Effect of Homocysteine Reduction by B-Vitamin Supplementation on Markers of Clotting Activation

Summary

Homocysteine may have an effect on risk of cardiovascular disease by stimulating procoagulant factors and/or impair anti-coagulant mechanisms or fibrinolysis. However, data in humans of such effects are sparse. In this intervention study, we examined the effect of homocysteine lowering by B-vitamin supplementation on prothrombin fragments 1 and 2 (F₁₊₂), thrombin-antithrombin complex (TAT), and fibrin degradation products (D-dimer). The study comprised 118 healthy volunteers, 50 with homocysteine > 16 µmol/L and 68 with homocysteine ≤ 16 µmol/L, who were randomized to placebo or highdose B-vitamin supplements (5 mg folic acid, 0.4 mg hydroxycobalamin, and 50 mg pyridoxine) daily for 8 weeks. Although homocysteine concentrations were 27.7% (p < 0.0001) reduced in the Bvitamin group compared to the placebo group, no effect on F₁₊₂ and TAT concentrations was observed. A 10.4% reduction was observed for D-dimer (p = 0.08).

In conclusion, it appears that in healthy subjects homocysteine reduction by B-vitamin supplementation has a modest beneficial effect on clotting activation.

Keywords

Homocysteine - B-vitamins - clotting activation - intervention - healthy volunteers

• References

• 1 Boushey CJ, Beresford SA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease Probable benefits of increasing folic acid intakes. JAMA 1995; 274: 1049-57.
• 2 Danesh J, Lewington S. Plasma homocysteine and coronary heart disease: systematic review of published epidemiological studies. J Cardiovasc Risk 1998; 05: 229-32.
• 3 Ueland PM, Refsum H, Beresford SAA, Vollset SE. The controversy over homocysteine and cardiovascular risk. Am J Clin Nutr 2000; 72: 324-32.
• 4 den-Heijer M, Rosendaal FR, Blom HJ, Gerrits WB, Bos GM. Hyperhomocysteinemia and venous thrombosis: a meta-analysis. Thromb Haemost 1998; 80: 874-7.
• 5 Brattstrom L, Wilcken DEL. Homocysteine and cardiovascular disease: cause or effect?. Am J Clin Nutr 2000; 72: 315-23.
• 6 Refsum H, Ueland P, Nygard O, Vollset SE. Homocysteine and cardiovascular disease. Ann Rev Med 1998; 49: 31-62.
• 7 Thambyrajah J, Townend JN. Homocysteine and atherothrombosis – mechanisms for injury. Eur Heart J 2000; 21: 967-74.
• 8 Stanger O, Weger M, Renner W, Konetschny R. Vascular dysfunction in hyperhomocyst(e)inemia Implications for atherothrombotic disease. Clin Chem Lab Med 2001; 39: 725-33.
• 9 Harpel PC. Homocysteine, atherogenesis and thrombosis. Fibrinolysis and Proteolysis 1997; 11 (Suppl. 01) 77-80.
• 10 Lentz SR. Homocysteine and vascular dysfunction. Life Sci 1997; 61: 1205-15.
• 11 Al-Obaidi MK, Philippou H, Stubbs PJ, Adami A, Amersey R, Noble MM, Lane DA. Relationships between homocysteine, factor VIIa, and thrombin generation in acute coronary syndromes. Circulation 2000; 101: 372-77.
• 12 Kristensen B, Malm J, Nilsson TK, Hultdin J, Carlberg B, Dahlen G, Olsson T. Hyperhomocysteinemia and hypofibrinolysis in young adults with ischemic stroke. Stroke 1999; 30: 974-80.
• 13 Kyrle PA, Stumpflen A, Hirschl M, Bialonczyk C, Herkner K, Speiser W, Weltermann A, Kaider A, Pabinger I, Lechner K, Eichinger S. Levels of prothrombin fragment F1+2 in patients with hyperhomocysteinemia and a history of venous thromboembolism. Thromb Haemost 1997; 78: 1327-31.
• 14 Nappo F, De-Rosa N, Marfella R, De-Lucia D, Ingrosso D, Perna AF, Farzati B, Giugliano D. Impairment of endothelial functions by acute hyperhomocysteinemia and reversal by antioxidant vitamins. JAMA 1999; 281: 2113-8.
• 15 Undas A, Domagala TB, Jankowski M, Szczeklik A. Treatment of hyperhomocysteinemia with folic acid and vitamins B-12 and B-6 attenuates thrombin generation. Thromb Res 1999; 95: 281-8.
• 16 Freyburger G, Labrouche S, Sassoust G, Rouanet F, Javorschi S, Parrot F. Mild hyperhomocysteinemia and hemostatic factors in patients with arterial vascular diseases. Thromb Haemost 1997; 77: 466-71.
• 17 MacCallum PK, Cooper JA, Martin J, Howarth DJ, Meade TW, Miller GJ. Haemostatic and lipid determinants of prothrombin fragment F1.2 and D-dimer in plasma. Thromb Haemost 2000; 83: 421-6.
• 18 Lopez Y, Paloma MJ, Rifon J, Cuesta B, Paramo JA. Measurement of prethrombotic markers in the assessment of acquired hypercoagulable states. Thromb Res 1999; 93: 71-8.
• 19 Cushman M, Psaty BM, Macy E, Bovill EG, Cornell ES, Kuller LH, Tracy RP. Correlates of thrombin markers in an elderly cohort free of clinical cardiovascular disease. Arterioscler Thromb Vasc Biol 1996; 16: 1163-9.
• 20 Mari D, Mannucci PM, Coppola R, Bottasso B, Bauer KA, Rosenberg RD. Hypercoagulability in centenarians: the paradox of successful aging. Blood 1995; 85: 3144-9.
• 21 Bauer KA. New markers for in vivo coagulation. Curr Opin Hematol 1994; 01: 341-6.
• 22 Bauer KA, Rosenberg RD. The pathophysiology of the prethrombotic state in humans: insights gained from studies using markers of hemostatic system activation. Blood 1987; 70: 343-50.
• 23 Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. Homocysteine Lowering Trialists’ Collaboration. BMJ 1998; 316: 894-8.
• 24 den Heijer M, Blom HJ, Gerrits WB, Rosendaal FR, Haak HL, Wijermans PW, Bos GM. Is hyperhomocysteinaemia a risk factor for recurrent venous thrombosis?. Lancet 1995; 345: 882-5.
• 25 den Heijer M, Brouwer IA, Bos GJ, Blom HJ, vanderPut NJ, Spaans AP, Rosendaal FR, Thomas CG, Haak HL, Wijermans PW, Gerrits WJ. Vitamin supplementation reduces blood homocysteine levels – A controlled trial in patients with venous thrombosis and healthy volunteers. Arterioscler Thromb Vasc Biol 1998; 18: 356-61.
• 26 Schrijver J, Speek AJ, Schreurs WHP. Semi-automated fluorometric determination of pyridoxal-5’-phosphate (vitamin B6) in whole blood by high-performance liquid chromatography (HPLC). Int Z Vitam Ernahrungsforsch Beih 1981; 51: 216-22.
• 27 Musial J, Pajak A, Undas A, Kawalec E, Topor MR, Pazucha T, Grzywacz M, Szczeklik A. Thrombin generation markers and coronary heart disease risk factors in a Polish population sample. Thromb Haemost 1997; 77: 697-700.
• 28 Giansante C, Fiotti N, Cattin L, Da-Col PG, Calabrese S. Fibrinogen, Ddimer and thrombin-antithrombin complexes in a random population sample: relationships with other cardiovascular risk factors. Thromb Haemost 1994; 71: 581-6.
• 29 Cushman M, Lemaitre RN, Kuller LH, Psaty BM, Macy EM, Sharrett AR, Tracy RP. Fibrinolytic activation markers predict myocardial infarction in the elderly The Cardiovascular Health Study. Arterioscler Thromb Vasc Biol 1999; 19: 493-8.
• 30 Miller GJ, Bauer KA, Barzegar S, Cooper JA, Rosenberg RD. Increased activation of the haemostatic system in men at high risk of fatal coronary heart disease. Thromb Haemost 1996; 75: 767-71.
• 31 Lowe GD, Yarnell JW, Sweetnam PM, Rumley A, Thomas HF, Elwood PC. 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.
• 32 Ridker PM, Hennekens CH, Cerskus A, Stampfer MJ. Plasma concentration of cross-linked fibrin degradation product (D-dimer) and the risk of future myocardial infarction among apparently healthy men. Circulation 1994; 90: 2236-40.
• 33 Elias A, Bonfils S, Daoud EM, Gauthier B, Sie P, Boccalon H, Boneu B. Influence of long term oral anticoagulants upon prothrombin fragment 1 + 2, thrombin-antithrombin III complex and D-Dimer levels in patients affected by proximal deep vein thrombosis. Thromb Haemost 1993; 69: 302-5.
• 34 Kuch B, Bobak M, Fobker M, Junker R, von-Eckardstein A, Marmot M, Hense HW. Associations between homocysteine and coagulation factors – A cross-sectional study in two populations of central Europe. Thromb Res 2001; 103: 265-73.
• 35 Kario K, Duell PB, Matsuo T, Sakata T, Kato H, Shimada K, Miyata T. 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.
• 36 Yarnell JW, Sweetnam PM, Rumley A, Lowe GD. Lifestyle and hemostatic risk factors for ischemic heart disease: the Caerphilly Study. Arterioscler Thromb Vasc Biol 2000; 20: 271-9.
• 37 Bayes-Genis A, Mateo J, Santalo M, Oliver A, Guindo J, Badimon L, Martinez RA, Fontcuberta J, Schwartz RS, De-Luna AB. D-Dimer is an early diagnostic marker of coronary ischemia in patients with chest pain. Am Heart J 2000; 140: 379-84.
• 38 Smith FB, Lee AJ, Fowkes FG, Price JF, Rumley A, Lowe GD. Hemostatic factors as predictors of ischemic heart disease and stroke in the Edinburgh Artery Study. Arterioscler Thromb Vasc Biol 1997; 17: 3321-25.
• 39 Estivals M, Pelzer H, Sie P, Pichon J, Boccalon H, Boneu B. Prothrombin fragment 1 + 2, thrombin-antithrombin III complexes and D-dimers in acute deep vein thrombosis: effects of heparin treatment. Br J Haematol 1991; 78: 421-4.