No effect of folic acid supplementation in the course of 1 year on haemostasis markers and C-reactive protein in older adults

Summary

Elevated homocysteine levels are associated with an increased cardiovascular disease (CVD) risk, but the underlying mechanism is still unclear. High homocysteine might affect the endothelium, and consequently lead to impaired haemostasis. In a randomized placebo controlled trial among 276 older adults with plasma total homocysteine concentrations above 13 mM at screening, we investigated the effect of homocysteine lowering by folic acid supplementation (0.8 mg/day) for 1 year on markers of endothelial function (vonWillebrand factor), coagulation (tissue factor, factor VIIa, fragments 1+2), and fibrinolysis (fibrin degradation products, tissue-type plasminogen activator), and inflammation (C-reactive protein). Despite a 24% reduction in plasma homocysteine concentration and four-fold increase in serum folate concentration in the folic acid group compared to the placebo group, there was no clear change in any of the haemostasis markers, nor CRP. Although homocysteine is associated with vascular disease risk in the general population, marked lowering of slightly elevated homocysteine concentrations by one-year folic acid supplementation does not influence haemostasis markers.

Keywords

Homocysteine - folic acid - haemostasis - homocysteine - intervention

• References

• 1 Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: 6000 events in 30 observational studies. JAMA 2002; 288: 2015-22.
• 2 Refsum H, Ueland P, Nygard O. et al. Homocysteine and cardiovascular disease. Ann Rev Med 1998; 49: 31-62.
• 3 Clarke R, Armitage J. Vitamin supplements and cardiovascular risk: review of the randomized trials of homocysteine-lowering vitamin supplements. Semin Thromb Hemost 2000; 26: 341-8.
• 4 Klerk M, Verhoef P, Clarke R. et al. MTHFR 677C>T polymorphism and risk of coronary heart disease: A meta-analysis. JAMA 2002; 288: 2023-31.
• 5 Thambyrajah J, Townend JN. Homocysteine and atherothrombosis – mechanisms for injury. Eur Heart J 2000; 21: 967-74.
• 6 Kyrle PA, Stumpflen A, Hirschl M. et al. Levels of prothrombin fragment F1+2 in patients with hyperhomocysteinemia and a history of venous thromboembolism. Thromb Haemost 1997; 78: 1327-31.
• 7 Kristensen B, Malm J, Nilsson TK. et al. Hyperhomocysteinemia and hypofibrinolysis in young adults with ischemic stroke. Stroke 1999; 30: 974-80.
• 8 de Valk-de Roo GW, Stehouwer CD, Lambert J. et al. Plasma homocysteine is weakly correlated with plasma endothelin and von Willebrand factor but not with endothelium-dependent vasodilatation in healthy postmenopausal women. Clin Chem 1999; 45: 1200-5.
• 9 Al-Obaidi MK, Philippou H, Stubbs PJ. et al. Relationships between homocysteine, factor VIIa, and thrombin generation in acute coronary syndromes. Circulation 2000; 101: 372-7.
• 10 Becker A, Van Hinsbergh VW, Kostense PJ. et al. Serum homocysteine is weakly associated with von Willebrand factor and soluble vascular cell adhesion molecule 1, but not with C-reactive protein in type 2 diabetic and non-diabetic subjects – The Hoorn Study. Eur J Clin Invest 2000; 30: 763-70.
• 11 Yarnell JW, Sweetnam PM, Rumley A. et al. Lifestyle and hemostatic risk factors for ischemic heart disease : the Caerphilly Study. Arterioscler Thromb Vasc Biol 2000; 20: 271-9.
• 12 Kario K, Duell PB, Matsuo T. et al. High plasma homocyst(e)ine levels in elderly Japanese patients are associated with increased cardiovascular disease risk independently from markers of coagulation activation and endothelial cell damage. Atherosclerosis 2001; 157: 441-9.
• 13 Kuch B, Bobak M, Fobker M. et al. Associations between homocysteine and coagulation factors – A crosssectional study in two populations of central Europe. Thromb Res 2001; 103: 265-73.
• 14 Rothenbacher D, Fischer HG, Hoffmeister A. et al. Homocysteine and methylenetetrahydrofolate reductase genotype: association with risk of coronary heart disease and relation to inflammatory, hemostatic, and lipid parameters. Atherosclerosis 2002; 162: 193-200.
• 15 Schreiner PJ, Wu KK, Malinow MR. et al. Hyperhomocyst( e)inemia and hemostatic factors: the atherosclerosis risk in communities study. Ann Epidemiol 2002; 12: 228-36.
• 16 Folsom AR. et al. B vitamin status and inflammatory markers. Atherosclerosis 2003; 169: 169-74.
• 17 Tofler GH. et al. Association between increased homocysteine levels and impaired fibrinolytic potential: potential mechanism for cardiovascular risk. Thromb Haemost 2002; 88: 799-804.
• 18 Van den Berg M, Boers GH, Franken DG. et al. Hyperhomocysteinaemia and endothelial dysfunction in young patients with peripheral arterial occlusive disease. Eur J Clin Invest 1995; 25: 176-81.
• 19 Constans J. et al. Three months supplementation of hyperhomocysteinaemic patients with folic acid and vitamin B6 improves biological markers of endothelial dysfunction. Br J Haematol 1999; 107: 776-8.
• 20 Thambyrajah J. et al. A randomized double-blind placebo-controlled trial of the effect of homocysteinelowering therapy with folic acid on endothelial function in patients with coronary artery disease. J Am Coll Cardiol 2001; 37: 1858-63.
• 21 Pullin CH, Ashfield-Watt PA, Burr ML. et al. Optimization of dietary folate or low-dose folic acid supplements lower homocysteine but do not enhance endothelial function in healthy adults, irrespective of the methylenetetrahydrofolate reductase (C677T) genotype. J Am Coll Cardiol 2001; 38: 1799-805.
• 22 Klerk M, Verhoef P, Verbruggen B. et al. Effect of homocysteine reduction by B-vitamin supplementation on markers of clotting activation. Thromb Haemost 2002; 88: 230-5.
• 23 Mayer O. et al. Treatment of hyperhomocysteinemia with folic acid: effects on homocysteine levels, coagulation status, and oxidative stress markers. J Cardiovasc Pharmacol 2002; 39: 851-7.
• 24 Mayer OJ, Simon J, Rosolova H. et al. The effects of folate supplementation on some coagulation parameters and oxidative status surrogates. Eur J Clin Pharmacol 2002; 58: 1-5.
• 25 Mangoni AA, Arya R, Ford E. et al. Effects of folic acid supplementation on inflammatory and thrombogenic markers in chronic smokers. A randomised controlled trial. Thromb Res 2003; 110: 13-7.
• 26 Vermeulen EG. et al. Homocysteine-lowering treatment with folic acid plus vitamin B6 lowers urinary albumin excretion but not plasma markers of endothelial function or C-reactive protein: further analysis of secondary end-points of a randomized clinical trial. Eur J Clin Invest 2003; 33: 209-15.
• 27 Ross R. Atherosclerosis–an inflammatory disease. N Engl J Med 1999; 340: 115-26.
• 28 Levi M, ten Cate H, van der Poll T. Endothelium: interface between coagulation and inflammation. Crit Care Med 2002; 30: S220-S224.
• 29 Ubbink JB, Hayward-Vermaak WJ, Bissbort S. Rapid high-performance liquid chromatographic assay for total homocysteine levels in human serum. J Chromatogr 1991; 565: 441-6.
• 30 Frosst P, Blom HJ, Milos R. et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase [letter]. Nat Genet 1995; 10: 111-3.
• 31 Kienast J, Thompson SG, Raskino C. et al. Prothrombin activation fragment 1 + 2 and thrombin antithrombin III complexes in patients with angina pectoris: relation to the presence and severity of coronary atherosclerosis. Thromb Haemost 1993; 70: 550-3.
• 32 Freyburger G, Labrouche S, Sassoust G. et al. Mild hyperhomocysteinemia and hemostatic factors in patients with arterial vascular diseases. Thromb Haemost 1997; 77: 466-71.
• 33 Blann AD, Miller JP, McCollum CN. von Willebrand factor and soluble E-selectin in the prediction of cardiovascular disease progression in hyperlipidaemia. Atherosclerosis 1997; 132: 151-6.
• 34 Folsom AR. et al. Prospective study of hemostatic factors and incidence of coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) Study. Circulation 1997; 96: 1102-8.
• 35 Lowe GD, Yarnell JW, Sweetnam PM. et al. Fibrin D-dimer, tissue plasminogen activator, plasminogen activator inhibitor, and the risk of major ischaemic heart disease in the Caerphilly Study. Thromb Haemost 1998; 79: 129-33.
• 36 Thogersen AM, Jansson JH, Boman K. et al. High plasminogen activator inhibitor and tissue plasminogen activator levels in plasma precede a first acute myocardial infarction in both men and women: evidence for the fibrinolytic system as an independent primary risk factor. Circulation 1998; 98: 2241-7.
• 37 Jager A, van Hinsbergh VW, Kostense PJ. et al. von Willebrand factor, C-reactive protein, and 5-year mortality in diabetic and nondiabetic subjects: the Hoorn Study. Arterioscler Thromb Vasc Biol 1999; 19: 3071-8.
• 38 Cushman M, Lemaitre RN, Kuller LH. et al. Fibrinolytic activation markers predict myocardial infarction in the elderly. The Cardiovascular Health Study. Arterioscler Thromb Vasc Biol 1999; 19: 493-8.
• 39 Lip GYH, Blann A. von Willebrand factor: A marker of endothelial dysfunction in vascular disorders?. Cardiovasc Res 1997; 34: 255-65.
• 40 Fryer RH, Wilson BD, Gubler DB. et al. Homocysteine, a risk factor for premature vascular disease and thrombosis, induces tissue factor activity in endothelial cells. Arterioscler Thromb 1993; 13: 1327-33.
• 41 Durand P, Prost M, Blache D. Pro-thrombotic effects of a folic acid deficient diet in rat platelets and macrophages related to elevated homocysteine and decreased n-3 polyunsaturated fatty acids. Atherosclerosis 1996; 121: 231-43.
• 42 Dardik R, Varon D, Tamarin I. et al. Homocysteine and oxidized low density lipoprotein enhanced platelet adhesion to endothelial cells under flow conditions: distinct mechanisms of thrombogenic modulation. Thromb Haemost 2000; 83: 338-44.
• 43 Hofmann MA, Lalla E, Lu Y. et al. Hyperhomocysteinemia enhances vascular inflammation and accelerates atherosclerosis in a murine model. J Clin Invest 2001; 107: 675-83.
• 44 Cushman M, Psaty BM, Macy E. et al. Correlates of thrombin markers in an elderly cohort free of clinical cardiovascular disease. Arterioscler Thromb Vasc Biol 1996; 16: 1163-9.
• 45 Lopez Y, Paloma MJ, Rifon J. et al. Measurement of prethrombotic markers in the assessment of acquired hypercoagulable states. Thromb Res 1999; 93: 71-8.
• 46 MacCallum PK, Cooper JA, Martin J. et al. Haemostatic and lipid determinants of prothrombin fragment F1.2 and D-dimer in plasma. Thromb Haemost 2000; 83: 421-6.
• 47 Lange H, Suryapranata H, de Luca G. et al. Folate therapie and in-stent restenosis after coronary stenting. N Engl J Med 2004; 350 (Suppl. 26) 2673-2681.
• 48 Undas A, Domagala TB, Jankowski M. et al. Treatment of hyperhomocysteinemia with folic acid and vitamins B-12 and B-6 attenuates thrombin generation. Thromb Res 1999; 95: 281-8.
• 49 Nappo F, DeRosa N, Marfella R. et al. Impairment of endothelial functions by acute hyperhomocysteinemia and reversal by antioxidant vitamins. JAMA 1999; 281: 2113-8.
• 50 Constans J, Blann AD, Resplandy F. et al. Endothelial dysfunction during acute methionine load in hyperhomocysteinaemic patients. Atherosclerosis 1999; 147: 411-3.
• 51 Coppola A, Davi G, DeStefano V. et al. Homocysteine, coagulation, platelet function, and thrombosis. Semin Thromb Hemost 2000; 26: 243-54.
• 52 Dusitanond P, Eikelboom JW, Hankey GJ. et al. Homocysteine-lowering treatment with folic acid, cobalamin, and pyridoxine does not reduce blood markers of inflammation, endothelial dysfunction, or hypercoagulability in patients with previous transient ischemic attack or stroke. A randomized substudy of the VITATOPS trial. Stroke 2005; 36: 144-6.