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The Coagulation-Fibrinolysis System in Patients With Leukoaraiosis and Binswanger Disease
Hidekazu Tomimoto, MD;
Ichiro Akiguchi, MD;
Ryo Ohtani, MD;
Hideo Yagi, MD;
Masutaro Kanda, MD;
Hiroshi Shibasaki, MD;
Yasumasa Yamamoto, MD
Arch Neurol. 2001;58:1620-1625.
ABSTRACT
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Background Hypercoagulability is observed in vascular dementia, including Binswanger
disease. However, the correlation between hypercoagulability, leukoaraiosis,
and dementia remains unclear.
Objective To examine how activation of the coagulation fibrinolysis correlates
with leukoaraiosis and dementia.
Patients and Methods Thrombin-antithrombin complex (TAT), prothrombin fragment1 + 2 (F1 + 2) and cross-linked D-dimer (XDP) were measured consecutively
in 18 subjects without dementia and with leukoaraiosis, and in 29 subjects
with subcortical vascular dementia and severe leukoaraiosis (Binswanger disease)
at either stable or deteriorating stages. They were compared with 19 patients
with old lacunar infarctions and 24 patients with other neurological diseases.
We also examined the indices of cognitive impairment and brain atrophy. In
each group, the ventricular area–cranial space area ratio was measured
by an image analyzer.
Results Patients with Binswanger disease who were exclusively at deteriorating
stages showed increased TAT and XDP levels and an increased ventricular area–cranial
space area ratio, as compared with the patients with other neurological diseases
(P<.001). The index of cognitive impairment in
patients at a deteriorating stage showed a decreasing trend vs that of patients
in the stable stage. Among the variables that were significantly associated
with a hypercoagulable condition (ie, age, scores on Mini-Mental State Examination
or the Hasegawa Dementia Rating Scale, Revised [MMSE/HDRS], white matter lesions,
ventricular area–cranial space area ratio, and C-reactive protein),
age (odds ratio [OR], 2.82) and MMSE/HDSR scores (OR, 0.43) survived as predictors
for coagulation activation, and C-reactive protein survived for fibrinolysis
activation (OR, 4.63) in multivariate analysis.
Conclusion Hypercoagulability in a subgroup of patients with Binswanger disease
and with more severe cognitive impairment and brain atrophy does not support
a triggering role for a coagulation-fibrinolysis system, although it may contribute
to worsening of neurological deficits.
INTRODUCTION
BINSWANGER DISEASE (BD) is a form of vascular dementia characterized
by diffuse white matter lesions and a varying degree of lacunar infarction
in the basal ganglia and white matter.1 Its
pathogenesis still remains uncertain, but fibrohyalinosis of the medullary
arteries resulting from long-standing hypertension has been thought to cause
the white matter lesions.2, 3
Previous investigations have revealed hematological disorders in patients
with BD. ß-Thromboglobulin, a marker of platelet activation, increases
in blood samples obtained from the internal jugular veins of patients with
BD, indicating the activation of platelets in the cerebral circulation.4 In patients with dementia, the coagulation-fibrinolysis
system is also activated,5 especially in those
with vascular dementia.6 Although there has
been no established therapy until recently, these observations may open a
new avenue for the treatment of vascular dementia with antiplatelet or antithrombin
drugs.7, 8
White matter lesions in small-artery diseases have previously been shown
to correlate with von Willebrand factor activity, but inversely with antithrombin
III, an inhibitory factor of the coagulation system regardless of cognitive
impairment.9 In our previous study,10 the coagulation markers were increased at the later
stages of BD; however, it remains unclear whether white matter lesions without
cognitive impairment are also associated with hypercoagulability. Our hypothesis
is that there may be a causal relationship between hypercoagulability and
dementia. To understand whether this may be a trigger or epiphenomenon during
cognitive decline, it is important to assess the coagulation-fibrinolysis
system during the preclinical or early stages of subcortical vascular dementia.
In the present study, we determined the causes of coagulation-fibrinolysis
system activation in patients with white matter lesions, manifesting dementia,
or no dementia and compared them with those in subjects with normal white
matter as the control group.
PATIENTS AND METHODS
PATIENTS AND CONTROL SUBJECTS
The study population consisted of 90 patients who were treated at our
institute and at affiliated hospitals from March 1997 to December 1999 (Table 1). These patients included 18 individuals
without dementia with diffuse white matter lesions (leukoaraiosis without
dementia group) and 29 patients with BD who had been assigned to this study
consecutively. The inclusion for the leukoaraiosis without dementia group
was based on the results of the clinical dementia rating (CDR) scale11 and magnetic resonance imaging (MRI) scans. All subjects
in the leukoaraiosis without dementia group had grade 2 or grade 3 white matter
lesions irrespective of the number of lacunar infarctions. The diagnosis of
BD was based on the clinical diagnostic criteria proposed by Bennett et al.12 Briefly, all of the patients had dementia, bilateral
diffuse subcortical hyperintense lesions (grade 3) on T2-weighted MRI scans,
and at least 2 of the following 3 clinical findings: (1) a vascular risk factor
or evidence of systemic vascular disease; (2) evidence of focal cerebrovascular
disease; and (3) evidence of "subcortical" cerebral dysfunction such as gait
disorders, parkinsonism, or incontinence. According to the neurological status,
the patients with BD were classified into either the stable or deteriorating
group. If there had been focal or subcortical cerebral dysfunction, as described
earlier, within the previous 3 months, then those patients were defined as
"deteriorating" based on their history, clinical profiles, and a follow-up
of their neurological findings.
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Table 1. Demographic Features of the Patients Evaluated*
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The lacunar infarction group consisted of 15 symptomatic patients at
the chronic stage and 4 asymptomatic patients. The other neurological disease
(OND) group consisted of 24 age-matched patients, excluding those with cerebrovascular
diseases (6 patients with cervical spondylosis: 3 each with vasovagal syncope
and neurosis; 2 each with dizziness, depression, essential tremor, and peripheral
neuropathy; and 1 each with migraine, brain tumor, restless leg syndrome,
and epilepsy). No one in the lacunar infarction or OND groups had significant
white matter lesions classified as grade 2 or grade 3 by the scale devised
by Schmidt et al.13
INVESTIGATIONS
The psychometric assessment consisted of CDR and Mini-Mental State Examination
administered in Japanese or the Hasegawa Dementia Rating Scale, Revised (MMSE/HDSR).
Peripheral blood samples were drawn from the antecubital vein of the nonparalyzed
arm, with minimal stasis, by means of a clean venipuncture. The blood samples
were collected into siliconized tubes that contained one-tenth volume of 3.8%
trisodium citrate, and were then centrifuged at 2300g
for 15 minutes at room temperature. These plasma samples were stored at -70°C
until used. The concentration of thrombin-antithrombin complex (TAT), prothrombin
fragment1 + 2 (F1 + 2), and cross-linked D-dimer (XDP)
was measured by enzyme-linked immunosorbent assays. Samples with TAT values
above the detection limit of the assays (60 ng/mL) were excluded from further
analysis because they were considered to be likely artifacts. In each patient,
brain MRI scans were performed to measure the size of the brain.
IMAGE ANALYSIS
Using computer-assisted image analysis of the MRI, the ventricular area–cranial
space area ratio was measured as an index of brain atrophy as previously described.14 Briefly, monochromatic photo images of the MRI at
the level of the basal ganglia and thalamus were digitized on a Macintosh
computer (PC7500; Apple Computers, Cupertino, Calif) with an LS-1000 film
scanner (Nikon, Tokyo, Japan) at a resolution of 1350 dots per inch. The images
were stored as 8-bit gray scale JPEG files (256 shades of gray), and the image
files were analyzed using National Institutes of Health image analyzer software
(National Institutes of Health, Bethesda, Md).
STATISTICAL ANALYSIS
The statistical significance of the intergroup differences was assessed
by the  2 test for categorical variables and by the Kruskal-Wallis
and Mann-Whitney U tests for continuous variables
using StatView II software (version 5.0 for Macintosh; SAS Institute, Cary,
NC). The association between the hemostatic markers and other variables was
first tested by a univariate logistic regression analysis. Covariates significant
at the P<.05 critical level were entered into
the multivariate model.
RESULTS
The 29 patients with BD all showed confluent or irregular periventricular
hyperintensities on their MRI scans, with varying degrees of lacunar infarction
in the basal ganglia and white matter. The severity of the dementia was mild
to severe, with CDR scores ranging from 1 to 3 and with MMSE/HDSR scores between
8/30 and 22/30. Other abnormal neurological findings included abulia, unsteady
gait, dysarthria, incontinence, sensory deficits, and hemiparesis. None of
the patients with BD fulfilled the modified version of the clinical criteria
on disseminated intravascular coagulation established by the Research Committee
of the Japanese Ministry of Health and Welfare (Tokyo).15
Family history was unremarkable in these patients.
The patients with BD were classified into the stable group (11 patients)
or the deteriorating group (18 patients who showed subacute aggravation of
either focal or "subcortical" cerebral dysfunctions) (Table 1). In the stable group, no obvious focal neurological deficits
had emerged during the past 3 months, whereas 6 of the 18 deteriorating patients
with BD had evidence of recent lacunar infarctions, and 4 of those showed
mild hemiparesis. The lacunae observed on the MRI scan were judged to be responsible
for the deterioration if they appeared to be fresh or if they corresponded
with the emerging neurological deficits or "subcortical" dysfunction. Antiplatelet
drugs were prescribed in 3 of the 11 stable patients with BD, and in 2 out
of the 18 deteriorating patients with BD before the aggravation. Anticoagulants
were not used in either group.
There were no significant differences in age between the leukoaraiosis
without dementia, BD, lacunar infarction, and OND groups (Table 1). Among demographic variables, hypertension and previous
stroke were more frequent in the former 3 groups, and microalbuminuria and
the elevated C-reactive protein (CRP) values were more frequent in the BD
group (Table 1).
The number of lacunae did not differ among the groups, except for the
OND group. No significant white matter lesions were observed in either the
OND or lacunar infarction group. The scores on the MMSE/HDSR and CDR remained
within the normal range in the leukoaraiosis without dementia, lacunar infarction,
and OND groups. On the contrary, the mean ± SD MMSE/HDSR scores were
16.9 ± 4.9 and 12.2 ± 5.8 in the stable and deteriorating BD
groups, respectively, and the mean ± SD CDR scores were 1.50 ±
0.58 and 2.31 ± 0.86, respectively, showing a trend toward worsening
in the latter BD group (P = .09 for the MMSE/HDSR
and P = .09 for the CDR). The mean ± SD ventricular
area–cranial space area ratios were 9.9 ± 3.2 in the leukoaraiosis
without dementia group, 10.3 ± 2.7 in the stable BD group, 12.6 ±
4.5 in the deteriorating BD group, 9.5 ± 2.2 in the lacunar infarction
group, and 7.0 ± 2.3 in the OND group. There were intergroup differences
in this ratio, with the deteriorating BD group's being higher (P<.01) than that of the OND group.
In the leukoaraiosis without dementia, stable BD, and lacunar infarction
groups, the TAT, F1 + 2, and XDP levels did not differ from those
in the OND group (Table 2). In
contrast, the patients with deteriorating BD showed higher TAT and XDP levels
(P<.001) as compared with patients in the OND
group. There were intergroup differences, with higher F1 + 2 and
fibrinogen values in the patients with BD (Table 2).
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Table 2. Indices of the Coagulation-Fibrinolysis System Among Different
Groups*
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The multivariable relationship between the 5 predictor variables and
the 2 outcome variables is presented in Table 3. Age, the MMSE/HDSR score, leukoaraiosis, ventricular area–cranial
space area ratio, and CRP levels were significant predictors for activation
of the coagulation-fibrinolysis system as determined by a TAT level of greater
than 7.0 ng/mL and and an XDP level of greater than 300 ng/mL. Age was a significant
predictor for an F1 + 2 level of greater than 1.8 nmol/mL. For
more definitive analysis, these parameters were entered into a multivariate
model as predictors of a TAT level of greater than 7.0 ng/mL and an XDP level
of greater than 300 ng/mL. Only age and the MMSE/HDSR scores were retained
in this model, with P<.10 as a predictor for the
TAT values and the CRP levels as a predictor for the XDP values.
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Table 3. Factors Associated With Activation of the Coagulation-Fibrinolysis
System Using a Logistic Regression Model*
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COMMENT
The white matter lesions are characterized pathologically by incomplete
infarction, état criblé, perivascular demyelination, and gliosis;
they correspond mostly to leukoaraiosis on radiological diagnosis.16, 17 A clinicopathologic correlation using
MRI and autopsy specimens underscores the validity of the diagnostic criteria
for BD,18 although the autopsy findings are
generally more comprehensive and decisive for the diagnosis of BD.
During the group comparisons, the coagulation-fibrinolysis system remained
normal in the leukoaraiosis without dementia group, but was activated in a
subgroup of the patients with BD (Table
2), who had been shown to have brain atrophy and more severe dementia.
On multivariate analysis, age and cognitive impairment were predictors for
coagulation activation, and the CRP levels were predictors for fibrinolysis
activation. Brain atrophy and leukoaraiosis were significantly correlated
with coagulation-fibrinolysis system activation on the univariate analysis;
however, these 2 factors were not independent predictors on the multivariate
analysis.
On the diffusion-weighted MRI scans, hyperintense lesions frequently
emerged in patients with a stepwise decline in vascular dementia.19 Therefore, the frequency of fresh lacunar infarctions
in the patients with deteriorating BD (33%) may vary depending on the sensitivity
of the detection method. However, since neurological deterioration frequently
occurs throughout an extended period, and the coagulation-fibrinolysis system
is not activated even at the acute stage of lacunar infarction without extensive
white matter lesions,20 the deterioration may
not necessarily result from the lacunar infarctions per se. It is more likely
that the deterioration observed in BD is related to diffuse small-artery disease
and subsequent microcirculatory disturbances, with or without lacunar infarction.
There may be a concern for artifactual increases in the TAT levels or
high variability resulting from its short half-life. However, this possibility
seems unlikely since the outlier TAT values were eliminated from the present
analysis, and the TAT levels strongly correlated to the D-dimer levels, which
have a much longer half-life. The hemostatic markers may be elevated in disseminated
intravascular coagulation, peripheral arterial disease, pancreatitis, pregnancy,
and metastatic carcinoma; however, none of these conditions were found in
a significant proportion in the present study. Hypercoagulability may also
be encountered in very elderly people, without any complications,21 but this possibility has been excluded. Considering
that hypercoagulability was not observed in the leukoaraiosis without dementia
group and was associated with brain atrophy or more severe dementia in the
BD group, other factors besides the coagulation-fibrinolysis system may be
a trigger for this pathologic process.
Cerebral blood flow is decreased, with oxygen extraction fraction being
elevated, in subjects with leukoaraiosis without dementia.22
Therefore, chronic cerebral ischemia may initiate the pathologic process of
white matter lesions. In a rat model, white matter lesions can be induced
by chronic cerebral hypoperfusion after clipping the common carotid arteries
bilaterally.23 Astroglia and microglia, being
activated in white matter lesions in both rat and humans,23, 24
may mediate the inflammatory response by secreting cytotoxic substances such
as proinflammatory cytokines, reactive oxygen intermediates, and nitric oxide,
and may thus contribute to their pathogenesis.
Both CRP and fibrinogen are acute phase–reactant in inflammation.
C-reactive protein enhances the production of tissue factor and proinflammatory
cytokines, interleukin 1, and tumor necrosis factor  by monocytes and
macrophages.25, 26 High CRP values
in association with elevated XDP levels in the patients with BD may result
from subclinical infection, but may alternatively reflect an inflammatory
response after cerebrovascular disease.27, 28, 29
An increase of fibrinogen has been previously reported in patients with BD.30, 31 It is generally agreed that high
levels of fibrinogen, one of the major determinants of plasma viscosity, have
a hemorheological effect, and may lead to a state of hypoperfusion that results
in impaired cerebral microcirculation.32 This
effect may be especially true in brains with BD, in which the medullary arteries,
arterioles, and capillaries are thickened by fibrohyalinosis.3
Although it may occur at the later stages of BD, thrombin generation
is likely to cause microcirculatory disturbances by way of endothelial activation.33 Thrombin may also damage neural tissues directly
by enhancing vascular permeability,34 inducing
apoptosis in the neurons35 and nitric oxide
in the glial cells, as well as by a suppression of neurite outgrowth.36 Several lines of clinical evidence also suggest that
activation of the coagulation-fibrinolysis system may further aggravate the
neurological status of patients with BD. First, white matter lesions and dementia
are frequently observed in hypercoagulable conditions related to activated
protein C resistance.37, 38 Second,
its sustained activation may be a risk for recurrence of ischemic cerebrovascular
diseases.39 Finally, antithrombin drugs seemed
to be effective in the treatment of vascular dementia, including BD, in preliminary
trials.9, 40 Therefore, further
studies seem warranted to determine whether coagulation-fibrinolysis system
activation may exacerbate the neurological dysfunction in patients with BD,
and whether those patients with coagulation-fibrinolysis system activation
have a poorer prognosis.
AUTHOR INFORMATION
Accepted for publication May 14, 2001.
This work was supported by a grant from the Takeda Medical Research
Foundation (Osaka, Japan) and a grant from the Sasagawa Foundation (Tokyo).
We are grateful to Midori Yotsutsuji, BA, Satoshi Ogura, MD (Koseikai
Takeda Hospital, Kyoto), and Masamiori Hayashi, MD (Kyoto Second Red Cross
Hospital, Kyoto) for their help in sampling the data.
From the Department of Neurology, Faculty of Medicine, Kyoto University,
Kyoto, Japan (Drs Tomimoto, Akiguchi, Ohtani, Yagi, Kanda, and Shibasaki),
and the Department of Neurology, Kyoto Second Red Cross Hospital, Kyoto (Dr
Yamamoto).
Corresponding author: Hidekazu Tomimoto, MD, Department of Neurology,
Faculty of Medicine, Kyoto University, Kyoto 606-8507, Japan (e-mail:
tomimoto{at}isola.kuhp.kyoto-u.ac.jp).
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