Skip to main content
NCBI home page
PLOS One logoLink to PLOS One
. 2021 Nov 8;16(11):e0259498. doi: 10.1371/journal.pone.0259498

Are elevated plasma fibrinogen associated with lung function? An 8-year follow-up of the ELSA study

Camila Thais Adam 1, Ione Jayce Ceola Schneider 1,*, Danielle Soares Rocha Vieira 1, Tauana Prestes Schmidt 1, Fernando Cesar Wehrmeister 2, Cesar de Oliveira 3
Editor: Emiliano Giardina4
PMCID: PMC8575306  PMID: 34748602

Abstract

Background

Fibrinogen is an important biomarker of inflammation, but findings from longitudinal studies that correlated fibrinogen with lung function in older adults are inconsistent.

Aim

To investigate the relationship between fibrinogen plasma levels and lung function impairment later in life.

Methods

Longitudinal analysis of 2,150 participants of the English Longitudinal Study of Ageing (ELSA) aged 50 years and older. Associations between changes in plasma fibrinogen between waves 2 (2004–05) and 4 (2008–09) and lung function in wave 6 (2012–13) were performed using multiple linear regression adjusted by potential confounders.

Results

Regarding the fibrinogen profile, 18.5% of the participants presented higher levels in both waves. In the adjusted models, the maintenance of high fibrinogen levels was associated with a significant reduction of lung function only for men. FEV1 showed a reduction of 0.17L, FVC of 0.22L, and the percentages predicted were 5.16% for FEV1 and 6.21% for FVC compared to those that maintained normal levels of fibrinogen.

Discussion

To the best of our knowledge, this was the first study investigating the relationship between changes in fibrinogen levels over a long follow-up period and lung function in older adults without pre-existing chronic diseases. ELSA has information on critical demographic and clinical parameters, which allowed to adjust for potential confounding factors.

Conclusion

It was found that the persistence of high levels of plasma fibrinogen in older English men, but not women, is associated with lung function decline. Therefore, plasma fibrinogen showed to be an important biomarker of pulmonary dysfunction in this population.

1. Introduction

Fibrinogen is a soluble protein involved in the blood clotting mechanism [1], and it is linked to pathological processes of lung diseases [2,3]. Inflammatory stimuli induce the lung’s alveolar epithelial cells to synthesize and secrete fibrinogen, demonstrating the importance of this biomarker in the inflammatory process [4,5]. In healthy lungs, low levels of fibrinogen are expected [6]. Experimental studies in animal models suggest that fibrinogen may be an essential effector molecule in airway disease [7,8]. Fibrinogen in the lungs can inactivate pulmonary surfactant, which causes increased surface-tension relationships, promote the expression of molecules that induces airway fibrosis, and activate plasminogen activator inhibitor type-1, leading to excess fibrin deposition in the airways and airway narrowing [9].

Fibrinogen plasma levels have been associated with reduced lung function in cross-sectional [10,11] and few longitudinal [12–14] analyses. Longitudinal studies were performed in the younger population [12,14] or individuals with pre-existing underlying diseases [13]. Other studies report that people with respiratory diseases had significantly higher levels of fibrinogen compared to controls [15–22]. However, the relationship between lung function and changes in systemic fibrinogen levels over time in community-dwelling older adults is not clear. Therefore, this study aimed to investigate the relationship between fibrinogen plasma levels and lung function changes later in life. We used eight years of data from a nationally representative sample of older English men and women. We hypothesized that there is a relationship between the change in plasma fibrinogen levels and lung function reduction overtime in an aging cohort.

2. Methods

2.1 Study population

Longitudinal study using data collected from the English Longitudinal Study of Ageing (ELSA), an ongoing panel study of community-dwelling men and women living in England aged 50 years and older that commenced in 2002. The ELSA sample was drawn from participants that had previously participated in the Health Survey for England. After baseline, follow-up interviews occur biannually and health examinations every four years. A detailed description of the study can be found elsewhere [23]. The National Research Ethics Service (London Multicentre Research Ethics Committee, MREC/01/2/91) approved the ELSA study. All participants gave written informed consent. Participants who had fibrinogen data from waves 2 and 4, and lung function tests at wave 6 were included in the study. The data collection process and methodology are fully described elsewhere [23]. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

2.2 Variables

2.2.1 Fibrinogen

Blood samples were taken from willing ELSA core members, except those who had clotting or bleeding disorders, had ever had fits or convulsions, were not willing to give their consent in writing, or were currently on anticoagulant drugs. Respondents over 80 years, those known to be diabetic and on treatment, those with a clotting or bleeding disorder or on anticoagulant drugs, those who had ever had fits, those who seemed frail, or respondents whose health was a cause for concern for the nurse were not asked to fast. Fibrinogen analysis was carried out by the Department of Haematology at the Royal Victoria Infirmary, The Newcastle Upon Tyne NHS Foundation Trust. The coagulation analyser MDA 180 (Organon Teknika, Durham, USA) was used with a modification of the Clauss thrombin clotting method by one citrate blue tube [23]. The measurement of fibrinogen was done in the ACL TOP CTS analyser. The Fibrinogen assay on the IL TOP is a clotting assay. Analyser prepares a 1 in 10 dilution of plasma in factor diluent, by aspirating 17μl of plasma and mixing it with 153μl of factor diluent. 100μl of the diluted plasma was dispensed into a reaction cuvette and incubated for 60 seconds at 37°C. 50μl of Fibrinogen-C XL reagent was added, and the reaction monitored at 405nm for up to 120 seconds. The analyser monitors the change in light transmission caused by the conversion of soluble fibrinogen in plasma to cross-linked insoluble fibrin, and the clotting time threshold is determined to be 37% of the total change. The clotting time is directly related to the concentration of fibrinogen in the plasma. This time is converted to concentration in g/L by the automatic use of a calibration curve. For the analyses, we created a variable called fibrinogen profile which considered plasma fibrinogen levels between waves 2 and 4 (normal levels in waves 2 and 4, normal in waves 2 and altered in wave 4, altered in wave 2 and normal in waves 4; altered in waves 2 and 4). Upper tertile values of fibrinogen were considered altered (≥3.8 g/L for wave 2 and ≥3.9 g/L for wave 4).

2.2.2 Lung function

A spirometer (NDD Easy On-PC) was used to evaluate forced expiratory volume in the first second (FEV1) and forced vital capacity (FVC). At least three acceptable measurements were obtained, and the largest FEV1 and FVC values were considered. Respondents were excluded if they had had abdominal or chest surgery in the preceding three weeks, had been admitted to hospital with a heart complaint in the previous six weeks, had had eye surgery in the prior four weeks, had a tracheotomy, or were pregnant. Further, the tests were not done if the ambient temperature was less than 15°C or more than 35°C, as this affects the accuracy of the readings. FEV1 and FVC were expressed in absolute values (in liters), and percentage of predicted [24] were used for the analyses. All the lung function values refer to wave 6.

2.2.3 Covariates

Sex (female, male), household wealth (in quintiles), physical activity level (sedentary, mild, moderate, high), smoking status (non-smoker, former smoker, current smoker), physical activity (sedentary, mild, moderate, high), presence of one or more chronic diseases (osteoarthritis, cancer, osteoporosis, dementia, depressive symptoms, Alzheimer’s and Parkinson’s diseases), presence of one or more cardiocirculatory diseases (high blood pressure, angina, heart attack, congestive heart failure, heart murmur, and abnormal heart rhythm) and the presence of lung diseases (chronic obstructive pulmonary disease and asthma).

2.3 Statistical analysis

The variables of the study were plasma fibrinogen levels between waves 2 and 4 (normal levels in waves 2 and 4, normal in wave 2 and changed in wave 4, changed in wave 2 and normal in wave 4; changed in waves 2 and 4). The continuous variables were age (years), body mass index (kg/m²), height (m), FEV1 (litres and percentage of predicted) and FVC (litters and percentage of predicted) [23].

Categorical variables were analysed with frequencies and their respective 95% confidence intervals (CI). Continuous variables were described as mean and standard deviation. Associations between fibrinogen profile and FEV1 (outcome) were performed using multiple linear regression adjusted by age, wealth, physical exercise, current smoking status, chronic diseases, lung diseases, body mass index, and height. Crude and adjusted regression coefficients and 95%CI were estimated. Cardiocirculatory diseases were not included in the adjusted model because of the collinearity with the fibrinogen levels. Analyses were sex-stratified. The following post-estimation tests were performed: Shapiro-Wilk and Shapiro-Francia test for normality and Breuschof-Pagan and Cook-Weisberg test for heteroskedasticity. We also performed the command margins to calculate the predictions of the marginal effects of the variable fibrinogen. This information is presented in plots. These procedures were repeated with absolute values of FVC and percentage of predicted FEV1 and FVC. Analyses were performed in Stata SE version 14.0.

3. Results

The analytical sample included 2,150 participants from the ELSA cohort who had fibrinogen data in waves 2 and 4 and lung function data in wave 6. Fig 1 presents the flowchart with the selection process between waves 2 and 6. The follow-up period was 8 years.

Fig 1. Flowchart describing the sample selection from waves 2 (2004/5), 4 (2008/9) and 6 (2012/13), The English Longitudinal Study of Ageing, England, 2004 to 2013.

Fig 1

Open in a new tab

Table 1 shows sociodemographic and health variables frequency distribution (all sample and sex-stratified). The majority of participants were female (55.9%), belonging to the lowest wealth quintile (24.0%), with moderate physical activity level (51.9%), classified as ex-smokers (54.2%), with chronic diseases (56.6%) and no pulmonary diseases (80.2%). Regarding the fibrinogen profile, 55.4% of the participants remained within the normal levels in waves 2 and 4, and 18.5% showed higher levels in both waves. The main differences found between men and women were related to smoking, physical activity, and the presence of chronic diseases. Women had lower FEV1 and FVC values than men. The FEV1 and FVC percentage of predicted values were similar for men and women.

Table 1. Descriptive analyses of participants from ELSA who presented complete data for fibrinogen in wave 2 (2004–05) and 4 (2008–09) and lung function in wave 6 (2012–13), The English Longitudinal Study of Ageing, England, 2004 to 2013.

Variables General Male Female
n % (95%CI) n % (95%CI) n % (95%CI)
Sex
Male 948 44.1 (42.0;46.2)
Female 1,202 55.9 (53.8;58.0)
Wealth
Lowest quintile (poorest) 264 12.5 (11.1;13.9) 104 11.1 (9.3;13.3) 160 13,5 (11.6;15.5)
2nd quintile 343 16.2 (14.7;17.8) 136 14.6 (12.5;17.0) 207 17.4 (15.4;19.7)
3rd quintile 497 23.4 (21.7;25.3) 218 23.4 (20.8;26.2) 279 23.5 (21.2;26.0)
4th quintile 507 23.9 (22.1;25.8) 239 25.6 (22.9;28.5) 268 22.6 (20.3;25.0)
Highest quintile (richest) 510 24.0 (22.3;25.9) 236 25.3 (22.6;28.2) 274 23.1 (20.8;25.5)
Smoking status
Non-smoker 795 37.0 (34.9;39.5) 265 27.9 (25.2;30.9) 530 44.1 (41.3;46.9)
Former smoker 1,166 54.2 (52.1;56.3) 595 62.9 (59.7;65.9) 570 47.4 (44.6;50.2)
Current smoker 189 8.8 (7.7;10.1) 87 9.2 (7.5;11.2) 102 8.5 (7.3;10.2)
Physical exercise
Sedentary 70 3.3 (2.6;4.1) 28 3.0 (2.0;4.2) 42 3.5 (2.6;4.7)
Low 296 13.8 (12.4;15.3) 93 9.8 (8.1;11.9) 203 16.9 (14.9;19.1)
Moderate 1,116 51.9 (49.8;54.0) 484 51.1 (47.9;54.2) 632 52.6 (49.7;55.4)
High 668 31.1 (29.1;33.1) 343 36.2 (33.2;39.3) 325 27.0 (24.6;29.6)
Chronic diseases
No 930 43.4 (41.3;45.5) 509 53.8 (50.6;57.0) 421 35.1 (32.5;37.9)
Yes 1,214 56.6 (54.5;58.8) 437 46.2 (43.0;49.4) 777 65.8 (62.1;67.5)
Lung diseases
No 1,725 80.2 (78.5;81.9) 781 82.4 (78.8;84;7) 944 78.5 (76.1;80.8)
Yes 425 19.8 (18.1;21.5) 167 17.6 (15.3;20.2) 258 21.5 (19.2;23.9)
Fibrinogen profile
Normal 1,191 55.4 (53.3;57.5) 575 60.6 (57.5;63.7) 616 51.2 (48.4;54.1)
Normal/changed 296 13.8 (12.4;15.3) 121 12.8 (10.8;15.0) 175 14.6 (12.7;16.7)
Changed/normal 265 12.3 (11.0;13.8) 105 11.1 (9.2;13.2) 160 13.3 (11.5;15.4)
Changed 398 18.5 (16.9;20.2) 147 15.5 (13.3;18.0) 251 20.9 (18.7;23.3)
n Mean (SD) n Mean (SD) n Mean (SD)
Age (years) 2,150 70.5 (7.1) 948 70.5 (7.1) 1,202 70.5 (7.1)
Height (cm) 2,143 165.1 (9.4) 941 172.8 (6.6) 1,202 159.2 (6.4)
Body mass index (kg/m²) 2,104 27.9 (4.6) 908 27.6 (3.6) 1,196 28.1 (5.3)
FEV1 (Liters) 2,103 2.3 (0.7) 928 2.7 (0.7) 1,175 1.9 (0.4)
FEV1 percentage of predicted 1,985 92.1 (16.6) 815 90.7 (15.6) 1,170 93.1 (17.2)
FVC (Liters) 2,129 3.2 (0.9) 940 3.9 (0.8) 1,189 2.7 (0.6)
FVC percentage of predicted 2,082 98.5 (15.7) 915 98.2 (15.7) 1,167 98.7 (15.7)
Open in a new tab

FEV1: Forced expiratory volume in the first second; FVC: Forced vital capacity.

95%CI: 95% confidence interval; SD: Standard deviation.

The associations between lung function parameters and fibrinogen categories are presented in Table 2. For men, in the crude analysis, the fibrinogen profile was associated with all pulmonary function measurements for all categories, except for FVC percentage of predicted in the changed/normal category. In the adjusted analysis, only the maintenance of high levels of fibrinogen was associated with a significant reduction of lung function measures. FEV1 showed a reduction of 0.17L, FVC of 0.22L, and the percentage of predicted was 5.16 percentage points for FEV1 and 6.21 percentage points for FVC compared to those that maintained normal levels of fibrinogen. Fig 2 shows the linear predictions of the mean values for each category for men.

Table 2. Regression of FEV1 (L), FVC (L), FEV1 percentage of predicted and FVC percentage of predicted, by gender, The English Longitudinal Study of Ageing, England, 2004 to 2013.

Lung function n Fibrinogen profile
Normal/changed Changed/normal Changed
Coefficient (95%CI) p-value Coefficient (95%CI) p-value Coefficient (95%CI) p-value
Men
FEV1 (L)
Crude 928 -0.21 (-0.33;-0.08) 0.002 -0.24 (-0.38;-0.10) 0.001 -0.42 (-0.54;-0.30) <0.001
Adjusted* 866 -0.06 (-0.17;0.04) 0.248 -0.05 (-0.16;0.06) 0.391 -0.17 (-0.27;-0.07) 0.001
Percentual predicted FEV1
Crude 815 -3.40 (-6.66;-0.13) 0.041 -2.08 (-5.47;1.30) 0.228 -7.93 (-11.0;-4.88) <0.001
Adjusted* 758 -1.86 (-5.05;1.33) 0.253 -0.11 (-3.46;3.23) 0.948 -5.16 (-8.31;-2.00) 0.001
FVC (L)
Crude 940 -0.25 (-0.41;-0.09) 0.002 -0.21 (-0.38;-0.04) 0.015 -0.50 (-0.65;-0.35) <0.001
Adjusted* 878 -0.07 (-0.20;0.05) 0.259 0.02 (-0.11;0.16) 0.753 -0.22 (-0.34;-0.09) 0.001
Percentual predicted FVC
Crude 915 -3.93 (-7.06;-0.81) 0.014 -0.65 (-3.89;2.58) 0.691 -8.39 (-11.22;-5.56) <0.001
Adjusted* 855 -3.10 (-6.22;0.02) 0.052 1.12 (-2.14;4.39) 0.499 -6.21 (-9.20;-3.22) <0.001
Women
FEV1 (L)
Crude 1,175 -0.07 (-0.15;0.01) 0.068 -0.03 (-0.11;0.04) 0.380 -0.16 (-0.22;-0.09) <0.001
Adjusted* 1,151 -0.01 (-0.06;0.06) 0.934 0.02 (-0.04;0.09) 0.415 -0.02 (-0.08;0.03) 0.406
Percentual predicted FEV1
Crude 1,170 -0.45 (-3.32;2.47) 0.764 0.30 (-2.73;3.33) 0.764 -2.96 (-5.45;-0.39) 0.024
Adjusted* 1,147 0.93 (-1.82;3.71) 0.505 1.46 (-1.42;4.33) 0.321 -0.28 (-2.84;2.28) 0.832
FVC (L)
Crude 1,189 -0.11 (-0.20;-0.01) 0.031 -0.08 (-0,18;0.02) 0.109 -0.22 (-0.31;-0.14) <0.001
Adjusted* 1,165 -0.01 (-0.09;0.06) 0.695 0.01 (-0.07;0.08) 0.856 -0.02 (-0.09;0.05) 0.563
Percentual predicted FVC
Crude 1,167 -2.02 (-4.69;0.64) 0.137 -1.39 (-4.14;1.37) 0.323 -4.10 (-6.43;-1,76) 0.001
Adjusted* 1,143 -0.37 (-2.93;2.20) 0.779 0.21 (-2.45;2,87) 0.875 -0.71 (-3.06;1.65) 0.554
Open in a new tab

95% CI: 95% Confidence intervals; FEV1: Forced expiratory volume in the first second; FVC: Forced vital capacity.

*Adjusted by age in exam, wealth in quintiles, physical exercise, current smoke habits, chronic diseases, lung diseases, height and body mass index.

Fig 2. Linear predictions for the FEV1 (L), FVC (L), FEV1 percent predicted and FVC percent predicted in men, The English Longitudinal Study of Ageing, England, 2004 to 2013.

Fig 2

Open in a new tab

For women, in the crude analysis, only the maintenance of the abnormal fibrinogen profile was associated with lung function measures. However, none of the categories were associated with lung function measures in women in the adjusted analysis (Table 2). Fig 3 shows the linear predictions of the mean values for each category for women.

Fig 3. Linear predictions for the FEV1 (L), FVC (L), FEV1 percentage of predicted and FVC percentage of predicted in women, The English Longitudinal Study of Ageing, England, 2004 to 2013.

Fig 3

Open in a new tab

4. Discussion

Our findings showed an inverse significant relationship between lung function and fibrinogen plasma levels in older English men, but not in women. Persistent high fibrinogen plasma levels in men were significantly associated with reduced lung function measures independently of age, wealth, physical activity, smoking, chronic diseases, lung diseases, body mass index and height.

To the best of our knowledge, this is the first study to investigate changes in fibrinogen levels over a long follow-up period and their relationship with lung function later in life in community-dwelling older adults without pre-existing lung and chronic diseases like chronic obstructive pulmonary disease, asthma, and cancer. Findings from longitudinal studies that correlated fibrinogen with lung function in other populations are inconsistent due to different methodological designs and statistical models used, making comparability of results difficult [12–14].

Some authors emphasized that systemic inflammation may be involved in the pathogenesis of chronic lung disorders and suggest that fibrinogen may accelerate lung function decline in young adults besides predispose them to airway diseases [12,14]. However, a study carried out in New Zealand, with adults aged 32 to 38 years, showed no significant association between fibrinogen and lung function in men at age 32. In women aged 32, FEV1 and FVC were inversely associated with fibrinogen. But in the longitudinal models, the authors did not find evidence that systemic inflammation predicted a decline in lung function [25]. Another study, using data from the Newcastle Thousand Families birth cohort at age 49–51 years, found significant inverse associations between both FEV1 and FVC and plasma fibrinogen concentration, even after adjustments for potential confounders, including early life indicators, total pack/years of cigarette smoked and contemporaneous BMI. However, their findings did not remain significant after adjustment for contemporary percent body fat [26].

ELSA findings demonstrate that lung function decline is independent of chronic and respiratory diseases [27]. ELSA has information on important demographic and clinical parameters, which allowed us to carefully adjust potential confounding factors in our study. The most important potential confounding factor was smoking, which in itself induces systemic inflammation and is a known risk factor for pulmonary function decrease [28]. It was reassuring that, even for non-smokers and individuals with cancer or COPD, there is a relationship between the maintenance of altered fibrinogen levels and the reduction in FEV1 and FVC only in men. Changes in fibrinogen levels i.e., altered to normal overtime were not associated with impaired lung function. For women, the changes in fibrinogen levels did not affect their lung function over time. So far, we cannot easily explain the sex difference in our results. It is necessary to assess whether this persists with advancing age in future ELSA cohort assessments. However, Hancox and colleagues showed that the association between inflammatory markers and lung function appears to be stronger in men than in women [25].

Data from 3,257 Japanese individuals showed that fibrinogen plasma levels were significantly associated with decreased FVC and FEV1 values in men with restrictive, obstructive, and mixed ventilatory dysfunctions. However, there was no association between fibrinogen plasma levels and the reduction of pulmonary function measurements in women [11]. These results are consistent with our findings.

The association between fibrinogen levels and lung function has been investigated in people with COPD and asthma, as well as smokers. Inflammatory markers are useful in COPD to identify the risk of exacerbations and mortality [29–32]. Besides that, circulating fibrinogen was significantly increased in subjects with heart disease, hypertension, and diabetes and coexistent COPD [33]. Hyun et al.[29] demonstrated that patients with COPD with high plasma fibrinogen concentrations and low 25-OH vitamin D presented lower pulmonary function, higher COPD severity index, and higher rate of severe exacerbations over 24 months.

In individuals with asthma and chronic cough, findings have shown that levels of plasma fibrinogen are higher than in those without chronic cough [34]. In smokers with symptoms but with preserved spirometry, fibrinogen levels were not associated with respiratory symptom burden, exacerbations, 6-minute walk distance, and FEV1 [35]. Previous studies have demonstrated that high fibrinogen levels increase, especially when lung disease is present, but our findings have shown that higher levels are involved in reduction of lung function even in older adults without respiratory dysfunctions, especially in men.

The present study has some strengths that should be considered. First, we used two well-validated measures i.e., fibrinogen and spirometry from a large population-based and nationally representative cohort of English adults aged 50 years and older. These measures were collected through well-standardized procedures. Both tests could provide valuable information about diagnosis and prognosis. Secondly, lung function evaluation was standardized with quality criteria [23]. Thirdly, we used the reference prediction equations for lung function, which have been validated for most countries [24]. This study also has some limitations that need to be recognized. Survival bias could be a potential limitation. Besides, the lack of cause-specific mortality data of individuals with lung impairment information during the follow-up period. Another potential limitation of this study is the unavailability of information about the hepatic function or chronic hepatic disease. The liver plays a key role in the blood coagulation process because it is the site of synthesis of all clotting factors and their inhibitors. Liver damage is commonly associated with impairment of haemostasis. The activation of blood coagulation process is associated with decreased lung function, and that systemic inflammation may contribute to this relation [36].

5. Conclusion

We found that persistent high levels of plasma fibrinogen in older English men, but not in women, are associated with a reduced lung function eight years later. Our findings suggest that plasma fibrinogen may be an important biomarker of pulmonary dysfunction.

Data Availability

The English Longitudinal Study of Ageing data are available to the scientific community from the UK Data Service for researchers who meet the criteria for access to confidential data, under conditions of the End User License http://ukdataservice.ac.uk/media/455131/cd137-enduserlicence.pdf. The data can be accessed from: https://beta.ukdataservice.ac.uk/datacatalogue/series/series?id=200011#!/access-data. Contact with the UK Data Service regarding access to the English Longitudinal Study of Ageing can be made through the website https://www.ukdataservice.ac.uk/about-us/contact, by phone +44 (0)1206 872143 or by email at help@ukdataservice.ac.uk.

Funding Statement

We declare that CTA received a scholarship from the Coordination for the Improvement of Higher Education Personnel (CAPES), (Financial Code 001). The National Research Council (CNPq) supports the FCW.

References

  • 1.Kamath S, Lip GYH (2003) Fibrinogen: biochemistry, epidemiology and determinants. QJM 96:711–729. 10.1093/qjmed/hcg129 [DOI] [PubMed] [Google Scholar]
  • 2.Taylor DR (2009) Risk assessment in asthma and COPD: a potential role for biomarkers? Thorax 64:261–4. 10.1136/thx.2008.098640 [DOI] [PubMed] [Google Scholar]
  • 3.Wedzicha JA, Seemungal TAR, MacCallum PK, et al. (2000) Acute exacerbations of chronic obstructive pulmonary disease are accompanied by elevations of plasma fibrinogen and serum IL-6 levels. Thromb Haemost 84:210–5. [PubMed] [Google Scholar]
  • 4.Simpson-Haidaris PJ, Courtney MA, Wright TW, et al. (1998) Induction of fibrinogen expression in the lung epithelium during Pneumocystis carinii pneumonia. Infect Immun 66:4431–9. doi: 10.1128/IAI.66.9.4431-4439.1998 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Guadiz G, Sporn LA, Goss RA, et al. (1997) Polarized secretion of fibrinogen by lung epithelial cells. Am J Respir Cell Mol Biol 17:60–9. 10.1165/ajrcmb.17.1.2730 [DOI] [PubMed] [Google Scholar]
  • 6.Tomashefski JF, Abramowsky CR, Chung-Park M, et al. (1992) Immunofluorescence studies of lung tissue in cystic fibrosis. Pediatr Pathol 12:313–24. 10.3109/15513819209023312 [DOI] [PubMed] [Google Scholar]
  • 7.Hattori N, Degen JL, Sisson TH, et al. (2000) Bleomycin-induced pulmonary fibrosis in fibrinogen-null mice. J Clin Invest 106:1341–50. 10.1172/JCI10531 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Ploplis VA, Wilberding J, McLennan L, et al. (2000) A total fibrinogen deficiency is compatible with the development of pulmonary fibrosis in mice. Am J Pathol 157:703–8. 10.1016/S0002-9440(10)64582-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Wagers SS, Norton RJ, Rinaldi LM, et al. (2004) Extravascular fibrin, plasminogen activator, plasminogen activator inhibitors, and airway hyperresponsiveness. J Clin Invest 114:104–111. 10.1172/JCI200419569 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Dahl M, Tybjaerg-Hansen A, Vestbo J, et al. (2001) Elevated plasma fibrinogen associated with reduced pulmonary function and increased risk of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 164:1008–11. 10.1164/ajrccm.164.6.2010067 [DOI] [PubMed] [Google Scholar]
  • 11.Shibata Y, Abe S, Inoue S, et al. (2013) Relationship between plasma fibrinogen levels and pulmonary function in the japanese population: the Takahata study. Int J Med Sci 10:1530–6. 10.7150/ijms.7256 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Thyagarajan B, Jacobs DR, Apostol GG, et al. (2006) Plasma fibrinogen and lung function: the CARDIA Study. Int J Epidemiol 35:1001–8. 10.1093/ije/dyl049 [DOI] [PubMed] [Google Scholar]
  • 13.Jiang R, Burke GL, Enright PL, et al. (2008) Inflammatory markers and longitudinal lung function decline in the elderly. Am J Epidemiol 168:602–10. 10.1093/aje/kwn174 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Kalhan R, Tran BT, Colangelo LA, et al. (2010) Systemic inflammation in young adults is associated with abnormal lung function in middle age. PLoS One 5:e11431. 10.1371/journal.pone.0011431 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Mannino DM, Ford ES, Redd SC (2003) Obstructive and restrictive lung disease and markers of inflammation: data from the Third National Health and Nutrition Examination. Am J Med 114:758–62. 10.1016/s0002-9343(03)00185-2 [DOI] [PubMed] [Google Scholar]
  • 16.Mannino DM, Valvi D, Mullerova H, Tal-Singer R (2012) Fibrinogen, COPD and mortality in a nationally representative U.S. cohort. COPD 9:359–66. 10.3109/15412555.2012.668249 [DOI] [PubMed] [Google Scholar]
  • 17.Alessandri C, Basili S, Violi F, et al. (1994) Hypercoagulability state in patients with chronic obstructive pulmonary disease. Chronic Obstructive Bronchitis and Haemostasis Group. Thromb Haemost 72:343–6. [PubMed] [Google Scholar]
  • 18.Eickhoff P, Valipour A, Kiss D, et al. (2008) Determinants of Systemic Vascular Function in Patients with Stable Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med 178:1211–1218. 10.1164/rccm.200709-1412OC [DOI] [PubMed] [Google Scholar]
  • 19.Valvi D, Mannino DM, Müllerova H, Tal-Singer R (2012) Fibrinogen, chronic obstructive pulmonary disease (COPD) and outcomes in two United States cohorts. Int J Chron Obstruct Pulmon Dis 7:173–82. 10.2147/COPD.S29892 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Ford ES, Cunningham TJ, Mannino DM (2015) Inflammatory markers and mortality among US adults with obstructive lung function. Respirology 20:587–93. 10.1111/resp.12499 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Valipour A, Schreder M, Wolzt M, et al. (2008) Circulating vascular endothelial growth factor and systemic inflammatory markers in patients with stable and exacerbated chronic obstructive pulmonary disease. Clin Sci 115:225–232. 10.1042/CS20070382 [DOI] [PubMed] [Google Scholar]
  • 22.Kunter E, Ilvan A, Ozmen N, et al. (2008) Effect of corticosteroids on hemostasis and pulmonary arterial pressure during chronic obstructive pulmonary disease exacerbation. Respiration 75:145–54. 10.1159/000097748 [DOI] [PubMed] [Google Scholar]
  • 23.Banks J, Batty G, Coughlin K, et al (2019) English Longitudinal Study of Ageing: Waves 0–8, 1998–2017. 29th Edition. UK Data Service. SN: 5050, London.
  • 24.Quanjer PH, Stanojevic S, Cole TJ, et al. (2012) Multi-ethnic reference values for spirometry for the 3-95-yr age range: The global lung function 2012 equations. Eur Respir J 40:1324–43. 10.1183/09031936.00080312 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Hancox RJ, Gray AR, Sears MR, Poulton R (2016) Systemic inflammation and lung function: A longitudinal analysis. Respir Med 111:54–9. 10.1016/j.rmed.2015.12.007 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Pearce MS, Hancox RJ, Parker L, Gibson GJ (2014) Lung function and plasma fibrinogen concentrations in the Newcastle Thousand Families birth cohort between age 49 and 51 years. Respirology 19:53–57. 10.1111/resp.12158 [DOI] [PubMed] [Google Scholar]
  • 27.Yohannes AM, Tampubolon G (2014) Changes in lung function in older people from the English Longitudinal Study of Ageing. Expert Rev Respir Med 8:515–21. 10.1586/17476348.2014.919226 [DOI] [PubMed] [Google Scholar]
  • 28.Gan WQ, Man SFP, Sin DD (2005) The interactions between cigarette smoking and reduced lung function on systemic inflammation. Chest 127:558–64. 10.1378/chest.127.2.558 [DOI] [PubMed] [Google Scholar]
  • 29.Hyun DG, Oh YM, Lee SWS Do, et al. (2019) Clinical Phenotypes, Comorbidities, and Exacerbations according to Serum 25-OH Vitamin D and Plasma Fibrinogen Levels in Chronic Obstructive Pulmonary Disease. J Korean Med Sci 34:e195. 10.3346/jkms.2019.34.e195 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Mouronte-Roibás C, Leiro-Fernández V, Ruano-Raviña A, et al. (2019) Predictive value of a series of inflammatory markers in COPD for lung cancer diagnosis: a case-control study. Respir Res 20:198. 10.1186/s12931-019-1155-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Shaw JG, Vaughan A, Dent AG, et al. (2014) Biomarkers of progression of chronic obstructive pulmonary disease (COPD). J Thorac Dis 6:1532–47. 10.3978/j.issn.2072-1439.2014.11.33 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Duvoix A, Dickens J, Haq I, et al. (2013) Blood fibrinogen as a biomarker of chronic obstructive pulmonary disease. Thorax 68:670–6. 10.1136/thoraxjnl-2012-201871 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Miller J, Edwards LD, Agustí A, et al. (2013) Comorbidity, systemic inflammation and outcomes in the ECLIPSE cohort. Respir Med 107:1376–84. 10.1016/j.rmed.2013.05.001 [DOI] [PubMed] [Google Scholar]
  • 34.Çolak Y, Afzal S, Lange P, et al. (2019) Role and Impact of Chronic Cough in Individuals with Asthma From the General Population. J allergy Clin Immunol Pract 7:1783-1792.e8. 10.1016/j.jaip.2019.02.021 [DOI] [PubMed] [Google Scholar]
  • 35.Garudadri S, Woodruff PG, Han MK, et al. (2019) Systemic Markers of Inflammation in Smokers With Symptoms Despite Preserved Spirometry in SPIROMICS. Chest 155:908–917. 10.1016/j.chest.2018.12.022 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Fogarty AW, Lewis SA, McKeever TM, et al. (2010) The Association Between Blood Coagulation Activity and Lung Function: A Population-Based Study. PLoS One 5:e15014. 10.1371/journal.pone.0015014 [DOI] [PMC free article] [PubMed] [Google Scholar]

Decision Letter 0

Emiliano Giardina

17 Jun 2021

PONE-D-20-39275

Are elevated plasma fibrinogen associated with lung function? An 8-year follow-up of the ELSA study

PLOS ONE

Dear Dr. Schneider,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Aug 01 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

  • A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

  • A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

  • An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Emiliano Giardina

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. In the methods section please provide details regarding how house hold wealth and physical exercise was stratified for analysis.

3. Thank you for stating the following in the Acknowledgments Section of your manuscript:

"The English Longitudinal Study of Ageing was developed by a team of researchers based at the University College London, NatCen Social Research, the Institute for Fiscal Studies and the University of Manchester. The NatCen Social Research collected the data. The National Institute of Aging Grant R01AG017644 and a consortium of UK government departments coordinated by the Economic and Social Research Council provide the funding."

We note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form.

Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows:

"Funders did not participate in the study design, data collection and analysis, decision

to publish or prepare the manuscript."

Please include your amended statements within your cover letter; we will change the online submission form on your behalf.

4. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For more information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions.

In your revised cover letter, please address the following prompts:

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially sensitive information, data are owned by a third-party organization, etc.) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories.

We will update your Data Availability statement on your behalf to reflect the information you provide.

5. PLOS requires an ORCID iD for the corresponding author in Editorial Manager on papers submitted after December 6th, 2016. Please ensure that you have an ORCID iD and that it is validated in Editorial Manager. To do this, go to ‘Update my Information’ (in the upper left-hand corner of the main menu), and click on the Fetch/Validate link next to the ORCID field. This will take you to the ORCID site and allow you to create a new iD or authenticate a pre-existing iD in Editorial Manager. Please see the following video for instructions on linking an ORCID iD to your Editorial Manager account: https://www.youtube.com/watch?v=_xcclfuvtxQ

6. Your ethics statement should only appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please delete it from any other section.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Partly

Reviewer #3: Partly

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Overall Impressions

This is an important scientific work that brings out the correlation between the level of fibrinogen and lung functions in old men. From the data and conclusion of the authors, significantly high levels of plasma fibrinogen are observed in the old men with lung problem. Thus the implementation of this parameter as a biomarker or indicator in the diagnosis and/or prognostics of lung dysfunction could be envisaged after a thorough follow up or control of this work.

Corrections

Minor

Page 2, Line 28. ‘percentages of predicted’ should read ‘percentages predicted’

Line 33. Conclusion: ‘We found’ should read ‘It was found’

Line 37. Key words: ‘Respiratory Function Tests’ should read ‘Respiratory Functions’

Page 4, Line 88. ‘plasma is dispensed’ should read ‘plasma was dispensed’

Line 88. ‘C XL reagent is added’ should read ‘C XL reagent was added’

Page 5, Line 103. ‘FEV1 and FVC expressed’ should read ‘FEV1 and FVC were expressed’

Page 7, Line 150. Table 1 ………. ‘ELSA who presented complete data from for fibrinogen’

Major

None detected

Reviewer #2: Thank you for inviting me to review the manuscript entitled “Are elevated plasma fibrinogen associated with lung function? An 8-year follow-up of the ELSA study” It is a good piece of work however, in my opinion it lacks novelty.

Reviewer #3: In this study, the authors reported that a high level of plasma fibrinogen in older English men, but not women, is associated with a decline in lung function. In my opinion, the study is interesting however, I have some major concerns regarding the study design and the inclusion criteria implied in this study. I would like the authors to address the following concerns;

1- The major concern is the inclusion of subjects with pulmonary diseases which affect the lung function in these subjects and thus affect the reliability of the results. These subjects should be excluded to express only the relationship between fibrinogen level and lung function.

2- It is not clear is there any subjects in this study with cardiocirculatiry disorder?

3- The study design regarding the timeline of fibrinogen assessment and Lung function evaluation should be further described briefly. What is meant by wave 2, 4, and 6? Please provide a brief clear description of this part in methodology.

4- Methods: Line 80: “those with a clotting or bleeding disorder or on anticoagulant drugs, those who had ever had…. were not asked to fast.” These cases were stated to be excluded. In this statement they were asked not to fast before sampling? Did you include these cases?

5- In table 2: the significance should be defined with p-values.

6- The limitations: Selection bias should be addressed as a limitation in this study.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Dr LUNGA Paul KEILAH

Reviewer #2: No

Reviewer #3: Yes: Muhammad Tarek Abdel Ghafar

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Attachment

Submitted filename: Review comments.pdf

Click here for additional data file. (261.8KB, pdf)
Attachment

Submitted filename: review.docx

Click here for additional data file. (11.4KB, docx)
PLoS One. 2021 Nov 8;16(11):e0259498. doi: 10.1371/journal.pone.0259498.r002

Author response to Decision Letter 0

16 Oct 2021

Dear Emiliano Giardina and Reviewers,

We would appreciate the consideration of our Research Article entitled “Are elevated fibrinogen plasma levels associated with lung function? An 8-year follow-up of the ELSA study” for publication in PLOS One.

Thank you for the reviewers' considerations and suggestions. After corrections we present a new version of the article, and we hope to be in agreement for publication.

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

We appreciated this comment, and we review the style of the document.

2. In the methods section please provide details regarding how house hold wealth and physical exercise was stratified for analysis.

Thanks for the comment. We added at the references that describle how these variables are stratified.

Socioeconomic position was based on the National Statistics Socio-Economic Classification (NS-SEC) and quintiles of total wealth, defined from the sum of financial, physical (e.g. businesses, land) and housing wealth, minus debts and pension payments (Banks J, Batty G, Coughlin K, et al (2019) English Longitudinal Study of Ageing: Waves 0-8, 1998-2017. 29th Edition. UK Data Service. SN: 5050, London)

Participants were asked how often they took part in three different types of physical activity: vigorous, moderate and low intensity. The response options were more than once a week, once a week, one to three times a month and hardly ever/never. For the purposes of the analysis, we derived a summary index of physical activity by summing responses to the three physical activity questions after they had been dichotomised around the frequency cut-point of once a week or more often. The derived summary index categorised physical activity as follows: (1) physical inactivity; (2) low-intensity but not vigorous/moderate-intensity physical activity at least once a week; and (3) vigorous/moderate-intensity physical activity at least once a week. (Demakakos, P., Hamer, M., Stamatakis, E. et al. Low-intensity physical activity is associated with reduced risk of incident type 2 diabetes in older adults: evidence from the English Longitudinal Study of Ageing. Diabetologia 53, 1877–1885 (2010). https://doi.org/10.1007/s00125-010-1785-x)

3. Thank you for stating the following in the Acknowledgments Section of your manuscript:

"The English Longitudinal Study of Ageing was developed by a team of researchers based at the University College London, NatCen Social Research, the Institute for Fiscal Studies and the University of Manchester. The NatCen Social Research collected the data. The National Institute of Aging Grant R01AG017644 and a consortium of UK government departments coordinated by the Economic and Social Research Council provide the funding."

We note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form.

Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows:

"Funders did not participate in the study design, data collection and analysis, decision

to publish or prepare the manuscript."

Please include your amended statements within your cover letter; we will change the online submission form on your behalf.

Thanks for the corrections, all were executed in the manuscript.

4. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For more information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions.

In your revised cover letter, please address the following prompts:

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially sensitive information, data are owned by a third-party organization, etc.) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories.

We will update your Data Availability statement on your behalf to reflect the information you provide.

Data Sharing

The English Longitudinal Study of Ageing data are available to the scientific community from the UK Data Service for researchers who meet the criteria for access to confidential data, under conditions of the End User License http://ukdataservice.ac.uk/media/455131/cd137-enduserlicence.pdf. The data can be accessed from: https://beta.ukdataservice.ac.uk/datacatalogue/series/series?id=200011#!/access-data. Contact with the UK Data Service regarding access to the English Longitudinal Study of Ageing can be made through the website https://www.ukdataservice.ac.uk/about-us/contact, by phone +44 (0)1206 872143 or by email at help@ukdataservice.ac.uk.

5. PLOS requires an ORCID iD for the corresponding author in Editorial Manager on papers submitted after December 6th, 2016. Please ensure that you have an ORCID iD and that it is validated in Editorial Manager. To do this, go to ‘Update my Information’ (in the upper left-hand corner of the main menu), and click on the Fetch/Validate link next to the ORCID field. This will take you to the ORCID site and allow you to create a new iD or authenticate a pre-existing iD in Editorial Manager. Please see the following video for instructions on linking an ORCID iD to your Editorial Manager account: https://www.youtube.com/watch?v=_xcclfuvtxQ

Thanks for the comments. The author Ione Schneider has two accounts in PLOS. One is related to username ione.schneider and the other one, to the username ione.jayce. We need to merge these two accounts to be able to validate with Ione’s ORCID (0000-0001-6339-7832).

6. Your ethics statement should only appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please delete it from any other section.

The paragraph on ethics statement was removed from the end and is only described in the methods section.

Reviewer #1:

Corrections

Page 2, Line 28. ‘percentages of predicted’ should read ‘percentages predicted’

Line 33. Conclusion: ‘We found’ should read ‘It was found’

Line 37. Key words: ‘Respiratory Function Tests’ should read ‘Respiratory Functions’

Page 4, Line 88. ‘plasma is dispensed’ should read ‘plasma was dispensed’

Line 88. ‘C XL reagent is added’ should read ‘C XL reagent was added’

Page 5, Line 103. ‘FEV1 and FVC expressed’ should read ‘FEV1 and FVC were expressed’

Page 7, Line 150. Table 1 ………. ‘ELSA who presented complete data from for fibrinogen’

Thanks for the corrections, all were executed in the manuscript.

Reviewer #2:

Thank you for inviting me to review the manuscript entitled “Are elevated plasma fibrinogen associated with lung function? An 8-year follow-up of the ELSA study” It is a good piece of work however, in my opinion it lacks novelty.

Thanks for the comments. This is the first time that the relation between lung function and fibrinogen is studied in the English population.

Reviewer #3:

In this study, the authors reported that a high level of plasma fibrinogen in older English men, but not women, is associated with a decline in lung function. In my opinion, the study is interesting however, I have some major concerns regarding the study design and the inclusion criteria implied in this study. I would like the authors to address the following concerns;

1- The major concern is the inclusion of subjects with pulmonary diseases which affect the lung function in these subjects and thus affect the reliability of the results. These subjects should be excluded to express only the relationship between fibrinogen level and lung function.

The questionnaire used contained information about self-reported lung diseases (COPD and asthma). Thus, this self-reported information was used as adjustment variables in the analyses and interactions and multicollinearity between variables were tested, which were not detected.

2- It is not clear is there any subjects in this study with cardiocirculatiry disorder?

The disease high blood pressure, angina, heart attack, congestive heart failure, heart murmur, and abnormal heart rhythm were classified in the presence of one or more. However, they were excluded due to multicollinearity.

3- The study design regarding the timeline of fibrinogen assessment and Lung function evaluation should be further described briefly. What is meant by wave 2, 4, and 6? Please provide a brief clear description of this part in methodology.

Thanks for the comments. We clarified the information about the timeline of fibrinogen and lung function between the waves.

4- Methods: Line 80: “those with a clotting or bleeding disorder or on anticoagulant drugs, those who had ever had…. were not asked to fast.” These cases were stated to be excluded. In this statement they were asked not to fast before sampling? Did you include these cases?

The members with described problems are not eligible to the blood sample. This way, these cases are not included in the analysis.

5- In table 2: the significance should be defined with p-values.

This information was updated at the table.

6- The limitations: Selection bias should be addressed as a limitation in this study.

Thanks for the comments. We addressed the selection bias to the limitations.

Thank you for your time and consideration.

Yours sincerely

Dr Ione Jayce Ceola Schneider

Affiliate Academic

University College London, Department

Attachment

Submitted filename: Response to Reviewers.docx

Click here for additional data file. (22.3KB, docx)

Decision Letter 1

Emiliano Giardina

21 Oct 2021

Are elevated plasma fibrinogen associated with lung function? An 8-year follow-up of the ELSA study

PONE-D-20-39275R1

Dear Dr. Schneider,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Emiliano Giardina

Academic Editor

PLOS ONE

Acceptance letter

Emiliano Giardina

26 Oct 2021

PONE-D-20-39275R1

Are elevated plasma fibrinogen associated with lung function? An 8-year follow-up of the ELSA study

Dear Dr. Schneider:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Emiliano Giardina

Academic Editor

PLOS ONE

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    Attachment

    Submitted filename: Review comments.pdf

    Click here for additional data file. (261.8KB, pdf)
    Attachment

    Submitted filename: review.docx

    Click here for additional data file. (11.4KB, docx)
    Attachment

    Submitted filename: Response to Reviewers.docx

    Click here for additional data file. (22.3KB, docx)

    Data Availability Statement

    The English Longitudinal Study of Ageing data are available to the scientific community from the UK Data Service for researchers who meet the criteria for access to confidential data, under conditions of the End User License http://ukdataservice.ac.uk/media/455131/cd137-enduserlicence.pdf. The data can be accessed from: https://beta.ukdataservice.ac.uk/datacatalogue/series/series?id=200011#!/access-data. Contact with the UK Data Service regarding access to the English Longitudinal Study of Ageing can be made through the website https://www.ukdataservice.ac.uk/about-us/contact, by phone +44 (0)1206 872143 or by email at help@ukdataservice.ac.uk.

    Articles from PLoS ONE are provided here courtesy of PLOS

    RESOURCES