan, B.M., Beilby, J.P., Nidorf, M., Thompson, P.L., and Hung, J. (1999) Hyper-Homocysteinemia but Not the C677T Mutation of Methylenetetrahydrofolate Reductase Is an Independent Risk Determinant of Carotid Wall Thickening. The Perth Carotid Ultrasound Disease Assessment Study (CUDAS), Circulation 99, 2383–2388.

    PubMed  CAS  Google Scholar 

  116. Spence, J.D., Malinow, M.R., Barnett, P.A., Marian, A.J., Freeman, D., and Hegele, R.A. (1999) Plasma Homocyst(e)ine Concentration, but Not MTHFR Genotype, Is Associated with Variation in Carotid Plaque Area, Stroke 30, 969–973.

    PubMed  CAS  Google Scholar 

  117. Brattström, L., Tangborn, L., Lagerstedt, C., Israelsson, B., and Hultber, B. (1991) Plasma Homocysteine in Venous Thromboembolism, Haemostasis 21, 51–57.

    PubMed  Google Scholar 

  118. Bienvenu, T., Ankri, A., Chadefaux, B., Montalescot, G., and Kamoun, P. (1993) Elevated Total Plasma Homocysteine, a Risk Factor for Thrombosis: Relation to Coagulation and Fibrinolytic Parameters, Thromb. Res. 70, 123–129.

    Article  PubMed  CAS  Google Scholar 

  119. den Hejier, M., Blom, H.J., Gerrits, W.B.J., Rosendaal, F.R., Haak, H.L., Wijermans, P.W., and Bos, G.M.J. (1995) Is Hyperhomocysteinaemia a Risk Factor for Recurrent Venous Thrombosis? Lancet 345, 882–885.

    Article  Google Scholar 

  120. den Heijer, M., Koster, T., Blom, H.J., Bos, G.M.J., Briet, E., Reitsma, P.H., Vanderbroucke, J.P., and Rosendaal, F.R. (1996) Hyperhomocysteinemia as a Risk Factor for Deep-Vein Thrombosis, N. Engl. J. Med. 334, 759–762.

    Article  Google Scholar 

  121. Simioni, P., Prandoni, P., Burlina, A., Tormene, D., Sardella, C., Ferrari, V., Beneditti, L., and Girolami, A. (1996) Hyperhomocysteinemia and Deep-Vein Thrombosis. A Case Control Study, Thromb. Haemostasis 76, 883–886.

    CAS  Google Scholar 

  122. Amundsen, T., Ueland, P.M., and Waage, A. (1995) Plasma Homocysteine Levels in Patients with Deep Venous Thrombosis, Arterioscler. Thromb. Vasc. Biol. 15, 1321–1323.

    PubMed  CAS  Google Scholar 

  123. Martinelli, I., Cattaneo, M., Panzeri, D., Taioli, E., and Mannucci, P.M. (1997) Risk Factors for Primary Deep Vein Thrombosis of the Upper Extremities, Ann. Intern. Med. 126, 707–711.

    PubMed  CAS  Google Scholar 

  124. den Heijer, M., Rosendaal, F.R., Blom, H.J., Gerrits, W.B.J., and Bos, G.M.J. (1998) Hyperhomocysteinemia and Venous Thrombosis: A Meta-Analysis, Thromb. Haemostasis 80, 874–877.

    Google Scholar 

  125. Ray, J.G. (1998) Meta-Analysis of Hyperhomocysteinemia as a Risk Factor for Venous Thromboembolic Disease, Arch. Intern. Med. 158, 2101–2106.

    Article  PubMed  CAS  Google Scholar 

  126. Kluijtmans, L.A.J., Boers, G.H.J., Verbruggen, B., Trijbels, F.J.M., Novakova, I.R.O., and Blom, H.J. (1998) Homozygous Cystathionine β-Synthase Deficiency, Combined with Factor V Leiden or Thermolabile Methylenetetrahydrofolate Reductase in the Risk of Venous Thrombosis, Blood 91, 2015–2018.

    PubMed  CAS  Google Scholar 

  127. Mandel, H., Brenner, B., Berant, M., Rosenberg, N., Lanir, N., Jakobs, C., Fowler, B., and Seligsohn, N. Coexistence of Hereditary Homocystinuria and Factor V Leiden—Effect on Thrombosis, N. Engl. J. Med. 334, 763–768.

  128. Ridker, P.M., Hennekens, C.H., Selhub, J., Miletich, J.P., Malinow, M.R., and Stampfer, M.J. (1997) Interrelation of Hyperhomocyst(e)inemia, Factor V Leiden, and Risk of Future Venous Thromboembolism, Circulation 95, 1777–1782.

    PubMed  CAS  Google Scholar 

  129. Cattaneo, M., Zighetti, M.L., Turner, R.M., Thompson, S.G., Lowe, G.D.O., Haverkate, F., Bertina, R.M., Turpie, A.G.G., Mannucci, P.M., and the ECAT DVT Study Group (1998) Fasting Plasma Homocysteine Levels Do Not Predict the Occurrence of Deep-Vein Thrombosis After Elective Hip Replacement Surgery, Neth. J. Med. 52, (Suppl.), S21.

    Google Scholar 

  130. Cattaneo, M., Monzani, M.L., Martinelli, I., Falcon, C.R., and Mannucci, P.M. (1998) Interrelation of Hyperhomocyst(e)inemia, Factor V Leiden, and Risk of Future Venous Thromboembolism, Circulation 97, 295.

    PubMed  CAS  Google Scholar 

  131. Eichinger, S., Stümpfen, A., Hirschl, M., Blalonczyk, C., Herkner, K., Stain, M., Schneider, B., Pabinger, I., Lechner, K., and Kyrle, P.A. (1998) Hyperhomocysteinemia Is a Risk Factor of Recurrent Venous Thromboembolism, Thromb. Haemostasis 80, 566–569.

    CAS  Google Scholar 

  132. Arruda, V.R., von Zuben, P.M., Chiaparini, L.C., Annichino-Bizzacchi, J.M., and Costa, F.F. (1997) The Mutation ALA677->VAL in the Methylene-Tetrahydrofolate Reductase Gene: A Risk Factor for Arterial Disease and Venous Thrombosis, Thromb. Haemostasis 77, 818–821.

    CAS  Google Scholar 

  133. Alhene-Gelas, M., Arnaud, E., Nicaud, V., Aubry, M.-L., Flessinger, J.-N., Aiach, M., and Emmerich, J. (1999) Venous Thromboembolic Disease and the Prothrombin, Methylenetetrahydrolfolate Reductase and Factor V Genes, Thromb. Haemostasis 81, 506–510.

    Google Scholar 

  134. Kluijtmans, L.A.J., den Heijer, M., Reitsma, P.H., Heil, S.G., Blom, H.J., and Rosendaal, F.R. (1998) Thermolabile Methylenetetrahydrofolate Reductase and Factor V Leiden in the Risk of Deep-Vein Thrombosis, Thromb. Haemostasis 79, 254–258.

    CAS  Google Scholar 

  135. Rintelen, C., Mannhalter, C., Lechner, K., Eichinger, S., Kyrle, P.A., Papagiannopoulos, M., Schneider, B., and Pabinger, I. (1999) No Evidence for an Increased Risk of Venous Thrombosis in Patients with Factor V Leiden by the Homozygous 677C to T Mutation in the Methylenetetrahydrofolate Reductase Gene, Blood Coagul. Fibrinolysis 10, 101—1—5.

    PubMed  CAS  Google Scholar 

  136. Salomon, O., Steinberg, D.M., Zivelin, A., Gitel, S., Dardik, R., Rosenberg, N., Berliner, S., Inbal, A., Mani, A., Lubetsky, A., Varon, D., Martinowitz, U., and Seligsohn, U. (1999) Single and Combined Prothrombotic Factors in Patients with Idiopathic Venous Thromboembolism: Prevalence and Risk Assessment, Arterioscler. Thromb. Vasc. Biol. 19, 511–518.

    PubMed  CAS  Google Scholar 

  137. Margaglione, M., D'Andrea, G., d'Addedda, M., Giuliani, N., Cappucci, G., Iannaccone, L., Vecchione, G., Grandone, E., Brancaccio, V., and Di Minno, G. (1998) The Methylenete-trahydrofolate Reductase TT677 Genotype Is Associated with Venous Thrombosis Independently of the Coexistence of the FV Leiden and the Prothrombin A20210 Mutation, Thromb. Haemostasis 79, 907–911.

    CAS  Google Scholar 

  138. Tosetto, A., Missiaglia, E., Frezzato, M., and Rodeghiero, F. (1997) The VITA Project: C677T Mutation in the Methylenetetrahydrofolate Reductase Gene and the Risk of Venous Thromboembolism, Br. J. Haematol. 97, 804–806.

    Article  PubMed  CAS  Google Scholar 

  139. den Heijer, M., Willems, H.P.J., Bos, G.M.J., Blom, H.J., Gerrits, W.B.J., and Rosendaal, F.R. (1999) Homocysteine, Serum Folate, Mutated Methylenetetrahydrofolate Reductase (Mthfr) and Factor V Leiden and the Risk of Venous Thrombosis, Thromb. Haemostasis (Suppl.), 271 (abstract).

  140. Cattaneo, M., Chantarangkul, V., Taioli, E., Hermida Santos, J., and Tagliabue, L. (1999) The G20210A Mutation of the Prothrombin Gene in Patients with Previous First Episodes of Deep-Vein Thrombosis: Prevalence and Association with Factor V G1691A, Methylenetetrahydrofolate Reductase C677T and Plasma Prothrombin Levels, Thromb. Res. 93, 1–8.

    Article  PubMed  CAS  Google Scholar 

  141. Malinow, M.R., Bostom, A.G., and Krauss, R.M. (1999) Homocyst(e)ine, Diet, and Cardiovascular Diseases: A Statement for Healthcare Professionals from the Nutrition Committee, American Heart Association, Circulation 99, 178–182.

    PubMed  CAS  Google Scholar 

  142. Cattaneo, M. (1999) Homocysteine and Cardiovascular Diseases, Circulation 100, e151.

    PubMed  CAS  Google Scholar 

  143. Nedrebo, B.G., Ericsson, U.B., Nygård, O., Refsum, H., Ueland, P.M., Aakvaag, A., Aanderud, S., and Lien, E.A. (1998) Plasma Total Homocysteine Levels in Hyperthyroid and Hypothyroid Patients, Metabolism 47, 89–93.

    Article  PubMed  CAS  Google Scholar 

  144. Cattaneo, M., Vecchi, M., Zighetti, M.L., Saibeni, S., Martinelli, I., Omodei, P., Mannucci, P.M., and de Franchis, R. (1998) High Prevalence of Hyperhomocysteinemia in Patients with Inflammatory Bowel Disease: A Pathogenic Link with Thromboembolic Complications?, Thromb. Haemostasis 80, 542–545.

    CAS  Google Scholar 

  145. Roubenoff, R., Dellaripa, P., Nadeau, M.R., Abad, L.W., Muldoon, B.A., Selhub, J., and Rosenberg, I.H. (1997) Abnormal Homocysteine Metabolism in Rheumatoid Arthritis, Arthritis Rheum 40, 718–722.

    PubMed  CAS  Google Scholar 

  146. Sunder-Plassmann, G., Floth, A., and Fodinger, M. (2000) Hy-perhomocysteinemia in Organ Transplantation, Curr. Opin. Urol. 10, 87–94.

    Article  PubMed  CAS  Google Scholar 

  147. Refsum, H., Wesenberg, F., and Ueland, P.M. (1991) Plasma Homocysteine in Children with Acute Lymphoblastic Leukemia. Changes During a Chemotherapeutic Regimen Including Methotrexate, Cancer Res. 51, 828–835.

    PubMed  CAS  Google Scholar 

  148. Tonon, G., Boyd, K., Lecchi, A., Lombardi, R., Porcella, A., and Cattaneo, M. (1997) Plasma Homocysteine Levels in 10 Patients with Polycythemia, Haematologica 82, 343–344.

    PubMed  CAS  Google Scholar 

  149. Hofman, M.A., Koll, B., Zumbach, M.S., Borces, V., Bierhaus, A., Henkels, M., Amiral, J., Fiehn, W., Ziegler, R., Wahl, P., and Nawroth, P.P. (1997) Hyperhomocyst(e)inemia and Endothelial Dysfunction in IDDM, Diabetes Care 20, 1880–1886.

    Google Scholar 

  150. Hoogeveen, E.K., Kostense, P.J., Beks, P.J., Mackaay, A.J., Jakobs, C., Bouter, L.M., Heine, R.J., and Stehouwer, C.D. (1998) Hyperhomocysteinemia Is Associated with an Increased Risk of Cardiovascular Disease, Especially in Non-Insulin-Dependent Diabetes Mellitus: A Population-Based Study, Arterioscler. Thromb. Vasc. Biol. 18, 133–138.

    PubMed  CAS  Google Scholar 

  151. Harker, L.A., Ross, R., Slichter, S.J., and Scott, C.R. (1976) Homocystine-Induced Arteriosclerosis: The Role of Endothelial Cell Injury and Platelet Response in Its Genesis, J. Clin. Investig. 58,731–741.

    PubMed  CAS  Google Scholar 

  152. Starkebaum, G., and Harlan, J.M. (1986) Endothelial Cell Injury Due to Copper-Catalyzed Hydrogen Peroxide Generation from Homocysteine, J. Clin. Investig. 77, 1370–1376.

    Article  PubMed  CAS  Google Scholar 

  153. Rodgers, G.M., and Kane, W.H. (1986) Activation of Endogenous Factor V by a Homocysteine-Induced Vascular Endothelial Cell Activator, J. Clin. Investig. 77, 1909–1916.

    PubMed  CAS  Google Scholar 

  154. Rodgers, G.M., and Conn, M.T. (1990) Homocysteine, an Atherogenic Stimulus, Reduces Protein C Activation by Arterial and Venous Endothelial Cells, Blood 75, 895–901.

    PubMed  CAS  Google Scholar 

  155. Lentz, S.R., and Sadler, J.E. (1991) Inhibition of Thrombomodulin Surface Expression and Protein C Activation by the Thrombogenic Agent Homocysteine, J. Clin. Investig. 88, 1906–1914.

    PubMed  CAS  Google Scholar 

  156. Hayashi, T., Honda, G., and Suzuki, K. (1992) An Atherogenic Stimulus Homocysteine Inhibits Cofactor Activity of Thrombomodulin and Enhances Thrombomodulin Expression in Human Umbilical Vein Endothelial Cells, Blood 79, 2930–2936.

    PubMed  CAS  Google Scholar 

  157. Hajjar, K.A. (1993) Homocysteine-Induced Modulation of Tissue Plasminogen Activator Binding to Its Endothelial Cell Membrane Receptor, J. Clin. Investig. 91, 2873–2879.

    PubMed  CAS  Google Scholar 

  158. Hajjar, K.A., Mauri, L., Jacovina, A.T., Zhong, F., Mirza, U.A., Padovan, J.C., and Chait, B.T. (1998) Tissue Plasminogen Activator Binding to Annexin II Tail Domain. Direct Modulation by Homocysteine, J. Biol. Chem. 273, 9987–9993.

    Article  PubMed  CAS  Google Scholar 

  159. Stamler, J.S., Osborne, J.A., Jaraki, O., Rabbani, L.E., Mullins, M., Singel, D., and Loscalzo, J. (1993) Adverse Vascular Effects of Homocysteine Are Modulated by Endothelium-Derived Relaxing Factor and Related Oxides of Nitrogen, J. Clin. Investig. 91, 308–318.

    PubMed  CAS  Google Scholar 

  160. Welch, G.N., Upchurch, G.R., Jr., and Loscalzo, J. (1997) Hyperhomocyst(e)inemia and Atherothrombosis, Ann. N.Y. Acad. Sci. 811, 48–58.

    PubMed  CAS  Google Scholar 

  161. Upchurch, G.R., Jr., Welch, G.N., Fabian, A.J., Freedman, J.E., Johnson, J.L., Keany, J.F., Jr., and Loscalzo, J. (1997) Homocyst(e)ine Decreases Bioavailable Nitric Oxide by a Mechanism Involving Glutathione Peroxidase, J. Biol. Chem. 272, 17012–17017.

    Article  PubMed  CAS  Google Scholar 

  162. Wang, J., Dudman, N.P.B., and Wilcken, D.E.L. (1993) Effects of Homocysteine and Related Compounds on Prostacycline Production by Cultured Human Vascular Endothelial Cells, Thromb. Haemostasis 70, 1047–1052.

    CAS  Google Scholar 

  163. Fryer, R.H., Wilson, B.D., Gubler, D.B., Fitzgerald, L.A., and Rodgers, G.M. (1993) Homocysteine, a Risk Factor for Premature Vascular Disease and Thrombosis, Induces Tissue Factor Activity in Endothelial Cells, Arterioscler Thromb. 13, 1327–1332.

    PubMed  CAS  Google Scholar 

  164. Nishinaga, M., Ozawa, T., and Shimada, K. (1993) Homocysteine, a Thrombogenic Agent, Suppresses Anticoagulant Heparan Sulfate Expression in Cultured Porcine Aortic Endothelial Cells, J. Clin. Investig. 92, 1381–1386.

    PubMed  CAS  Google Scholar 

  165. Broekman, M.J., Haijar, K.A., Marcus, A.J., Lev, E., Islam, N., Safier, L.B., and Fliessbach, J. (1994) Homocysteine Inhibits ecto-ADPase Activity of Human Umbilical Vein Endothelial Cells, Blood 84 (Suppl. 1), 77 (Abstr.)

    Google Scholar 

  166. Tsai, J.-C., Perrella, M.A., Yoshizumi, M., Hsieh, C.M., Haber, E., Schlegel, R., and Lee, M.E. (1994) Promotion of Vascular Smooth Muscle Cell Growth by Homocysteine: A Link to Atherosclerosis, Proc. Natl. Acad. Sci. USA 91, 6369–6373.

    Article  PubMed  CAS  Google Scholar 

  167. Majors, A., Ehrhart, L.A., and Pezacka, E.H. (1997) Homocysteine as a Risk Factor for Vascular Disease. Enhanced Collagen Production and Accumulation by Smooth Muscle Cells, Arterioscler. Thromb. Vasc. Biol. 17, 2074–2081.

    PubMed  CAS  Google Scholar 

  168. Outinen, P.A., Sood, S.K., Pfeifer, S.I., Pamidi, S., Podor, T.J., Li, J., Weitz, J.I., and Austin, R.C. (1999) Homocysteine-Induced Endoplasmic Reticulum Stress and Growth Arrest Leads to Specific Changes in Gene Expression in Human Vascular Endothelial Cells, Blood 94, 959–967.

    PubMed  CAS  Google Scholar 

  169. Xu, D., Neville, R., and Finkel, T. (2000) Homocysteine Accelerates Endothelial Cell Senescence, FEBS Lett. 470, 2024.

    Article  Google Scholar 

  170. Lentz, S.R., Sobey, C.G., Piegors, D.J., Bhopatkar, M.Y., Faraci, F.M., Malinow, M.R., and Heistad, D.D. (1996) Vascular Dysfunction in Monkeys with Diet-Induced Hyperhomocysteinemia, J. Clin. Investig. 98, 24–29.

    PubMed  CAS  Google Scholar 

  171. Cattaneo, M., Martinelli,I., Faioni, E., Franchi, F., Zighetti, M.L., and Mannucci, P.M. (1998) Plasma Levels of Activated Protein C in Healthy Subjects and Patients with Previous Venous Thromboembolism. Relationship with Plasma Homocysteine Levels, Arterioscler. Thromb. Vasc. Biol. 18, 1371–1375.

    PubMed  CAS  Google Scholar 

  172. Coppola, A., Cerbone, A.M., Guiotto, G., Soriente, L., Piemontino, U., Rugiada, F., Viganò D'Angelo, S., Della Valle, P., Mancini, F.P., Davì, G., Di Minno, G., and Patrono, C. (1997) A Hypercoagulable State in Homocystinuria Due to Homozygous Cystathionine-β-Synthase Deficiency, Thromb. Haemostasis (Suppl.), 528.

  173. Di Minno, G., Davì, G., Margaglione, M., Cirillo, F., Grandone, E., Ciabattoni, G., Catalano, I., Strisciuglio, P., Andria, G., Patrono, C., and Mancini, M. (1993) Abnormally High Thromboxane Biosynthesis in Homozygous Homocystinuria. Evidence for Platelet Involvement and Probucol-Sensitive Mechanism, J. Clin. Investig. 92, 1400–1406.

    PubMed  Google Scholar 

  174. Woo, K.S., Chook, P., Lolin, Y.I., Cheung, A.S.P., Chan, L.T., Sun, Y.Y., Sanderson, J.E., Metreweli, C., and Celermajer, D.S. (1997) Hyperhomocyst(e)inemia Is a Risk Factor for Arterial Endothelial Dysfunction in Humans, Circulation 96, 2542–2544.

    PubMed  CAS  Google Scholar 

  175. Tawakol, A., Omland, T., Gerhard, M., Wu, J.T., and Creager, M.A. (1997) Hyperhomocyst(e)inemia Is Associated with Impaired Endothelium-Dependent Vasodilation in Humans, Circulation 95, 1119–1121.

    PubMed  CAS  Google Scholar 

  176. Chambers, J.C., McGregor, A., Jean-Marie, J., and Kooner, J.S. (1998) Acute Hyperhomocysteinaemia and Endothelial Dysfunction, Lancet 351, 36–37.

    Article  PubMed  CAS  Google Scholar 

  177. Bellamy, M.F., McDowell, I.F.W., Ramsey, M.W., Brownlee, M., Bones, C., Newcombe, R.G., and Lewis, M.J. (1998) Hyperhomocysteinemia After an Oral Methionine Load Acutely Imparis Endothelial Function in Healthy Adults, Circulation 98, 1848–1852.

    PubMed  CAS  Google Scholar 

  178. Chambers, J.C., McGregor, A., Jean-Marie, J., Obeid, O.A., and Kooner, J.S. (1999) Demonstration of Rapid Onset Vascular Endothelial Dysfunction After Hyperhomocysteinemia, an Effect Reversible with Vitamin C Therapy, Circulation 99, 1156–1160.

    PubMed  CAS  Google Scholar 

  179. Nappo, F., De Rosa, N., Marfella, R., De Lucia, D., Ingrosso, D., Perna, A.F., Farzati, B., and Giugliano, D. (1999) Impairment of Endothelial Functions by Acute Hyperhomocysteinemia and Reversal by Antioxidant Vitamins, J. Am. Med. Assoc. 281, 2113–2118.

    Article  CAS  Google Scholar 

  180. Kanani, P.M., Sinkey, C.A., Browning, R.L., Allaman, M., Knapp, H.R., and Haynes, W.G. (1999) Role of Oxidant Stress in Endothelial Dysfunction Produced by Experimental Hyperhomocyst(e)inemia in Humans, Circulation 100, 1161–1168.

    PubMed  CAS  Google Scholar 

  181. Chao, C.-L., Kuo, T.-L., and Lee, Y.-T. (2000) Effects of Methionine-Induced Hyperhomocysteinemia on Endothelium-Dependent Vasodilation and Oxidative Status in Healthy Adults, Circulation 101, 485–490.

    PubMed  CAS  Google Scholar 

  182. McDonald, C.C., Alexander, F.E., White, W., Forrest, A.P., and Stewart, H.J. (1995) Cardiac and Vascular Morbidity in Women Receiving Adjuvant Tamoxifen for Breast Cancer in a Randomized Trial, Br. Med. J. 311, 977–980.

    CAS  Google Scholar 

  183. Hussein, W.I., Green, R., Jacobsen, D.W., and Faiman, C. (1999) Normalization of Hyperhomocysteinemia with L-Thyroxine in Hypothyroidism, Ann. Intern. Med. 131, 348–351.

    PubMed  CAS  Google Scholar 

  184. Brattström, L. (1996) Vitamins as Homocysteine-Lowering Agents, J. Nutr. 126, 1276S-1280S.

    PubMed  Google Scholar 

  185. Ubbink, J.B., Vermaak, W.J.H., van der Merwe, A., Becker, P.J., Delport, R., and Potgeieter, H.C. (1994) Vitamin Requirements for the Treatment of Hyperhomocysteinemia in Humans, J. Nutr. 124, 1927–1933.

    PubMed  CAS  Google Scholar 

  186. den Heijer, M., Brower, I.A., Bos, G.M., Blom, H.J., van der Put, N.M., Spaans, A.P., Rosendaal, F.R., Thomas, C.M., Haak, H.L., Wijermans, P.W., and Gerrits, W.B. (1998) Vitamin Supplementation Reduces Blood Homocysteine Levels: A Controlled Trial in Patients with Venous Thrombosis and Healthy Volunteers, Arterioscler. Thromb. Vasc. Biol. 18, 356–361.

    Google Scholar 

  187. Homocysteine Lowering Trialists' Collaboration (1998) Lowering Blood Homocysteine with Folic Acid Based Supplements: Meta-Analysis of Randomised Trials, Br. Med. J. 316, 894–898.

    Google Scholar 

  188. Brouwer, I.A., van Dusseldorp,M., Thomas, C.M.G., Duran, M., Hautvast, J.G.A.J., Eskes, T.K.A.B., and Steegers-Theunissen, R.P.M. (1999) Low-Dose Folic Acid Supplementation Decreases Plasma Homocysteine Concentrations: A Randomized Trial, Am. J. Clin. Nutr. 69, 99–104.

    PubMed  CAS  Google Scholar 

  189. Beaulieu, A.J., Gohh, R.Y., Han, H., Hakas, D., Jaques, P.F., Selhub, J., and Bostom, A.G. (1999) Enhanced Reduction of Fasting Total Homocysteine Levels with Supraphysiological Versus Standard Multivitamin Dose Folic Acid Supplementation in Renal Transplant Recipients, Arterioscler. Thromb. Vasc. Biol. 19, 2918–2921.

    PubMed  CAS  Google Scholar 

  190. Bostom, A.G., Gohh, R.Y., Beaulieau, A.J., Nadeau, M.R., Hume, A.L., Jaques, P.F., Selhub, J., and Rosenberg, I.H. (1997) Treatment of Hyperhomocysteinemia in Renal Transplant Recipients. A Randomized, Placebo-Controlled Trial, Ann. Intern. Med. 127, 1089–1092.

    PubMed  CAS  Google Scholar 

  191. Malinow, M.R., Duell, P.B., Hess, D.L., Anderson, P.H., Kruger, W.D., Phillipson, B.E., Gluckman, R.A., Block, P.C., and Upson, B.M. (1998) Reduction of Plasma Homocyst(e)ine Levels by Breakfast Cereal Fortified with Folic Acid in Patients with Coronary Heart Disease, N. Engl. J. Med. 338, 1009–1015.

    Article  PubMed  CAS  Google Scholar 

  192. Chait, A., Malinow, M.R., Nevin, D.N., Morris, C.D., Eastgard, R.L., Kris-Etherton, P., Pi-Sunyer, F.X., Oparil, S., Resnick, L.M., Stern, J.S., Haynes, R.B., Hatton, D.C., Metz, J.A., Clark, S., McMahon, M., Holcomb, S., Reusser, M.E., Snyder, G.W., and McCarron, D.A. (1999) Increased Dietary Micronutrients Decrease Serum Homocysteine Concentrations in Patients at High Risk of Cardiovascular Disease, Am. J. Clin. Nutr. 70, 881–887.

    PubMed  CAS  Google Scholar 

  193. Jaques, P.F., Selhub, J., Bostom, A.G., Wilson, P.W.F., and Rosenberg, I.H. (1999) The Effect of Folic Acid Fortification on Plasma Folate and Total Homocysteine Concentrations, N. Engl. J. Med. 340, 1449–1454.

    Article  Google Scholar 

  194. Rimm, E.B., Walter, W.C., Hu, F.B., Sampson, L., Colditz, G.A., Manson, J.E., Hennekens, C., and Stampfer, M.J. (1998) Folate and Vitamin B6 from Diet and Supplements in Relation to Risk of Coronary Heart Disease Among Women, J. Am. Med. Assoc. 279, 359–364.

    Article  CAS  Google Scholar 

  195. Tucker, K.L., Mahnken, B., Wilson, P.W.F., Jaques, P., and Selhub, J. (1996) Folic Acid Fortification of the Food Supply. Potential Benefits and Risks for the Elderly Population, J. Am. Med. Assoc. 276, 1879–1885.

    Article  CAS  Google Scholar 

  196. Hackam, D.G., Peterson, J.C., and Spence, J.D. (2000) What Levels of Plasma Homocyst(e)ine Should Be Treated? Effects of Vitamin Therapy on Progression of Carotid Atherosclerosis in Patients with Homocyst(e)ine Levels Above and Below 14 μmol/L, Am. J. Hypertens. 13, 105–110.

    Article  PubMed  CAS  Google Scholar 

  197. Rabkin, S.W., and Sackett, D.L. (1987) Arterial Thromboembolism. Epidemiology, in Hemostasis and Thrombosis. Basic Principles and Clinical Practice (Colman, R.W., Hirsh, J., Marder, V.J., and Salzman, E.W., eds.), pp. 1273–1289, J.B. Lippincott, Philadelphia.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Department of Internal Medicine, IRCCS Ospedale Maggiore, University of Milano, Via Pace 9, 20122, Milano, Italy

    Marco Cattaneo

Authors
  1. Marco Cattaneo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marco Cattaneo.

About this article

Cite this article

Cattaneo, M. Hyperhomocysteinemia and thrombosis. Lipids 36 (Suppl 1), S13–S26 (2001). https://doi.org/10.1007/s11745-001-0677-9

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11745-001-0677-9

Keywords

Search

Navigation