J.Neurol.Sci.

[Turk]

Journal of Neurological Sciences [Turkish] 24:(1)# 10;64-69, 2007

http://www.jns.dergisi.org/text.php3?id=135
Research Article
The Role Of Acute Phase Reactants In Acute Ischemic Stroke
Ufuk EMRE1, Ufuk ERGN2, Aysun NAL1, zlem COKUN2, H.Turul ATASOY1, Hulya
YILDIZ3, mit GEDKOLU2, E.Levent NAN2
1
Zonguldak Karaelmas University , Medical Faculty, Department of Neurology , Zonguldak, Trkiye
2
Ministry of Health, Ankara Resarch Hospital, Department of Neurology, Ankara, Trkiye 3Ministry of
Health, Kazan Hospital, Department of Neurology, Ankara, Trkiye
Abstract
Inflammatory factors play an important role in the pathogenesis of ischemic stroke. The aim of our
study was to determine the influence of fibrinogen, C-reactive protein and other acute-phase reactant
levels in acute ischemic stroke. This study involves forty -three patients. The control group was
formed out of thirty-seven. The blood samples were drawn to measure serum fibrinogen, ferritin, CRP
levels, white blood cell (WBC), erythrocyte sedimentation rate (ESR). Within 24-72 hours, the
patients serum fibrinogen, ferritin and CRP values were higher than the control group. In addition, the
levels of fibrinogen and CRP were found to be higher than the patients whose clinical health was poor.
Acute phase proteins level such a fibrinogen, CRP, ferritin increase after acute ischemic stroke. These
findings support a possible role of an inflammatory stimulus in the acute ischemic stroke.
Keywords: Acute Ischemic Stroke, Fibrinogen, Acute Phase Reactants
Akut skemik Strokta Akut Faz Reaktanlarnn Rol
zet
skemik strok patogenezinde inflamatuar faktrler nemli rol oynar. Bu almada, akut iskemik
strokta fibrinojen, C-reaktif protein ve dier akut faz reaktanlarnn dzeylerini saptamay amaladk.
almaya 43 hasta dahil edildi. Kontrol grubu 37 kiiden oluturuldu. lk 24-72 saat iinde serum
fibrinogen, ferritin, CRP dzeyi, beyaz kre(BK),Eritrosit sedimantasyon hz (ESH) lmleri iin
kan rnekleri alnd. lk 24-72 saat iinde, hastalarn serum fibrinojen, ferritin ve CRP deerleri
kontrol grubundan yksekti. Klinii kt olan hastalarda fibrinojen ve CRP dzeyleri daha yksek
bulundu. Fibrinojen, CRP, ferritin gibi akut faz proteinlerin dzeyi akut iskemik strok sonras artar. Bu
bulgular akut iskemik stokta inflamatuar stimulusun muhtemel bir rol olduunu desteklemektedir.
Anahtar Kelimeler: Akut iskemik strok, Fibrinojen, Akut faz reaktanlar

INTRODUCTION as CRP strongly predicts the risk of carotid

Stroke is the third cause of mortality and
the first cause of disability. Recent
literatures have demonstrated that
inflammation contributes to all phases of
atherosclerosis. The results of researches
suggest that atherosclerosis is an
inflammatory disease(9). In acute phase of
cerebrovascular diseases, biochemical
markers of inflammation could be useful to
predict severity of stroke(18). Fibrinogen is
a well known acute phase protein and risk
factor for myocardial infarction and stroke.
High fibrinogen levels represent an acute
phase response in early acute stroke(24).
One of other inflammatory markers, such
stenosis, first stroke and post stroke
mortality (16). In addition, increased CRP
levels are related with poor prognosis in
short follow-up period(6). There are some
evidences about the significant role of iron
(Fe+2) in cerebral damage(4). The role of
iron in acute ischemic stroke has been
investigated; as a result of this research,
there may be relationship between high
iron level and poor prognosis(11).
In this study, we aimed to evaluate the role
of fibrinogen, C-reactive protein and other
acute-phase proteins levels in the patients
with acute ischemic stroke, in acute period
(the first 24-72 hours).

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METHODS CT scan of the brain was performed in first

Forty-three patients (23 female, 20 male)
who have been diagnosed as acute
ischemic stroke, in neurology department
of Ankara Hospital, between June 2001
and December 2001 were included in this
study. The average of ages was 64,9 11,6.
The control group, age and sex matched,
included 37 people ( 24 female, 13 male),
admitted to neurology clinic, all of them
have no known vascular risk factors. In
control group, the average of ages was
62,4 12.
Exclusion criteria for all subjects were
trauma, severe liver disease, renal failure,
cancer, cerebral hemorrhage, acute
myocardial infract, deep vein thrombosis,
anti-coagulant or iron treatments, chronic
inflammatory diseases, fever or acute
inflammatory or infectious conditions. In
addition, there werent any surgical
operation or invasive operations (e.g.
angiography) within the last 3-6 months.
24-72 hours for all patients. Blood samples
were obtained within 24-72 hours after
qualifying stroke. Serum fibrinogen,
ferritin, CRP, white blood cell (WBC) and
erythrocyte sedimentation rate (ESR) were
measured.
The fibrinogen level was measured by
Date Behring automation; the normal range
is 189-350 mg/dl. The levels of CRP were
determined by immuno nephelometric ,
latex-enhanced assay (Dade Behring).
The time of stroke was indicated as the
period between the initiation of stroke and
the time the blood sample had been
obtained.
The stroke severity score (SSS) performed
by Wang was used to determine the degree
of affection from stroke (26) (Table I). In
this scale the high score indicates severity
of the stroke.

Table-I: Stroke severity classification

Consciousness level
Consciousness (0)
Subconsciousness(1)
Unconsciousness (2)
Aphasia
Mixed aphasia (2)
Sensorial aphasia (1)
Motor aphasia (1)
Absent of aphasia (0)
Cranial nerve involvement (CNI)
Tree CNI (3)
Two CNI (2)
One CNI (1)
No CNI (0)
Motor examination
Quadriplegia (4)
Hemiplegia (3)
Hemiparesis (2)
Monoparesis (1)
None (0)
Sensory examination
Hypoestesia (+) (1)
Hypoestesia (-) (0)
Cerebellar examination
Bilateral involvement (2)
Unilateral involvement (1)
None (0)
Urinary incontinence
Positive (1)
Negative (0)

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J.Neurol.Sci.[Turk]
RESULTS
There was no difference between the age
of patient and control group (p>0,005, t
test).
The fibrinogen level was higher in patient
group (p< 0,001).
The ferritin (102,67) and CRP (25,53)
(mean=10,5) values of patient group were
higher than the control group (635)
(median=51,3) (p<0,01), (4,83)
(mean=3,13) (p<0,001) within 3 days.
WBC counts in the patients (10 062 37)
were higher than the control group (7
20016) (p<0,001).
Regarding the levels of hematocrit
(p>0,05), iron (p>0,01), transferrin
(p>0,05), capacity of binding total serum
iron (p>0,05), ESR values (29,816)
(mean=24) (23,813)(mean=21) and
platelet counts (250 697,874) (265
783,855 )(p>0,05); there were no
difference between two groups.
By using spearsman correlation analysis,
there was a relationship between
fibrinogen levels of patients and stroke
severity score (p<0,05)(r=3814), which
indicated the increase in the fibrinogen
levels was associated with stroke severity.
There was a statistically significant relation
between SSS and levels of CRP in the
patient group (p<0,05)(r=,3379).
A significant relation between levels of
CRP and ferritin within the first 24-72
hours (p<0,01) was found based on the
research results. On the contrary, it was
proved that there was no relation between
SSS and ferritin values (p>0,05)(r=, 1636).
There was a correlation between level of
fibrinogen and CRP (p<0,05), ESR
(p<0,01) (analysis of Pearson correlation).
According to this data, increased
fibrinogen levels were found to associate
with increased CRP and ESR.
STATISTICAL METHODS
The variables found were compared
according to values of standard deflection
and median values. Median values between
66
groups were determined by using student t
test, Mann-Whitney U, Chi-square,
Pearson correlation coefficient, Spearman
correlation coefficient and Kruskal-Wallis
variant analysis.
DISCUSSION
Atherosclerosis is a response to vessel wall
injury, in which many features of an
inflammatory process take part (11). In other
words, there is growing evidence that
inflammation plays an important role in the
pathophysiology of stroke(22). Brain tissue
is damaged after acute ischemic stroke, is
mediated partly by inflammation induced
by ischaemiareperfusion (I/R) injury.
Inflammatory mechanisms contribute to
stroke risk via various interrelated
mechanisms. The inflammatory parameters
such as CRP, fibrinogen or leukocyte
counts measured before ischemia are
independent predictors of first or recurrent
ischemic stroke (19).
Fibrinogen is involved in primary
hemostasis, platelet aggregation, and
leukocyte-endothelial cell interactions and
is the major determinant of whole blood
and plasma viscosity (23). Fibrinogen levels
increase after an acute stroke (11). In the
past, the phenomenon was attributed
almost exclusively to an acute-phase
reaction due to brain tissue necrosis.
However, plasma viscosity and fibrinogen
significantly increase in patients with
transient ischemic attacks, suggesting that
fibrinogen levels are elevated before the
stroke (12). Similarly, in this study,
fibrinogen levels of patient group has been
found higher than the control group. There
was also difference between the values of
first 24 hours and 48-72 hours. Regarding
the time, the concentration of fibrinogen
increased.
In this study, a positive correlation
between SSS and fibrinogen levels in the
acute period was observed, which has
indicated relation between poor outcome
and fibrinogen. Similarly, Cojocaru et al
reported that high significant values of
J.Neurol.Sci.[Turk]
ferritin and CRP, fibrinogen, C3, alpha 1-
antitrypsin (AAT), alpha 1-chymotrypsin
were observed in patients with poor
outcome(3).
Another significant point to be considered
here is that genetic predisposition of the
inflammatory host response may be an
important codeterminant for atherogenesis
and stroke risk(17). In addition to the
genetic factors, for some researchers
gender can also be accepted as an
important factor in the levels of fibrinogen.
For example, Ernest et al reported that
women have higher values of fibrinogen
than men(11). However, in this study, no
differences between sexes in terms of
fibrinogen concentration (both patient
group and control group) were found
For the patients with acute ischemic stroke,
levels of acute phase proteins (CRP,
fibrinogen, AAT..) were found high, which
suggests that ischemic necrosis is
associated with inflammatory reactions(2).
Brain ischemia elicits an inflammatory
response with a rapid accumulation of
granulocytes and later of mononuclear
leukocytes around the infarct zone(10). In a
recent study, increased levels of CRP are
reported to be associated with a worse
outcome in patients with ischemic stroke(6).
Napoli et al reported elevated levels of
CRP after ischemic stroke can identify
patients with increased risk for disability
and mortality(5). Elevated levels of CRP
can reflect the extent of brain infarction(6,7).
CRP concentration is an independent
predictor of survival after ischemic stroke.
These findings are consistent with the role
for inflammation in acute ischemic stroke,
as well as with the hypothesis that elevated
CRP may predict future cardiovascular
mortality(21). Briefly, the fibrinogen and
CRP have a close relationship as
inflammatory markers in the acute phase of
ischemic stroke(25). In this study, which
supports the previous ones, it has been
found out that CRP levels in the patient
were higher than in the control group
levels. There is a relation between CRP
67
and SSS. There is higher CRP level in the
patients whose clinical health was poor and
high SSS
Studies demonstrate that leukocyte count
independently predicts ischemic risk(14,20).
Leukocytes, including macrophages and
lympho-cytes, play an important role in the
initiation and propagation of the
atherosclerotic process(8). In this study, the
white blood count in the patients was
higher than the controls in the acute period.
On the contrary, there was no difference in
the ESR values between the two groups.
It is suggested that high serum ferritin
levels within the first day of hospitalization
for an acute ischemic stroke are related to
poor prognosis(4). Oxidative metabolism
during ischaemic stroke together with high
iron content in the brain synergise to
increase the oxidative damage. High
plasma ferritin, as a measurement of iron
stores, and high cerebrospinal fluid ferritin
have been related to poor outcome in
stroke patients(1). Serum ferritin level and
large size of lesion were independently
associated with mortality. Increased serum
ferritin levels correlate to severity of stroke
and the size of the lesion(13).
In this study, concentration of ferritin was
higher in the patient group within the first
24-72 hours and is correlated with levels of
fibrinogen and CRP. However, there is no
relation between ferritin and SSS levels.
The levels of ferritin may be different in
the stroke subtypes. In this study, the
stroke subtypes and the lesion sizes were
not determined. Like ferritin, the
evaluation of all other parameters via these
two tables is undoubtedly significant.
Thus, an important question to be asked at
this step is that if the results would have
changed if the subtypes and the lesion sizes
were taken into consideration. In fact, this
might be a limitation of this study.
In conclusion, the inflammatory reactions
in which acute phase reactants play role,
are activated in acute ischemic stroke and
generally, this state relates to severity of
disease. The results of this study supported
J.Neurol.Sci.[Turk]
the argument that mainly fibrinogen,
ferittin and CRP increase after acute
ischemic stroke and they have a close
relationship. Decreasing these factors in
the acute period (e.g. iron chelating agents,
anti-inflammatory agents), may be useful
in terms of cerebral injury. Exercise,
giving up smoking and clofibrate may
decrease fibrinogen levels. Moreover,
ancrod has been reported to decrease
fibrinogen levels(15). These parameters will
be important to follow both healthy people
and patients with stroke in terms of
vascular disease in the future.
Correspondence to
Ufuk Emre
E-mail: ufuemr@gmail.com
Received by: November 19 2006
Revised by: November 21 2006
Accepted : December 14 2006
The Online Journal of Neurological
Sciences (Turkish) 1984-2005
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Journal of Neurological Sciences (Turkish)
Abbr: J. Neurol. Sci.[Turk]
ISSNe 1302-1664
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