Homocysteine and thrombosis: from basic science to clinical evidence

Anetta Undas; Jan Brożek; Andrzej Szczeklik

doi:10.1160/TH05-05-0313

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2005; 94(05): 907-915
DOI: 10.1160/TH05-05-0313

Review Article

Schattauer GmbH

Homocysteine and thrombosis: from basic science to clinical evidence

Anetta Undas

¹Department of Medicine, Jagiellonian University School of Medicine, Krakow, Poland

,

Jan Brożek

¹Department of Medicine, Jagiellonian University School of Medicine, Krakow, Poland

,

Andrzej Szczeklik

¹Department of Medicine, Jagiellonian University School of Medicine, Krakow, Poland

› Author Affiliations

Abstract

Summary

Homocysteine is a sulfhydryl-containing amino acid formed during the metabolism of methionine. Rapidly accumulating evidence links elevated homocysteine levels to thrombosis via several mechanisms such as increased tissue factor expression, attenuated anticoagulant processes, enhanced platelet reactivity, increased thrombin generation, augmented factor V activity, impaired fibrinolytic potential, and vascular injury, including endothelial dysfunction. Molecular mechanisms underlying prothrombotic actions of homocysteine are incompletely understood and involve oxidative stress, DNA hypomethylation, and proinflammatory effects. Current evidence from retrospective and prospective studies supports the concept that higher total plasma homocysteine concentration is associated with increased risk of coronary artery disease, stroke, and venous thromboembolism. Hyperhomocysteinemia is currently considered a relatively weak prothrombotic factor. It is still unclear whether administration of vitamins, that reduce homocysteine levels acting as cofactors of the enzymes involved in the methionine metabolism, may decrease the risk of arterial and/or venous thromboembolic events. Ongoing clinical trials might help clarify this issue.

Keywords

Homocysteine - thrombosis - coagulation - vitamins

Full Text

References

References
1 Welch GN, Loscalzo J. Homocysteine and atherothrombosis. N Engl J Med 1998; 338: 1042-50.
2 Kang SS, Zhou J, Wong PWK. et al. Intermediate hyperhomocysteinemia: a thermolabile variant of methylenetetrahydrofolate reductase. Am J Hum Genet 1988; 43: 414-21.
3 D’Angelo A, Mazzola G, Fermo I. Gene-gene and gene-environment interactions in mild hyperhomocysteinemia. Pathophysiol Haemost Thromb 2003; 33: 337-41.
4 Domagala TB, Undas A, Twardowska M. et al. Pathogenesis of vascular disease in hyperhomocysteinemia. J Cardiovasc Risk 1998; 5: 239-47.
5 Rees MM, Rodgers GM. Homocysteinemia: association of a metabolic disorder with vascular disease and thrombosis. Thromb Res 1993; 71: 337-59.
6 Lee R, Frenkel EP. Hyperhomocysteinemia and thrombosis. Hematol Oncol Clin N Am 2003; 17: 85-102.
7 Ubbink JB, Becker PJ, Delpot R. et al. Variability of post-methionine load plasma homocysteine assays. Clin Chim Acta 2003; 330: 111-9.
8 Xu D. Homocysteine accelerates endothelial cell senescence. FEBS Lett 2000; 470: 20-4.
9 Wall RT, Harlan JM, Harker LA. et al. In vitro effects of hyperlipoproteinemic sera on human endothelium: inhibition of endothelial cell migration by familial hypercholesterolemic sera. Thromb Res 1980; 17: 753-65.
10 de Groot PG, Willems C, Boers GH. et al. Endothelial cell dysfunction in homocystinuria. Eur J Clin Invest 1983; 13: 405-10.
11 Blundell G. Homocysteine mediated endothelial cell toxicity and its amelioration. Atherosclerosis 1996; 122: 163-72.
12 Hossain GS, van Thienen JV, Werstuck GH. et al. TDAG51 is induced by homocysteine, promotes detachment- mediated programmed cell death, and contributes to development of atherosclerosis in hyperhomocysteinemia. J Biol Chem 2003; 278: 30317-27.
13 Zhang C, Cai Y, Adachi MT. et al. Homocysteine induces programmed cell death in human vascular endothelial cells through activation of the unfolded protein response. J Biol Chem 2001; 276: 35867-74.
14 Austin RC, Lentz SR, Werstuck GH. Role of hyperhomocysteinemia in endothelial dysfunction and atherothrombotic disease. Cell Death Differ 2004; 11: S56-S64.
15 Faraci FM, Lentz SR. Hyperhomocysteinemia, oxidative stress, and cerebral vascular dysfunction. Stroke 2004; 35: 345-7.
16 Weiss N. Mechanisms of increased vascular oxidant stress in hyperhomocysteinemia and its impact on endothelial function. Curr Drug Metab 2005; 6: 27-36.
17 Schlaich MP, John S, Jacobi J. et al. Mildly elevated homocysteine concentrations impair endothelium dependent vasodilatation in hypercholesterolemic patients. Atherosclerosis 2000; 153: 383-9.
18 Topol G, Brunet A, Millanvoye E. et al. Homocysteine induces oxidative stress by uncoupling of NO synthase through reduction of tetrahydrobiopterin. Free Radic Biol Med 2004; 36: 1532-41.
19 Mosharov E, Cranford MR, Banerjee R. The quantitatively important relationship between homocysteine metabolism and glutathione synthesis by the transsulfuration pathway and its regulation by redox changes. Biochemistry 2000; 39: 13005-11.
20 Wood JL, Graham A. Structural requirements for oxidation of low density lipoprotein by thiols. FEBS Lett 1995; 366: 75-80.
21 Voutilainen S, Morrow JD, Roberts 2nd LJ. et al. Enhanced in vivo lipid peroxidation at elevated plasma total homocysteine levels. Arterioscler Thromb Vasc Biol 1999; 19: 1263-6.
22 Ingrosso D, Cimmino A, Perna AF. et al. Folate treatment and unbalanced methylation and changes of allelic expression induced by hyperhomocysteinaemia in patients with uraemia. Lancet 2003; 361: 1693-7.
23 Boger RH, Bode-Boger SM, Sydow K. et al. Plasma concentration of asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, is elevated in monkeys with hyperhomocyst(e)inemia. Arterioscler Thromb Vasc Biol 2000; 20: 1557-64.
24 Stuhlinger MC, Tsao PS, Her JH. et al. Homocysteine impairs the nitric oxide synthase pathway: role of asymmetric dimethylarginine. Circulation 2001; 104: 2569-75.
25 Stuhlinger MC, Oka RK, Graf EE. et al. Endothelial dysfunction induced by hyperhomocyst(e)inemia: role of asymmetric dimethylarginine. Circulation 2003; 108: 933-8.
26 Outinen PA, Sood SK, Pfeifer SI. et al. Homocysteine- induced endoplasmic reticulum stress and growth arrest leads to specific changes in gene expression in human vascular endothelial cells. Blood 1999; 94: 959-67.
27 Jakubowski H. Molecular basis of homocysteine toxicity in humans. Cell Mol Life Sci 2004; 61: 470-87.
28 Jakubowski H. The determination of homocysteine- thiolactone in biological samples. Analyt Biochem 2002; 308: 112-9.
29 Jakubowski H, Zhang L, Bardeguez A. et al. Homocysteine thiolactone and protein homocysteinylation in human endothelial cells: implications for atherosclerosis. Circ Res 2000; 87: 45-51.
30 Jakubowski H. Protein homocysteinylation: Possible mechanism underlying pathological consequences of elevated homocysteine levels. FASEB J 1999; 13: 2277-83.
31 Glowacki R, Jakubowski H. Cross-talk between Cys-34 and lysine residues in human serum albumin revealed by N-homocysteinylation. J Biol Chem 2004; 279: 10864-71.
32 Undas A, Perla J, Lacinski M. et al. Autoantibodies against N-homocysteinylated proteins in humans: implications for atherosclerosis. Stroke 2004; 35: 1299-304.
33 Undas A, Jankowski M, Twardowska M. et al. Autoantibodies against N-homocysteinylated albumin as a marker of early coronary artery disease. Thromb Haemost 2005; 93: 346-50.
34 Harker LA, Slichter SJ, Scott CR. et al. Homocystinemia: Vascular injury and arterial thrombosis. N Engl J Med 1968; 291: 537-43.
35 Hill-Zobel RL, Pyeritz RE, Scheffel U. et al. Kinetics and distribution of 111indium-labeled platelets in patients with homocystinuria. N Engl J Med 1982; 307: 781-6.
36 Uhlemann ER, TenPas JH, Lucky AW. et al. Platelet survival and morphology in homocystinuria due to cystathionine synthase deficiency. N Engl J Med 1976; 295: 1283-6.
37 Di Minno G, Davi G, Margaglione M. et al. Abnormally high thromboxane biosynthesis in homozygous homocystinuria: evidence for platelet involvement and probucol-sensitive mechanism. J Clin Invest 1993; 92: 1400-6.
38 Coppola A, Davi G, De Stefano V. et al. Homocysteine, coagulation, platelet function, and thrombosis. Semin Thromb Haemost 2000; 26: 243-54.
39 Davi G, Di Minno G, Coppola A. et al. Oxidative stress and platelet activation in homozygous homocystinuria. Circulation 2001; 104: 1124-8.
40 Leoncini G, Pascale R, Signorello MG. Effects of homocysteine on L-arginine transport and nitric oxide formation in human platelets. Eur J Clin Invest 2003; 33: 713-9.
41 Durand P, Lussier-Cacan S, Blanche D. Acute methionine load-induced hyperhomocysteinemia enhances platelet aggregation, thromboxane biosynthesis, and macrophage-derived tissue factor activity in rats. FASEB J 1997; 11: 1157-68.
42 Domagala TB, Undas A, Sydor WJ. et al. Thrombin formation in platelet-rich plasma after oral methionine loading. Thromb Res 2002; 105: 503-6.
43 Mann KG. Biochemistry and physiology of blood coagulation. Thromb Haemost 1999; 82: 165-74.
44 Morrissey JH. Tissue factor: an enzyme cofactor and true receptor. Thromb Haemost 2002; 86: 66-74.
45 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.
46 Khajurla A, Houston DS. Induction of monocyte tissue factor expression by homocysteine: a possible mechanism for thrombosis. Blood 2000; 96: 966-72.
47 Marcucci R, Prisco D, Brunelli T. et al. Tissue factor and homocysteine levels in ischemic heart disease are associated with angiographically documented clinical recurrences after coronary angioplasty. Thromb Haemost 2000; 83: 826-32.
48 Cella G, Burlina A, Sbarai A. et al. Tissue factor pathway inhibitor levels in patients with homocystinuria. Thromb Res 2000; 98: 375-81.
49 Munnich A, Saudubray J-M, Dautzenberg M-D. et al. Diet-responsive proconvertin (Factor VII) deficiency in homocystinuria. J Pediatr 1983; 102: 730-4.
50 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.
51 Weiler H, Isermann BH. Thrombomodulin. J Thromb Haemost 2003; 1: 1515-24.
52 Kalafatis M, Rand MD, Mann KG. The mechanism of inactivation of human factor V and human factor Va by activated protein C. J Biol Chem 1994; 269: 31869-80.
53 Hayashi T, Honda G, Suzuki K. An atherogenic stimulus homocysteine inhibits cofactor activity of thrombomodulin and enhances thrombomodulin expression in human umbilical vein endothelial cells. Blood 1992; 79: 2930-6.
54 Rodgers GM, Conn MT. Homocysteine, an atherogenic stimulus, reduces protein C activation by arterial and venous endothelial cells. Blood 1990; 75: 895-901.
55 Lentz SR, Sadler JE. Inhibition of thrombomodulin surface expression and protein C activation by the thrombogenic agent homocysteine. J Clin Invest 1991; 88: 1906-14.
56 Lentz SR, Sobey CG, Piegors DJ. et al. Vascular dysfunction in monkeys with diet-induced hyperhomocyst( e)inemia. J Clin Invest 1996; 98: 24-9.
57 Dayal S, Bottiglieri T, Arning E. et al. Endothelial dysfunction and elevation of S-adenosylhomocysteine in cystathionine beta-synthese-deficient mice. Circ Res 2001; 88: 1203-9.
58 Rodgers GM, Kane WH. Activation of endogenous factor V by a homocysteine-induced vascular endothelial cell activator. J Clin Invest 1986; 77: 1909-16.
59 Undas A, Williams EB, Butenas S. et al. Homocysteine inhibits inactivation of factor Va by activated protein C. J Biol Chem 2001; 276: 4389-97.
60 Lentz SR, Piegors DJ, Fernandez JA. et al. Effect of hyperhomocysteinemia on protein C activation and activity. Blood 2002; 100: 2108-12.
61 Zarychanski R, Houston DS. Plasma homocysteine concentration is not associated with activated protein C resistance in patients investigated for hypercoagulability. Thromb Haemost 2004; 91: 1115-22.
62 Giannini MJ, Coleman M, Innerfield I. Antithrombin activity in homocystinuria. Lancet 1975; i: 1094.
63 Palareti G, Salardi S, Piazzi S. et al. Blood coagulation changes in homocystinuria: Effects of pyridoxine and other specific therapy. J Pediatr 1986; 109: 1001-6.
64 Nishinaga M, Ozawa T, Shimada K. Homocysteine, a thrombogenic agent, suppresses anticoagulant sulfate expression in cultured porcine aortic endothelial cells. J Clin Invest 1993; 92: 1381-6.
65 Kyrle PA, Stumpflen A, Hirschl M. et al. Levels of prothrombin fragment 1+2 in patients with hyperhomocysteinemia and a history of venous thromboembolism. Thromb Haemost 1997; 78: 1327-31.
66 Cattaneo M, Franchi F, Zighetti ML. et al. Plasma levels of activated protein C in healthy subjects and patients with previous venous thromboembolism: relationships with plasma homocysteine levels. Arterioscler Thromb Vasc Biol 1998; 18: 1371-5.
67 Undas A, Domagala TB, Jankowski M. et al. Treatment of hyperhomocysteinemia with folic acid and vitamin B12 and B6 attenuates thrombin generation. Thromb Res 1999; 95: 281-8.
68 Domagala TB, Undas A, Celinska-Lowenhoff M. et al. Thrombin generation in response to methionine loading test in patients with ischemic heart disease. J Thromb Haemost. 2003: P0435 [poster].
69 Gerdes VE, Kremer Hovinga HA, Ten Cate H. et al. Homocysteine and markers of coagulation and endothelial cell activation. J Thromb Haemost 2004; 2: 445-51.
70 Nappo F, DeRosa N, DeMarfella R. et al. Impairment of endothelial functions in acute hyperhomocysteinemia and reversal by antioxidant vitamins. JAMA 1999; 281: 2113-8.
71 Sauls DL, Wolberg AS, Hoffman M. Elevated plasma homocysteine leads to alterations in fibrin clot structure and stability: implications for the mechanism of thrombosis in hyperhomocysteinemia. J Thromb Haemost 2003; 1: 300-6.
72 Ebbesen LS, Christiansen K, Ingerslev J. Hyperhomocysteinemia due to folate deficiency is thrombogenic in rats. J Nutr 2003; 133: 2250-5.
73 Lauricella AM, Quintana IL, Kordich LC. Effects of homocysteine thiol group on fibrin networks: another possible mechanism of harm. Thromb Res 2002; 107: 75-9.
74 Ratnoff OD. Activation of Hageman factor by L-homocystine. Science 1968; 162: 1007-9.
75 Hajjar KA. Homocysteine-induced modulation of tissue plasminogen activator binding to its endothelial cell membrane receptor. J Clin Invest 1993; 91: 2873-9.
76 Hajjar KA, Mauri L, Jacovina AT. et al. Tissue plasminogen activator binding to the annexin II tail domain. Direct modulation by homocysteine. J Biol Chem 1998; 273: 9987-93.
77 Harpel PC, Chang VT, Borth W. Homocysteine and other sulfhydryl compounds enhance the binding of lipoprotein( a) to fibrin: a potential biochemical link between thrombosis, atherogenesis, and sulfhydryl compound metabolism. Proc Natl Acad Sci USA 1992; 89: 10193-7.
78 Tofler GH, D’Agostino RB, Jacques PF. et al. Association between increased homocysteine levels and impaired fibrinolytic potential: potential mechanism for cardiovascular risk. Thromb Haemost 2002; 88: 799-804.
79 Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005; 352: 1685-95.
80 Larkin M. Kilmer McCully: pioneer of the homocysteine theory. Lancet 1998; 352: 1364-6.
81 Stampfer MJ, Malinow MR, Willett WC. et al. A prospective study of plasma homocysteine and risk of myocardial infarction in US physicians. JAMA 1992; 268: 877-81.
82 Al-Obaidi MK, Stubbs PJ, Collinson P. et al. Elevated homocysteine levels are associated with increased ischemic myocardial injury in acute coronary syndromes. J Am Coll Cardiol 2000; 36: 1217-22.
83 Omland T, Samuelsson A, Hartford M. et al. Serum homocysteine concentration as an indicator of survival in patients with acute coronary syndromes. Arch Intern Med 2000; 160: 1834-40.
84 Facila L, Nunez JE, Bertomeu GV. et al. Early determination of homocysteine levels in acute coronary syndromes, is it an independent prognostic factor?. Int J Cardiol 2005; 100: 275-9.
85 Zylberstein DE, Bentsson C, Bjorkelund C. et al. Serum homocysteine in relation to mortality and morbidity from coronary heart disease. A 24-year followup of the population study of women in Gothenburg. Circulation 2004; 109: 601-6.
86 Clarke R, Collins R, Lewington S. et al. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA 2002; 288: 2015-22.
87 Eikelboom JW, Lonn E, Genest J. et al. Homocyst( e)ine and cardiovascular disease: a critical review of the epidemiologic evidence. Ann Intern Med 1999; 131: 363-75.
88 Wald DS, Law M, Morris JK. Homocysteine and cardiovascular: evidence on causality from a metaanalysis. Br Med J 2002; 325: 1202-9.
89 Brattstrom L, Tengborn L, Lagerstedt C. et al. Plasma homocysteine in venous thromboembolism. Haemostasis 1991; 21: 51-7.
90 den Heijer M, Rosendaal FR, Blom HJ. et al. Hyperhomocysteinemia and venous thrombosis: a metaanalysis. Thromb Haemost 1998; 80: 874-7.
91 den Heijer M, Lewington S, Clarke R. Homocysteine, MTHFR and risk of venous thrombosis: a metaanalysis of published epidemiological studies. J Thromb Haemost 2005; 3: 292-9.
92 Ridker PM. Interrelation of hyperhomocysteinemia, factor V Leiden, and risk of future thromboembolism. Circulation 1997; 95: 1777-81.
93 De Stefano V, Casorelli I, Rossi E. et al. interaction between hyperhomocysteinemia and inherited thrombophilic factors in venous thromboembolism. Semin Thromb Haemost 2000; 26: 305-9.
94 Buller HR, Agnelli G, Hull RD. et al. Antithrombotic therapy for venous thromboembolic disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126 (Suppl. 01) 401S-428S.
95 Homocysteine Lowering Trialists Collaboration. Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomized trials. BMJ 1998; 316: 894-8.
96 Wald DS, Bishop L, Wald NJ. et al. Randomized trial of folic acid supplementation and serum homocysteine levels. Arch Intern Med 2001; 161: 695-700.
97 Wilcken DE, Wilcken B. The natural history of vascular disease in homocystinuria and the effects of treatment. J Inherit Metab Dis 1997; 20: 295-300.
98 Robinson K, Arheart K, Refsum H. et al. Low circulating folate and vitamin B6 concentrations. Risk factors for stroke, peripheral vascular disease, and coronary artery disease. Circulation 1998; 97: 437-43.
99 Rimm EB, Willett WC, Hu FB. et al. Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women. JAMA 1998; 279: 359-64.
100 Toole JF, Malinow MR, Chambless LE. et al. Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA 2004; 291: 565-75.
101 Lange H, Suryapranata H, De Luca G. et al. Folate therapy and in-stent restenosis after coronary stenting. N Engl J Med 2004; 350: 2673-81.