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The Open Biomarkers Journal
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RESEARCH ARTICLE
Plasma Fibrinogen as a Biomarker of Stable and Exacerbated Chronic
Obstructive Pulmonary Disease
1,*
1
2
2
Kashifa Ehsan , Sibgha Zulfiqar , Amber Hassan and Humaira Waseem
1
Federal Post Graduate Medical Institute (FPGMI), Sheikh Zayed, Lahore, Pakistan
Faculty of Allied Health Sciences, Research Unit, The University of Lahore, Lahore, Pakistan
2
Abstract:
Study Design:
An experimental, comparative, cross-sectional study
Place and Duration of Study:
Department of Physiology, Federal Post Graduate Medical Institute (FPGMI), Sheikh Zayed Medical Complex Lahore, Pakistan from August 2013
to 2014
Background:
Chronic Obstructive Pulmonary Disease (COPD) is a preventable and treatable disease, but is a partially reversible chronic inflammatory condition
characterized by airway obstruction. COPD remains under-diagnosed and under-treated because the only available diagnostic method at present is
testing lung functions by spirometry which is not helpful to determine the severity and clinical outcomes of the disease. Circulating biomarkers are
under consideration for various diseases worldwide. Plasma fibrinogen is emerging as one of the most promising biomarkers of COPD in smokers.
Objective:
The objective of this study is to investigate if plasma fibrinogen can serve as a diagnostic biomarker of COPD in smokers, and if its further higher
levels are seen in the exacerbated state of the disease in comparison to the stable disease.
Materials and Methods:
75 middle-aged to old-age smokers of either gender were selected. Lung functions of every participant were measured to determine Forced
Expiratory Volume in the first second (FEV1), Forced Vital Capacity (FVC), and the ratio of FEV1/FVC by spirometry. On the basis of the results
of the tests, subjects were divided into three groups; firstly, the control group of chronic smokers without COPD, secondly, smokers with COPD in
a stable state, and thirdly, patients in an exacerbated state of COPD. Plasma fibrinogen was quantitatively estimated in every individual of all three
groups by the Clauss method using the Hemostat Fibrinogen kit.
Results:
The average Plasma fibrinogen level was found to be 235.008 mg/dl in healthy smokers (control group), while an average of 440.12mg/dl was
measured in patients with stable COPD. The difference in plasma fibrinogen levels was found to be significant, having a p-value of (0.000). In the
third group with declined lung function predicting acute exacerbated COPD, fibrinogen was found to be > 453.2 mg/dl, which was significantly
higher than in the stable disease group (p-value > 0.0017)
Conclusion:
Plasma fibrinogen level measurement is a reliable and accessible test in terms of a diagnostic marker of COPD, as compared to conventional lung
function testing done in the past.
Keywords: Smokers, Chronic Obstructive Pulmonary Disease (COPD), Plasma fibrinogen level, Lung function testing by spirometry FEVI,
FEV1/FVC ratio, Inflammatory biomarker.
Article History
Received: January 05, 2021
Revised: February 11, 2021
DOI: 10.2174/1875318302111010048, 2021, 11, 48-53
Accepted: March 2, 2021
Plasma Fibrinogen as a Biomarker of Stable
1. INTRODUCTION
Chronic Obstructive Pulmonary Disease (COPD) is
defined as a multicomponent, preventable, treatable, partially
irreversible chronic inflammatory, respiratory disease with
extra pulmonary manifestations. It is characterized by
progressive and persistent airflow limitation, usually resulting
from the chronic inflammatory reaction of smaller airways due
to tobacco smoking and other inhaled toxins [1, 2]. COPD has
different phenotypes and is believed to encompass a spectrum
of diseases, such as “emphysema,” destruction of gas-exchange
area of alveoli at one end, and “chronic bronchitis” at the other,
which may precede or follow COPD [3, 4]. This disease,
unfortunately, remains underdiagnosed or misdiagnosed since
most of the time, it is considered to be the same airway
obstruction that is seen in bronchial asthma. COPD and asthma
can easily be differentiated by the variability of the airflow
obstruction in asthma due to the hypersensitive allergic
response of airways to any foreign agent (i.e., exacerbations).
COPD is a chronic disease with slow progression, and
obstruction remains in the stable state markedly over several
months. Although the same structural changes are seen in both
ailments, there are some obvious differences in airway
functioning [5]. COPD can be classified as stable or
exacerbated COPD on the basis of disease severity, clinical
presentation, and lung function tests by spirometry [6, 7].
Cigarette smoking is the strongest risk factor in the
development of COPD worldwide, and the current knowledge
on COPD and its associated morbidity and mortality comes
from those analyses which are made in smoking-related COPD
[8,9]. The smoking burden is usually measured in pack-year,
and to calculate the pack-year, smokers are asked to report the
average number of cigarettes smoked per day in the duration in
years. One pack-year means smoking an average of one pack
(20 cigarettes) every day for one complete year [10]. The packyears calculation assumes the same weightage for both duration
of smoking and cigarettes/day though the relative contribution
of the duration of smoking versus cigarettes/day toward COPD
is not known [11]. The current strategy to diagnose COPD on
clinical grounds or additionally by the measurement of
respiratory functions by spirometry potentially leaves many
patients underdiagnosed and sometimes over-diagnosed.
Globally, 10 – 95% under-diagnosis and 5 – 60% overdiagnosis of disease are prevalent due to the unavailability of
spirometry in rural areas of the developing countries, untrained
technical operators to perform the test, and their lack of skill in
interpretating the results of spirometry [12,13]. The diagnosis
of COPD can only be declared if patients have a combination
of certain symptoms, “a post-bronchodilator fixed ratio of
Forced Expiratory Volume in 1st second and Forced Vital
Capacity, i.e., FEV1/FVC < 0.7, measured by spirometry [14].
Hence in the absence of any reliable and accurate diagnostic
criteria, there is a dire need to search for some authenticated
markers for the diagnosis of COPD. Effective therapeutic
interventions are not possible without a proper and accurate
diagnosis of any disease. Conversely, an overdiagnosis or
false-positive diagnosis may also cause the true underlying
* Address correspondence to this author at the Federal Post Graduate Medical
Institute (FPGMI), Sheikh Zayed, Lahore, Pakistan;
E-mail: kashifamimi@gmail.com
The Open Biomarkers Journal, 2021, Volume 11 49
diagnosis to be missed. Therefore, it has been hypothesized
that to diagnose COPD and its clinical progression, biomarkers
should be searched as a suitable substitute for previously used
diagnostic tools [15]. Various body compartments like breath
condensate, blood, sputum, bronchoalveolar lavage, and urine
as samples are tested for the detection of biomarkers. CCL-18,
Surfactant protein-D (SP-D), CC-16 (Clara cell protein-16),
MMPs 8 and 9 (matrix metalloproteinase), IL-6 and 8
(Interleukin), and CRP (C-reactive protein) are distinguishable
blood biomarkers which are considered to be the potential
diagnostic markers for COPD, but none of them has been
proved to be significant in this context [16, 17]. Amongst all
other biomarkers under consideration, fibrinogen is found to
play a pivotal role in diagnosing COPD. Fibrinogen is
glycoprotein, which is synthesized in hepatocytes and serves as
an essential coagulation factor when released into blood
circulation. In COPD, the inflammatory role of fibrinogen as
an acute-phase reactant makes it an ideal biomarker [18, 19].
Fibrinogen, an inflammatory marker, is found to be increased
not only due to coagulation but also following a tissue injury.
The plasma levels of fibrinogen proved to be a predictor of
acute exacerbations of COPD as well [20]. Plasma fibrinogen
levels, along with other factors like blood cells, may predict the
frequency of the attack and clinical phenotype of COPD;
frequency of exacerbations of disease is also determined by
these biomarkers [21].
The
comprehensive
meta-analysis
of
different
observational studies though proved the hypothesis of
circulating fibrinogen as a biomarker, but still, nearly all
qualified studies are measuring the circulating fibrinogen
concentration only once, and there is no long-term change
evaluation in the development of COPD. Furthermore,
measurement bias is also suspected because no identical
method is used to assay circulating fibrinogen across studies.
Thereby, future well-performed studies on larger scales are
suggested for drawing a conclusion, and for refusing or
confirming our findings [19].
In almost all components of the disease (progression,
severity, associated co-morbidities, mortality, diagnosis, and
treatment strategies), plasma fibrinogen levels show a
significant correlation with COPD. An inverse relationship was
found between baseline fibrinogen levels and pulmonary
functions, i.e., if fibrinogen is higher than normal at the
beginning of COPD, declined FEV1 and FVC will be observed
over the course of the disease [22]. This difference was
observed in current smokers and non-smokers as well.
Moreover, higher baseline fibrinogen levels were also
associated with an increased incidence of admissions with an
exacerbation of COPD. It has been studied that there is a
promising relationship between raised plasma fibrinogen at
baseline in individuals with COPD and the development of
frequent exacerbations of disease and hospitalization as well
[23].
2. METHODOLOGY
A comparative cross-sectional study was conducted in the
Physiology Department of Sheikh Zayed Postgraduate Medical
Institute, Sheikh Zayed Hospital Pulmonology Department,
50 The Open Biomarkers Journal, 2021, Volume 11
Lahore, in collaboration with the Combined Military Hospital.
The total 75 patients were divided into 3 groups (controls = 25,
exacerbated = 25 and stable COPD = 25 patients). Gender
matched, young adults (20 - 39 years of age) to old aged (60 80 years of age) individuals with a history of smoking at least
10 pack-years (20 cigarettes/day for 1 complete year = 1 packyear) were included in the three groups. All the normal and
healthy individuals without a history of COPD were included
as controls. Patients diagnosed with COPD according to GOLD
criteria, having a history of smoking of more than 10 packyears (20 cigarettes/ day for 1 complete year = 1 pack year) and
a state of exacerbation free period of 3-4 months, were enrolled
as stable cases. Patients with diagnosed COPD in an
exacerbated state, having a history of acute attacks in the last
few days to 1 week,presented in the emergency department or
already hospitalized, were enrolled as exacerbated cases. The
exclusion criteria included diagnosed cases of asthma or other
chronic respiratory diseases on the basis of spirometric
findings, patients with history of malignancy or serious comorbidities that would prevent the study completion and
patients diagnosed with active pulmonary tuberculosis or
bronchiectasis due to old complicated TB. The study was
started after the approval from the Ethical Review Board of
Federal Post Graduate Medical Institute Sheikh Zayed Medical
Complex Lahore. Data including name, age, weight, height,
history of smoking, and other diseases in the past were
recorded through a questionnaire. A detailed present and past
history were recorded, and a physical examination was
performed. A 6-minute walk test was performed to measure the
grading of dyspnoea on all the participants except those who
were unable to take a single step due to shortness of breath
(exacerbated COPD cases). After observing all aseptic
measures, 3cc of blood was obtained from the cubital vein
using venepuncture in 3.2% sodium citrate containing vial. The
plasma was separated from blood by centrifugation at the rate
of 5000 revolutions per minute for 10 minutes. It was then
stored in an aliquot and kept frozen at -20C till the required test
was performed. The test was then conducted by indirect
coagulation clauss method in haematology laboratory of
Combined Military Hospital Lahore after due permission from
the authorities. A human Hemostat fibrinogen kit was used for
the estimation of fibrinogen levels
The obtained data was entered and analysed by using SPSS
22.0. The data for quantitative variables, i.e., age, BMI,
smoking pack years, FEV1, FEV1/FVC, FEV1 pp, fibrinogen
levels in blood and the qualitative variables, i.e., grading of
dyspnoea and gold staging of COPD were described by using
descriptive statistics, i.e., mean ± SD for the three groups. The
comparison of these variables among groups was studied by
using one-way ANOVA; p-value of ≤ 0.05 was considered
significant.
3. RESULTS
In control group, the majority of the patients were adults
(12 (80%)) and middle-aged (11 (44%)), having normal weight
(13 (52%)) and smoking 10 - 12 packs of cigarettes per year
(19 (76.0%)). In the exacerbated group, the majority of the
patients were middle aged (17 (68%)), having normal BMI (16
(64%)) and smoking 21 - 40 packs of cigarette per year. In the
Ehsan et al.
stable COPD group, the majority of the patients were old aged
(12 (16%)), having normal BMI (18 (72%)) and smoking 10 12 packs of cigarette per year (Tables 1.1-1.3).
Table 1.1. This table represents the groups division for this
study.
Groups
Variables
Control Exacerbated Stable
Adults (15 - 40)
12 (80%)
1 (4%)
8 (32%)
Middle aged (41 - 60)
11 (44%)
17 (68%)
5 (20%)
Table 1.2. Body Mass Index.
BMI
Underweight
4 (12%)
4 (16%)
Normal
13 (52%)
16 (64%)
Overweight
8 (32%)
5 (20%)
Table 1.3. Personal history of patients.
Smoking Status
10 - 12 Packs per year
19 (76.0%) 8 (32%) 17 (68%)
21 - 30 Packs per year
4 (16%)
6 (24%) 6 (24.0%)
31 - 40 Packs per year
2 (8%)
10 (40%) 1 (4.0%)
> 40 Packs per year
0 (0%)
1 (4.0%) 1 (4.0%)
3.1. Clinical History of Patients
According to Tables 2.1-2.4, in the control group, the
majority of the patients had grade 2 dyspnea, low FEV1
(Below 3 L) (16 (64%)) and normal FEV/FVC (24 (96%)). In
the exacerbated group, the majority of the patients had grade 4
dyspnea (21 (84%)), stage 3 COPD 15 (60%), very low (Below
1 L) (21 (84%)) and low FEV1/FVC (19 (76%)). In the stable
COPD group, the majority of the patients had G3 dyspnea (19
(76%)), stage 1 of COPD (18 (72%)), FEV1 Low (Below 2 L)
(19 (76%)) and Very low FEV1/FVC (20 (80%)).
Table 2.1. This table shows the Grading of Dyspnea.
Grading of Dyspnea
G1
7 (28%)
0 (0%)
0 (0%)
G2
16 (64%)
1 (4%)
4 (16%)
G3
2 (8%)
3 (12%)
19 (76%)
G4
0 (0%)
21 (84%)
2 (4%)
Table 2.2. This table shows the stages of COPD.
Stages of COPD
Stage 1
0 (0%)
0 (0%)
18 (72%)
Stage 2
0 (0%)
5 (20%)
3 (12%)
Stage 3
0 (0%)
15 (60%)
4 (16%)
Stage 4
0 (0%)
5 (20%)
0 (0%)
Table 2.3. This table represents Forced Expiratory Volume
in 1 second (FEV1).
Forced Expiratory Volume in 1 second (FEV1)
Normal (3 - 4 L)
7 (28%)
Low (Below 3 L)
16 (64%)
1 (4%)
4 (16%)
Low (Below 2 L)
2 (8%)
3 (12%)
19 (76%)
Very Low (Below 1 L)
0 (0%)
21 (84%)
2 (8%)
0 (0%)
0 (0%)
The Open Biomarkers Journal, 2021, Volume 11 51
Plasma Fibrinogen as a Biomarker of Stable
Table 2.4. The table represents the results of FEV1/FVC.
FEV1/FVC
Normal (> 80)
24 (96%)
1 (4.0%)
Low (< 80)
1 (4.0%)
19 (76%)
5 (20%)
Very low (< 60)
0 (0.0%)
5 (20%)
20 (80%)
0 (0.0%)
Plasma fibrinogen levels were compared among the three
groups. Mean ± SD of plasma fibrinogen levels were 453.24 ±
81.92 mg/dl in the exacerbated COPD group, 400.12 ± 81.45
mg/dl in the stable COPD group, and 235.01 ± 45.015 in the
healthy controls. It was seen that plasma fibrinogen levels were
raised in patients in an exacerbated state of COPD and also in
patients having stable COPD (p-value = 0.000) (Fig. 1).
COPD, cigarette smoking and its contribution to COPD disease
is interestingly found to be mediated by elevated plasma
fibrinogen, which though could not be reliably investigated in
the present study due to the unreliable history of individual
participants of the study, yet we agree that further explorations
on the fact are needed. Importantly, plasma fibrinogen is a
biomarker that is easy to assay and can be easily proposed as a
more practical and useful approach toward clinical
management of COPD. There are certain limitations of the
study; firstly, it is a cross-sectional study with a small sample
size, therefore, there are fair chances that it might have affected
the analysis of statistical power of the results. Multiple
prospective and extensive studies on COPD patients have been
conducted worldwide, but still, in Asians, no significant
research has been done. Secondly, plasma fibrinogen
concentration was only measured once, therefore, we could not
evaluate the long-term effects of the change of fibrinogen on
the progression of COPD. Thirdly, the usefulness of fibrinogen
levels could not be investigated for predicting mortality with
COPD. Thereby, drawing a conclusion is not possible until
some longitudinal, large-scale, and well-performed studies
confirm or refuse the results of our study.
CONCLUSION
Fig (1). Comparison of plasma Fibrinogen levels in stable COPD,
exacerbated and control group (p-value <. 0001*).
4. DISCUSSION
The aim of this research work was to determine a
diagnostic biomarker for a misdiagnosed and consequently
wrongly treated disease of COPD; for this purpose, plasma
fibrinogen was considered a surrogate endpoint biomarker. The
association of plasma fibrinogen levels with COPD and its
severity was examined in 75 individuals who were smokers,
and 50 of them were confirmed patients of COPD, diagnosed
by their reduced pulmonary functions. The key finding of this
experimental work suggests that a significant, concentrationdependent relation exists between COPD and its increasing
severity and higher circulating fibrinogen. Fibrinogen in the
human body is a plasma protein synthesized in the liver
mainly; it is converted into fibrin during blood coagulation
[24]. It has been observed that fibrinogen synthesis is upregulated as a major acute-phase reactant in response to
inflammation, and this is a major clinical feature of COPD
[25]. In addition, evidence also exists that the risk of
exacerbation of COPD is increased with elevated fibrinogen
plasma [26]. Furthermore, fibrinogen concentration is
correlated with impaired lung functions and is related to
increased mortality among patients with COPD [27]. Plasma
fibrinogen is hence reasonably speculated as a promising
clinical biomarker in predicting the risk and severity of COPD
[28]. Based on various meta-analyses, a significant relationship
between severity of COPD and circulating fibrinogen has been
established [29 - 34]. Another important fact is a possible
interaction between cigarette smoking and plasma fibrinogen.
Amongst the established risk factors for the development of
The plasma inflammatory biomarker profile, identified in
patients with COPD in a stable and exacerbated state,
represents a valuable tool for the replacement of lung function
testing in the assessment and clinical presentation of COPD.
The need for biomarkers to identify the heterogeneity of COPD
and characterize and continuously improve the identification of
disease progressors is mandatory for the efficient management
of the disease. Our study is the first research on the population
of Pakistan to consider plasma biomarker fibrinogen level as a
significant indicator for COPD. We have concluded that easy
to assay, plasma fibrinogen levels may serve as a useful marker
for earlier detection of the potential causes of COPD. If
measured prospectively during close follow-up, fibrinogen
levels can serve as a prognostic marker as well. Consequently,
plasma fibrinogen will help in improving the clinical outcome
and for the effective treatment of COPD.
ETHICS APPROVAL AND CONSENT TO PARTICIPATE
This study has been approved by the institutional review
board of the 'Federal PostGraduate Medical Institute, Sheikh
Zayed Hospital National Health Research Complex Lahore,
Pakistan. (Registration number: Institutional Review Board,
Ref No: F-39/NHRC/Admin/IRB/86 IRB No:1274).
HUMAN AND ANIMAL RIGHTS
No Animals were used in this research. All human research
procedures followed were in accordance with the ethical
standards of the committee responsible for human
experimentation (institutional and national), and with the
Helsinki Declaration of 1975, as revised in 2013.
CONSENT FOR PUBLICATION
Patients were informed about this study.
52 The Open Biomarkers Journal, 2021, Volume 11
AVAILABILITY OF DATA AND MATERIALS
The data supporting this study is present within the
manuscript.
FUNDING
Ehsan et al.
[14]
[15]
None.
CONFLICT OF INTEREST
The authors declare no conflict of interest financial or
otherwise.
ACKNOWLEDGEMENTS
[16]
[17]
Declared none.
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