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Coagulopathy and embolic signal in cancer patients with ischemic stroke.

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Coagulopathy and Embolic Signal in
Cancer Patients with Ischemic Stroke
Jin Myoung Seok, MD,1 Seon Gyeong Kim, MD,1,2 Ji Won Kim, MD,1
Chin-Sang Chung, MD, PhD,1 Gyeong-Moon Kim, MD, PhD,1
Kwang Ho Lee, MD, PhD,1 and Oh Young Bang, MD, PhD1
Objective: It has been reported that embolic signal (ES) detected by transcranial Doppler (TCD) has clinical
significance, especially in patients with recent stroke attributable to arterial or cardiac embolism. Therefore, we
conducted this study to determine whether the prevalence of ES is high in ischemic stroke patients with cancer
and related to hypercoagulopathy.
Methods: We prospectively studied cancer patients with acute ischemic stroke within the middle cerebral artery
(MCA) distribution on diffusion-weighted imaging. Conventional stroke mechanisms (CSMs) were determined using
cardiologic and vascular studies. Additionally, the coagulation status was assessed based on the serum D-dimer
levels, and TCD monitoring was performed on both MCAs for 30 minutes to detect ES. Clinical features including
vascular risk factors, characteristics of ischemic stroke, and cancer and laboratory findings associated with the
presence of ES were evaluated.
Results: A total of 74 patients were finally included in this study. ES was more commonly observed in patients
without CSMs (22 of 38 patients, 57.9%) than in those with CSMs (12 of 36 patients, 33.3%) ( p ⫽ 0.034).
Moreover, ES was more commonly detected in patients with high D-dimer levels ( p ⬍ 0.001), and D-dimer levels
were significantly correlated with the number of ESs in patients without CSMs (r ⫽ 0.732, p ⬍ 0.001), but were
poorly correlated in patients with CSMs (r ⫽ 0.152, p ⫽ 0.375). Higher levels of D-dimer (odds ratio [OR], 1.082
per 1␮g/ml increase; 95% confidence interval [CI], 1.014 –1.154) and adenocarcinoma (OR, 3.829; 95% CI, 1.23–
13.052) were independently associated with the presence of ES. The use of anticoagulants dramatically decreased
the D-dimer levels.
Interpretation: A high prevalence of ES was observed in cancer patients with ischemic stroke, especially in those
without CSMs. Elevated D-dimer levels were independently associated with ES, and decreased dramatically with
the use of anticoagulants.
ANN NEUROL 2010;68:213–219
ystemic cancer and ischemic stroke are both common
among the elderly. Additionally, an association between cancer and cerebrovascular disease has been reported,1 However, the stroke mechanisms in patients with
cancer vary and may differ from those in patients without
cancer.2 Therefore, it is important to identify stroke
mechanisms in cancer patients. Although patients with
systemic cancer usually show poor outcomes, their survival is increasing with the development of cancer medicine. Thus, the incidence of cancer stroke will rise, which
will necessitate the development of treatment and preventive strategies.
Systemic cancer is related to ischemic stroke via various mechanisms1– 8; however, the main mechanisms of
stroke in cancer patients are largely unknown. Although
coagulopathy has been proposed as an important cause of
ischemic stroke in cancer patients,7–9 there is currently no
direct evidence of the role of coagulopathy in the development of stroke in cancer patients.
The present study was conducted to investigate the
prevalence and factors associated with cerebral microemboli detected with transcranial Doppler (TCD) monitoring of cancer patients with acute ischemic stroke. In addition, laboratory and TCD features were used to evaluate
Published online in Wiley InterScience ( DOI: 10.1002/ana.22050
Received Dec 15, 2009, and in revised form Mar 10, 2010. Accepted for publication Apr 2, 2010.
Address correspondence to Dr Bang, Department of Neurology, the Neuroscience Center, Samsung Medical Center, Sungkyunkwan University
School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul 135-710, Korea. E-mail:
From the 1Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul; and 2Department of
Neurology, Namyangju Hanyang General Hospital, Gyeonggi-do, Korea.
Additional Supporting Information can be found in the online version of this article.
© 2010 American Neurological Association
of Neurology
the clinical implications of hypercoagulability and the use
of anticoagulation in stroke prevention in cancer patients.
Patients and Methods
Between January 2006 and August 2009, we prospectively studied consecutive cancer patients with acute ischemic stroke or
transient ischemic attack. Patients were registered at Samsung
Medical Center, South Korea, and were identified as having: (1)
active cancer, excluding primary intracranial tumor; (2) suffered
focal symptoms and relevant lesions within the middle cerebral
artery (MCA) distribution as seen with diffusion-weighted imaging (DWI); and (3) undergone diagnostic workups, including
vascular and cardiologic studies. Active cancer was defined as a
diagnosis of cancer within 6 months prior to enrollment, any
treatment for cancer within the previous 6 months, or recurrent
or metastatic cancer, as previously described.10 The following
patients were excluded from the study: (1) those who had not
undergone magnetic resonance imaging (MRI) or for whom no
relevant lesions were observed on DWI, (2) those in whom serum D-dimer was not examined within 24 hours of the onset of
stroke, (3) those who had undergone complete remission of cancer or only had a remote history of cancer, (4) those who had
not undergone TCD monitoring for embolic signal (ES) within
7 days of the onset of stroke, and (5) those who had incomplete
workups for stroke etiology (either vascular or cardiologic studies) (Fig 1). The local institutional reviewer boards approved this
For all patients, age, gender, and stroke risk factors including
hypertension, diabetes mellitus, hyperlipidemia, atrial fibrillation, ischemic heart disease, and tobacco consumption were collected. Data related to stroke or cancer including clinical symptoms and signs, type of cancer and pathology, the presence of
systemic metastasis, and the time from cancer diagnosis to stroke
onset were recorded. Routine laboratory data were collected for
all patients (routine blood tests and coagulation studies, including prothrombin time, activated partial thromboplastin time, fibrinogen, and D-dimer), and all patients underwent electrocardiography, echocardiography, and brain MRI. Stroke
mechanisms were assigned independently by 2 neurologists using criteria from the Trial of Org 10172 in Acute Stroke Treatment (TOAST) and finalized by consensus.11 Patients were
grouped into 2 groups, according to the presence of conventional stroke mechanisms (CSMs), such as atherosclerosis, cardioembolism, small-artery occlusion: (1) the CSM group and (2)
the cryptogenic group.
TCD Methods
TCD (Pioneer TC 8080; Nicolet Vascular, Madison, WI) was
used to monitor both MCAs with insonation depths of 40 to
60mm for microemboli using 2 2MHz probes fixed with a
head-frame (Marc 500, Spencer Technologies, Northborough,
MA). All ESs were automatically saved to computer hard disk
for review, and all analyses were performed blinded to individual
patient details. Bilateral recordings were performed for 30 minutes with supine position. Patients who had ⱖ1 ES during the
30 minutes of TCD recording were classified as ES positive.
Statistical Analysis
Continuous data are shown as mean ⫾ standard deviation,
whereas categorical variables are presented as absolute and relative frequencies. We analyzed the differences between ESnegative patients and ES-positive patients and among the groups
of patients based on the number of ESs (no ES vs 1 ES vs 2– 4
ESs vs ⱖ5 ESs) using the chi-square test, Fisher exact test, or by
linear association for categorical variables. A Student t test, the
Mann-Whitney U test, or the Kruskal-Wallis test were used to
evaluate continuous variables. Spearman correlation coefficient
was used to analyze the association between the D-dimer level
and the number of ESs. In addition, multivariate logistic regression analysis was conducted to evaluate the independent contribution of factors that influenced the detection of ES with TCD
monitoring. Variables from univariate analyses at p ⬍ 0.1 were
considered to represent explanatory variables and were evaluated
together by multivariate analysis. Results are given as odds ratio
(OR) with the 95% confidence interval (CI). A value of p ⬍
0.05 was considered significant. All statistical analyses were performed using commercially available software (SPSS for windows, version 15.0; SPSS Inc., Chicago, IL).
FIGURE 1: Patient selection. DWI ⴝ diffusion-weighted
imaging; TCD ⴝ transcranial Doppler; ES ⴝ embolic signal.
Patient Characteristics
Of the 147 patients who were diagnosed as having ischemic stroke with cancer, 74 (44 men and 30 women; age,
63.9 ⫾ 10.3 years) were included in this study (see Fig
1). The characteristics of the patients that were and were
not included did not differ, except that older patients
were more commonly excluded (Supplementary Table).
The mean number of ESs observed during the initial TCD studies was 6.4 ⫾ 9.8, ranging from 0 to 50,
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Seok et al: Embolic Signal in Stroke
and ES was observed in 34 patients (45.9%, the ESpositive group). The mean interval between symptom onset and TCD study was 4.4 ⫾ 3.5 days, and this value
did not differ between the ES-positive and ES-negative
groups ( p ⬎ 0.05).
The clinical characteristics of patients with and
without ES based on TCD monitoring are presented in
Table 1. The age, gender, and risk factor profile did not
differ between the ES-negative and ES-positive groups.
There were 36 (48.6%) patients who had CSMs (22 atherosclerosis; 7 atrial fibrillation; 5 small-artery occlusion; 1
infective endocarditis; 1 antiphospholipid antibody syndrome), and 38 (51.4%) patients had no CSMs. The
mean time interval between stroke onset and the diagnosis
of cancer was 14.1 ⫾ 24.1 months, which did not differ
between groups. Patients with ischemic stroke had various
types of primary cancers, with lung (31.1%), gastroesophageal (16.2%), colorectal (14.9%), and gynecologic
(6.8%) being the most common. The primary cancer
types were not significantly different between the groups.
Systemic metastasis (31 patients, 41.9%) and adenocarcinoma type (50 patients, 67.6%) were very common, and
a higher prevalence of ES was observed in patients with
metastasis and adenocarcinoma ( p ⫽ 0.006 and p ⫽
0.003, respectively). ES-positive patients had significantly
higher levels of D-dimer but lower levels of fibrinogen
than ES-negative patients ( p ⬍ 0.001 and p ⬍ 0.022,
respectively). When patients were further divided into
those with no ES, 1 ES, 2 to 4 ESs, and ⱖ5 ESs, the
D-dimer levels and the prevalence of adenocardinoma increased as the number of ESs increased ( p ⫽ 0.001 and p
⫽ 0.003, respectively).
Embolic Signals in Patients with and without
Conventional Stroke Mechanisms
ES was more commonly observed in patients without
CSMs (22 of 38 patients, 57.9%) than in those with
CSMs (12 of 36 patients, 33.3%) ( p ⫽ 0.034). Among
the CSMs, ES was most commonly observed in patients
with large artery atherosclerotic stroke (10 patients,
45.5%), and ES was observed in 1 patient each with atrial
fibrillation and infective endocarditis. The numbers of
ESs among stroke subtypes are shown in Figure 2A.
Spearman correlation analysis showed that the number of
ESs was significantly correlated with D-dimer levels (r ⫽
0.470, p ⬍ 0.001). However, the correlation between
D-dimer levels and the number of ESs differed depending
on the presence of CSMs. Specifically, there was a highly
significant correlation between D-dimer levels and the
number of ESs among patients without CSMs (r ⫽
0.732, p ⬍ 0.001), whereas no correlation was observed
August, 2010
among patients with CSMs (r ⫽ 0.152, p ⫽ 0.375) (see
Fig 2B, C).
Multivariate Testing
Clinical and laboratory features independently associated
with the presence of ES were analyzed by multiple logistic
regression analysis. After adjusting for covariates, we
found that higher D-dimer levels (OR, 1.082 per 1␮g/ml
increase; 95% CI, 1.014 –1.154) and adenocarcinoma
type (OR, 3.829; 95% CI, 123–13.052) were independently associated with the presence of ES at the time of
stroke onset (Table 2).
Effects of Anticoagulants on D-Dimer Levels
and ES
The D-dimer levels were serially monitored in 29 of 39
patients who received anticoagulants (time intervals,
3.8 ⫾ 2.3 days between samplings). Figure 3 shows the
changes in D-dimer levels after the use of anticoagulants
(unfractioned heparin, low molecular heparin, or warfarin
use with international normalized ratio levels ⬎1.5). The
levels of D-dimer dramatically decreased with the use of
anticoagulants in most patients, and the follow-up levels
(8.20 ⫾ 10.92␮g/ml) were significantly lower than initial
levels (22.92 ⫾ 24.81␮g/ml) (Wilcoxon signed rank test,
p ⫽ 0.001). During hospitalization, there were 3 reported
cases of recurrent ischemic stroke. These patients did not
have CSMs (the cryptogenic stroke group), but had persistently elevated D-dimer levels and positive ES on
follow-up TCD while undergoing treatment. A sample
case is shown in the Supplementary Figure.
The major findings of the present study are (1) the frequency of ES suggestive of embolic-origin is very high in
cancer patients with acute ischemic stroke, (2) certain
clinical and laboratory (D-dimer levels) findings determine the occurrence of ES in cancer patients with ischemic stroke, and (3) serum D-dimer levels are dramatically reduced after the use of anticoagulants.
The detection of ES has been reported to have clinical significance in that it clarifies embolism of either arterial or cardiac embolism.12,13 Several previous studies
have evaluated the clinical implications of ES detected by
TCD in ischemic stroke patients.14 –16 However, no previous studies have been conducted to evaluate the presence of ES on TCD in patients with cancer. To the best
of our knowledge, this report is the first clinical study
regarding the presence of microembolic signals during
TCD monitoring of ischemic stroke patients with cancer,
thus providing valuable comparative data on the prevalence of ES in this patient group. In the present study, ES
of Neurology
TABLE 1: Patient Characteristics
ES Negative
p, ES
ES Positive
1 ES
2-4 ESs
>5 ESs
No. of patients (%)
n ⫽ 40 (54.1)
n ⫽ 34 (45.9)
n ⫽ 10
n ⫽ 12
n ⫽ 12
Age, yr (SD)
66.0 (9.7)
61.4 (10.5)
62.8 (11.9)
63.5 (7.7)
58.2 (11.8)
Male gender, No. (%)
26 (65.0)
18 (52.9)
6 (60.0)
5 (41.7)
7 (58.3)
Hypertension, No. (%)
22 (55.0)
12 (35.3)
2 (20.0)
5 (41.7)
5 (41.7)
Diabetes mellitus, No. (%)
12 (30.0)
9 (26.5)
2 (20.0)
5 (41.7)
2 (16.7)
Hyperlipidemia, No. (%)
9 (22.5)
5 (14.7)
0 (0)
3 (25.0)
2 (16.7)
Risk factors
Atrial fibrillation, No. (%)
5 (12.5)
1 (2.9)
0 (0)
1 (8.3)
0 (0)
Smoking, No. (%)
12 (30.0)
11 (32.4)
4 (40.0)
5 (41.7)
2 (16.7)
10 (25.0)
13 (38.2)
4 (40.0)
6 (50.0)
3 (25.0)
12 (30.0)
11 (32.4)
4 (40.0)
2 (16.7)
5 (41.7)
Cancer profiles
Primary cancer type, No. (%)
3 (7.5)
3 (8.8)
1 (10.0)
2 (16.7)
0 (0)
3 (7.5)
2 (5.9)
1 (10.0)
1 (8.3)
0 (0)
12 (30.0)
5 (14.7)
0 (0)
1 (8.3)
4 (33.3)
11 (27.5)
20 (58.8)
7 (70.0)
6 (50.0)
7 (58.3)
Systemic metastasis, No. (%)
Adenocarcinoma, No. (%)
21 (52.5)
29 (85.3)
8 (80.0)
10 (83.3)
11 (91.7)
Time interval between stroke
onset and the diagnosis of
cancer, mo (SD)
14.4 (24.2)
13.7 (24.3)
20.4 (37.3)
11.8 (16.6)
9.9 (17.2)
1.13 (0.18)
1.19 (0.38)
1.31 (0.65)
1.10 (0.17)
1.19 (0.19)
aPTT, s (SD)
37.35 (5.91)
36.75 (8.31)
39.20 (13.25)
34.03 (4.40)
37.43 (5.50)
Platelet count ⫻ 10 /l (SD)
201.0 (95.1)
211.6 (122.9)
186.4 (110.8)
172.5 (97.7)
271.8 (139.7)
Mean D-dimer, ␮g/ml (SD)
3.37 (6.20)
19.73 (23.91)
11.02 (13.49)
14.63 (22.12)
32.10 (28.51)
Coagulation study findings
Mean fibrinogen, mg/dl (SD)
389.5 (165.9)
300.3 (149.2)
274.5 (108.5)
352.9 (173.9)
271.0 (153.5)
Time interval between symptom
onset and TCD study, days
4.7 (4.1)
4.1 (2.5)
5.2 (2.3)
3.0 (1.8)
4.2 (3.1)
13 (32.5)
16 (47.1)
2 (20.0)
7 (58.3)
7 (58.3)
4 (10.0)
2 (5.9)
1 (10.0)
0 (0)
1 (8.3)
Unfractioned heparin
13 (32.5)
11 (32.4)
3 (30.0)
4 (33.3)
4 (33.3)
Low molecular weight
1 (2.5)
1 (2.9)
1 (10.0)
0 (0)
0 (0)
9 (22.5)
4 (11.8)
3 (30.0)
1 (8.3)
0 (0)
1.85 (2.20)
1.03 (1.47)
2.10 (1.91)
0.83 (1.26)
0.33 (0.49)
Stroke treatment, No. (%)a
Antiplatelet agents
Time from the start of
anticoagulants to TCD, days
At the time of TCD study.
INR ranges of 1.5 or more.
ES ⫽ embolic signal; SD ⫽ standard deviation; PT ⫽ prothrombin time; INR ⫽ international normalized ratio; aPTT ⫽
activated partial thromboplastin time; TCD ⫽ transcranial Doppler.
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Seok et al: Embolic Signal in Stroke
FIGURE 2: Numbers of embolic signals (ES) on transcranial
Doppler for each stroke subtype (A). Scatterplot shows the
correlation between the number of embolic signals and
D-dimer levels by subtypes of ischemic stroke; (B) Cryptogenic stroke mechanism group and (C) Conventional stroke
mechanism group.
was observed in almost 50% of cancer patients with acute
ischemic stroke, which is much higher than has previously
been reported in unselected stroke patients.12
The mechanisms of stroke in cancer patients are still
unsettled.1,7 We recently demonstrated that ischemic
strokes outside of conventional mechanisms occur in a
large number of cancer patients based on registration data
from a large multicenter, and that risk factor profiles,
August, 2010
DWI pattern, and D-dimer levels differ depending on the
mechanisms of stroke.2 In the present study, CSMs based
on the TOAST criteria were not found in approximately
50% of patients evaluated, and ES was more commonly
observed in patients without CSMs than in those with
CSMs. Accordingly, it is possible that most ischemic
strokes in patients without CSMs were caused by embolism, possibly related to coagulopathy. Our data suggest
that the TCD data on ES, along with the results of stroke
workups, could be helpful for determining the mechanisms of ischemic stroke in patients with cancer, providing a clue for identifying optimal strategies to prevent the
occurrence of ischemic stroke in cancer patients.
Hypercoagulable state is a common condition in patients with cancer. However, there is still no consensus
whether hypercoagulable state is more important than
conventional risk factors in causing cerebrovascular disease
in patients with cancer.7–9,17 We evaluated the status of
coagulation using D-dimer levels. D-dimer is a plasminderived degradation product of cross-linked fibrin that is
present in elevated levels in patients with hypercoagulability.18,19 Several studies have shown that D-dimer can be
used for diagnosis, for risk evaluation, and as a treatment
marker in thrombogenic states such as deep vein thromobosis.20 –22 In the present study, the D-dimer levels of patients who were found to have ES were much higher than
those of patients who did not have ES, and elevated
D-dimer levels were an independent predictor for the detection of ES. These results suggests that ES detected by
TCD could be associated with the hypercoagulable state
assessed by the D-dimer level. We also found that the
D-dimer levels of patients with cryptogenic mechanism
(possibly cancer-related coagulopathy) were much higher
than those of patients with CSMs, and there was a highly
significant correlation between D-dimer levels and the
number of ESs in patients without CSMs. Our results
and those of previous studies suggest that there is a good
correlation between D-dimer level and the tumor burden,
and that D-dimer levels are correlated with the stage of
disease and the number of metastases.23–25 This close association between the D-dimer level and ES on TCD in
patients without CSMs provides evidence of cancerrelated coagulopathy. These findings indicate that the
pathophysiology of strokes in cancer patients depends on
the degree of coagulation abnormalities, and that the detection of ES by TCD may provide clues regarding the
cancer-specific mechanism related to hypercoagulopathy.
Biomarkers may be useful for screening of possible
mechanisms of stroke and as a guide for their prevention
and treatment. One well-known example in which a
biomarker is used for these purposes is C-reactive protein
of Neurology
TABLE 2: Logistic Regression Analysis: Odds Ratios (95% Confidence Intervals) for Having Embolic Signals
Clinical findings
Age, per 1 year increase
Systemic metastasis
Cryptogenic stroke
Laboratory findings
D-dimer per 1␮g/ml
Fibrinogen per 1mg/dl
Pathologic type
Model 1a
Model 2
Multivariate Testing
Multivariate Testing
1.096 (1.024-1.172)
1.082 (1.014-1.154)
3.829 (1.123-13.052)
Not considering pathologic type of primary cancer.
N/A ⫽ not assessed.
in atherosclerotic stroke.26 However, the effects of reducing C-reactive protein in stroke prevention may be limited and cannot be expected to occur within short-term
intervals. Conversely, the results of the present study
showed that anticoagulants dramatically reduced the levels
of D-dimer. Thus, anticoagulant use may be effective for
the treatment of cancer patients with ischemic stroke, especially those without CSMs. However, longitudinal
follow-up studies of treatment response are needed to
demonstrate the clinical value of anticoagulant use in cancer patients with ischemic stroke. A recent clinical trial
showed that anticoagulant reduces the incidence of
FIGURE 3: Changes in D-dimer levels after treatment of
thromboembolic events in patients with metastatic or locally advanced cancer who are receiving chemotherapy.27
In addition, our present results suggest that ES and
D-dimer can act as a surrogate endpoints in clinical trials.
Moreover, there have been numerous efforts to demonstrate candidate biomarkers for cancer-related thrombosis,
especially venous thromboembolism.28 Further clinical trials in cancer patients with ischemic stroke considering
these laboratory findings are need.
The strengths of this study include the consecutive
recruitment of patients with comprehensive evaluations to
assign stroke mechanisms and the novel approach using
serologic biomarkers and TCD monitoring. However,
there are several limitations to our study. First, determining whether there is an actual causal effect of hypercoagulability in the pathogenesis of cryptogenic stroke in cancer
patients requires further studies. It could be difficult to
definitively attribute a stroke mechanism to hypercoagulability based on D-dimers alone.7,20 We could not preclude this possibility, because the effect of treatment and
complications of cancers such as infection were not considered in this study. Substances in tumor cells such as
cysteine proteases and tissue factor have procoagulant or
thromboplastin-like activity.6 Further studies regarding
the precise molecular mechanisms of cancer-related coagulopathy that consider treatment and complication status
are needed.6 In addition, although the results of the
present study suggest that anticoagulant use may be helpVolume 68, No. 2
Seok et al: Embolic Signal in Stroke
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ful, particularly in patients where coagulation abnormality
is the principle mechanism of stroke, longitudinal longterm follow-up data are needed to prove or disprove our
results. Second, the lack of a uniform treatment strategy
and the delay before the TCD study may have affected
the ES findings. Serial TCD monitoring could not be
performed in most patients because of acute illness due to
systemic cancer or stroke itself. Finally, the data evaluated
here were from a unique population; namely, Korean patients with cancer. Accordingly, further investigations of
different study populations are warranted.
In conclusion, a high prevalence of ES was observed
in cancer patients with ischemic stroke, especially in those
without CSMs. Elevated D-dimer levels were independently associated with ES, and decreased dramatically
with the use of anticoagulants. Our present data provide
evidence of the association of hypercoagulability and ischemic stroke in cancer patients and also suggest that serum
D-dimer levels and ES on TCD could play a role as surrogate markers in the application of anticoagulants in cancer patients with ischemic stroke.
This study was supported by a grant from the Korean
Healthcare technology R&D Project, Ministry of Health
and Welfare (A080044) and Samsung Biomedical Research Institute (SBRI) C-A9-216-1 to O.Y.B.
Potential Conflicts of Interest
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coagulopathy, stroki, cancer, patients, ischemia, signali, emboli
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