Biomarkers of Inflammation: Fibrinogen, Fibrinogen Activity

Optimal Takeaways

Fibrinogen is a clotting factor protein and acute-phase reactant. Elevated levels are associated with cardiovascular disease, peripheral artery disease, and stroke.

Fibrinogen is also considered a biomarker of inflammation and elevations occur with infection, tissue damage, and neurological disorders. Low levels are associated with clotting disorders and may be observed with compromised hepatic function as it is produced in the liver. Fibrinogen is most commonly measured as fibrinogen activity.

Standard Range: 175 - 425 mg/dL (5.14 - 12.50 umol/L)

The ODX Range: 175 - 300 mg/dL (5.15 – 8.82 umol/L)  

Low levels of fibrinogen may be associated with genetic factors, liver disease, malnutrition, advanced cancer, disseminated intravascular coagulation, blood transfusions, and prolonged prothrombin time. Medications that reduce fibrinogen include anabolic steroids, androgens, phenobarbital, valproic acid, streptokinase, asparaginase, and tissue plasminogen activators. A level below 100 mg/dL may compromise hemostasis (Pagana 2022). Low fibrinogen is also associated with recurrent miscarriage (Mohamed 2021).

High levels of fibrinogen may be seen in active inflammatory bowel disease (Chen 2021), systemic inflammation (Pahwa 2022), pollution exposure (Croft 2018), acute inflammation, tissue necrosis, coronary heart disease, peripheral artery disease, stroke, trauma, severe illness, acute infection, rheumatoid arthritis, cigarette smoking, significant stress, vigorous exercise, and estrogen and oral contraceptive use (Pagana 2022).

Elevated fibrinogen may also be associated with compromised blood-brain barrier, neurological disorders (Petersen 2018), non-alcoholic fatty liver (Yu 2018), and vascular and nonvascular mortality, especially cancer (Danesh 2005).

Overview

Fibrinogen, also called “Factor 1,” is produced in the liver and functions as an acute-phase reactant and clotting factor. Levels increase sharply in association with tissue inflammation and necrosis. Although traditionally used to identify bleeding disorders, elevated levels are associated with heart disease, myocardial infarction, stroke, and peripheral artery disease (Pagana 2022). Fibrinogen is most commonly measured as fibrinogen activity, which reflects the amount of active fibrinogen in a blood clot. If fibrinogen activity is low or abnormal, then fibrinogen antigen testing may be indicated (Testing.com).

Elevated fibrinogen is also associated with infection and immunological derangement and is considered a biomarker of systemic inflammation. Fibrinogen itself may promote persistent low-grade inflammation (Luyendyk 2019). A review of NHANES data revealed that elevated fibrinogen was associated with elevated CRP and GGT and was considered a direct link between having cardiovascular disease and dying from it (Pieters 2021).

Further evaluation of the NHANES Linked Mortality Cohort found that higher fibrinogen was associated with increased mortality. Individuals with the lowest baseline fibrinogen of 118-320 mg/dL (3.5-9.4 umol/L) had the lowest cardiovascular and overall mortality compared to those with a fibrinogen greater than 320 mg/dL (9.4 umol/L). Mortality risk increased as fibrinogen increased, with the highest risk associated with a fibrinogen of 420-993 mg/dL (12.35-29.19 umol/L). Those with more elevated fibrinogen also tended to have higher CRP, blood pressure, total and LDL cholesterol, and triglycerides; be diabetic or hypertensive; have poorer diet quality; smoke; and either drank heavily or not at all Fibrinogen quartiles in the study were as follows: lowest, 118 to less than 321 mg/dL; second, 321 to less than 370 mg/dL; third, 370 to less than 420 mg/dL; and highest, 420–993 mg/dL. Researchers note that diet quality modifies the association between CRP and CVD mortality (Liu 2020).

In individuals with established coronary artery disease, fibrinogen levels of 280 mg/dL (8.23 umol/L) or above were independently associated with a significantly increased risk of major adverse cardiovascular events (MACEs) in the two years following nonemergent percutaneous coronary intervention (Ang 2017). An earlier meta-analysis of 18 long-term prospective studies had demonstrated that a higher mean fibrinogen of 350 versus 450 mg/dL (10.3 versus 7.4 umol/L) was significantly associated with increased CHD (Danesh 1998).

A 2005 meta-analysis of 31 prospective studies confirmed increased cardiovascular risk as fibrinogen levels increased. The analysis included 154,211 subjects with baseline fibrinogen below 562 mg/dL (16.52 umol/L) and no known coronary artery disease or stroke history. Results revealed that for every 100 mg/dL (2.94 umol/L) increase in fibrinogen above baseline, the risk of coronary heart disease and stroke increased at least 1.8-fold (Danesh 2005).

Air pollution is associated with increased fibrinogen, including in those with cardiovascular disease. In one study of 135 myocardial infarction patients, fibrinogen levels increased by 3.1% for each 5.6 ug/m3 rise in particulate matter pollution. However, that increase was blunted and reduced to 0.9% in subjects with a higher percentage of serum omega-3 fatty acids from fish oil (over 5.12%) but not from omega-3 alpha-linolenic acid, a precursor to long-chain omega-3s EPA and DHA (Croft 2018).

Fibrinogen and its conversion to fibrin may also trigger inflammation and scarring in the brain, activate microglia and macrophages, and promote cognitive decline, especially in a compromised blood-brain barrier. Research suggests it may play a role in neurological disorders such as Alzheimer’s, multiple sclerosis, brain trauma, and neurological injury in susceptible individuals (Petersen 2018).

Fibrinogen increases with the severity of inflammation and disease in IBD as well. A fibrinogen above 3.22 mg/dL (9.47 mol/L) in ulcerative colitis or above 3.87 mg/dL (11.38 mol/L) in Crohn’s may indicate active disease (Chen 2021).

Low fibrinogen can also have adverse consequences, including disrupted hemostasis and miscarriage. In one case-control study of 100 women, 50 with recurrent miscarriages, mean fibrinogen levels were significantly lower in cases than in controls, i.e., 149.9 mg/dL (4.4 umol/L) versus 284.3 mg/dL (8.36 umol/L), respectively, Approximately 32% of those with a history of miscarriage experienced three miscarriages, while 68% experienced more than three miscarriages (Mohamed 2021).

References

Ang, Lawrence et al. “Elevated Baseline Serum Fibrinogen: Effect on 2-Year Major Adverse Cardiovascular Events Following Percutaneous Coronary Intervention.” Journal of the American Heart Association vol. 6,11 e006580. 18 Nov. 2017, doi:10.1161/JAHA.117.006580

Chen, Xiao-Fu et al. “Predictive value of fibrinogen in identifying inflammatory bowel disease in active stage.” BMC gastroenterology vol. 21,1 472. 15 Dec. 2021, doi:10.1186/s12876-021-02040-9

Croft, Daniel et al. “Do elevated blood levels of omega-3 fatty acids modify effects of particulate air pollutants on fibrinogen?.” Air quality, atmosphere, & health vol. 11,7 (2018): 791-799. doi:10.1007/s11869-018-0586-0

Danesh, J et al. “Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: meta-analyses of prospective studies.” JAMA vol. 279,18 (1998): 1477-82. doi:10.1001/jama.279.18.1477

Danesh J, Lewington S, Thompson SG, et al. Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality: an individual participant meta-analysis. JAMA. 2005 Oct 12;294(14):1799-809.

Davalos, Dimitrios, and Katerina Akassoglou. “Fibrinogen as a key regulator of inflammation in disease.” Seminars in immunopathology vol. 34,1 (2012): 43-62. doi:10.1007/s00281-011-0290-8

Liu, Junxiu et al. “Associations of C-reactive protein and fibrinogen with mortality from all-causes, cardiovascular disease and cancer among U.S. adults.” Preventive medicine vol. 139 (2020): 106044. doi:10.1016/j.ypmed.2020.106044

Luyendyk, James P et al. “The multifaceted role of fibrinogen in tissue injury and inflammation.” Blood vol. 133,6 (2019): 511-520. doi:10.1182/blood-2018-07-818211

Mohamed, Eman Ibrahim, Maye M. Merghani, and Nihad Elsadig Babiker. "Estimation of Fibrinogen level among Sudanese women with recurrent miscarriage." Journal of Drug Delivery and Therapeutics 11.6-S (2021): 140-144.

Pagana, Kathleen Deska, et al. Mosby's Diagnostic and Laboratory Test Reference. 16th ed., Mosby, 2022. 

Pahwa, Roma, et al. “Chronic Inflammation.” StatPearls, StatPearls Publishing, 8 August 2022.

Petersen, Mark A et al. “Fibrinogen in neurological diseases: mechanisms, imaging and therapeutics.” Nature reviews. Neuroscience vol. 19,5 (2018): 283-301. doi:10.1038/nrn.2018.13    

Pieters, Marlien et al. “Biomarker association with cardiovascular disease and mortality - The role of fibrinogen. A report from the NHANES study.” Thrombosis research vol. 198 (2021): 182-189. doi:10.1016/j.thromres.2020.12.009

Testing.com. Fibrinogen Test. https://www.testing.com/tests/fibrinogn/.

Yu, En et al. “Inflammatory Biomarkers and Risk of Atherosclerotic Cardiovascular Disease.” Open medicine (Warsaw, Poland) vol. 13 208-213. 24 May. 2018, doi:10.1515/med-2018-0032