American Journal of Respiratory and Critical Care Medicine

We tested whether increased concentrations of the acute-phase reactant fibrinogen correlate with pulmonary function and rate of chronic obstructive pulmonary disease (COPD) hospitalization. We measured plasma fibrinogen and forced expiratory volume in 1 s (FEV1), and assessed prospectively COPD hospitalizations in 8,955 adults from the Danish general population. Smokers with plasma fibrinogen in the upper and middle tertile ( > 3.3 and 2.7–3.3 g/L) had 7% (95% confidence interval [CI]: 5–8%) and 2% (0–3%) lower percentage predicted FEV1 than smokers with fibrinogen in the lower tertile ( < 2.7 g/L). The equivalent decreases in nonsmokers were 6% (4–7%) and 0% ( − 1–2%), respectively. Individuals with plasma fibrinogen in the upper and middle tertile had COPD hospitalization rates of 93 and 60 compared with 52 per 10,000 person-years in individuals with fibrinogen in the lower tertile (log-rank: p < 0.001 and p = 0.31). After adjusting for age, body mass index, sex, pack-years, and recent respiratory infections, relative risks for COPD hospitalization were 1.7 (95% CI: 1.1–2.6) and 1.4 (0.9–2.1) in individuals with fibrinogen in the upper and middle versus lower tertile. In conclusion, elevated plasma fibrinogen was associated with reduced FEV1 and increased risk of COPD. This could not be explained by smoking alone.

Keywords: fibrinogen; pulmonary function; epidemiology; airway inflammation; COPD

Up to 90% of chronic obstructive pulmonary disease (COPD) can be accounted for by cigarette smoking (1). Among smokers, the induction of lung inflammation together with oxidative stress is thought to tip the balance of proteolytic enzymes and their inhibitors toward increased breakdown of elastic tissue (1-3). Over time, this may lead to reduced lung function and COPD (1-3). A potential central player in this chronic inflammatory process is interleukin (IL)-6, which is capable of modulating number and/or activity of important inflammatory cells (4-6) and proteases (7-9). IL-6 is synthesized by airway epithelium, macrophages, and several other cells at sites of inflammation in response to environmental stress (6, 10, 11), that is, smoking or other factors. Even when produced chronically in lesser amounts, IL-6 has major systemic effect on the acute-phase response (12). It is therefore possible that acute-phase reactants may be used as markers of airway inflammation, rather than solely as a general marker of the inflammatory stimulus of cigarette smoke inhalation (13).

Fibrinogen, an acute phase reactant and a blood clotting factor, is synthesized by hepatocytes and released in large amounts into the circulation primarily in response to IL-6 stimulation (12, 14). It is therefore possible that fibrinogen could be used as a noninvasive measurement of ongoing airway inflammation and lung tissue destruction.

We used a sample of 8,955 adults from the Danish general population, the Copenhagen City Heart Study, to test whether increased fibrinogen concentrations correlate with pulmonary function and COPD hospitalization rates. These analyses were done in smokers and nonsmokers separately and/or after adjustment for smoking, to exclude the possibility that the associations observed could be due to smoking alone.

All subjects included in this study participated in the third examination of the Copenhagen City Heart Study, a prospective epidemiological study initiated in 1976–1978 (15-17). The participants, aged 20 to 93 yr, were selected at random after age stratification in 10-yr age groups from residents of Copenhagen. Of 10,049 participants, 8,955 individuals had plasma fibrinogen measured. Less than 1% were nonwhite and 99% were of Danish descent. All subjects gave informed consent. The study was approved by the ethics committee for the City of Copenhagen and Frederiksberg (# 100.2039/91).

All subjects indicated whether they were never smokers, ex-smokers, or current smokers; because fibrinogen is increased in current smokers only (13), in this study “smokers” are current smokers and “nonsmokers” are never smokers and ex-smokers combined. An estimate of lifetime tobacco exposure (in pack-years) was calculated as daily tobacco consumption (g) times duration of smoking (yr) divided by 20 (g/pack). We also asked participants for information on inhalation, long-term occupational exposure to dust or welding fumes, and recent respiratory infection (“Have you within the 4 wk prior to this examination had a cold, bronchitis, or lung infection?”). Chronic bronchitis was defined as bringing up phlegm at least 3 mo continuously every year. COPD hospitalizations were assessed via the Danish National Hospital Discharge Register using World Health Organization (WHO) International Classification of Diseases (ICD), 10th edition, #J40-J44. Plasma fibrinogen was measured by a standard colorimetric assay (Boehringer Mannheim, Mannheim, Germany).

Forced expiratory volume in 1 s (FEV1) was measured with an electronic spirometer (model N403, Monaghan, Littleton, CO) in 1976– 1978 and 1981–1983 and with a dry wedge spirometer (Vitalograph, Maidenhead, UK) in 1991–1994. The highest of three FEV1 values was used in the analyses as absolute value and as percentage of predicted value using internally derived reference values based on a subsample of healthy never smokers (18). Annual change in FEV1 (in ml/yr) was calculated as FEV1 (in ml) obtained at the latest measurement minus the FEV1 value obtained at the first measurement, times 365.25 divided by the number of days between the two measurements (in yr−1).

Statistical analyses were performed with SPSS (Chicago, IL). The smoothed relation between fibrinogen and FEV1 was investigated using local linear regression as described (19).

Fibrinogen was adjusted for variation due to age and body mass index (BMI) by analysis of variance (ANOVA); in our sample, age and BMI were the most important predictors of fibrinogen levels and together explained 17% of the variation in fibrinogen. If the analyses excluded participants previously hospitalized for ischemic heart disease (ICD, 10th ed.: #I20–I25; n = 959), the results were similar.

Cumulative incidence of COPD hospitalizations from 1991 to 1997 was plotted using Kaplan–Meier curves, with the log-rank test as a measure of significance between tertiles of fibrinogen. Cox regression analysis allowing for age, body mass index, sex, pack-years, and recent respiratory infection examined the role of fibrinogen tertiles on time to first hospitalization from COPD, using hazard ratio's (relative risks) with 95% confidence intervals (CIs).

In both smokers and nonsmokers, there was an inverse relation between FEV1 and plasma fibrinogen (Figure 1). Smokers had higher plasma fibrinogen concentrations than nonsmokers (Table 1). Several other characteristics also differed by smoking status (Table 1).

Table 1.  CHARACTERISTICS OF PARTICIPANTS*

NonsmokersSmokers
Women/men2,753/1,9552,341/2,155
Age62 (25–83)58 (27–80)
Body mass index26 (19–36)25 (18–35)
Plasma fibrinogen2.9 (1.8–4.7)3.1 (1.9–5.1)
FEV1 % predicted100 (50–134)91 (41–125)
Chronic bronchitis349 (7%)906 (20%)
Occupational dust720 (15%)999 (22%)
Pack-years0 (0–68)28 (2–84)
Inhalation3595 (81%)

*Values are number of individuals (percent of all) or medians (2.5 percentile–97.5 percentile). Nonsmokers = ex-smokers and never smokers. FEV1 = forced expiratory volume in 1 s. Chronic bronchitis = bringing up phlegm at least 3 mo continuously every year. p < 0.001 for all comparisons between smokers and nonsmokers by Mann– Whitney U test or χ2 test.

Smokers with plasma fibrinogen in the upper and middle tertile (> 3.3 and 2.7–3.3 g/L) had 7% (95% CI: 5–8%) and 2% (0–3%) lower percentage predicted FEV1 than smokers with fibrinogen in the lower tertile (< 2.7 g/L) (Figure 2). Similar results were obtained when smokers were stratified in those smoking > 20 g tobacco/d (Δ = 6% [4–8%] and 2% [−1–4%]) and those smoking < 20 g tobacco/d (Δ = 9% [7– 10%] and 2% [1–4%]).

Nonsmokers with plasma fibrinogen in the upper tertile had 6% (4–7%) lower percentage predicted FEV1 than nonsmokers with fibrinogen in the lower tertile (Figure 2), whereas FEV1 % predicted did not differ between nonsmokers with fibrinogen in the middle and lower tertile (Δ = 0% [−1–2%]). In accordance with this difference between smokers and nonsmokers, smoking status interacted with fibrinogen on FEV1 % predicted (analysis of covariance: p < 0.001).

Of the 8,955 individuals examined, 2,373 (26%) had a respiratory infection within the last 4 wk of spirometry. Individuals with recent respiratory infection and plasma fibrinogen in the upper and middle tertile had 7% (5–10%) and 2% (0–4%) lower percentage predicted FEV1 than individuals with recent respiratory infection and fibrinogen in the lower tertile. Individuals without recent respiratory infection and plasma fibrinogen in the upper and middle tertile had 7% (6–9%) and 1% (0–3%) lower percentage predicted FEV1 than individuals without recent respiratory infection and fibrinogen in the lower tertile.

On step-up analysis of covariance, plasma fibrinogen was a weak independent predictor of FEV1 in both smokers and nonsmokers (Table 2). The middle and upper tertile of plasma fibrinogen compared with the lower tertile was associated with lower FEV1 of 59 and 169 ml in smokers and of 25 and 121 ml in nonsmokers, respectively.

Table 2.  INDEPENDENT PREDICTORS OF FORCED EXPIRATORY VOLUME IN 1 s (FEV1) IN SMOKERS AND NONSMOKERS BY STEP-UP ANALYSIS OF COVARIANCE*

FEV1 in SmokersFEV1 in Nonsmokers
RankIndependent VariableΔR2 FEV1 (95% CI)RankIndependent VariableΔR2 FEV1 * (95% CI)
1.Age, yr0.407−38 (−40 to −37)1.Age, yr0.493−32 (−34 to −31)
2.Height, cm0.20837 (34 to 40)2.Height, cm0.18435 (33 to 38)
3.Chronic bronchitis0.016−237 (−280 to −195)3.Women0.016−514 (−560 to −468)
4.Women0.015−430 (−479 to −382)4.Pack-years0.018−6 (−7 to −5)
5.Plasma fibrinogen0.0075.Chronic bronchitis0.007−273 (−334 to −211)
 < 2.7 g/L
 2.7–3.3 g/L−59 (−103 to −15)6.Plasma fibrinogen0.003
 > 3.3 g/L−169 (−214 to −124) < 2.7 g/L
 2.7–3.3 g/L−25 (−64 to 14)
6.Inhalation0.005−191 (−237 to −145) > 3.3 g/L−121 (−164 to −79)
7.Occupational dust0.004−145 (−188 to −103)7.Occupational dust0.002−105 (−150 to −60)
8.Tobacco consumption, g/d0.002−5 (−6 to −3)

Definition of abbreviation: ΔR2 = change in R2 produced by adding the independent covariate to a model already containing all previously ranked independent predictors.

*To approach normal distribution, FEV1 was square-root transformed before analysis, but regression coefficients are shown for untransformed values. p < 0.001 for all covariates included in the models, analyzed using the F statistic.

Change in FEV1 in ml (regression coefficient) and 95% CI. When the model in smokers included pack-years instead of tobacco consumption, the results for plasma fibrinogen were similar.

Smokers with plasma fibrinogen in the upper tertile had an excess annual decline in FEV1 of 6 ml (3–9 ml) compared with smokers with fibrinogen in the lower tertile. Annual decline in FEV1 did not differ between smokers with fibrinogen in the middle and lower tertile (Δ = −1 ml [−4–2 ml]). Nonsmokers with plasma fibrinogen in the upper tertile had an excess annual decline in FEV1 of 4 ml (2–7 ml) compared with nonsmokers with fibrinogen in the lower tertile. Annual decline in FEV1 did not differ between nonsmokers with fibrinogen in the middle and lower tertile (Δ = −1 ml [−4–2 ml]).

Individuals with plasma fibrinogen in the upper and middle tertile had COPD hospitalization rates of 93 and 60 per 10,000 person-years compared with 52 per 10,000 person-years in individuals with fibrinogen in the lower tertile (Figure 3). After adjusting for age, body mass index, pack-years, sex, and recent respiratory infections, relative risks for COPD hospitalization were 1.7 (95% CI: 1.1–2.6) and 1.4 (0.9–2.1) in individuals with fibrinogen in the upper and middle versus lower tertile, respectively.

Our results demonstrate that increased levels of plasma fibrinogen are associated with reduced lung function and increased risk of COPD, and that these associations are independent of smoking status. The associations were also independent of other potential confounders such as age, chronic bronchitis, sex, occupational dust, and recent respiratory infections.

In consistency with our findings, elevated plasma fibrinogen levels have been observed in some inflammatory lung diseases (20-23). Moreover, in a recent study, serum levels of α1-antitrypsin, another acute phase reactant, was inversely related with single-breath transfer factor for carbon monooxide (24). Because IL-6 is the primary cytokine regulating the expression of fibrinogen and α1-antitrypsin (12, 14, 25), our findings and the above study may suggest a role for IL-6-type cytokines in the pathological processes, which leads to reduced lung function.

Because the upper tertile of plasma fibrinogen (versus lower and middle tertiles combined) had 45% sensitivity and 68% specificity in predicting COPD hospitalizations, and a positive predictive value and a negative predictive value of 4% and 98%, the potential clinical utility of fibrinogen in predicting COPD appear limited. Furthermore, as we studied a sample of the adult Danish white general population, generalizability of our data to other populations or races may potentially be constrained. Even though our prospective data seem to suggest that fibrinogen is an independent predictor of COPD hospitalizations, it should be pointed out that causality of the association between reduced FEV1 and increased plasma fibrinogen cannot be verified using cross-sectional data. In this study, bias caused by investigators' knowledge of disease or risk-factor status seems unlikely, because we measured plasma fibrinogen without prior knowledge of disease status or lung function test results.

In conclusion, elevated plasma fibrinogen was associated with reduced FEV1 and increased risk of COPD. This could not be explained by smoking alone.

This study was supported by the Danish Lung Association, the Danish Heart Foundation, the Danish Medical Research Council, Løvens Kemiske Fabrik's Fond, and Beckett-Fonden.

1. Piquette CA, Rennard SI, Snider GL. Chronic bronchitis and emphysema. In: Murray JF, Nadel JA, editors. Textbook of Respiratory Medicine, 3rd ed. Philadelphia: WB Saunders; 2000. p. 1187–1245.
2. Barnes PJ. Chronic obstructive pulmonary disease. N Engl J Med 2000;343;269–280.
3. MacNee WOxidants/antioxidants and COPD. Chest1172000303s317s
4. Chomarat P, Banchereau J, Davoust J, Palucka AKIL-6 switches the differentiation of monocytes from dendritic cells to macrophages. Nat Immunol12000510514
5. Suwa T, Hogg JC, Klut ME, Hards J, Eeden SFInterleukin-6 changes deformability of neutrophils and induces their sequestration in the lung. Am J Respir Crit Care Med1632001970976
6. Park CS, Chung SW, Ki SY, Lim GI, Uh ST, Kim YH, Choi DI, Pa JS, Lee DW, Kitaichi MIncreased levels of interleukin-6 are associated with lymphocytosis in bronchoalveolar lavage fluids of idiopathic nonspecific interstitial pneumonia. Am J Respir Crit Care Med162200011621168
7. Johnson JL, Moore EE, Tamura DY, Zallen G, Biffl WL, Silliman CCInterleukin-6 augments neutrophil cytotoxic potential via selective enhancement of elastase release. J Surg Res7619989194
8. Gerber A, Wille A, Welte T, Ansorge S, Buhling FInterleukin-6 and transforming growth factor-beta1 control gene expression of cathepsins b and 1 in human lung epithelial cells. J Interferon Cytokine Res2120011119
9. Solis-Herruzo JA, Rippe RA, Schrum LW, Torre PDL, Garcia I, Jeffrey JJ, Muños-Yagüe T, Brenner DAInterleukin-6 increases rat metalloproteinase-13 gene expression through stimulation of activator protein 1 transcription factor in cultured fibroblasts. J Biol Chem27419993091930926
10. Martin LD, Rochelle LG, Fischer BM, Krunkovsky TM, Adler KBAirway epithelium as an effector of inflammation: molecular regulation of secondary mediators. Eur Respir J10199721392146
11. Vanden Berghe W, Vermeulen L, Wilde GD, Bossher KD, Boone E, Haegeman G. Signal transduction by tumor necrosis factor and gene regulation of the inflammatory cytokine interleukin-6. Biochem Pharmacol 2000;60:1185–1195.
12. Gabay C, Kushner IAcute-phase proteins and other systemic responses to inflammation. N Engl J Med3401999448454
13. Eliasson M. The epidemiology of fibrinogen and fibrinolysis. Determinants of plasma fibrinogen levels and fibrinolytic variables in the population of northern Sweden. Umeå: Umeå University Medical Dissertations; 1995. p. 42–54.
14. Castell JV, Gómez-Lechón MJ, David M, Andus T, Geiger T, Trullenque R, Fabra R, Heinrich PCInterleukin-6 is the major regulator of acute phase protein synthesis in adult human hepatocytes. FEBS Lett2421989237239
15. Appleyard M, Hansen A, Schnohr P, Jensen G, Nyboe J. The Copenhagen City Heart Study: Østerbroundersøgelsen: a book of tables with data from the first examination (1976–78) and a five year follow-up (1981–1983). Scand J Soc Med 1989;170(Suppl 41):1–160.
16. Tybjærg-Hansen A, Steffensen R, Meinertz H, Schnohr P, Nordestgaard BGAssociation of mutations in the apolipoprotein b gene with hypercholesterolemia and risk of ischemic heart disease. N Engl J Med338199815771584
17. Dahl M, Tybjærg-Hansen A, Lange P, Nordestgaard BGΔF508 heterozygosity in cystic fibrosis and susceptibility to asthma. Lancet351199819111913
18. Lange P, Nyboe J, Jensen G, Schnohr P, Appleyard MVentilatory function impairment and risk of cardiovascular death and fatal or non- fatal myocardial infarction. Eur Respir J4199110801087
19. SPSS Base 8.0 for Windows User's Guide and SPSS Interactive Graphics 8.0. Chicago, IL: SPSS Inc.; 1998.
20. Jousilahti P, Salomaa V, Rasi V, Vahtera ESymptoms of chronic bronchitis, haemostatic factors, and coronary heart disease risk. Atherosclerosis1421999403407
21. Haider AW, Larson MG, O'Donnel CJ, Evans JC, Wilson PWF, Levy DThe association of chronic cough with the risk of myocardial infarction: the framingham heart study. Am J Med1061999279284
22. Enright P, Ward BJ, Tracy RP, Lasser ECAsthma and its association with cardiovascular disease in the elderly. J Asthma3319964553
23. Alessandri C, Basili S, Violi F, Ferroni P, Gazzaniga PP, Cordova CHypercoagulability state in patients with chronic obstructive pulmonary disease. Thromb Haemost721994343346
24. Welle I, Bakke PS, Eide GE, Gulsvik A. Relationship between two biological inflammatory markers and single-breath transfer factor for carbon monoxide (TLCO) in a general population sample (abstract). Eur Respir J 1999;14(Suppl 30):S133.
25. Morgan K, Kalsheker NARegulation of the proteinase inhibitor (SERPIN) gene alpha1-antitrypsin: a paradigm for other SERPINs. Int J Biochem Cell Biol29199715011511
Correspondence and requests for reprints should be addressed to Dr. Børge G. Nordestgaard, Department of Clinical Biochemistry 54M1, Herlev University Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark. E-mail:

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