THE MINISTRY OF EDUCATION
THE MINISTRY OF
MILITARY MEDICAL UNIVERSITY
LE VAN MINH
INVESTIGATION ON CLINICAL FEATURES, BRAIN
IMAGING, A NUMBER OF RIKS FACTORS AND THE
VALUE OF D-DIMER IN DIAGNOSIS OF CEREBRAL
Code: 62 72 01 47
MD-PhD. THESIS SUMMARY
HANOI - 2014
THE THESIS WAS COMPLETED AT MILITARY
A.Prof. Dr. PHAN VIET NGA
A. Prof. Dr.PHAM NGOC HOA
The thesis will be upheld before the University Grade Thesis
The thesis can be found at:
- National library
- Military medical university’s library
Cerebral venous thrombosis (CVT) is estimated to account
for 0.5% of all strokes in adults. In recent years, with the present of
non-invasive and high accuracy diagnostic techniques such as
magnetic resonance imaging and computed tomography, the rate of
diagnosis of CVT also increases.
Congenital Thrombophilia states account a high rate in white
skin peoples and make up 15-30% cases of patients with venous
thrombosis. D-dimer test is an inexpensive and commonly available
method which has high performance in diagnosis of CVT as proven
by some prospective and meta-analytic studies. Moreover, at present
there is no published study on the role of D-dimer test in the
diagnosis of CVT in our country.
In Vietnam, there have been many studies on aspects of
stroke. However, there are few studies on CVT, therefore we
decided to study CVT with the following objectives:
OBJECTIVES OF THE STUDY
1. To describe some clinical features and brain images of CVT.
2. To review some risk factors of CVT.
3. To determine the sensitivity, specificity, positive predictive value
and negative predictive value of D-dimer test in the diagnosis of
NEW CONTRIBUTION OF THE THESIS
1. Our study described some clinical features and brain images of
2. Our study found some genetic and acquired risk factors of CVT.
3. Our study successfully determined the role of D-dimer test in the
diagnosis of CVT.
The thesis includes 115 pages, with 4 chapters, 43 tables, 16 charts,
1 diagram, 8 Vietnamese references and 83 English references. 3 pages
forewords, 35 pages overview, 19 pages subjects and methods, 24
pages results, 31 pages discussion, 2 pages conclusion, 1 page
Chapter 1 - OVERVIEW
1.1.1. Anatomy of cerebral veins and sinous
The veins of the brain have no muscular tissue in their thin
walls and possess no valves as compared to other types of veins.
They emerge from the brain and lie in the subarachnoid space.
They pierce the arachnoid mater and the meningeal layer of the
dura and drain into the cranial venous sinuses. Blood from both
brain is drained by cerebral veins into dural sinuses and then into
the jugular. Cerebral veins is divided into 3 important groups
which are superfical cerebral veins, deep cerebral veins and
posterior fossa veins.
1.1.3. Pathogenesis of cerebral venous thrombosis
Causes of CVT are diverse. According to the hypothesis of
Rudolf Vichow: there are 3 basic factors contributing in the
formation of venous thrombosis: venous congestion; hypercoagulable
state; vascular injuries. Most of the main factors causing thrombosis
are venous congestion and hypercoagulable state.
Clinical symptoms of CVT are diverse, non-specific and the
symptom onset in cerebral venous thrombosis is usually subacute
(2 days to 1 month), in some cases it can be acute (2 days or less)
and simulate arterial stroke (20-30%). In patients presenting isolated
intracranial hypertension like brain tumor, the onset of symptoms an
be chronic. Depending on the location of the thrombosis and the
collateral blood flow, and patient’s age, the range of clinical
astonishingly varied, and its clinical presentation is extremely
variable and unspecific. The progression of deep CVT may be
gradually severe or variable depending on the status of intracranial
pressure with or without accompanied seizures. Besides, CVT is
often symmetry and hemorrhagic transformation of the lesion is quite
1.3.2. Magnetic resonance imaging
22.214.171.124. Magnetic resonance imaging (MRI)
Magnetic resonance imaging in combination with magnetic
resonance venography (MRV) imaging provide a best non-invasive
technique for the diagnosis of CVT which is considered as a gold
standard and can replace invasive conventional cerebral angiography
and is used as a leading mean of diagnosis in case with clinical
suspicion of cerebral venous thrombosis.
Advantages of magnetic
resonance imaging are it can survey the blood flow and allow us to
see the direct imaging of the venous sinous thrombosis and brain
1.3.4. D-dimer in diagnosis of cerebral venous thrombosis
126.96.36.199. Biochemical characteristics of D-dimer
D-dimer, the final product of plasma in-mediated degradation
of fibrin-rich thrombi. It is a small protein chain in blood after a
clot is fibrinated. After the formation of a clot, the hemolytic path
is triggered with plasminogen is activated to plasmin. Then plasmin
cut fibrin at E-D bonds to form separate D-D segments called Ddimer (2D).
1.4. RISK FACTORS
These risk factors are often related to Virchow's triad. The
markers such as: antithrombin, protein C, protein S, V Leiden factor
or activated protein C are considered as point markers of congenital
thrombophilia. The deficiency of antithrombin (AT), protein C (PC)
or protein S (PS) or the present of V Leiden factor (FVL) will
increase the risk of thrombosis, each factor is listed hereunder.
Chapter 2: SUBJECTS AND METHODS OF THE STUDY
2.1. SUBJECTS OF THE STUDY
2.1.1. Group of patients with cerebral venous thrombosis
We chose patients ≥ 16 years old who had been diagnosed
with CVT at the Department of Neurology, Cho Ray Hospital from
January 2010 to May 2012 based on the following inclusion criteria:
INCLUSION CRITERIA patients had all criteria as follows:
Clinically suspected to have CVT: when the patients got one of
the following criteria:
Abnormal headache with acute, subacute or chronic onset
and a history did not relate to cluster headache, migraine
headache or muscle tension headache.
Atypical headache accompanying vomiting and did not
reponse to conventional treatment methods.
Clinical signs of brain injury (focal neurological signs,
seizures, disorders of consciousness).
Images of ischemic stroke on computerized tomography film
showed atypically distribution along cerebral artery.
b) Found images of CVT by using routine magnetic resonance
imaging in combination with magnetic resonance imaging of
vein and/or routine magnetic imaging in combination with
computerized tomography of cerebral vein and/or cerebral
angiography with DSA technique.
1. Patients using anticoagulants.
2. Patients were diagnosed with deep vein thrombosis or
pulmonary embolism and/or calf vein thrombosis.
3. Patients with signs of disseminated intravascular coagulation.
4. Patients had experienced major surgery or severe trauma
within 3 months.
5. Patients did not agree to participate in the study.
2.1.2. Control group
We chose 57 people who came for periodic health
examination at Cho Ray Hospital and they voluntarily participated in
the study. All these cases were carefully clinically examined and
tested. Protein S, Protein C, ATIII, V Leiden factor, D-dimer.
2.2. METHODS OF THE STUDY
This is a prospective, cross-sectional descriptive study with
2.2.1. Clinical study
All patients were clinically evaluated risk factors according
to a common data collection form and were treated according to a
unique regime at the Department of Neurology, Cho Ray Hospital.
2.2.2. Subclinical study
All patient with clinical signs of CVT were examined the
Investigation on features of CVT images using magnetic
Investigation on rick factor protein S.
Investigation on risk factor protein C.
Investigation on ATIII risk factor.
Investigation on V Leiden risk factor.
Investigation on blood D-dimer concentration.
Chapter 3 - RESULTS OF THE STUDY
3.1. SOME GENERAL CHARACTERISTICS OF PATIENTS
There were 59 patients with cerebral venous thrombosis
(experimental group) and 57 people in the control group. The
male/female ratio in the experimental group was 1/0.78, and in the
control group was 1/0.72.
The percent of patients aged 21 to 50 accounted a majority of
both groups, wherein, the experimental group had 47 patients
(82.46%), and the control group had 41 patients (71.93%). The
percent of patients aged less than 20 was mostly equivalent between
both groups (6.78% vs 7.02%). In the experimental group, the
percent of patients with subacute onset was 79.7%, patients with
acute onset was 11.8% and patients with chronic onset was 8.5%.
3.2. CLINICAL CHARACTERISTICS
Table 3.7: Clinical symptoms on admission
Number of patients
Cranial nerve palsy
3.3. IMAGING CHARACTERISTICS
3.3.2. Location of cerebral venous thrombosis
Table 3.16: Characteristics on location of cerebral venous thrombosis
of 57 patients tested by magnetic resonance imaging
Superior sagittal sinus
Inferior sagittal sinus
Deep cerebral veins
Internal jugular veins
≥ 2 veins had blood clots
Comment: The location of cerebral veins mostly affected by
thrombosis on the images obtained by magnetic resonance imaging
was superior sagittal sinuses with 43 cases (75.54%), next to
transverse sinuses with 37 cases (64.91%).
3.3.3. Brain parenchymal abnormalities on magnetic resonance
Among 57 patients with CVT, patients with hemorrhagic
transformation accounted the highest percent (36.84%), followed by
patients with infarction alone (22.81%), and hemorrhage (21.05%).
Subarachnoid hemorrhage accounted smallest percent (10.53%).
3.4. RISK FACTORS OF CVT
3.4.1. Risk factors of primary thrombophilia
Table 3.20: Prevalence of primary thrombophilia
Number of patients
V Leiden factor
≥ 2 risk factors
≥ 3 risk factors
4 risk factors
3.4.2. Factors of acquired thrombophilia
Table 3.25: Status of administration with oral contraceptive drugs in
Number of patients
2 = 4.2; p = 0.04; OR = 4.05 (CI 95%, 0.88-25.1)
Table 3.26: Status of pregnancy in female patients
Number of patients
2 = 1.06 ; p = 0.361
Comment: There was no statistically significant difference on CVT
between pregnancy group and non-pregnancy group with p = 0.361.
Table 3.27: Puerperium characteristics on female patients
Number of patients
2 = 7.5 ; p = 0.006
Comment: There was a statistically significant difference on
number of patients with CVT between Puerperium group and control
3.5. CHARACTERISTICS OF D-DIMER TEST
3.5.1. Comparison of mean D-dimer concentration between two
Table 3.29: D-dimer concentration (µg/L) of patients
1272.5 - 2509
115.03 - 177.35
Non-uniform variance T-test t = -5.63; p = 0.000
3.5.3. Identify the cut off of D-dimer test
Table 3.31: Cut off of D-dimer concentration
Cut off (µg/L)
Area under ROC
Chapter 4 - DISCUSSION
4.1.SOME GENERAL CHARACTERISTICS OF PATIENTS
In all 59 cases with CVT, we diagnosed based on clinical
criteria and had CVT images obtained using magnetic resonance
imaging, computerized tomography and DSA.
In our study, the percent of female patients with CVT was
higher than percent of male patients with CVT (55.93% vs 44.7%),
with the female/male ratio was 1/0.78. According to the study of
Tanislav, among 39 patients with CVT, the percent of female patients
was significantly higher than the percent of male patients (71% vs
29%). According to the study of Khealani, among 109 patients, the
percent of female patients was higher than the percent of male
patients (53% vs 47%).
Overall, our study was similar to other studies of other
authors with the percent of female patients with CVT was higher than
the percent of male patients, especially female patients in
childbearing age, this suggested that the risk of CVT may relate to
pregnancy, puerperium and birth control drugs.
Mean age of patients in our study was 37.8, wherein percent
of patients aged from 21 to 50 was 82.46%, percent of patients aged
> 50 was 13.56%.
According to the study of Nguyen Ngoc Hung on 37 patients
with CVT, the mean age was 38.7. A retrospective study on 48
patients with CVT of Terazzi et al. in 2004 showed that the mean age
of CVT patients was 44.8. According to the study of Ferro, in 624
patients with CVT, there was 92.8% of patients < 65 years old.
Thus, according to above stated studies, the mean age of
adult patients with CVT was 32.7 to 44.8. Result of mean age in our
study was also withing this range and was not significantly different
to other studies of other authors worldwide.
Onset time and diagnosis time
In our study, the number of patients with subacute onset
accounted the highest percent (79.7%) followed by acute onset.
According to Paciaroni, onset of CVT is commonly subacute (2 days
to 1 month) with 50-80% of all cases, but sometimes it suddenly
occurs with acute onset (< 2 days) like stroke (20-30% of all cases).
In some cases, the clinical symptoms of CVT are similar to cerebral
tumors, and there are few cases CVT occurs with clinical signs are
increased intracranial pressure, and chronic symptoms at the onset
(>1 month), 10-20%. According to the study of Terazzi, in 48
patients with CVT, the percent of patients with acute onset was 44%,
subacute onset was 35% and chronic onset was 21%. In general, the
onset characteristics of CVT are varied, but the majority of patients
have cubacute onset and our study data was equivalent to the result of
4.2. CLINICAL CHARACTERISTICS
4.2.1. Symptoms and onset time
Headache: In our study, the headache was most common
with a rate of 98.31% of all cases. This result is similar to the result
of the study of Le Van Thinh and Trinh Tien Luc with headache
accounted 88%. In general, it is like other studies of other authors,
headache was most common and presented with highest rate in these
Paraparesis: Similar to results of other studies of other
authors, our study found that the symptom of paraparesis ranked the
2nd position after headache with a percent of 57.63%. Signs of this
symptom were mainly 4th degree (25.5%), 3rd degree (13.5%), 2nd
degree (10.6%). According to the study of Tanislav et al., this
symptom also ranked the 2nd position after headache (69%) with a
rate of 44%. In general, the percent of patients with paraparesis
symptom in our study was equivalent to results from others studies of
other authors and the similar point is this symptom ranked that 2nd or
3rd position among other clinical signs.
Seizures: In our study, the percent of seizures symptom
ranked a 3rd position after headache and paraparesis. According to
the study of Le Van Thing and Trinh Tien Luc, seizures symptom
accounted 32%, ranked the 3rd position after headache and cranial
nerve paralysis. According to the study of Ferro, seizures symptom
accounted 39% in patients < 65 years old, and 45% in patients >= 65
Consciousness disorders: In our study, percent of patients
with consciousness disorcers accounted 37.29%, ranked the 4th
position among other symptoms. Wherein, mild consciousness
disorders was most common with 30.5% while severe consciousness
disorders accounted 6.8%. According to the study of Bruijin in 59
patients with CVT (equal to the number of patients in our study), the
percent of patients with consciousness disorders was 39%. Wherein,
mild consciousness disorders accounted 23.7%, and severe symptom
accounted 15.3%. Overall, the percent of CVT patients with
consciousness disorders symptom in the studies of domestic and
foreign authors was not as high as other symptoms, from 21% to
39%, the percent of our study was within this range and similar to
results of other authors.
Cranial nerve palsy: In our study, the percent of patients with
cranial nerve palsy was 32.2%. According to the study of Le Van
Thinh and Trinh Tien Luc, the percent of patients with cranial nerve
palsy was 48%. According to the study of Paciaroni, the percent of
patients with cranial nerve palsy was 12%, this symptom commonly
occurred in III, IV, V, VI, VII, VIII, IX, X and XI.These nerves
could be injured separately or link to other nerves. Almost authors
did not recognize cranial nerve analysis in their studies, might be due
to small sample size then they only recognized that patients had focal
neurological dificits, such as in the study of Fink, this author only
general recorded that 60% of patients had focal neurological dificits.
Overall, the cranial nerve palsy symptom on patients with CVT was
not as common as other symptoms and accounted from 12% to 48%,
the percent in our study was 32.2%.
Papilledema: According to the results of our study, the
percent of patients with papilledema was 30.5%. This symptom
varied depending on studies of other authors (table 4.39). According
to the study of Stolz, papilledema accounted 40%. According to the
study of Ferro, among 624 patients there was only 29% of patients <
65 years old and 14% of patients ≥ 65 years old had this symptom,
ranked after headache and positioning nerve sign and seizures.
Overall, the percent of patients with papilledema in our study was
smaller than results from studies of other authors, this could be due to
the percent of patients exhibited increased cranial pressure in our
study was higher than results from studies of other authors.
4.3. IMAGING CHARACTERISTICS
4.3.2. The location of the venous sinous thrombosis
Because in our study patients were diagnosed by magnetic
resonance imaging then we only discuss and compare our study
results to other authors based on this group (57 patients). The
location of the venous sinous thrombosis system which was highest
percent was superior sagittal sinuses (75.54%), followed by
transverse sinuses (64.91%), sigmoid sinuses (63.1%), and cortical
veins (40.35%). The remaining veins and sinus were less common
such as: straight sinuses 14.4%, juglar veins 8.77%, deep cerebral
veins 7.02%, inferior sagittal sinuses 5.26% (3 cases), cavernous
sinuses 2% (2 cases). The number of patients with ≥ 2 veins or
sinouses thrombosis accounted 41/57 cases (71.93%).
According to the study of Zubkov, among 59 patients
diagnosed by routine magnetic resonance imaging in combination
with magnetic resonance veinography, there were 34% (19 cases) of
all patients had images of brain parenchymal injuries on the magnetic
resonance images and this author compared the percent of patients
with thrombisis on 2 groups of patients. Among patients with brain
parenchymal injuries, thrombosis were most common in transverse
sinuses with 78.9% (15 cases), followed by superior sagittal sinuses
57.8% (11 cases), sigmoid sinuses 47.3% (9 cases), straight sinuses
26.3% (5 cases), Galen veins 26.3% (5 cases), other position
thrombosis were not significant. Among 37 patients without cerebral
injuries, blood clots were most common in veins of transverse
sinuses with 86.4% (32 cases), sigmoid sinuses 43.2% (16 cases),
superior sagittal sinuses 24.3% (9 cases), straight sinuses 8.1% (3
Overall, we recognized that: Location of thrombosis occurred
with highest percent in superior sagittal sinuses (36% to 97.8%);
followed by transverse sinuses and sigmoid sinuses (43% to 83%);
cortical veins accounted a high varied percent range (3% to 43.2%),
this might be due to the previous studies did not apply GRE pulse
sequence then the possibility of false negative results was relatively
high. Percent of straight sinuses with blood clots ranged from 8.1%
to 34.4%; deep cerebral veins ranged from 7.02% to 25.3%. Other
rare veinous sinouses thrombosis were not mentioned in studies of
other authors are cavenous sinuses, inferior sagittal sinuses and
jugular veins. In most cases, when occurred CVT, cases with just one
vein or sinous thrombosis were rare, percent of cases with ≥ 2
position thrombosis ranged from 54.7% to 71.93%. Thus, percent of
venous sinous thrombosis in our study was within the range of other
4.3.3. Brain parenchymal abnormalities on magnetic resonance
Based on the images obtained by magnetic resonance
imaging, we found that the percent of patients with CVT
accompanied parenchymal injuries was 84.21%, hemorrhagic
infarction accounted a highest percent 36.84%, followed by
infarction (22.81%); parenchymal hemorrhage 21.05%, subarachnoid
According to the results from the study of Terazzi in 48
patients with CVT, among 44 patients were tested by computerized
tomography, there were 9 cases (21%) suspected to have CVT
(empty Delta sign, rope sign), 11 patients (25%) were completely
normal on imeges of computerized tomography, 24 patients (55%)
had signs of cerebral hemorrhage or ischemic injuries. Among 19
patients were tested again by computerized tomography, there were 5
cases had signs of CVT. Also, in this study, there were 42 cases
diagnosed with CVT by magnetic resonance imaging, wherein 12
cases (29%) had signs of CVT alone, 15 cases (36%) related to
parenchymal hemorrhage and infarction. 12 cases (29%) had
parenchymal hemorrhage or infarction alone.
Overall, by comparing to results of studies of domestic and
foreign authors, we found that our study results were relatively
equivalent to results of other authors. Wherein, percent of patients
with infarction ranged from 19.4% to 70%; parenchymal hemorrhage
ranged from 10.2% to 57%; subarachnoid hemorrhage ranged from
8% to 10.53%. However, percent of patients with subarachnoid
hemorrhage in our study was higher than results from other studies,
this might be due to the diversity of injuries in CVT.
4.4. RISK FACTORS OF CEREBRAL VENOUS THROMBOSIS
4.4.1.Factors of primary thrombophilia
According to results of our study, in patients with primary
thrombophilia, V Leiden factor accounted the highest percent,
followed by decreased protein S, decreased protein C, decreased
ATIII. Compared to control group, we found that OR of protein C
was highest, followed by V Leiden factor, ATIII. We could not
calculate OR of protein S because there was no case with decreased
protein S in control group.
According to the study of Bombeli , when analyzed 51
patients with CVT among 260 patients with venous thrombosis
(cerebral veins, portal veins, retinal veins, upper limb veins, lower
limb vein) and 120 healthy controls, he recognized that V Leiden
factor accounted the highest percent 13.7% with OR 2.1 (CI 95%:
0.7-6), percent of decreased protein S was 2% with OR 2.4 (CI 95%:
0.1-38.3); percent of decreased protein C and ATII was 2%, he could
not calculate OR of protein C and ATIII due to limitation of sample
size. According to the study of Martinelli in 121 patients with CVT,
the percent of V Leiden factor was highest with OR = 4.7 (CI 95%:
1.8-11.8), followed by decreased protein C, decreased protein S and
decreased ATIII. Due to limitation of sample size then the author