Association Between Increased Homocysteine Levels and Impaired Fibrinolytic Potential: Potential Mechanism for Cardiovascular Risk

Geoffrey H. Tofler; Ralph B. D’Agostino; Paul F. Jacques; Andrew G. Bostom; Peter W. F. Wilson; Izabela Lipinska; Murray A. Mittleman; Jacob Selhub

doi:10.1055/s-0037-1613305

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2002; 88(05): 799-804
DOI: 10.1055/s-0037-1613305

Review Article

Schattauer GmbH

Association Between Increased Homocysteine Levels and Impaired Fibrinolytic Potential: Potential Mechanism for Cardiovascular Risk

Geoffrey H. Tofler

¹Royal North Shore Hospital, Australia

,

Ralph B. D’Agostino

²Boston University Department of Mathematics

,

Paul F. Jacques

³USDA Human Nutrition Research Center on Aging at Tufts University

,

Andrew G. Bostom

³USDA Human Nutrition Research Center on Aging at Tufts University

,

Peter W. F. Wilson

⁴National Heart, Lung and Blood Institute’s Framingham Heart Study

,

Izabela Lipinska

⁵Beth Israel Deaconess Medical Center

,

Murray A. Mittleman

⁵Beth Israel Deaconess Medical Center

,

Jacob Selhub

³USDA Human Nutrition Research Center on Aging at Tufts University

› Author Affiliations

Abstract

Summary

Background

Elevated homocysteine levels increase cardiovascular risk although the mechanism is not well understood. Since thrombosis plays an important role in plaque development and acute coronary syndromes, hyperhomocysteinemia may increase risk by increasing the thrombotic potential.

Methods and Results

Hemostatic risk factors were measured in 3216 individuals (1451 men and 1765 women) free of cardiovascular disease who participated in cycle 5 of the Framingham Offspring Study. An increase in homocysteine level was associated with a rise in plasminogen activator inhibitor (PAI-1), tissue plasminogen activator (TPA) antigen, von Willebrand factor and fibrinogen level. After regression analyses adjusting for covariates, there remained significant associations between homocysteine and PAI-1 and TPA antigen.

Conclusion

Increasing homocysteine levels are associated with impaired fibrinolytic potential, as indicated by increased PAI-1 and TPA antigen levels. These data suggest that folic acid and other homocysteine lowering therapies may decrease cardiac events through a reduction in thrombotic tendency.

Keywords

Homocysteine - cardiovascular disease - thrombosis

Full Text

References

References
1 Selhub J, Jacques PF, Bostom AG, D’Agostino RB, Wilson PW, Belanger AJ, O’Leary DH, Wolf PA, Schaefer EJ, Rosenberg IH. Association between plasma homocysteine concentrations and extracranial carotidartery stenosis. N Engl J Med 1995; 332: 286-91.
2 Graham IM, Daly LE, Refsum HM, Robinson K, Brattstrom LE, Ueland PM, Palma-Reis RJ, Boers GHJ, Sheahan RG, Israelsson B, Uiterwaal CS, Meleady R, McMaster D, Verhoef P, Witteman J, Rubba P, Bellet H, Wautrecht JC, de Valk HW, Sales ACLuis, Parrot-Roulaud FM, Soon KTan, Higgins I, Garcon D, Medrano MJ, Candito M, Evans AE, Andria G. Plasma homocysteine as a risk factor for vascular disease: The European Concerted Action Project. JAMA 1997; 277: 1775-81.
3 Stampfer MJ, Malinow R, Willett WC, Newcomer LM, Upson B, Ullmann D, Tishler PV, Hennekens CH. A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US Physicians. JAMA 1992; 268: 877-81.
4 Boushey CJ, Beresford SAA, 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.
5 Franken DG, Boers GHJ, Blom HJ, Trijbels FJM, Kloppenborg PWC. Treatment of Mild Hyperhomocysteinemia in Vascular Disease Patients. Arterioscler Thromb 1994; 14: 465-70.
6 Tawakol A, Omland T, Gerhard M, Wu JT, Creager MA. Hyperhomocysteinemia is associated with impaired endothelium-dependent vasodilation in humans. Circulation 1997; 95: 1119-21.
7 Welch GN, Loscalzo J. Homocysteine and Atherothrombosis. N Engl J Med 1998; 338: 1042-50.
8 Mancini FP, Di Minno G. Hyperhomocysteinemia and thrombosis: the search for a link. Nutr Metab Cardiovasc Dis 1996; 06: 168-77.
9 Clauss A. Gerinnungsphysiologische Schnellmethode zur Bestimmung des Fibrinogens. Acta Hematol 1957; 17: 237-47.
10 Ranby M, Bergsdorf N, Nilsson T, Mellbring G, Winblad B, Bucht A. Age dependence of tissue plasminogen activator concentrations in plasma, as studied by an improved enzyme linked immunosorbent assay. Clin Chem 1986; 32: 2160-5.
11 Marckmann P, Sandstrom B, Jepersen J. The variability of and associations between measures of blood coagulation, fibrinolysis and blood lipids. Atherosclerosis 1992; 96 (02) 35-44.
12 Juhan-Vague I, Alessi MC. Plasminogen activator inhibitor 1 and atherothrombosis. Thromb Haemost 1993; 70: 138-43.
13 Gebara OCE, Mittleman MA, Sutherland P, Lipinska I, Matheney T, Welty FK, Wilson PWF, Levy D, Muller JE, Tofler GH. Association between increased estrogen status and increased fibrinolytic potential in the Framingham Offspring Study. Circulation 1995; 91: 1952-8.
14 Dicheck D, Quartermous T. Thrombin regulation of mRNA levels of tissue plasminogen activator and plasminogen activator inhibitor 1 in cultured umbilical vein endothelial cells. Blood 1989; 222-8.
15 Wilcken DEL, Wilcken B. The pathogenesis of coronary artery disease. A possible role for methionine metabolism. J Clin Invest 1976; 57: 1079-82.
16 Folsom AR, Nieto FJ, McGovern PG, Tsai MY, Malinow MR, Eckfeldt JH, Hess DL, David CE. 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 1998; 98: 204-10.
17 Christen WG, Ajani UA, Glynn RJ, Hennekens CH. Blood levels of homocysteine and increased risks of cardiovascular disease: causal or casual?. Arch Int Med 2000; 160: 422-34.
18 Shemin D, Lapane KL, Bausserman L, Kanaan E, Kahn S, Dworkin L, Bostom AG. Plasma total homocysteine and hemodialysis access thrombosis: A prospective study. J Am Soc Nephrol 1999; 10: 1095-9.
19 Davies MJ, Thomas AC. Plaque fissuring – the cause of acute myocardial infarction, sudden ischemic death, and crescendo angina. Br Heart J 1985; 53: 363-73.
20 Muller JE, Abela GS, Nesto RW, Tofler GH. Triggers, acute risk factors and vulnerable plaques: The lexicon of a new frontier. J Am Coll Cardiol 1994; 23: 809-13.
21 Meade TW, Mellows S, Brozovic M, Miller GJ, Chakrabarti RR, North WR, Haines AP, Stirling Y, Imeson JD, Thompson SG. Haemostatic function and ischaemic heart disease: principal results of the Northwick Park Heart Study. Lancet 1986; 02: 533-7.
22 Jadhav PP, Tofler GH. Hemostatic risk factors for Cardiovascular Disease. in Willich SN, Muller JE. (eds). Triggering of acute coronary syndromes. Dordrecht: Kluwer academic publishers; 1996: 135-51.
23 Jansson JH, Nilsson TK, Johnson O. von Willebrand factor in plasma: a novel risk factor for recurrent myocardial infarction and death. Br Heart J 1991; 66: 351-5.
24 Ernst E, Resch KL. Fibrinogen as a cardiovascular risk factor: A metaanalysis and review of the literature. Ann Int Med 1993; 118: 956-63.
25 Kruithof EKO. Plasminogen activator inhibitor type 1: biochemical, biological and clinical aspects. Fibrinolysis 1988; 02: 59-70.
26 Loskutoff DJ, Sawdey M, Mumuro J. Type 1 Plasminogen Activator Inhibitor. In Progress in Hemostasis and Thrombosis. Vol 9. Coller BS. Ed. WB Saunders; Philadelphia PA: 87-115.
27 Francis RB, Kawanishi D, Baruchi T, Mahner P, Rahimtoola S, Feinstein DI. Impaired fibrinolysis in coronary artery disease. Am Heart J 1988; 115: 776-80.
28 Prins MH, Hirsh J. A critical review of the relationship between impaired fibrinolysis and myocardial infarction. Am Heart J 1991; 122: 545-51.
29 Hamsten A, Wiman B, de Faire U, Blomback M. Increased plasma levels of rapid inhibitor of tissue plasminogen activator in young survivors of myocardial infarction. N Engl J Med 1985; 313: 1557-63.
30 Andreotti F, Davies GJ, Hackett DR. Major circadian fluctuations in fibrinolytic factors and possible relevance to time of onset of myocardial infarction, sudden cardiac death and stroke. Am J Cardiol 1988; 62: 635-7.
31 Ridker PM, Vaughan DE, Stampfer MJ, Manson JE, Hennekens CH. Endogenous tissue-type plasminogen activator and risk of myocardial infarction. Lancet 1993; 341: 1165-8.
32 Jansson JH, Nilsson TK, Olofsson BO. Tissue plasminogen activator and other risk factors of cardiovascular disease in patients with severe angina pectoris. Eur Heart J 1991; 12: 157-61.
33 Rees MM, Rodgers GM. Homocysteinemia: Association of a metabolic disorder with vascular disease and thrombosis. Thrombosis Research 1993; 71: 337-59.
34 Bienvenu T, Ankri A, Chadefaux B, Montalescot G, Kamoun P. Elevated total plasma homocysteine, a risk factor for thrombosis. Relation to coagulation and fibrinolytic factors. Thrombosis Research 1993; 70: 123-9.
35 Harker LA, Slichter SJ, Scott CR, Ross R. Homocystinemia. Vascular injury and arterial thrombosis. N Engl J Med 1974; 291: 537-43.
36 Starkebaum G, Harlan JM. Endothelial cell injury due to copper-catalyzed hydrogen peroxide generation from homocysteine. J Clin Invest 1986; 77: 1370-6.
37 Stamler JS, Osborne JA, Jaraki O, Rabbani LE, Mullins M, Singel D, Loscalzo J. Adverse vascular effects of homocysteine are modulated by endothelial-derived relaxing factor and related oxides of nitrogen. J Clin Invest 1993; 91: 308-18.
38 van den Berg M, Boers GHJ, Franken DG, Blom HJ, van Kamp GJ, Jakobs C, Rauwerda JA, Kluft C, Stehouwert CDA. Hyperhomocysteinemia and endothelial dysfunction in young patients with peripheral arterial occlusive disease. Eur J Clin Invest 1995; 25: 176-81.
39 Hajjar KA. Homocysteine-induced modulation of tissue plasminogen activator binding to its endothelial cell membrane receptor. J Clin Invest 1993; 91: 2873-9.
40 Schnyder G, Roffi M, Pin R, Flammer Y, Lange H, Eberli FR, Meier B, Turi ZG, Hess OM. Decreased rate of coronary restenosis after lowering of plasma homocysteine levels. N Engl J Med 2001; 345: 1593-600.
41 Lentz SR, Sadler JE. Homocysteine inhibits von Willebrand Factor processing and secretion by preventing transport from the endoplasmic reticulum. Blood 1993; 81: 683-9.
42 Selhub J, D’Angelo A. Hyperhomocysteinemia and thrombosis: Acquired conditions. Thromb Hemost 1997; 78: 527-31.
43 Rolland PH, Friggi A, Barlainer A, Piquet P, Latrille V, Faye MM. Hyperhomocysteinemia induced vascular damage in the minipig. Circulation 1995; 09: 1161-74.
44 Fryer RH, Wilson BD, Gubler DB, Fitzgerald LA, Rodgers GM. Homocysteine, a risk factor for premature vascular disease and thrombosis, induces tissue factor activity in endothelial cells. Arterioscler Thromb 1993; 13: 1327-33.
45 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.
46 Munnich A, Saudubray J-M, Dautzenberg MS, Parvy P, Ogier H, Girot R, Manigne P, Frezal J. Diet-responsive proconvertin (Factor VII) deficiency in homocysteinuria. J Pediatr 1983; 102: 730-4.