Hyperhomocysteinemia and Venous Thromboembolism

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. Severe hyperhomocysteinemia (homocystinuria), due to inherited metabolic defects of Hcy metabolism, is associated with very high risk of venous thromboembolism (VTE); treatment with vitamins is associated with dramatic decrease of VTE risk. Several case-control and prospective studies showed that also mild/moderate hyperhomocysteinemia (which is caused by the interaction of environmental factors with mild genetic abnormalities of Hcy metabolism) is associated with heightened risk of VTE; however, it is uncertain whether treatment with vitamins also decreases the VTE risk in these patients.

KEYWORDS

Venous thrombosis - pulmonary embolism - hyperhomocysteinemia - homocystinuria - folate

REFERENCES

• 1 Refsum H, Smith A D, Ueland P M et al.. Facts and recommendations about total homocysteine determinations: an expert opinion.  Clin Chem. 2004;  50 3-32
• 2 Finkelstein J D. Methionine metabolism in mammals.  J Nutr Biochem. 1990;  1 228-257
• 3 Jacques P F, Bostom A G, Wilson P W, Rich S, Rosenberg I H, Selhub J. Determinants of plasma total homocysteine concentration in the Framingham Offspring cohort.  Am J Clin Nutr. 2001;  73 613-621
• 4 Nygård O, Refsum H, Ueland P M, Vollset S E. Major lifestyle determinants of plasma total homocysteine distribution: the Hordaland Homocysteine Study.  Am J Clin Nutr. 1998;  67 263-270
• 5 Mezzano D, Munoz X, Martinez C et al.. Vegetarians and cardiovascular risk factors: hemostasis, inflammatory markers and plasma homocysteine.  Thromb Haemost. 1999;  81 913-917
• 6 Mann N J, Li D, Sinclair A J et al.. The effect of diet on plasma homocysteine concentrations in healthy male subjects.  Eur J Clin Nutr. 1999;  53 895-899
• 7 van Asselt D Z, de Groot L C, van Staveren W A. Role of cobalamin intake and atrophic gastritis in mild cobalamin deficiency in older Dutch subjects.  Am J Clin Nutr. 1998;  68 328-334
• 8 Cattaneo M. Hyperhomocysteinemia, atherosclerosis and thrombosis.  Thromb Haemost. 1999;  81 165-176
• 9 Mudd S H, Levy H L, Skovby F. Disorders of transulfuration. In: Scriver CR, Beaudet AL, Sly WS, et al The Metabolic and Molecular Bases of Inherited Disease. New York; McGraw-Hill 1995: 1279-1327
• 10 Rozen R. Molecular genetics of methylenetetrahydrofolate reductase deficiency.  J Inherit Metab Dis. 1996;  19 589-594
• 11 Kang S-S, Zhou J, Wong P WK, Kowalisyn J, Strokosch G. Intermediate homocysteinemia: a termolabile variant of methylenetetrahydrofolate reductase.  Am J Hum Genet. 1988;  43 414-421
• 12 Frosst P, Blom H J, Milos R et al.. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase.  Nat Genet. 1995;  10 111-113
• 13 Kluijtmans L A, Young I S, Boreham C A. Genetic and nutritional factors contributing to hyperhomocysteinemia in young adults.  Blood. 2003;  101 2483-2488
• 14 Souto J C, Almasy L, Borrell M. Genetic susceptibility to thrombosis and its relationship to physiological risk factors: the GAIT study. Genetic Analysis of Idiopathic Thrombophilia.  Am J Hum Genet. 2000;  67 1452-1459
• 15 Jee S H, Song K S, Shim W H. Major gene evidence after MTHFR-segregation analysis of serum homocysteine in families of patients undergoing coronary arteriography.  Hum Genet. 2002;  111 128-135
• 16 Ueland P M, Refsum H, Stabler S P, Malinow R M, Andersson A, Allen R H. Total homocysteine in plasma or serum. Methods and clinical implications.  Clin Chem. 1993;  39 1764-1779
• 17 Tripodi A, Chantarangkul V, Lombardi R, Lecchi A, Mannucci P M, Cattaneo M. Multicenter study of homocysteine measurement. Performance characteristics of different methods, influence of standards on interlaboratory agreement of results.  Thromb Haemost. 2001;  85 291-295
• 18 Pfeiffer C M, Huff D L, Smith S J, Miller D T, Gunter E W. Comparison of plasma total homocysteine measurements in 14 laboratories: an international study.  Clin Chem. 1999;  45 1261-1268
• 19 Hanson N Q, Eckfeldt J H, Schwinchtenberg K, Aras Ö, Tsai M Y. Interlaboratory variation of plasma total homocysteine measurements: results of three successive homocysteine proficiency testing surveys.  Clin Chem. 2002;  48 1539-1545
• 20 Fowler B, Sardharwalla I B, Robins A J. The detection of heterozygotes for homocystinuria by oral loading with L-methionine.  Biochem J. 1971;  122 23-24
• 21 Boers G HJ, Fowler B, Smals A GH et al.. 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. 1985;  69 164-169
• 22 Falcon C R, Cattaneo M, Panzeri D, Martinelli I, Mannucci P M. High prevalence of hyperhomocyst(e)inemia in patients with juvenile venous thrombosis.  Arterioscler Thromb. 1994;  14 1080-1083
• 23 Fermo I, Viganò-D'Angelo S, Paroni R, Mazzola G, Calori G, D'Angelo A. Prevalence of moderate hyperhomocysteinemia in patients with early-onset venous and arterial occlusive disease.  Ann Intern Med. 1995;  123 747-753
• 24 Cattaneo M, Martinelli I, Mannucci P M. Hyperhomocysteinemia as a risk factor for deep-vein thrombosis.  N Engl J Med. 1996;  335 974-975
• 25 Graham I M, Daly L E, Refsum H M et al.. Plasma homocysteine as a risk factor for vascular disease. The European Concerted Action Project.  JAMA. 1997;  277 1775-1781
• 26 Ubbink J B, Becker P J, Vermaak W J, Delport R. Results of B-vitamin supplementation study used in a prediction model to define a reference range for plasma homocysteine.  Clin Chem. 1995;  41 1033-1037
• 27 Mandel H, Brenner B, Berant M et al.. Coexistence of hereditary homocystinuria and factor V Leiden-effect on thrombosis.  N Engl J Med. 1996;  334 763-768
• 28 Quere I, Lamarti H, Chadefaux-Vekemans B. Thrombophilia, homocystinuria and factor V Leiden-effects on thrombosis.  N Engl J Med. 1996;  335 289
• 29 Kluijtmans L AJ, Boers G HJ, Verbruggen B, Trijbels F JM, Novakova I RO, Blom H J. Homozygous cystathionine β-synthase deficiency, combined with factor V Leiden or thermolabile methylenetetrahydrofolate reductase in the risk of venous thrombosis.  Blood. 1998;  91 2015-2018
• 30 Yap S, O'Donnell K A, O'Neill C, Mayne P D, Thornton P, Naughten E. Factor V Leiden (Arg506Gln), a confounding genetic risk factor but not mandatory for the occurrence of venous thromboembolism in homozygotes and obligate heterozygotes for cystathionine beta-synthase deficiency.  Thromb Haemost. 1999;  81 502-505
• 31 Brattström L, Tangborn L, Lagerstedt C, Israelsson B, Hultber B. Plasma homocysteine in venous thromboembolism.  Haemostasis. 1991;  21 51-57
• 32 Bienvenu T, Ankri A, Chadefaux B, Montalescot G, Kamoun P. Elevated total plasma homocysteine, a risk factor for thrombosis: relation to coagulation and fibrinolytic parameters.  Thromb Res. 1993;  70 123-129
• 33 den Heijer M, Rosendaal F R, Blom H J, Gerrits W BJ, Bos G MJ. Hyperhomocysteinemia and venous thrombosis: a meta-analysis.  Thromb Haemost. 1998;  80 874-877
• 34 Ray J G. Meta-analysis of hyperhomocysteinemia as a risk factor for venous thromboembolic disease.  Arch Intern Med. 1998;  158 2101-2106
• 35 den Heijer M, Lewington S, Clarke R. Homocysteine, MTHFR and risk of venous thrombosis: a meta-analysis of published epidemiological studies.  J Thromb Haemost. 2005;  3 292-299
• 36 Martinelli I, Battaglioli P, Pedotti P, Cattaneo M, Mannucci P M. Hyper-homocysteinemia and cerebral vein thrombosis.  Blood. 2003;  102 1363-1366
• 37 Marcucci R, Bertini L, Giusti B et al.. Thrombophilic risk factors in patients with central retinal vein occlusion.  Thromb Haemost. 2001;  86 772-776
• 38 Cahill M T, Stinnett S S, Fekrat S. Meta-analysis of plasma homocysteine, serum folate, serum vitamin B(12), and thermolabile MTHFR genotype as risk factors for retinal vascular occlusive disease.  Am J Ophthalmol. 2003;  136 1136-1150
• 39 Martinelli I, Cattaneo M, Panzeri D, Taioli E, Mannucci P M. Risk factors for primary deep vein thrombosis of the upper extremities.  Ann Intern Med. 1997;  126 707-711
• 40 Ridker P M, Hennekens C H, Selhub J, Miletich J P, Malinow M R, Stampfer M J. Interrelation of hyperhomocyst(e)inemia, factor V Leiden, and risk of future venous thromboembolism.  Circulation. 1997;  95 1777-1782
• 41 Cattaneo M, Zighetti M L, Turner R M. et al and the ECAT DVT Study Group . Fasting plasma homocysteine levels do not predict the occurrence of deep-vein thrombosis after elective hip replacement surgery.  Neth J Med. 1998;  52(suppl) S21
• 42 Tsai A W, Cushman M, Tsai M Y et al.. Serum homocysteine, thermolabile variant of methylene tetrahydrofolate reductase (MTHFR), and venous thromboembolism: Longitudinal Investigation of Thromboembolism Etiology (LITE).  Am J Hematol. 2003;  72 192-200
• 43 Eichinger S, Stümpfen A, Hirschl M et al.. Hyperhomocysteinemia is a risk factor of recurrent venous thromboembolism.  Thromb Haemost. 1998;  80 566-569
• 44 Keijzer M B, den Heijer M, Blom H J et al.. Interaction between hyperhomocysteinemia, mutated methylenetetrahydrofolatereductase (MTHFR) and inherited thrombophilic factors in recurrent venous thrombosis.  Thromb Haemost. 2002;  88 723-728
• 45 Wald D S, Law M, Morris J K. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis.  BMJ. 2002;  325 1202-1206
• 46 Ray J G, Shmorgun D, Chan W S. Common C677T polymorphism of the methylenetetrahydrofolate gene and the risk of venous thromboembolism. Meta-analysis of 31 studies.  Pathophysiol Haemost Thromb. 2002;  32 51-58
• 47 Frederiksen J, Juul K, Grande P et al.. Methylenetetrahydrofolate reductase polymorphism (C677T), hyperhomocysteinemia, and risk of ischemic cardiovascular disease and venous thromboembolism: prospective and case-control studies from the Copenhagen City Heart Study.  Blood. 2004;  104 3046-3051
• 48 Cattaneo M, Tsai M Y, Bucciarelli P et al.. 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. 1997;  17 1662-1666
• 49 Cattaneo M, Chantarangkul V, Taioli E, Hermida Santos J, Tagliabue L. 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. 1999;  93 1-8
• 50 Margaglione M, D'Andrea G, d'Addedda M et al.. The methylenetetrahydrofolate reductase TT677 genotype is associated with venous thrombosis independently of the coexistence of the factor V Leiden and the prothrombin A20210 mutation.  Thromb Haemost. 1998;  79 907-911
• 51 Salomon O, Steinberg D M, Zivelin A et al.. Single and combined prothrombotic factors in patients with idiiopathic venous thromboembolism: prevalence and risk assessment.  Arterioscler Thromb Vasc Biol. 1999;  19 511-518
• 52 Akar N, Akar E, Akcay R, Avcu F, Yalcin A, Cin S. Effect of methylenetetrahydrofolate reductase 677 C-T, 1298 A-C, and 1317 T-C on factor V 1691 mutation in Turkish deep vein thrombosis patients.  Thromb Res. 2000;  97 163-167
• 53 Alhenc-Gelas M, Arnaud E, Nicaud V et al.. Venous thromboembolic disease and the prothrombin, methylenetetrahydrolfolate reductase and factor V genes.  Thromb Haemost. 1999;  81 506-510
• 54 Kluijtmans L AJ, den Heijer M, Reitsma P H, Heil S G, Blom H J, Rosendaal F R. Thermolabile methylenetetrahydrofolate reductase and factor V Leiden in the risk of deep-vein thrombosis.  Thromb Haemost. 1998;  79 254-258
• 55 Brown K, Luddington R, Baglin T. Effect of the MTHFR C677T variant on risk of venous thromboembolism: interaction with factor V Leiden and prothrombin (F2G20210A) mutations.  Br J Haematol. 1998;  103 42-44
• 56 De Stefano V, Casorelli I, Rossi E, Zappacosta B, Leone G. Interaction between hyperhomocysteinemia and inherited thrombophilic factors in venous thromboembolism.  Semin Thromb Hemost. 2000;  26 305-311
• 57 Epstein F H. The epidemiology of coronary heart disease: a review.  J Chronic Dis. 1965;  18 735-774
• 58 Wilhelmsen L, Wedel H, Tibbins G. Multivariate analysis of risk factors for coronary heart disease.  Circulation. 1973;  48 950-958
• 59 Rabkin S W, Sackett D L. Arterial thromboembolism. Epidemiology. In: Colman RW, Hirsh J, Marder VJ, Salzman EW Hemostasis and Thrombosis. Basic Principles and Clinical Practice. Philadelphia; J.B. Lippincott 1987: 1273-1289
• 60 Yap S, Boers G H, Wilcken B et al.. Vascular outcome in patients with homocystinuria due to cystathionine beta-synthase deficiency treated chronically: a multicenter observational study.  Arterioscler Thromb Vasc Biol. 2001;  21 2080-2085
• 61 Quere I, Perneger T V, Zittoun J et al.. Red blood cell methylfolate and plasma homocysteine as risk factors for venous thromboembolism: a matched case-control study.  Lancet. 2002;  359 747-752
• 62 Cattaneo M, Lombardi R, Lecchi A, Bucciarelli P, Mannucci P M. Low plasma levels of vitamin B(6) are independently associated with a heightened risk of deep-vein thrombosis.  Circulation. 2001;  104 2442-2446
• 63 Ubbink J B, Vermaak W JH, van der Merwe A, Becker P J, Delport R, Potgeieter H C. Vitamin requirements for the treatment of hyperhomocysteinemia in humans.  J Nutr. 1994;  124 1927-1933
• 64 den Heijer M, Brower I A, Bos G M et al.. Vitamin supplementation reduces blood homocysteine levels. A controlled trial in patients with venous thrombosis and healthy volunteers.  Arterioscler Thromb Vasc Biol. 1998;  18 356-361
• 65 Homocysteine Lowering Trialists' Collaboration . Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials.  BMJ. 1998;  316 894-898
• 66 Hansson P O, Werlin L, Tibblin G, Eriksson H. Deep vein thrombosis and pulmonary embolism in the general population.  Arch Intern Med. 1997;  157 1665-1670
• 67 Heit J A, Silverstein M D, Mohr D N et al.. The epidemiology of venous thromboembolism in the community.  Thromb Haemost. 2001;  86 452-463
• 68 Den Heijer M, Willems H PJ, Blom H J et al.. Homocysteine lowering by B vitamins and the secondary prevention of deep-vein thrombosis and pulmonary embolism. A randomized, placebo-controlled, double blind trial.  Blood. 2006;  , In press
• 69 Cattaneo M. Hyperhomocysteinemia: an important risk factor for cardiovascular disease? Potentially, yes.  J Thromb Haemost. 2003;  1 1878-1879