Fibrinogen is a soluble precursor of the insoluble fibrin, the major component of a blood clot. Fibrinogen is a glycoprotein, which consists of three pairs of polypeptide chains, Aa, Bb, and γ.2
Several laboratory methods exist to determine fibrinogen levels, including clot-based methods and immunoassays such as RIA, nephelometric, and EIA methods. The clot-based method measures functional fibrinogen, while immunoassays measure antigenic fibrinogen, which may or may not be able to participate in clot formation.
Therefore, different methods may give results that vary from each other. The immunoturbidimetric method uses antibodies directed against fibrinogen to detect and quantify levels of fibrinogen and expresses the results in mg/dL. This test is not a functional fibrinogen test. In the Framingham offspring study, the immunologic method for fibrinogen showed a stronger association with cardiovascular disease than the clot-based method, suggesting that it may be a useful screening tool to identify individuals at increased thrombotic risk.1
Figure 1 is borrowed from Stefanadi et al.3 and describes the initial events involved in the pathogenesis of atherosclerosis. Risk factors lead to endothelial dysfunction, which coincides with uncoupling of endothelial nitric oxide synthase and the simultaneous production of reactive oxygen species from intracellular sources such as NADPH oxidase. A local inflammatory cascade is triggered, with the production of cytokines and growth factors by inflammatory cells, which in turn leads to intima thickening, smooth-muscle cell proliferation, and extracellular matrix destabilization.
Apart from the contribution to the coagulation cascade (Figure 1), fibrinogen participates in the formation of atherosclerotic plaque during early stages, since it can directly incorporate in the arterial wall and turn into fibrin as well as decomposition products. Additionally, it binds to high-density lipoprotein (HDL) and produces even greater amounts of it.4 Simultaneously, fibrinogen, as well as its decomposition products, mediate the transportation of adhesion molecules in the surface of endothelium and their further migration to the intima.5 It should be mentioned that fibrinogen and the products of its decomposition, trigger proliferation and migration of smooth-muscle cells.6-8 In regard to the inflammatory aspect of fibrinogen, inflammatory process is mainly mediated by the interaction of fibrinogen-leukocytes mediated by integrins.
The two main receptors of fibrinogen on the surface of leukocytes include MAC 1 and alpha X beta 2. Monocytes are able to induce the junction of fibrinogen to the receptor MAC–1.9,10 The ability of the receptor MAC–1 to attach to fibrinogen is a result of changes that slip into the receptor during the process of cellular proliferation. Furthermore, fibrinogen binds to the intracellular adhesion molecule 1 (ICAM-1) and increases the interaction of monocytes-endothelial cells. Through this process, ICAM-1 forms a binding molecule of the cellular surface for MAC–1 integrin and has an important role in the adhesion of leukocytes on vascular endothelium.11-13 Additionally, fibrinogen increases the concentration of ICAM-1 proteins on the surface of endothelial cells leading to the rise of leukocytes on the surface of endothelial cells, even in conditions characterized by the presence of increased shear stress.14
Moreover, the binding of fibrinogen to ICAM-1 mediates platelet adhesion. The interaction of fibrinogen with the cells that express ICAM-1 is linked to augmented cell proliferation.15 Upon its binding to the surface receptor of leukocytes, fibrinogen promotes a chemotactic response playing a crucial role in inflammatory process.16 One of the proposed mechanisms through which fibrinogen induces inflammatory changes in leukocytes includes the rise of intracellular calcium and increased expression of neutrophil activation factors. These processes result to increased phagocytosis, leukocyte toxicity (mediated by antibodies), and delay of apoptosis.17
Several studies have examined the role of fibrinogen levels in the prediction of atherosclerosis and future cardiovascular disease (CVD) events (Table 1). The Framingham study18,19 found that fibrinogen levels were linked to cardiovascular risk. In males, as well as females, the risk for MI and stroke increased progressively along with fibrinogen levels. The effect of fibrinogen levels on cardiovascular risk was even greater in young individuals. In addition, it has been shown that its effect was similar to the effect of known risk factors such as hypertension, diabetes mellitus, and smoking, while in multivariate analysis it constituted an independent predictive marker for coronary artery disease (CAD). For both sexes, the risk of cardiovascular disease was correlated positively to antecedent fibrinogen values higher than the 1.3 to 7.0 g/L (126 to 696 mg/dL) range.
Interestingly, the magnitude of the risk diminished with advancing age in women, but not in men. Many years after the Framingham study, the ECAT study20 showed that plasma fibrinogen was a strong and independent risk factor for MI and sudden death, particularly in patients with pre-existing CAD. The association between fibrinogen and future coronary events was characterized by an odds ratio of 1.31 (95% CI, 1.07-1.61). Recently, a meta-analysis of the Fibrinogen Studies Collaboration21 recruiting subjects without history of CVD reported that the age- and sex-adjusted hazard ratio for 1 g/L increase of fibrinogen levels for CAD was 2.42 (95% CI, 2.24-2.60), stroke 2.06 (95% CI, 1.83-2.33), other vascular mortality 2.76 (95% CI, 2.28-3.35), and other non-vascular mortality 2.03 (95% CI, 1.90-2.18). Further information regarding the potency of fibrinogen in predicting future CVD events has been offered through other studies. The AtheroGene study22 aimed to evaluate the potential clinical use of CRP and fibrinogen in patients already suffering from CAD. Fibrinogen was associated with future cardiovascular events, such as an increment of one standard deviation of fibrinogen with a 1.27-fold (95% CI 1.12–1.43, p < 0.0005) increase in HR in the models adjusted for age and sex. Additive to the results of the Atherogene study were the results of Retterstol et al.23 After adjusting for age, ejection fraction, total serum cholesterol, smoking, and hypertension, patients in the top quartile of fibrinogen (> or = 4.0 g/L) had a relative risk (RR) of 1.8 (95% CI 1.0- 3.6, p = 0.07) for death of all causes. The top quartile of fibrinogen was a stronger predictor of cardiac death, RR = 2.2 (95% CI 1.1-4.4, p = 0.03), while the effect on the endpoint major cardiac event was not significant, RR = 1.1 (95% CI 0.6-1.9, p = 0.69). Moreover, the ARIC study24 evaluated the relationship of fibrinogen levels with the risk of peripheral artery disease (PAD) in patients with diabetes mellitus, but not PAD. The results showed that the adjusted RR for the highest quartiles of fibrinogen was 1.70 (95% CI: 1.17-2.47). Furthermore, an interesting study by Panagiotakos et al.25 showed that in individuals with heterozygous familial hypercholesterolemia, fibrinogen levels are among the strong predictors of CHD. Finally, it appears that thrombotic and inflammatory mechanisms are probably both implicated in the effects of fibrinogen as this has been evaluated by several studies,13-17 indicating that this acute-phase glycoprotein is able to act as an inflammatory as well as a thrombotic marker.
Lifestyle factors that have been shown to lower circulating fibrinogen include:
- Weight loss (as appropriate)2
- Smoking cessation2
- Diet rich in fruits, vegetables, and whole grains (e.g., Mediterranean diet)34
- Moderate alcohol intake (dependent on ApoE genotype)2,34,35
- Increased intake of omega-3 fatty acids2,36-39
- Increased consumption of magnesium-rich foods40
- Stress management2
Although fibrinogen is not a primary therapeutic target, certain medications indicated for treatment of other CVD risk factors have been shown to lower circulating concentrations of this marker. Use of these medications to treat underlying conditions (e.g., dyslipidemia, prediabetes, diabetes) may have a beneficial effect on fibrinogen levels:
- Stec JJ, Silbershatz H, et al. Association of fibrinogen with cardiovascular risk factors and cardiovascular disease in the Framingham Offspring Population. Circulation 2000;102(14):1634-8.
- Kamath S, Lip GY. Fibrinogen: biochemistry, epidemiology and determinants. QJM 2003;96(10):711-29.
- Stefanadi E, Tousoulis D, et al. Inflammatory biomarkers predicting events in atherosclerosis. Curr Med Chem 2010;17(16):1690-707.
- Ernst E, Resch KL. Fibrinogen as a cardiovascular risk factor: a meta-analysis and review of the literature. Ann Intern Med 1993;118(12):956-63.
- Miyao Y, Yasue H, et al. Elevated plasma interleukin-6 levels in patients with acute myocardial infarction. Am Heart J 1993;126(6):1299-304.
- Smith EB, Keen GA, et al. Fate of fibrinogen in human arterial intima. Arteriosclerosis 1990;10(2):263-75.
- Stroncek DF, Shankar RA, et al. The subcellular distribution of myeloid-related protein 8 (MRP8) and MRP14 in human neutrophils. J Transl Med 2005;3:36.
- Thompson WD, Smith EB. Atherosclerosis and the coagulation system. J Pathol 1989;159(2):97-106.
- Altieri DC, Bader R, et al. Oligospecificity of the cellular adhesion receptor Mac-1 encompasses an inducible recognition specificity for fibrinogen. J Cell Biol 1988;107(5):1893-900.
- Colman RW. Interactions between the contact system, neutrophils and fibrinogen. Adv Exp Med Biol 1990;281:105-20.
- van de Stolpe A, Jacobs N, et al. Fibrinogen binding to ICAM-1 on EA.hy 926 endothelial cells is dependent on an intact cytoskeleton. Thromb Haemost 1996;75(1):182-9.
- Duperray A, Languino LR, et al. Molecular identification of a novel fibrinogen binding site on the first domain of ICAM-1 regulating leukocyte-endothelium bridging. J Biol Chem 1997;272(1):435-41.
- Harley SL, Sturge J, et al. Regulation by fibrinogen and its products of intercellular adhesion molecule-1 expression in human saphenous vein endothelial cells. Arterioscler Thromb Vasc Biol 2000;20(3):652-8.
- Kaperonis EA, Liapis CD, et al. Inflammation and atherosclerosis. Eur J Vasc Endovasc Surg 2006;31(4):386-93.
- Gardiner EE, D’Souza SE. A mitogenic action for fibrinogen mediated through intercellular adhesion molecule-1. J Biol Chem 1997;272(24):15474-80.
- Forsyth CB, Solovjov DA, et al. Integrin alpha(M)beta(2)-mediated cell migration to fibrinogen and its recognition peptides. J Exp Med 2001;193(10):1123-33.
- Rubel C, Fernandez GC, et al. Fibrinogen promotes neutrophil activation and delays apoptosis. J Immunol 2001;166(3):2002-10.
- Kannel WB, D’Agostino RB, et al. Diabetes, fibrinogen, and risk of cardiovascular disease: the Framingham experience. Am Heart J 1990;120(3):672-6.
- Kannel WB, Wolf PA, et al. Fibrinogen and risk of cardiovascular disease. The Framingham Study. JAMA 1987;258(9):1183-6.
- Juhan-Vague I, Thompson SG, et al. Involvement of the hemostatic system in the insulin resistance syndrome. A study of 1500 patients with angina pectoris. The ECAT Angina Pectoris Study Group. Arterioscler Thromb 1993;13(12):1865-73.
- Fibrinogen Studies C, Danesh J, et al. Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality: an individual participant meta-analysis. JAMA 2005;294(14):1799-809.
- Sinning JM, Bickel C, et al. Impact of C-reactive protein and fibrinogen on cardiovascular prognosis in patients with stable angina pectoris: the AtheroGene study. Eur Heart J 2006;27(24):2962-8.
- Retterstol L, Kierulf P, et al. Plasma fibrinogen level and long-term prognosis in Norwegian middle-aged patients with previous myocardial infarction. A 10 year follow-up study. J Intern Med 2001;249(6):511-8.
- Wattanakit K, Folsom AR, et al. Risk factors for peripheral arterial disease incidence in persons with diabetes: the Atherosclerosis Risk in Communities (ARIC) Study. Atherosclerosis 2005;180(2):389-97.
- Panagiotakos DB, Pitsavos C, et al. Importance of LDL/HDL cholesterol ratio as a predictor for coronary heart disease events in patients with heterozygous familial hypercholesterolaemia: a 15-year follow-up (1987-2002). Curr Med Res Opin 2003;19(2):89-94.
- Meade TW, Mellows S, et al. Haemostatic function and ischaemic heart disease: principal results of the Northwick Park Heart Study. Lancet 1986;2(8506):533-7.
- Heinrich J, Balleisen L, et al. Fibrinogen and factor VII in the prediction of coronary risk. Results from the PROCAM study in healthy men. Arterioscler Thromb 1994;14(1):54-9.
- Benderly M, Graff E, et al. Fibrinogen is a predictor of mortality in coronary heart disease patients. The Bezafibrate Infarction Prevention (BIP) Study Group. Arterioscler Thromb Vasc Biol 1996;16(3):351-6.
- Woodward M, Lowe GD, et al. 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(1):55-62.
- Sharp DS, Abbott RD, et al. Plasma fibrinogen and coronary heart disease in elderly Japanese-American men. Arterioscler Thromb Vasc Biol 1996;16(2):262-8.
- Levenson J, Giral P, et al. Fibrinogen and silent atherosclerosis in subjects with cardiovascular risk factors. Arterioscler Thromb Vasc Biol 1995;15(9):1263-8.
- Woodward M, Lowe GD, et al. Epidemiology of coagulation factors, inhibitors and activation markers: The Third Glasgow MONICA Survey. II. Relationships to cardiovascular risk factors and prevalent cardiovascular disease. Br J Haematol 1997;97(4):785-97.
- Rodriguez Cristobal JJ, Alonso-Villaverde Grote C, et al. Randomised clinical trial of an intensive intervention in the primary care setting of patients with high plasma fibrinogen in the primary prevention of cardiovascular disease. BMC Res Notes 2012;5:126.
- Chrysohoou C, Panagiotakos DB, et al. Adherence to the Mediterranean diet attenuates inflammation and coagulation process in healthy adults: The ATTICA Study. J Am Coll Cardiol 2004;44(1):152-8.
- Imhof A, Woodward M, et al. Overall alcohol intake, beer, wine, and systemic markers of inflammation in western Europe: results from three MONICA samples (Augsburg, Glasgow, Lille). Eur Heart J 2004;25(23):2092-100.
- Hassen LJ, Ueshima H, et al. Significant inverse association of marine n-3 fatty acids with plasma fibrinogen levels in Japanese in Japan but not in whites or Japanese Americans. Eur J Clin Nutr 2012;66(3):329-35.
- Kalogeropoulos N, Panagiotakos DB, et al. Unsaturated fatty acids are inversely associated and n-6/n-3 ratios are positively related to inflammation and coagulation markers in plasma of apparently healthy adults. Clin Chim Acta 2010;411(7-8):584-91.
- Derosa G, Maffioli P, et al. Effects of long chain omega-3 fatty acids on metalloproteinases and their inhibitors in combined dyslipidemia patients. Expert Opin Pharmacother 2009;10(8):1239-47.
- Hartweg J, Farmer AJ, et al. Potential impact of omega-3 treatment on cardiovascular disease in type 2 diabetes. Curr Opin Lipidol 2009;20(1):30-8.
- Moslehi N, Vafa M, et al. Effects of oral magnesium supplementation on inflammatory markers in middle-aged overweight women. J Res Med Sci 2012;17(7):607-14.
- Guyton JR, Blazing MA, et al. Extended-release niacin vs gemfibrozil for the treatment of low levels of high-density lipoprotein cholesterol. Niaspan-Gemfibrozil Study Group. Arch Intern Med 2000;160(8):1177-84.
- Chesney CM, Elam MB, et al. Effect of niacin, warfarin, and antioxidant therapy on coagulation parameters in patients with peripheral arterial disease in the Arterial Disease Multiple Intervention Trial (ADMIT). Am Heart J 2000;140(4):631-6.
- Tanne D, Benderly M, et al. A prospective study of plasma fibrinogen levels and the risk of stroke among participants in the bezafibrate infarction prevention study. Am J Med 2001;111(6):457-63.
- Krysiak R, Gdula-Dymek A, et al. Effect of metformin on selected parameters of hemostasis in fenofibrate-treated patients with impaired glucose tolerance. Pharmacol Rep 2013;65(1):208-13.
- Krysiak R, Okopien B. Haemostatic effects of metformin in simvastatin-treated volunteers with impaired fasting glucose. Basic Clin Pharmacol Toxicol 2012;111(6):380-4.