You are on page 1of 6

J Thromb Thrombolysis (2008) 26:97102

DOI 10.1007/s11239-007-0073-1

Microalbuminuria, von Willebrand factor and fibrinogen levels


as markers of the severity in COPD exacerbation
Mehmet Polatli Aysel C
akir Orhan Cildag
A. Zahit Bolaman Cigdem Yenisey 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 occurring 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 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

M. Polatli (&)  A. Cakir  O. Cildag


Department of Pulmonology, Adnan Menderes University
Hospital, Aydin, Turkey
e-mail: mpolatli@ttnet.net.tr
A. Z. Bolaman
Department of Haematology, Adnan Menderes University
Hospital, Aydin, Turkey
C. Yenisey
Department of Biochemistry, Adnan Menderes University
Hospital, Aydin, Turkey
Y. Yenicerioglu
Department of Nephrology, Adnan Menderes University
Hospital, Aydin, Turkey

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 endothelial 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

123

98

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 clinical 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 patients medical history
before the exacerbation, preexisting comorbidities, symptoms, physical examination, arterial blood gas measurements, 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 increase in vascular permeability. One possible mechanism

123

M. Polatli et al.

of increased vascular permeability is that it is due to


abnormal endothelial function [6].
The damage smoking produces to the endothelial structures 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 coagulation, 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 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?
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

Microalbuminuria, von Willebrand factor and fibrinogen levels

COPD (SCOPD), and acute exacerbation of COPD


(COPDAE), and in healthy control groups (CG). In addition to this, the relationship of the pulmonary functions of
these parameters to the arterial blood gases was investigated. A total of 59 patients admitted to our hospital due to
COPD, 33 with stable COPD and 26 with acute exacerbation 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, connective tissue disease, hypoalbuminia were excluded.
Pulmonary function test was performed using a spirometer (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 antecubital 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.

99

The burden of cigarette smoking was found to be


33.64 10.33, 45.04 10.36, and 21.56 13.13 packyears 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, FEF2575). 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 significant 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 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).
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 difference 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 elevation 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.

123

100

M. Polatli et al.

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)

SCOPDAECOPD
(P*)

SCOPDCG
(P**)

AECOPDCG
(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)
FVC % predicted

3.03 0.86
79.62 15.53

2.40 0.66
66.68 18.92

3.54 0.76
94.64 17.32

0.005

0.009

0.001

0.0001

0.0001

0.0001

FEV1(L)

1.69 0.59

1.03 0.38

2.71 0.57

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

289.99 39.9

0.001

0.013

0.0001

142.85 57.16

0.017

NS

0.004

Fibrinogen

346.88 92.3

vWF

178.26 118.3 257.39 157

447.67 128

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
HCO3

7.42 0.002
24.69 2.12

7.411 0.006

NS

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

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 relationship 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. reported 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].

123

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 elevated levels of proteinuria in a particular patient requires a
further search for the renal diseases [18].
Tobacco consumption decreases the glomerular filtration rate, filtration fraction, and renal blood flow in healthy
individuals, which increases renovascular resistance, and
then causes the thickening of renal arterioles, and a functional 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.

Microalbuminuria, von Willebrand factor and fibrinogen levels

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 dysfunction 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 correlation 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, thrombomodulin and plasminogen activator inhibitor-1 also substantiate
the above-mentioned view [22]. The association of microalbuminuria with cardiovascular diseases observed in studies that have been done is thought to be associated with the
disturbance in the balance between coagulation and fibrinolitic 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 fibrinogen 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 subendothelial 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 subclinic. However, the disturbances in coagulation or fibrinolytic 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

101

levels of vWF may be helpful in predicting the individuals


at higher risks [26]. vWF is not only caused by endothelium damaged in the site of infection, but also released
from the endothelium in other tissues depending on acutephase 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 elevated 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 coagulation 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 significant being independent of the amount of cigarettes consumed 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 noninvasive 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 statistically 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
infectiontriggered 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-sectional 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, longitudinal studies are needed to investigate whether changes
in vWF, fibrinogen, and microalbuminuria are associated
with changes in inflammation in COPD.

123

102

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 developing 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.

References
1. NHLBI/WHO Global Initiative for Chronic Obstructive Lung
Disease (GOLD) Workshop Report. Global strategy for the
diagnosis, management, and prevention of chronic obstructive
pulmonary disease. Revised 2006. http://www.goldcopd.com)
2. Gan WQ, Man SFP, Senthilselvan A, Sin DD (2004) Association
between chronic obstructive pulmonary disease and systemic
inflammation: a systematic review and a metaanalysis. Thorax
59:574580
3. Agusti AGN, Jones PW (2006) Outcomes and markers in the
assessment of chronic obstructive pulmonary disease. Eur Respir
J 27:822827
4. Cines DB, Pollak ES, Buck CA et al (1998) Endothelial cells in
physiology and in the pathophysiology of vascular disorders.
Blood 91:35273561
5. Sin DD, Anthonisen NR, Soriano JB, Agusti AG (2006) Mortality
in COPD: role of comorbidities. Eur Respir J 28:12451257
6. Paisley KE, Beaman M, Tooke JE et al (2003) Endothelial dysfunction and inflammation in asymtomatic proteinuria. Kidney
Int 63:624633
7. Becattini C, Agnelli G (2002) Pathogenesis of venous thromboembolism. Curr Opin Pulm Med 8(5):360364
8. Lopes AA, Maeda N, Bydlowski S (1998) Abnormalities in circulating von Willebrand factor and survival in pulmonary
hypertension. Am J Med 105:2126
9. Blann AD (1991) Increased circulating levels of von Willebrand
factor antigen in smokers may be due to lipid peroxides. Med Sci
Res 19:535536
10. Kannel WB, Wolf PA, Castelli WP et al (1987) Fibrinogen and
risk of cardiovascular disease. JAMA 258:11831186
11. American Thoracic Society (1995) Standardization of spirometry.
Am J Respir Crit Care Med 152:11071136
12. Autospiro Pal (1994) Operating instructions [product information].
Minato Medical Science Company Ltd, Osaka, Japan, pp 137
13. Hansen JM, Olsen NV, Feldt-Rasmussen B et al (1994) Albuminuria and overall capillary permeability of albumin in acute
altitude hypoxia. J Appl Physiol 76(5):19221927
14. Gogo A, Ciaccia A, Legorini C et al (2003) Proteinuria in COPD
patients with and without respiratory failure. Chest 123:652653

123

M. Polatli et al.
15. Sklar AH, Chaudhary BA (1988) Reversible proteinuria in
obstructive sleep apnea syndrome. Arch Intern Med 148:8789
16. Kilburn K, Dowell A (1971) Renal function in respiratory failure.
Effects of hypoxia, hyperoxia,and hypercapnia. Arch Intern Med
127:754762
17. Komurcuoglu A, Kalenci S, Kalenci D, et al (2002) Kronik obstruktif akciger hastalgnda mikroalbuminuri. Toraks Dergisi 31
34 (In Turkish)
18. Casserly LF, Chow N, Ali S et al (2001) Proteinuria in obstructive sleep apnea. Kidney Int 60:14841489
19. Pinto-Sietsma S, Mulder J, Janssen W et al (2000) Smoking is
related to albuminuria and abnormal renal function in nondiabetic
persons. Ann Intern Med 133:585591
20. Szakmany T, Molnar Z (2004) Increased glomerular permeability
and pulmonary dysfunction following major surgery: correlation
of microalbuminuria and PaO2/FiO2 ratio. Acta Anaesthesiol
Scand 48:704710
21. Pontremoli R, Nicolella C, Viazzi F et al (1998) Microalbuminuria is an early marker of target organ damage in essential
hypertension. Am J hypertens 11:430438
22. Hillege H, Fidler V, Gilles P et al (2002) Urinary albumin
excretion predicts cardiovascular and noncardiovascular mortality in general population. Circulation 106:17771782
23. Hirano T, Ookubo K, Kashiwazaki K et al (2000) Vascular
endothelial markers, von willebrand factor and thrombomodulin
index, are specifically elevated in type 2 diabetic patients with
nephropathy:comparison of primary renal disease. Clin Chim
Acta 299:6575
24. Jensen J, Myrup B, Borch-Johnsen K et al (1995) Aspects of
haemostatic function in healthy subjects with microalbuminuria.
A potential atherosclerotic risk factor. Thromb Res 77:423430
25. Rosemberg RD, Bauer KA (1994) The heparin antithrombin
system: a natural anticoagluant mechanism. In: Colman RW,
Hirsh J, Marder VJ, Salzman EW (eds) Haemostasis and
thrombosis: basic principles and clinical practice. Lippincott,
Philadelphia, pp 837860
26. Mannucci PM (1998) Von Willebrand Factor: A marker of
endothelial damage? Arterioscler Thromb Vasc Biol 18:1359
1362
_
27. McGill S, Ahmed N, Christou N (1998) Increased
plasma von
Willebrand factor in the systemic inflammatory response syndrome is derived from generalized endothelial cell activation.
Crit Care Med 26:296300
28. Kannel WB, DAgostino R, Belanger AJ (1987) Fibrinogen,
cigarette smoking and risk of cardiovascular disease: insights
from the Framingham study. Am Heart J 113:10061010
29. Maat MPM de, Pietersma A, Kofflard M et al (1996) Association
of plasma fibrinogen levels with coronary artery disease, smoking
and inflammatory markers. Atherosclerosis 121:185191
30. Dahl M, Hansen AT, 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 164:10081011
31. Boldy DA, Short PE, Cowen P et al (1998) Plasma levels of von
Willebrand Factor antigen in acute bronchitis and in a normal
population. Respir Med 92:395400