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Received: 17 December 2020    Revised: 21 January 2021    Accepted: 24 January 2021

DOI: 10.1002/jcla.23733

RESEARCH ARTICLE

Coagulation dysfunction in patients with AECOPD and its

relation to infection and hypercapnia

Mei Liu1 | Ruixue Hu1 | Xuqin Jiang1,2 | Xiaodong Mei1,2

1
Department of Respiratory and Critical
Care Medicine, Affiliated Provincial ABSTRACT
Hospital, Anhui Medical University, Hefei,
Background: Patients with chronic obstructive pulmonary disease (COPD) often have
China
2
Department of Respiratory and Critical
coagulation abnormalities. However, the factors that lead to coagulation dysfunction
Care Medicine, Affiliated First Hospital, in acute exacerbation of COPD (AECOPD) remain insufficiently explored. This study
University of Science and Technology of
China, Hefei, China
aimed to investigate the factors affecting coagulation status in patients with COPD
and their influence on thrombosis.
Correspondence
Xuqin Jiang, Department of Respiratory
Methods: Data of COPD patients, including 135 cases in acute exacerbation stage and
and Critical Care Medicine, Affiliated 44 cases in stable stage from Nov 2016 to Nov 2019 in our hospital, were collected.
Provincial Hospital, Anhui Medical
University, Hefei 23001, China.
Healthy people (n = 135) were enrolled as the controls. The coagulation parameters,
Email: [email protected] blood gas indexes and blood routine examination results were collected and analyzed.
Xiaodong Mei, Department of Respiratory Results: White blood count (WBC), neutrophil count, neutrophil percentage (N%),
and Critical Care Medicine, Affiliated
platelet (PLT), prothrombin time (PT), international normalized ratio (INR), fibrinogen
First Hospital, University of Science and
Technology of China, Hefei 23001, China (FIB), and activated partial thromboplastin time (APTT) increased, plasma thrombin
Email: [email protected]
time (TT) decreased in AECOPD group compared with the control group. In AECOPD
Funding information group, PT, APTT, and FIB were positively correlated with neutrophils and C-­reaction
Science and Technology Foundation of
protein levels. PT was positively correlated with PCO2 and negatively with pH.
Anhui Province, China, Grant/Award
Number: 1704f0804007 Thrombosis was observed in five acute exacerbation and three stable stage COPD
patients.
Conclusions: Patients with AECOPD presented abnormal coagulation status, which
was correlated to infection and hypercapnia and might be potentially the risk factor
of thrombosis.

KEYWORDS
AECOPD, coagulation, hypercapnia, infection, inflammation, thrombosis

1  |  I NTRO D U C TI O N respiratory disease-­attributable deaths.1 It is estimated that COPD

will become the fourth largest cause of death in the world and po-
Chronic obstructive pulmonary disease (COPD) is one of the tentially the direct cause of 4.4 million deaths. 2 This will place a
common chronic airway obstructive diseases, characterized by significant burden on economic and healthcare systems through-
persistent respiratory symptoms and airflow limitation. Chronic out the world. Although the inflammation in the early stage of
respiratory diseases was recognised as the third leading cause of COPD only involves the trachea and lung, hypoxia and further
death in 2017 and COPD was the most common cause of chronic acute inflammation are systemic. In acute exacerbation stage,

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© 2021 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC

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patients developed respiratory failure often have circulatory and autoimmune, renal, gastrointestinal and hepatic diseases, and cur-
3,4
coagulation dysfunction, which was considered the cause of rent use of anticoagulants.
thrombosis events in the patients. 3 The coagulation abnormality The study was approved by the Ethic Committee of Affiliated
could cause pulmonary embolism, 5 myocardial infarction, cerebral First Hospital, University of Science and Technology of China (num-
infarction, and other thrombosis events in COPD patients. 6 These ber: 2020-­P-­0 80), and the study was designed in accordance with
events often lead to extended hospital stay, poor prognosis, and the Declaration of Helsinki.
even increased mortality.
The coagulation dysfunction and its role in COPD have been
explored for years. Actually, the presence of coagulation abnor- 2.2  |  Data collection
malities in smokers had been reported long ago as blood coagu-
lation abnormalities existed in smokers and even in the passive Demographic and baseline laboratory variables including blood rou-
smokers.7 The factors involved in abnormal coagulation in COPD tine, coagulation, blood gas, inflammatory indicators were collected.
have also been reported. For example, acidosis could affect the In AECOPD patients, these data were collected when the patient
8
coagulation status in COPD patients. Respiratory bacterial infec- was admitted to hospital.
tions, lipoprotein-­associated phospholipase A2, myeloperoxidase,
and vascular endothelial growth factor could change the coagu-
lation status, which could be the high risk factors of thrombotic 2.3  |  Statistical analysis
9
events. However, the factors lead to coagulation dysfunction in
patients with acute exacerbation of chronic obstructive pulmo- Statistical analysis was performed using SPSS 22.0 (Statistical
nary disease (AECOPD) remain insufficient explored. Obviously, Package for the Social Sciences) statistical software. Data were
finding out the causes of coagulation dysfunction in AECOPD presented as number of cases, mean ± standard deviation (SD), or
would help control the abnormality and secondary thrombosis median with interquartile range (IQR). All data were tested for nor-
risks. In this study, the coagulation status in patients with COPD mal distribution by Kolmogorov-­Smirnov test. Data for normally dis-
was investigated and some factors such as infection and hyper- tributed variables were expressed as medians with IQR and tested
capnia were found to be related to the coagulation abnormality by Mann-­Whitney test. Statistical analysis for multiple comparisons
and thrombosis in those patients. was analyzed by Kruskal-­Wallis test for non-­normally distributed
variables. Pearson correlation was used to investigate the relation-
ship between changes in coagulation and inflammatory markers.
2  |   M ATE R I A L S A N D M E TH O DS Statistical significance was defined as p < 0.05. A two-­
sided p-­
value < 0.05 was considered significant for all analyses.
2.1  |  Study design

A retrospective clinical study was performed to investigate the 3  |  R E S U LT S

factors correlated to abnormal coagulation status in COPD. The
study was designed to collect the data of patients with COPD who 3.1  |  Demographic data
were in acute exacerbation stage and hospitalized in Affiliated
First Hospital, University of Science and Technology of China A total of 135 AECOPD, 44 stable stage COPD patients, and 135
from November 2016 to November 2019. Inclusion criterion was a healthy controls were enrolled in this study. There were no sig-
clear confirmed clinical diagnosis of COPD. The diagnosis of COPD nificant differences in age, gender between AECOPD, SCOPD, and
was established by pulmonary specialists based on clinical mani-
festations as chronic and progressive dyspnea, cough, sputum TA B L E 1  Demographic characteristics of the subjects

production, and a former history of abnormal spirometry testing AECOPD SCOPD Controls
as FEV1/FVC < 0.70 after bronchodilator inhalation. The patients
Number 135 44 135
had only one diagnosis as COPD and hospitalized due to any of
Gender (M/F) 102/33 34/10 96/39
the following as exacerbated cough, expectoration, and dyspnea.
Age (years) 72.46 ± 9.19 67.67 + 10.75 62.96 + 9.97
Stable stage COPD (SCOPD) patients were those outpatients who
Course of 12.76 ± 10.46 11.51 ± 11.54 N/A
had been diagnosed as COPD and no exacerbated symptoms. The
disease
controls were those who were in good general health with normal (years)
spirometry results, no history of cigarette smoking, had gastroin-
Cases of 5 3 0
testinal polyps found in routine annual health examination, and thrombosis
planned to be operated. Exclusion criteria for both stages of COPD
Abbreviations: AECOPD, acute exacerbation of chronic obstructive
patients were a history of other pulmonary diseases, infective and pulmonary disease; SCOPD, stable chronic obstructive pulmonary
inflammatory diseases, neoplastic pathologies, hematological, disease.
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the control groups. No significant difference in disease course be- and the differences were statistically significant. There was no sig-
tween AECOPD and SCOPD patients was found. The demographic nificant difference in FIB and APTT between the stable stage COPD
characteristics of the subjects were summarized in Table 1. Several and control group. See Table 3. In addition, 48.9% (66/135) AECOPD
cases of thrombosis were found in AECOPD and SCOPD patients, patients had abnormal increased D-­dimer levels, while 27.8% (5/18)
respectively. stable stage COPD cases were abnormal in D-­dimer levels. Abnormal
D-­dimer levels were more often seen in AECOPD than in the stable
COPD patients (p < 0.05).
3.2  |  Laboratory examination parameters: blood
routine, CRP, and blood gas analysis
3.4  |  Factors influencing coagulation status
Data showed a significant difference in WBC count number and
neutrophil percentage between AECOPD patients and the con- The results of cross-­correlation analysis between various factors and
trols (p < 0.01). There was no significant difference in platelet coagulation indexes in AECOPD patients are showed as Figure 1.
count between any two of the three groups, while MPV decreased APTT, PT, and FIB levels were positive correlated with blood neu-
in AECOPD group (p < 0.01). No significant differences in WBC, trophil counts. Among which, PT (rs = 0.317, p = 0.000) and FIB
N%, PLT were observed between the SCOPD and control group, as (rs = 0.234, p = 0.006) were statistically significantly. Those coagu-
shown in Table 2. The data of blood gas analysis in AECOPD patients lation parameters were also positively correlated with serum CRP
in this study were collected and retrieved finally in 89 cases. The levels statistical significantly, as suggested by the correlation coef-
results showed that some patients had blood gas abnormality and ficients for PT (rs = 0.256), APTT (rs = 0.245), FIB (rs = 0.611). In ad-
acidosis. Among them, 36 (40.5%) cases had an arterial blood pH dition, results showed that D-­dimer level was positively correlated
lower than 7.35 and 60 (67.4%) cases had an elevated arterial carbon with serum CRP levels. In 38 patients with abnormal blood gas anal-
dioxide concentration level over 50 mmHg. ysis indexes, PT level was negatively correlated with pH (rs = 0.259),
positively correlated with PaCO2 levels (rs = 0.301), indicating ab-
normal coagulation status was correlated to hypercapnia and acido-
3.3  |  Blood coagulation parameters sis. See Figure 1.

Prothrombin time (PT), activated partial thromboplastin time

(APTT), fibrinogen (FIB), and international normalized ratio (INR) 4  |  D I S C U S S I O N
in patients with AECOPD elevated significantly, and thrombin
time (TT) was lower compared with the controls (16.80 vs 17.60, Patients with COPD often have coagulation abnormalities. Compared
p < 0.05). Compared with stable COPD group, PT, APTT, FIB, INR, with non-­COPD patients, the risk of thrombosis10 and cardiovascu-
and other indicators in the AECOPD group were significantly higher lar events in COPD patients is higher, particularly following an acute

TA B L E 2  Blood routine and CRP levels of the subjects

Normal rang AECOPD SCOPD Healthy controls P1 P2 P3

RBC (10 ~ 12/L) 3.50–­5.50 (M) 4.69 ± 0.71 (M) 4.58 ± 0.52 (M) 4.82 ± 0.57 (M) 0.122 (M) 0.462 (M) 0.031 (M)
3.8–­5.10 (F) 4.41 ± 0.58 (F) 4.64 ± 0.51 (F) 4.25 ± 0.27 (F) 0.214 (F) 0.101 (F) 0.033 (F)
Hb (g/L) 130–­175 (M) 140.66 ± 19.38 142.26 ± 15.85 148.07 ± 10.10 (M) 0.000 (M) 0.640 (M) 0.020 (M)
115–­150 (F) (M) (M) 130.05 ± 7.79 (F) 0.233 (F) 0.437 (F) 0.882 (F)
126.92 ± 14.37 131.00 ± 12.94
(F) (F)
PLT (10 ~ 9/L) 125–­350 198.93 ± 64.02 181.75 ± 56.19 199.36 ± 48.05 0.583 0.122 0.066
MPV (fL) 9.4–­12.5 10.40 (9.30 10.40 11.20 (10.20 0.000 0.668 0.023
11.40) (9.50–­11.50) 12.20)
WBC (10 ~ 9/L) 3.50–­9.50 8.59 ± 5.86 6.42 ± 1.40 6.18 ± 1.36 0.000 0.003 0.815
N (%) 40–­75 73.78 ± 12.15 58.68 ± 10.56 58.35 ± 7.63 0.000 0.000 0.084
CRP (mg/L) 0–­10.0 21.20 (7.33 1.80 (1.40 2.70) -­ -­ 0.000 -­
78.50)

Note:: Data shown as mean ± SD, median (or interquartile range), P1 represents the difference between AECOPD and the controls, P2 represents
AECOPD and SCOPD, P3 represents SCOPD and the controls.
Abbreviations: AECOPD, acute exacerbation of chronic obstructive pulmonary disease; CRP, C-­reactive protein; Hb, hemoglobin; MPV, mean platelet
volume; N%, Percentage of neutrophils; PLT, platelet; RBC, red blood cell; SCOPD, stable Chronic obstructive pulmonary disease; WBC, white blood
cell.
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F I G U R E 1  Correlation between coagulation parameters and inflammatory markers in AECOPD patients. PT, APTT, and FIB were positive
correlated with blood neutrophil counts and CRP levels. D-­dimer level was positively correlated with serum CRP levels. PT level was
negatively correlated with pH (rs = 0.259) and positively correlated with PaCO2 levels

exacerbation.11 In this study, the coagulation dysfunctions observed with the stable stage COPD patients, indicating a bacterial infec-
in COPD patients were found correlated with infection and hyper- tion existed in the AECOPD patients, see Table 2. In fact, those
capnia, and potentially related to the lower limb thrombosis. patients were mostly hospitalized after a confirmed respiratory
The deterioration of CODP is usually triggered by respira- infection with symptoms as exacerbated cough and spitting pu-
tory infection with bacteria or virus respiratory infections. In this rulent sputum and a history of failed clinic treatments. In addition
study, an elevation of neutrophil number was observed compared to neutrophils, CRP is also often used to characterize the systemic
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TA B L E 3  Comparison of coagulation parameters between AECOPD, SCOPD patients, and the controls

Normal rang AECOPD SCOPD Controls P1 P2 P3

TT (s) 11–­21 16.80 (15.90 17.90) 16.75 (15.63 17.60 (16.70 0.000 0.816 0.007
18.18) 18.80)
PT (s) 10.50–­16.00 12.70 (11.70 11.90 (10.33 10.70 (10.20 0.000 0.002 0.014
13.70) 12.98) 11.90)
APTT (s) 20–­4 0 35.60 (31.50 33.05 (28.38 28.70 (25.00 0.000 0.015 0.057
39.70) 36.33) 34.70)
FIB (g/L) 2.0–­4.6 3.93 (3.06 5.12) 2.94 (2.53 3.61) 2.69 (2.28 3.13) 0.000 0.000 0.154
INR 0.9–­1.1 0.98 (0.91 1.11) 0.93 (0.87 1.02) 0.89 (0.85 0.93) 0.000 0.007 0.032
D-­dimer (mg/L) 0–­0.5 0.56 (0.30 1.07) 0.38 (0.21 0.57) -­ -­ 0.034 -­

Note:: Data shown as median (interquartile range), P1 represents the difference between AECOPD and the controls, P2 represents AECOPD and
SCOPD, P3 represents SCOPD and the controls.
Abbreviations: AECOPD, acute exacerbation of chronic obstructive pulmonary disease; APTT, activated partial thromboplastin time; FIB, fibrinogen;
INR, international normalized ratio; PT, prothrombin time; SCOPD, stable Chronic obstructive pulmonary disease; TT, plasma thrombin time.

inflammation.12 In the AECOPD group, CRP level increased re- higher percentage of AECOPD patients had elevated blood D-­dimer
markably compared with that in the stable stage patients. The level than the stable patients (48.9%, 66/135 vs 27.8%, 5/18 cases,
changes of neutrophils and CRP suggested that the existed sys- p < 0.05), implying a thrombosis possibility in COPD especially the
temic inflammation mainly caused by the infection when the dis- acute exacerbation stage patients.
ease exacerbated. The acute exacerbation of COPD often occurs The correlation analysis showed that several coagulation pa-
after respiratory tract infection, and the infection could increase rameters were positively correlated with blood neutrophils number,
various inflammatory mediators, cytokines, cells, and antibodies. CRP level, and arterial blood carbon dioxide concentration. D-­dimer
These changes could increase the blood viscosity and affect the level was correlated with serum CRP level. These results indicated a
blood coagulation.12,13 correlation between coagulation dysfunction and infection-­related
There are a wide range of interactions between coagulation and inflammation and hypercapnia. As five AECOPD patients and three
inflammations,10,13,14 and the activation of one system may enhance SCOPD patients occurred low limb thrombosis, it was reasonable
the activation of the other. Coagulation disorder during systemic in- to deduce that coagulation dysfunction in COPD patients was re-
flammation is an imbalance or dysfunction of tissue factor-­mediated lated to infection, hypercapnia, and acid-­base disturbance, and the
thrombin production and normal physiological anticoagulant mech- dysfunction could be an important risk factor for the occurrence of
anisms.15 When infection occurs, tissue factor rapidly increases in thrombosis.
response to inflammatory cytokines, infection factors, free radicals, Some limitations existed in this study. Firstly, the exacerbation
or other harmful stimuli. Then, activation of coagulation factors trig- time before hospital admission of patients was not the same and
gers the coagulation.16 These could partially explain the coagulation the difference might affect coagulation parameter results. Secondly,
disturbances in AECOPD patients as they often have an enhanced each patient was given oxygen therapy after admission. The oxy-
systemic inflammation when in acute exacerbation stage. gen partial pressure data cannot be evaluated; therefore, the rela-
Respiratory failure is a common complication of AECOPD and tionship between hypoxia and coagulation dysfunction cannot be
often leads to extend hospital stay and poor prognosis. Some pa- analyzed. Thirdly, this was a retrospective study, and the number
tients could have severe hypercapnia in the late acute exacerbation of enrolled subjects was limited. The controls were not absolute
stage. In this investigation, 60 (67.4%) patients had hypercapnia with healthy people as they were found with polyps in routine physical
arterial carbon dioxide concentration level over 50 mmHg and 36 examination and planned to be operated, although no symptoms and
(40.5%) cases had acidosis. The high concentration of blood carbon signs presented. Finally, the whole data of patients in hospital and
dioxide and acidosis can cause dysfunction of coagulation factors8 later after discharge presenting the dynamic changes of coagulation
and blood endothelial cell damage, as reported by other researchers.6 status and occurrence of thrombosis could not be obtained. A more
Coagulation dysfunction was rather common in AECOPD pa- extensive study including more patients and more parameters is ob-
13,17
tients. In this observation, PT and APTT were significantly viously needed.
prolonged and FIB was evidently elevated in the AECOPD patients
(Table 3). The prolongation of the coagulation parameters (such
as APTT and PT) might be caused by the consumption of clotting 5  |  CO N C LU S I O N
18,19
factors, indicating that coagulation dysfunction in AECOPD pa-
tients is a complex process. In summary, this study revealed that coagulation dysfunction existed
D-­dimer is an indicator of thrombosis3 and suggested to be a in AECOPD patients. The abnormal coagulation was correlated to in-
prognostic biomarker for mortality in AECOPD. 20 In this study, a fection and hypercapnia and might be the main cause of thrombosis
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in the patients. To understand the cause of coagulation abnormality 8. White H, Bird R, Sosnowski K, Jones M. An in vitro analysis of the
in COPD patients and take proper measurers might be of help in effect of acidosis on coagulation in chronic disease states -­a throm-
boelastograph study. Clin Med. 2016;16(3):230-­234.
managing the disease.
9. Seri A, Marta DS, Madalan A, Popescu M, Tiglea AI, Moldoveanu
E. Lipoprotein-­associated phospholipase A2, myeloperoxidase and
AC K N OW L E D G M E N T vascular endothelial growth factor -­predictors of high vascular
This work was supported by the Science and Technology Foundation risk in respiratory bacterial infections. Journal of medicine and life.
2016;9(4):429-­433.
of Anhui Province, China (1704f0804007).
10. Marongiu F, Mameli A, Grandone E, Barcellona D. Pulmonary
thrombosis: a clinical pathological entity distinct from pulmonary
C O N FL I C T O F I N T E R E S T embolism? Semin Thromb Hemost. 2019;45(8):778-­783.
The authors declare that they have no conflict of interest. 11. Børvik T, Brækkan SK, Enga K, et al. COPD and risk of venous
thromboembolism and mortality in a general population. Eur Respir
J. 2016;47(2):473-­481.
DATA AVA I L A B I L I T Y S TAT E M E N T 12. van der Vorm LN, Li L, Huskens D, et al. Acute exacerbations of
The data that support the findings of this study are available from COPD are associated with a prothrombotic state through platelet-­
the corresponding author upon reasonable request. monocyte complexes, endothelial activation and increased throm-
bin generation. Respir Med. 2020;171:106094.
13. Husebø GR, Gabazza EC, D'Alessandro Gabazza C, et al. Coagulation
ORCID markers as predictors for clinical events in COPD. Respirology.
Xiaodong Mei  https://orcid.org/0000-0002-7629-9200 2021;26(4):342-­351.
14. MacCallum PK. Markers of hemostasis and systemic inflammation
in heart disease and atherosclerosis in smokers. Proc Am Thorac Soc.
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