10.1007_s11239-007-0073-1

Microalbuminuria, von Willebrand factor and fibrinogen levelsas markers of the severity in COPD exacerbation

Mehmet Polatli Æ Aysel Cakir Æ Orhan Cildag ÆA. Zahit Bolaman Æ Cigdem Yenisey Æ Yavuz Yenicerioglu

Published online: 10 July 2007

� Springer Science+Business Media, LLC 2007

Abstract In COPD, the systemic effects of the disease

reflect the structural and/or biochemical alterations occur-

ring in the structures or organs other than the lungs in

relation to the characteristics of the primary disease. The

disorders of endothelial structures due to COPD may lead

vascular pathologies, such as ischemic heart disease,

stroke, to occur more commonly in those with COPD. On

consideration of the fact that the vascular endothelium is a

major site in which the systemic effect of the inflammation

occurs, should von Willebrand Factor, a clotting factor of

endothelium origin, and the plasma level of fibrinogen vary

with the severity of the disease in COPD, the variability of

arterial blood gas values, and the stability or exacerbation

of the disease? Considering the fact that microalbuminuria

is an indirect manifestation of the renal endothelial per-

meability and/or renal perfusion; should there be an asso-

ciation between microalbuminuria and the severity of

COPD? Therefore, in order to assess the effect of the

systemic inflammation in COPD on the vascular

endothelium, we compared the levels of the plasma vWF,

fibrinogen, 24-h urine microalbuminuria of those with

stable COPD (33 patients) and exacerbation of COPD (26

patients) with those of the controls (16 healthy subjects).

The mean age was 63.42 « 10.29, 68.00 « 9.77 and

59.63 « 14.10 years in SCOPD, COPDAE, and CG,

respectively. The level of microalbuminuria was found to

increase significantly in COPDAE group, compared to that

of the controls (P = 0.004). When we investigated the

relation between smoking burden and microalbuminuria,

vWF, fibrinogen levels, the amount of consumption and

positive relationship were found significant. (r = 0.336,

P = 0.003 between smoking pack-years and vWF,

r = 0.403, P = 0.001 between smoking pack-years and

fibrinogen, and r = 0.262, P = 0.02 between smoking

pack-years and microalbuminuria). The levels of vWF and

fibrinogen are AECOPD > SCOPD > CG, with the highest

being in AECOPD, and the difference among the groups

was statistically significant. The relationship between the

level of hypoxemia and microalbuminuria, fibrinogen and

vWF was found to be significant (r = –0.360, P = 0.005

between oxygen saturation and microalbuminuria,

r = –0.359, P = 0.005 between the level of PaO2 and

fibrinogen, and r = –0.336, P = 0.009 between PaO2 and

vWF). In conclusion, the levels of plasma vWF, fibrinogen,

and microalbuminuria may be helpful in grading the

severity of COPD exacerbation. The related increase in

these markers may represent a possible pathophysiological

mechanism behind the increased vascular morbidity of

patients with COPD and detecting indirectly the endothe-

lial dysfunction as a manifestation of systemic outcomes

due to COPD and in detecting earlier the cases in which

the risk for developing the associated complications are

higher. We suggest that further studies are necessary to

investigate the impact of antithrombotic treatment on

M. Polatli (&) � A. Cakir � O. Cildag

Department of Pulmonology, Adnan Menderes University

Hospital, Aydin, Turkey

e-mail: [email protected]

A. Z. Bolaman

Department of Haematology, Adnan Menderes University


C. Yenisey

Department of Biochemistry, Adnan Menderes University


Y. Yenicerioglu

Department of Nephrology, Adnan Menderes University


123

J Thromb Thrombolysis (2008) 26:97–102

DOI 10.1007/s11239-007-0073-1

microalbuminuria, plasma vWF and fibrinogen as markers

of endothelial dysfunction coexisting COPD exacerbation.

Keywords COPD � Exacerbation � Systemic

inflammation � Endothelial dysfunction � vWF �Fibrinogen � Microalbuminuria � Thrombosis �Antithrombotic treatment

Introduction

Chronic obstructive pulmonary disease (COPD) is a

preventable and treatable disease state characterized by

airflow limitation that is not fully reversible. The airflow

limitation is usually progressive and is associated with an

abnormal inflammatory response of the lungs to noxious

particles or gases, especially those of tobacco smoking.

Despite its major pulmonary effects, COPD have also

systemic effects that may contribute to the severity in

individual patients [1].

In COPD, the systemic effects of the disease reflect the

structural and/or biochemical alterations occurring in

the structures or organs other than the lungs in relation to

the characteristics of the primary disease. As in many other

inflammatory diseases, may COPD occur with systemic

symptoms [2].

Reflecting the multicomponent nature of the disorder,

there is extensive heterogeneity among patients with COPD

in terms of clinical presentation, disease severity and rate of

disease progression. It is increasingly apparent that a single

marker is unlikely to be predictive of clinical outcome in all

patients with COPD, given the diverse range of pathological

mechanisms involved. Furthermore, with the variable clini-

cal presentation of COPD, a single outcome is unlikely to

provide a full assessment of the impact of COPD across all

patients [3]. COPD exacerbation definition is based on only

clinical findings such as cough, sputum color and dyspnea

according to recent guidelines. Assessment of the severity of

an exacerbation depends on the patient’s medical history

before the exacerbation, preexisting comorbidities, symp-

toms, physical examination, arterial blood gas measure-

ments, and other laboratory tests [1].

Endothelial cells in the human body play a central role

in the control of vascular tone, permeability, blood flow,

coagulation, thrombolysis, inflammation, tissue repair and

growth [4]. The disorders of endothelial structures due to

COPD may lead vascular pathologies, such as ischemic

heart disease, stroke, to occur more commonly in those

with COPD [5].

Evidence suggests that proteinuria does not solely reflect

renal pathology but is also associated with a systemic in-

crease in vascular permeability. One possible mechanism

of increased vascular permeability is that it is due to

abnormal endothelial function [6].

The damage smoking produces to the endothelial struc-

tures also causes some alterations in coagulation system. The

endothelial damage leads to the extravasations of the tissue

factor into bloodstream, resulting in the activation of coag-

ulation, and the rapid production of thrombin. However, the

circulating inhibitory mechanisms tend to inhibit the

thrombin production stimulated by cytokines [7].

Von Willebrand Factor (vWF) is a clotting factor of

glycoprotein origin which is synthesized by megacaryocyte

and endothelial cells. Because endothelial cells are likely to

be stimulated by many of factors in vascular disorders,

plasma antigenic activity of vWF is expected to rise in

these instances as a consequence of endothelial cell

dysfunction [8].

Affecting either the circulatory or cell-membrane lipids,

the free radicals occurring due to smoking cause cell

damage, thereby elevating the levels of vWF [9].

Fibrinogen, an acute phase reactant, is a blood protein

which is synthesized in the liver, found in plasma, and

plays a prominent role in clotting. The increase of plasma

fibrinogen, as it is associated with endothelial damage, has

been found to be associated with the risk for cardiovascular

disease [10].

The probable association of the systemic inflammation

with vascular endothelium and coagulopathy in COPD

suggests that there may be some questions that still remain

to be answered. On consideration of the fact that the vas-

cular endothelium is a major site in which the systemic

effect of the inflammation occurs, should von Willebrand

Factor, a clotting factor of endothelium origin, and the

plasma level of fibrinogen vary with the severity of the

disease in COPD, the variability of arterial blood gas

values, and the stability or exacerbation of the disease?

Again, considering the fact that microalbuminuria is an

indirect manifestation of the renal endothelial permeability

and/or renal perfusion; should there be an association

between microalbuminuria and the severity of COPD?

Therefore, in order to assess the effect of the systemic

inflammation in COPD on the vascular endothelium, we

compared the levels of the plasma vWF, fibrinogen, 24-h

urine microalbuminiuria of those with stable COPD and

exacerbation of COPD with those of the controls. We also

investigated the relationships of these parameters with the

spirometric parameters and arterial blood gases.

Material and method

The levels of plasma vWF, fibrinogen, and 24-h urine

microalbuminuria in the patients diagnosed as having

COPD in our clinic were compared in those with stable

98 M. Polatli et al.

123

COPD (SCOPD), and acute exacerbation of COPD

(COPDAE), and in healthy control groups (CG). In addi-

tion to this, the relationship of the pulmonary functions of

these parameters to the arterial blood gases was investi-

gated. A total of 59 patients admitted to our hospital due to

COPD, 33 with stable COPD and 26 with acute exacer-

bation of COPD, and 16 controls of the same age group

were enrolled in this study.

Smoking history was considered smoking pack-years,

which was calculated by multiplying the daily cigarette

consumption by the number of years of smoking.

Establishing the diagnosis of COPD was achieved by

performing the pulmonary function test and all the subjects

were evaluated by the findings from detailed history,

physical examination, chest roentgenography, arterial

blood gases. Those with previous history of diabetes

mellitus, renal disease, peripheral vascular disease, con-

nective tissue disease, hypoalbuminia were excluded.

Pulmonary function test was performed using a spi-

rometer (Autospiro Pal, Minato Medical Science Company,

Ltd, Osaka, Japan) according to ATS criteria [11].

Forced vital capacity (FVC), FEV1, FEV1/FVC, and

maximal expiratory flow-volume curves were determined.

PFT measurements and the calculation of the predicted

values were performed by PFT software (Autospiro Pal)

according to the Europe reference mode (i.e., a database in

the software that calculates the predicted values according

to age, sex, height, and body weight), using methods

devised by Knudson and Lindall [12]. For the reversibility

test, the spirometric measurements were repeated 15 min

after inhalation of 400 lg of salbutamol.

Microalbuminuria is conventionally defined as urinary

albumin excretion between 30 and 300 mg per 24 h for

timed 24 h urine collections and the amount of albumin at

such level were measured by more precise than routine

methods using chemiluminescence method (Immulite-1

instrument).

Venous blood samples were obtained from the antecu-

bital vein after an overnight fast of 12 h. Fibrinogen, were

measured with immunonephelometric centrifugal method

using ACL Futur instruments (ACL Advanced Chemistry,

Atlanta, GA). Von Willebrand factor was measured with

immunological assay using ACL Futur instruments and

kits.

Results

In the present study, 59 patients with COPD (33 SCOPD,

26 COPDAE) and 16 controls of the same age group were

evaluated. The mean age was 63.42 « 10.29, 68.00 « 9.77

and 59.63 « 14.10 years in SCOPD, COPDAE, and CG,

respectively.

The burden of cigarette smoking was found to be

33.64 « 10.33, 45.04 « 10.36, and 21.56 « 13.13 pack-

years in SCOPD, COPDAE, and CG, respectively.

We found a significant correlation (r = –0.461,

P < 0.001) between smoking pack-years and the parameters

of respiratory function (FVC, FEV1/FVC, FEF25–75). A

significant correlation was also found between the burden of

smoking and the other parameters measured (r = 0.262,

P = 0.023 was found between smoking and 24-h urinary

microalbuminuria; r = 0.403, P = 0.001 between smoking

and the level of blood fibrinogen; and r = 0.336, P = 0.003

between smoking and vWF). However, there was no sig-

nificant correlation between the level of microalbuminuria

and vWF and the level of plasma fibrinogen.

The relationship between the level of hypoxemia and

microalbuminuria, fibrinogen and vWF was found to be

significant (r = –0.360, P = 0.005 between oxygen satu-

ration and microalbuminuria, r = –0.359, P = 0.005

between the level of PaO2 and fibrinogen, and r = –0.336,

P = 0.009 between PaO2 and vWF).

When SCOPD and COPDAE groups were compared in

terms of the levels of fibrinogen, the level of fibrinogen was

significantly higher in COPDAE group than in both

SCOPD group and the control group. Similarly, we also

found a more considerable increase in the level of vWF in

COPDAE group than in SCOPD group and the controls

(P < 0.05) (Table 1).

Although the level of microalbuminuria was found to

increase significantly in COPDAE group, compared to that

of the controls (P = 0.004), there was no significant dif-

ference between SCOPD and COPDAE, and between

SCOPD and CG (P > 0.05). When we investigated the

relation between smoking burden and microalbuminuria,

vWF, fibrinogen levels, the amount of consumption and

positive relationship were found significant (P < 0.05).

(r = 0.336, P = 0.003 between smoking pack-years and

vWF, r = 0.403, P = 0.001 between smoking pack-years

and fibrinogen, and r = 0.262, P = 0.02 between smoking

pack-years and microalbuminuria).

Discussion

In the present study, the level of microalbuminuria was

found to be much higher in COPD exacerbation group than

in both stable COPD and the control group, and that ele-

vation in the level of microalbuminuria is statistically

significant compared with that of the controls. Significantly

lower PaO2 in the AECOPD compared with those of the

controls and a significant inverse correlation between SaO2

and microalbuminuria indicates that hypoxemia has an

effect on microalbuminuria.

Microalbuminuria, von Willebrand factor and fibrinogen levels 99

123

The alterations in arterial blood gas values may affect

renal function. With increased sympathetic activity due to

hypoxemia, the capillary permeability increases, thus

resulting in proteinuria. This is not affected by the increase

in blood pressure, renal filtration rate, and altered renal

tubular function [13]. In a study carried out 102 patients

whose serum protein levels are similar, a significant rela-

tionship between lower PaO2 level and increased urinary

protein excretion was found [14]. The vasoconstriction due

to hypoxemia, and glomerular albumin filtration due to

respiratory acidosis in patients with cor pulmonale having

sleep apnea syndrome increase. This mechanism may

account for short term proteinuria occurring in COPD

patients [15].

Having investigated the response of the renal functions

to hypoxia, hyperoxia, and hypercapnia, Kilburn et al. re-

ported that increasing the blood flow is a compensatory

mechanism for hypoxemia which is necessary for the renal

oxygenation. On consideration of the renal response to the

partial pressure of oxygen in the blood, when PaO2 falls,

the blood and urine flow from the kidneys increases,

however, when PaO2 is below 40 mmHg or PaCO2 is over

65 mmHg, the renal function decreases. These effects

account, in part, for the fluid retention in patients with cor

pulmonale having severe hypercapnia and/or hypoxia in

whom acute respiratory failure develops [16].

In another study, it has been shown that elevated

microalbuminuria levels of the COPD patients with acute

exacerbation are associated with hypoxemia, and improved

with therapy. However, no relationship has been found

between microalbuminuria and mortality and spirometric

parameters [17].

Nevertheless, the values of proteinuria at the level of

nephrotic syndrome are not common in hypoxemic and/or

pulmonary hypertensive character, and determining ele-

vated levels of proteinuria in a particular patient requires a

further search for the renal diseases [18].

Tobacco consumption decreases the glomerular filtra-

tion rate, filtration fraction, and renal blood flow in healthy

individuals, which increases renovascular resistance, and

then causes the thickening of renal arterioles, and a func-

tional impairment of renal blood flow. Consequently, the

filtration rate in those with normal glomerular filtration rate

is decreased. However, small repeated episodes of transient

renal hypoperfusion may damage some glomeruli and

finally result in structural alterations as hypertrophy and

hyperfiltration in remnant glomeruli, thus increasing the

glomerular filtration rate, and albumin excretion [19].

Tobacco addiction is the most important risk factor of

developing COPD. In the present study, we also found the

relationship between the increase in cigarette consumption

and in the amount of microalbuminuria significant.

Table 1 Demographic variables, smoking history, lung function, microalbuminuria, fibrinogen, vWF, arterial blood gas values in the study

groups

SCOPD

(n = 33)

AECOPD

(n = 26)

Control group(CG)

(n = 16)

SCOPD–AECOPD

(P*)

SCOPD–CG

(P**)

AECOPD–CG

(P***)

Age 63.42 ± 10.29 68.00 ± 9.77 59.63 ± 14.10 NS NS NS

Smoking history

(Pack-years)

33.64 ± 10.33 45.04 ± 10.36 21.56 ± 13.13 0.0001 0.002 0.001

FVC (L) 3.03 ± 0.86 2.40 ± 0.66 3.54 ± 0.76 0.005 0.009 0.001

FVC % predicted 79.62 ± 15.53 66.68 ± 18.92 94.64 ± 17.32

FEV1(L) 1.69 ± 0.59 1.03 ± 0.38 2.71 ± 0.57 0.0001 0.0001 0.0001

FEV1 % predicted 56.89 ± 15.13 37.11 ± 13.79 91.66 ± 15.47

FEV1/FVC 55.94 ± 10.54 43.55 ± 12.93 76.67 ± 3.74 0.0001 0.0001 0.0001

Microalbuminuria 20.98 ± 28.74 34.99 ± 46.35 10.47 ± 8.08 NS NS 0.004

Fibrinogen 346.88 ± 92.3 447.67 ± 128 289.99 ± 39.9 0.001 0.013 0.0001

vWF 178.26 ± 118.3 257.39 ± 157 142.85 ± 57.16 0.017 NS 0.004

PaO2 80.59 ± 7.80 58.07 ± 8.36 0.0001

SaO2 95.24 ± 2.39 89.10 ± 6.68 0.0001

PaCO2 38.18 ± 4.31 43.55 ± 12.49 NS

pH 7.42 ± 0.002 7.411 ± 0.006 NS

HCO3 24.69 ± 2.12 26.66 ± 4.63 NS

P*: Comparison of SCOPD and AECOPD patients

P**: Comparison of SCOPD and CG

P***: Comparison of AECOPD and CG

NS: Not significant


123

Smoking may also induce albuminuria and abnormal renal

function through advanced glycation end products [19].

Microalbuminuria may occur in chronic disease cases,

as well as acutely-developing pathologies. The fact that an

inverse relationship between microalbuminuria and the

PaO2/FiO2 ratio is also found in intensive care patients

suggests that microalbuminuria may be a predictor of

determining the risk for developing multiple organ dys-

function syndrome (MODS) early in critically ill patients,

and determining the responsiveness of the patients with

respiratory failure to therapy [20].

In patients with hypertension, there is a significant cor-

relation between an increased level of microalbuminuria and

morbidity and mortality. The reason for this is probably the

prevalent vascular damage associated with the severity of

the disease [21]. The presence of the relationship between

microalbuminuria and vWF and fibrinogen, thrombomodu-

lin and plasminogen activator inhibitor-1 also substantiate

the above-mentioned view [22]. The association of micro-

albuminuria with cardiovascular diseases observed in stud-

ies that have been done is thought to be associated with the

disturbance in the balance between coagulation and fibri-

nolitic systems. The levels of plasma vWF in diabetics with

micro and macroalbuminuria are increased significantly,

suggesting that even in early diabetic nefropathy, prevalent

vascular disease is present [23]. A similar relationship has

also been shown in terms of fibrinogen, an acute phase

reactant. Jensen et al. [24] found in healthy individuals with

microalbuminuria an increase in the level of plasma fibrin-

ogen although not statistically significant.

The arterial wall has both protecting and aggravating

role in the formation of thrombosis. Coagulation factors do

not normally interact with intact endothelial structure that

builds up a protective barrier between blood and suben-

dothelial tissue. Endothelium inactivates thrombin,

decreases its production, and also produces substances

having antithrombotic and vasodilatory effects. [25].

Smoking is a potent risk factor for atherosclerosis and

acute coronary thrombosis because of its damage to

endothelial cells. There are deposits of thrombus and small

necrotic areas on atheroma plaques that are mostly sub-

clinic. However, the disturbances in coagulation or fibri-

nolytic systems lead to an enlargement of these lesions,

thus causing the obliteration of the artery [2]. Elevated

plasma levels of endotoxin and TNF-a are associated with

inflammation, and are considered to cause thrombotic

events by increasing the effect of tissue factor on monocyte

and endothelial surfaces. vWF levels may increase in

relation to the damaged endothelial cells, as well as to

inflammatory mediators such as histamine, endotoxin,

IL-1, TNF, leukotrienes, or hemostatic mediators such as

thrombin, fibrin, plasmin, adenine nucleotides. Therefore,

while in monitoring the diagnosis and treatment, elevated

levels of vWF may be helpful in predicting the individuals

at higher risks [26]. vWF is not only caused by endothe-

lium damaged in the site of infection, but also released

from the endothelium in other tissues depending on acute-

phase reactants and cytokines released from the site of

inflammation. Cytokinemia observed in inflammatory

events causes the activation of endothelial cells, thus

leading to an increase in the level of vWF [27].

The level of blood fibrinogen increases in healthy

smokers. Having given up smoking, this effect decreases

one half and then falls to its normal values [28]. The ele-

vated levels of plasma fibrinogen in smokers, even before

symptoms develop, may be explained by the damage

smoking produces to the cell structure and to the coagu-

lation system. Vascular endothelial damage also increases

the level of fibrinogen, another clotting factor like vWF

[29]. The probable effect of smoking may be due to an

increased release of fibrinogen from the liver by cytokines

such as IL-6, IL-1b and TNF-a [2].

Dahl et al. [30] found an increase in the fibrinogen level

associated with a decrease in pulmonary function signifi-

cant being independent of the amount of cigarettes con-

sumed in COPD. It is believed that IL-6 is the main

cytokine responsible for the release of fibrinogen and it is

therefore possible that fibrinogen could be used as a non-

invasive measurement of ongoing airway inflammation and

lung tissue destruction.

In our study, there was no linear, significant relationship

between the level of microalbuminuria and the plasma

levels of vWF and fibrinogen, which was probably caused

by the fact that there was no linear correlation between

microalbuminuria and prothrombotic factors. However, we

observed that there was a significant increase in the vWF

and fibrinogen levels in parallel to the decrease in the

partial pressure of oxygen in arterial blood gas. In our study

groups, the levels of vWF and fibrinogen are

AECOPD > SCOPD > CG, with the highest being in

AECOPD, and the difference among the groups was sta-

tistically significant. A significant positive relationship was

also found between pack-years of tobacco smoking and the

levels of vWF and fibrinogen. Plasma vWF levels are

found to be elevated in 40% of acute bronchitis due to

infection—triggered release of cytokines. When regular

smokers smoke 3 cigarettes within a half hour, the plasma

level of vWF is increased significantly [31].

A potential limitation in this study was its cross-sec-

tional design. However, the findings of this study have

some important implications for the identification of

endothelial dysfunction in COPD exacerbation and for the

management and prognosis of these patients. Thus, longi-

tudinal studies are needed to investigate whether changes

in vWF, fibrinogen, and microalbuminuria are associated

with changes in inflammation in COPD.

Microalbuminuria, von Willebrand factor and fibrinogen levels 101

123

In conclusion, the levels of plasma vWF, fibrinogen, and

microalbuminuria may be helpful in grading the severity of

COPD exacerbation. The related increase in these markers

may represent a possible pathophysiological mechanism

behind the increased vascular morbidity of patients with

COPD and detecting indirectly the endothelial dysfunction

as a manifestation of systemic outcomes due to COPD and

in detecting earlier the cases in which the risk for devel-

oping the associated complications are higher. We suggest

that further studies are necessary to investigate the impact

of antithrombotic treatment on microalbuminuria, plasma

vWF and fibrinogen as markers of endothelial dysfunction

coexisting COPD exacerbation.

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