Fibrin(ogen) in cardiovascular disease: an update

Summary

The notion that fibrinogen is strongly, consistently, and independently related to cardiovascular risk has been widely accepted. The evidence is based on numerous prospective epidemiological studies and clinical observations. In meta-analysis, an association between even modest increases (10%) in fibrino-gen and future coronary heart disease (CHD) endpoints has been found with an odds ratio for CHD of 1.8; 95% CI, 1.6 to 2.0, if the top tertile of the fibrinogen distribution was compared to the bottom tertile; but fibrinogen levels were also associated with unstable and stable coronary artery disease, and coronary complications after interventions. Similar results have been obtained for incident stroke, progression of peripheral arterial disease, and finally for total mortality. The reasons however, why fibrinogen is elevated in cardiovascular disease and in atherosclerosis in general, are only incompletely under-stood; but all cells involved in the atherogenetic process are able to produce cytokines which induce an acute phase reaction, and thus increase fibrinogen plasma levels. The potential pathophysiological mechanisms by which elevated fibrinogen levels mediate cardiovascular risk are manyfold: It forms the substrate for thrombin and represents the final step in the coagulation cascade; it is essential for platelet aggregation; it modulates endothelial function;it promotes smooth muscle cell proliferation and migration; it interacts with the binding of plas-min with its receptor, and finally it represents a major acute phase protein. Whether or not fibrinogen is causally involved in atherothrombogenesis still remains to be determined, and even though other unsolved issues await conclusive answers, fibrino-gen has emerged as an important additional marker of cardiovascular risk.

Theme paper: Part of this paper was originally presented at the joint meetings of the 16th International Congress of the International Society of Fibrinolysis and Proteolysis (ISFP) and the 17th International Fibrinogen Workshop of the International Fibrinogen Research Society (IFRS) held in Munich, Germany, September, 2002.

Keywords

Fibrinogen - cardiovascular risk. epidemiology - clinical evidence - determinants - mechanisms - therapeutic interventions

• References

• 1 Ross R. Arteriosclerosis - an inflammatory disease. N Engl J Med 1999; 340: 115-26.
• 2 Libby P. Current concepts of the pathogenesis of the acute coronary syndromes. Circulation 2001; 104: 365-72.
• 3 Danesh J, Collins R, Appleby P, Peto R. Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease. J Am Med Assoc 1998; 279: 1477-82.
• 4 Ernst E, Koenig W. Fibrinogen and cardiovascular risk. Vascular Medicine 1997; 2: 115-25.
• 5 Maresca G, Di Blasio A, Marchioli R, Di Minno G. Measuring plasma fibrinogen to predict stroke and myocardial infarction. An update. Arterioscler Thromb Vasc Biol 1999; 19: 1368-77.
• 6 Lind P, Hedblad B, Stavenov L, Janzon L, Eriksson KF, Lindgärde F. Influence of plasma fibrinogen levels on the incidence of myocardial infarction and death is modified by other inflammation-sensitive proteins. A long-term cohort study. Arterioscler Thromb Vasc Biol 2001; 21: 452-8.
• 7 Engström G, Lind P, Hedblad B, Stavenow L, Janzon L, Lindgärde F. Effects of cholesterol and inflammation-sensitive plasma preoteins on incidence of myocardial infarction and stroke in men. Circulation 2002; 105: 2632-7.
• 8 Cantin B, Despres JP, Lamarche B, Moorjani S, Lupien PJ, Bogaty P, Bergeron J, Dagenais GR. Association of fibrinogen and lipoprotein (a) as a coronary heart disease risk factor in men (The Quebec Cardiovascular Study). Am J Cardiol 2002; 89: 662-6.
• 9 Cooper JA, Miller GJ, Bauer KA, Morrissey JH, Meade TW, Howarth DJ, Barzegar S, Mitchell JP, Rosenberg RD. Comparison of novel hemostatic factors and conventional risk factors for prediction of coronary heart disease. Circulation 2000; 102: 2816-22.
• 10 Woodward M, Lowe GDO, Rumley A, Tun-stall-Pedoe H. Fibrinogen as a risk factor for coronary heart disease and mortality in middle-aged men and women. The Scottish Heart Health Study. Eur Heart J 1998; 19: 55-62.
• 11 Saito I, Folsom AR, Brancati FL, Duncan BB, Chambless LE, McGovern PG. Nontraditional risk factors for coronary heart disease incidence among persons with diabetes: The Atherosclerosis Risk in Communities (ARIC) Study. Ann Intern Med 2000; 133: 81-91.
• 12 Smith FB, Lee AJ, Fowkes FRG, 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.
• 13 Smith FB, Rumley A, Lee AJ, Leng GC, Fowkes FG, Lowe GD. Haemostatic factors and prediction of ischaemic heart disease and stroke in claudicants. Br J Haematol 1998; 100: 758-63.
• 14 Koch M, Kutkuhn B, Grabensee B, Ritz E. Apolipoprotein A, fibrinogen, age, and history of stroke are predictors of death in dialysed diabetic patients: a prospective study in 412 subjects. Nephrol Dial Transplant 1997; 12: 2603-2611.
• 15 Sweetnam PM, Thomas HF, Yarnell JWG, Beswick AD, Baker IA, Elwood PC. Fibrin-ogen, viscosity and the 10-year incidence of ischaemic heart disease. The Caerphilly and Speedwell Studies. Eur Heart J 1996; 17: 1814-20.
• 16 Koenig W, Sund M, Filipiak B, Döring A, Löwel H, Ernst E. Plasma viscosity and the risk of coronary heart disease. Results from the MONICA-Augsburg Cohort Study 1984 -1992. Arterioscler Thromb Vasc Biol 1998; 18: 768-72.
• 17 Festa A, Dàgostino R, Tracy RP, Haffner SM. Elevated levels of acute-phase proteins and plasminogen activator inhibitor-1 predict the development of type 2 diabetes. The Insulin Resistance Atherosclerosis Study. Diabetes 2002; 51: 1131-7.
• 18 Yano K, Grove JS, Chen R, Rodriguez BL, Curb DJ, Tracy RP. Plasma fibrinogen as a predictor of total and cause-specificmortality in elderly Japanes-American men. Arterioscler Thromb Vasc Biol 2001; 21: 1065-70.
• 19 Salomaa V, Rasi V, Kulathinal S, Vahtera E, Jauhiainen M, Ehnholm C, Pekkanen J. Hemostatic factors as predictors of coronary events and total mortality. The FINRISK ’92 Hemostasis Study. Arterioscler Thromb Vasc Biol 2002; 22: 353-358.
• 20 Jose J, Selvakumar D, Selvakumar R, Kanagasapabathy AS, Jeyaseelan L. Plasma fibrinogen - an independent risk factor for ischaemic heart disease. Indian Heart J 1998; 50: 45-8.
• 21 Markovitz JH, Kulkarni K, Goldschmidt-Clermont P, Kiefe CI, Rustagi P, Sekar P, Nanda N. Increased platelet activation and fibrinogen in Asian Indians. Eur Heart J 1998; 19: 720-6.
• 22 Folsom AR, Pankow JS, Williams RR, Evans GW, Province MA, Eckfeldt JH. Fibrinogen, plasminogen activator inhibitor-1, and carotid intima-media wall thickness in the NHLBI Family Heart Study. Thromb Haemost 1998; 2: 400-4.
• 23 Rosenson RS. Myocardial injury: the acute phase response and lipoprotein metabolism. J Am Coll Cardiol 1993; 22: 933-40.
• 24 Lowe GDO. The impact of fibrinogen on arterial disease. Excerpta Medica. 1993
• 25 Eichner JE, Moore WE, McKee PA, Schechter E, Reynolds DW, Qi H, Comp PC. Fibrinogen levels in women having coronary angiography. Am J Cardiol 1996; 78: 15-8.
• 26 Tribouilloy C, Peltier M, Colas L, Senni M, Ganry O, Rey JL, Lesbre JP. Fibrinogen is an independent marker for thoracic aortic artherosclerosis. Am J Cardiol 1998; 81: 321-6.
• 27 Danielsen R, Önundarson PT, Thors H, Vidarsson B, Morrissey JH. Activated and total coagulation factor VII, and fibrinogen in coronary artery disease. Scand Cardiovasc J 1998; 32: 87-95.
• 28 Kruskal JB, Commerford PJ, Franks JJ, Kirsch RE. Fibrin and fibrinogen-related antigens in patients with stable and unstable coronary artery disease. N Engl J Med 1987; 317: 1361-5.
• 29 Becker RC, Cannon CP, Bovill EG, Tracy RP, Thompson B, Knatterud GL, Randall A, Braunwald B. Prognostic value of plasma fibrinogen concentration in patients with unstable angina and non-Q-wave myocardial infarction (TIMI IIIB Trial). Am J Cardiol 1996; 78: 142-7.
• 30 Toss H, Lindahl B, Siegbahn A, Wallentin L. Prognostic influence of increased fibrinogen and C-reactive protein levels in unstable coronary artery disease. Circulation 1997; 96: 4204-10.
• 31 Lindahl B, Toss H, Siegbahn A, Venge P, Wallentin L. for the FRISC Study Group. Markers of myocardial damage and inflammation in relation to long-term mortality in unstable coronary artery disease. N Engl J Med 2000; 343: 1139-47.
• 32 Verheggen PW, de Maat MP, Cats VM, Haverkate F, Zwinderman AH, Kluft C, Bruschke AV. Inflammatory status as a main determinant of outcome in patients with unstable angina, independent of coagulation activation and endothelial cell function. Eur Heart J 1999; 20: 567-74.
• 33 Green FR. Fibrinogen polymorphisms and atherothrombotic disease. Annals of the New York Academy of Sciences 2001; 936: 549-59.
• 34 Iacoviello L, Vischetti M, Zito F, Donato MB. Genes encoding fibrinogen and cardiovascular risk. Hypertension 2001; 38: 1199-203.
• 35 Carter AM, Mansfield MW, Stickland MH, Grant PJ. β-Fibrinogen gene - 455 G/A poly-morphism and fibrinogen levels. Risk factors for coronary artery disease in subjects with NIDDM. Diabetes Care 1996; 19: 1265-8.
• 36 Humphries SE, Henry JA, Montgomenry HE. Gene-environment interaction in the determination of levels of haemostatic variables involved in thrombosis and fibrinolysis. Blood Coagul Fibrinolysis 1999; 10 (01) Suppl S17-S21.
• 37 Zito F, Di Castelnuovo A, Amore C, D’Orazio A, Donati MB, Iacoviello L. Bcl I polymorphism in the fibrinogen beta-chain gene is associated with the risk of familial myocardial infarction by increasing plasma fibrinogen levels. A case-control study in a sample of GISSI-2 patients. Arterioscler Thromb Vasc Biol 1997; 17: 3489-94.
• 38 Tybjaerg-Hansen A, Agerholm-Larsen B, Humphries SE, Abildgaard S, Schnohr P, Nordestgaard BG. A common mutation (G-455-A) in the beta-fibrinogen promoter is an independent predictor of plasma fibrino-gen, but not of ischemic heart disease. A study of 9,127 individuals based on the Copenhagen City Heart Study. J Clin Invest 1997; 99: 3034-9.
• 39 Montgomery HE, Clarkson P, Nwose OM, Mikailidis DP, Jagroop IA, Dollery C, Moult J, Benhizia F, Deanfield J, Jubb M, World M, McEwan JR, Winder A, Humphries S. The acute rise in plasma fibrinogen concentration with exercise is influenced by the G-453-A polymorphism of the beta-fibrinogen gene. Arterioscler Thromb Vasc Biol 1996; 16: 386-91.
• 40 Margaglione M, Cappucci G, Colaizzo D, Pirro L, Vecchione G, Grandone E, Di Minno G. Fibrinogen plasma level in an apparently healthy general population - relation to environmental and genetic determinants. Thromb Haemost 1998; 80: 805-10.
• 41 Folsom AR. Fibrinogen and cardiovascular risk markers. Blood Coagul Fibrinolysis 1999; 10 (Suppl. 01) Suppl S13-S16.
• 42 Scarabin PY, Aillaud MF, Amouyel P, Evans A, Luc G, Ferrieres J, Arveiler D, Juhan-Vague I. Associations of fibrinogen, factor VII and PAI-1 with baseline findings among 10,500 male participants in a prospective study of myocardial infarction. The Prime Study. Thromb Haemost 1998; 80: 749-56.
• 43 Stec JJ, Silbershatz H, Tofler GH, Matheney TH, Sutherland P, Lipinska I, Massaro JM, Wilson PF, Muller JE, D’Agostino Sr. RB. Association of fibrinogen with cardiovascular risk factors and cardiovascular disease in the Framingham offspring population. Circulation 2000; 102: 1634-8.
• 44 Folsom AR, Peacock JM, Nieto FJ, Rosamond WD, Eigenbrodt ML, Davis CE, Wu KK. Plasma fibrinogen and incident hypertension in the Atherosclerosis Risk in Communities (ARIC) Study. J Hypertens 1998; 16: 1579-83.
• 45 Junker R, Heinrich J, Schulte H, Erren M, Assmann G. Hemostasis in normotensive and hypertensive men: results of the PROCAM study. The prospective cardiovascular Munster study. J Hypertens 1998; 16: 917-23.
• 46 Welty FK, Mittleman MA, Wilson PW, Sutherland PA, Matheney TH, Lipinska I, Muller JE, Levy D, Tofler GH. Hypobetalipoproteinemia is associated with low levels of heostatic risk factors in the Framingham Offspring Population. Circulation 1997; 95: 825-30.
• 47 Wannamethee SG, Lowe GDO, Whincup PH, Rumley A, Walker M, Lennon L. Physical activity and hemostatic and inflammatory variables in elderly men. Circulation 2002; 105: 1785-90.
• 48 Mukamal KJ, Jadhav PP, D’Agostino RB, Massaro JM, Mittleman MA, Lipinska I, Sutherland PA, Matheney T, Levy D, Wilson PW, Ellison RC, Silbershatz H, Muller JE, Tofler GH. Alcohol consumption and hemo-static factors. Analysis of the Framingham Offspring Cohort. Circulation 2001; 104: 1367-73.
• 49 Danesh J, Peto R. Risk factors for coronary heart disease and infection with Helicobcter pylori: meta-analysis of 18 studies. Br Med J 1998; 316: 1130-1132.
• 50 Regnstrom J, Jovinge S, Bavenholm P, Erics-son CG, De Faire U, Hamsten A, Hellenius ML, Nilsson J, Tornvall P. Helicobacter pylori seropositivity is not associated with inflammatory parameters, lipid concentrations and degree of coronary artery disease. J Intern Med 1998; 243: 109-13.
• 51 Koenig W, Rothenbacher D, Hoffmeister A, Miller M, Bode G, Adler G, Hombach V, Marz W, Pepys MB, Brenner H. Infection with Helicobacter pylori is not a major independent risk factor for stable coronary heart disease. Lack of a role of cytotoxin-associated protein A-positive strains and absence of a systemic inflammatory response. Circulation 1999; 100: 2326-31.
• 52 Toss H, Gnarpe J, Gnarpe H, Siegbahn A, Lindahl B, Wallentin L. Increased fibrinogen levels are associated with persistent Chlamydia penumoniae infection in unstable coronary artery disease. Eur Heart J 1998; 19: 570-7.
• 53 Hoffmeister A, Rothenbacher D, Wanner P, Bode G, Persson K, Brenner H, Hombach V, Koenig W. Seropositivity to chlamydial lipopolysaccharide and Chlamydia pneumoniae, systemic inflammation and stable coronary artery disease. Negative results of a case-control study. J Am Coll Cardiol 2000; 35: 112-8.
• 54 Torgano G, Cosentini R, Mandelli C, Perondi R, Blasi F, Bertinieri G, Tien TV, Ceriani G, Tarsia P, Arosio C, Ranzi ML. Treatment of Helicobacter pylori and Chlamydia pneumoniae infections decreases fibrinogen plasma levels in patients with ischemic heart disease. Circulation 1999; 99: 1555-9.
• 55 Anderson JL, Muhlestein JB, Carlquist J, Allen A, Trehan S, Nielson C, Hall S, Brady J, Egger M, Horne B, Lim T. Randomized secondary prevention trial of azithromycin in patients with coronary artery disease and serological evidence for Chlamydia pneumoniae infection. Circulation 1999; 99: 1540-7.
• 56 Hicks RC, Golledge J, Mir-Hasseine R, Powell JT. Vasoactive effects of fibrinogen on saphenous vein. Nature 1996; 379: 818-20.
• 57 Retzinger GS, DeAnglis AP, Patuto SJ. Adsorption of fibrinogen to droplets of liquid hydrophobic Phases. Functionality of the bound protein and biological implications. Arterioscler Thromb Vasc Biol 1998; 18: 1948-57.
• 58 Rabbani LE, Loscalzo J. Recent observations on the role of hemostatic determinants in the development of the atherothrombotic plaque. Atherosclerosis 1994; 105: 1-7.
• 59 Schneider DJ, Taatjes DJ, Howard DB, Sobel BE. Increased reactivity of platelets induced by fibrinogen independent of ist bindings to the IIb-IIIa surface glycoprotein. A potential contributor to cardiovascular risk. J Am Coll Cardiol 1999; 33: 261-6.
• 60 Fatah K, Hamsten A, Blomback B, Blomback M. Fibrin gel network characteristics and coronary heart disease: Relations to plasma fibrinogen concentration, acute phase protein, serum lipoproteins and coronary atherosclerosis. Thromb Haemost 1992; 68: 130-5.
• 61 Scrutton MC, Ross-Murphy SB, Bennett GM, Stirling Y, Meade TW. Changes in clot deformability - a possible explanation for the epidemiological association between plasma fibrinogen concentration and myocardial infarction. Blood Coagul Fibrinolysis 1994; 5: 719-23.
• 62 McDonagh J, Lee MH. How does hyperfibrinogenemia lead to thrombosis?. Fibrinolysis & Proteolysis 1997; 11 (Suppl. 01) Suppl 13-7.
• 63 Koenig W, Ernst E. The possible role of hemorheology in atherothrombogenesis. Atherosclerosis 1992; 94: 93-107.
• 64 Biasucci LM, Vitelli A, Liuzzo G, Altamura S, Caligiuri G, Monaco C, Rebuzzi AG, Ciliberto G, Maseri A. Elevated levels of interleukin-6 in unstable angina. Circulation 1996; 94: 874-7.
• 65 Danesh J, Collins R, Peto R. Chronic infections and coronary heart disease. Is there a link?. Lancet 1997; 350: 430-6.
• 66 Folsom AR, Wu KK, Rosamond WD, Sharrett AR, Chambless LE. Prospective Study of hemostatic factors and incidence of coronary heart disease. The Atherosclerosis Risk in Communities (ARIC) Study. Circulation 1997; 96: 1102-8.
• 67 Imhof A, Koenig W. Exercise and thrombosis. In: Cardiology Clinics. Balady G. Ed Philadelphia: WBSaunders; 2001: 389-400.
• 68 Koenig W, Hoffmeister A, Hombach V. Hyperfibrinogenemia and cardiovascular risk: possible strategies for intervention.Fibrinolysis & Proteolysis. 1997. Supplement 41-6.
• 69 Kockx M, Gervois PP, Poulain P, Derudas B, Peters JM, Gonzalez FJ, Princen HM, Kooistra T, Staels B. Fibrates suppress fibrino-gen gene expression in rodents via activation of the peroxisome proliferator-activated receptor-α. Blood 1999; 93: 2991-8.
• 70 Staels B, Koenig W, Habib A, Merval R, Lebret M, Torra IP, Delerive P, Fadel A, Chinetti G, Fruchart JC, Najib J, Maclouf J, Tedgui A. Activation of human aortic smooth-muscle cells is inhibited by PPARα but not by PPARγ activators. Nature 1998; 393: 790-3.
• 71 Palazon CP, Alfon J, Gaffney P, Berrozpe M, Royo T, Badimon L. Effects of reducing LDL and increasing HDL with gemfibrozil in experimental coronary lesion development and thrombotic risk. Atherosclerosis 1998; 136: 333-45.
• 72 Behar S for the BIP Study Group. Lowering fibrinogen levels: clinical update. Blood Coagul Fibrinolysis 1999; 10 (01) Supplement S41-S43.
• 73 Rosenson RS, Tangney CC, Schaefer EJ. Comparative study of HMG-CoA reductase inhibitors on fibrinogen. Atherosclerosis 2001; 155: 463-6.
• 74 Prisco D, Paniccia R, Bandinelli B, Gori AM, Attanasio M, Giusti B, Comeglio M, Abbate R, Gensini GF, Serneri GG. Effect of low-dose heparin on fibrinogen levels in patients with chronic ischemic heart disease. Int J Clin Lab Res 1998; 28: 170-3.
• 75 The Writing Group for the Estradiol Clotting Factors Study. Effects on haemostasis of hormone replacement therapy with transdermal estradiol and oral sequential medroxyprogesterone acetate: A 1-year, double-blind, placebo-controlled study. Thromb Haemost 1996; 75: 476-80.
• 76 Fröhlich M, Schunkert H, Hense HW, Tropitzsch A, Hendricks P, Doring A, Riegger GA, Koenig W. Effects of hormone replacement therapies on fibrinogen and plasma viscosity in postmenopausal women. Br J Haematol 100 1998; 577-81.
• 77 Lip GY, Blann AD, Jones AF, Beevers DG. Effects of hormone-replacement therapy on hemostatic factors, lipid factors, and endothelial function in women undergoing surgical menopause: Implications for prevention of atherosclerosis. Am Heart J 1997; 134: 764-71.
• 78 Walsh BW, Kuller LH, Wild RA, Paul S, Farmer M, Lawrence JB, Shah AS, Anderson PW. Effects of raloxifene on serum lipids and coagulation factors in healthy postmenopausal women. JAMA 1998; 279: 1445-51.
• 79 Giri S, Thompson PD, Taxel P, Contois JH, Otvos J, Allen R, Ens G, Wu AH, Waters DD. Oral estrogen improves serum lipids, homo-cysteine and fibrinolysis in elderly men. Atherosclerosis 1998; 137: 359-66.
• 80 O’Keefe Jr. JH, Kim SC, Hall RR, Cochran VC, Lawhorn SL, McCallister BD. Estrogen replacement therapy after coronary angioplasty in women. J Am Coll Cardiol 1997; 29: 1-5.
• 81 Grady D, Herrington D, Bittner V, Blumenthal R, Davidson M, Hlatky M, Hsia J, Hulley S, Herd A, Khan S, Newby LK, Waters D, Vittinghoff E, Wenger N. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA 2002; 288: 49-57.
• 82 Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, Kotchen JM, Ockene J. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA 2002; 288: 321-33.
• 83 Rosenson RS, Tangney CC, Hafner JM. Intra-individual variability of fibrinogen levels and cardiovascular profile. Arterioscler Thromb 1994; 14: 1928-32.
• 84 Rosenson RS, Koenig W. Clinical utility of inflammatory markers in the management of the coronary heart disease patient. Am J Cardiol 2003 (Supplement) (in press).