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Plasma D-Dimer Levels Are Associated with Stroke

Subtypes and Infarction Volume in Patients with Acute


Ischemic Stroke
Wen-Jie Zi, Jie Shuai*
Department of Neurology, Xin Qiao Hospital, Third Military Medical University, Chongqing, P. R. China
Abstract
Background: It has been suggested that modestly elevated circulating D-dimer values may be associated with acute
ischemic stroke (AIS). Thus, the purpose of this study was to investigate the association between plasma D -dimer level at
admission and AIS in Chinese population.
Methods: In a prospective observational study, plasma D-dimer levels were measured using a particle-enhanced,
immunoturbidimetric assay on admission in 240 Chinese patients with AIS. The National Institutes of Health Stroke Scale
(NIHSS) score was assessed on admission blinded to D-dimer levels.
Results: Plasma median D-dimer levels were significantly (P =0.000) higher in AIS patients as compared to healthy controls
(0.88; interquartiler range [IQR], 0.282.11 mg/L and 0.31; IQR, 0.170.74 mg/L). D-dimer levels increased with increasing
severity of stroke as defined by the NIHSS score(r =0.179, p=0.005) and infarct volume(r =0.425, p=0.000). Those positive
trends still existed even after correcting for possible confounding factors (P =0.012, 0.000; respectively). Based on the
Receiver operating characteristic (ROC) curve, the optimal cut-off value of plasma D-dimer levels as an indicator for
diagnosis of cardioembolic strokes was projected to be 0.91 mg/L, which yielded a sensitivity of 83.7% and a specificity of
81.5%, the area under the curve was 0.862(95% confidence interval [CI], 0.8110.912).
Conclusion: We had shown that plasma D-dimer levels increased with increasing severity of stroke as defined by the NIHSS
score and infarct volume. These associations were independent other possible variables. In addition, cardioembolic strokes
can be distinguished from other stroke etiologies by measuring plasma D-dimer levels very early (048hours from stroke
symptom onset).
Citation: Zi W-J, Shuai J (2014) Plasma D-Dimer Levels Are Associated with Stroke Subtypes and Infarction Volume in Patients with Acute Ischemic Stroke. PLoS
ONE 9(1): e86465. doi:10.1371/journal.pone.0086465
Editor: Jinglu Ai, St Michaels Hospital, University of Toronto, Canada
Received October 16, 2013; Accepted December 11, 2013; Published January 20, 2014
Copyright: 2014 Zi, Shuai. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The authors have no support or funding to report.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: crcr10010@outlook.com
Introduction
Acute ischemic stroke (AIS) is one of the major causes of death
worldwide [1]. Timely intervention can dramatically improve
outcome and reduce disability. It causes a great financial burden,
since one-third of surviving stroke patients remain dependent in
daily activities. Similarly, stroke places a tremendous burden on
health resources in China [2].
D-dimer, the final product of plasma in-mediated degradation
of fibrin-rich thrombi, has emerged as a simple blood test that can
be used in diagnostic algorithms for the exclusion of venous
thromboembolism. D-dimer levels have certain advantages over
other measures of thrombin generation, because it is resistant to ex
vivo activation, relatively stable, and has a long half-life [3]. The
concentration of D-dimer reflects the extent of fibrin turnover in
the circulation, because this antigen is present in several
degradation products from the cleavage of cross linked fibrin by
plasmin[4].
It has been suggested that modestly elevated circulating D-
dimer values reflect minor increases in blood coagulation,
thrombin formation, and turnover of cross linked intravascular
fibrin (which is partly intra-arterial in origin) and that these
increases may be associated with coronary heart disease [5]. D-
dimer is known to be positively associated with coronary heart
disease incidence and its recurrence, which is largely in dependent
of conventional risk factors [56]. In addition, elevated D-dimer
concentrations have been reported to be associated with cerebral
venous sinus thrombosis [7], acute pulmonary embolism [8],
spontaneous intracerebral hemorrhage [9], long-term neurologic
outcomes in Childhood-Onset Arterial Ischemic Stroke [10].
Previous studies also have suggested that D-dimer levels may be
associated specifically with subtypes [11], assessing prognosis [12
13] and unfavorable outcome in ischemic stroke patients. Some
studies have suggested that D-dimer can be seen as an outcome
predictor in ischemic stroke and an indicator of severity of
traumatic brain injury [1415].
Unfortunately, there has been little research on the associations
between plasma D-dimer level and AIS in the Chinese patients.
Thus, the purpose of this study was to investigate the association
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between plasma D-dimer levels at admission and subtypes, infarct
size and severity in the Chinese patients with AIS.
Methods
Patients and Study Design
We conducted a prospective cohort study at the neurology
department from December 2010 to October 2012. All patients
with first-ever AIS were included. All patients were admitted
within 24 hours of experiencing a new focal or global neurological
event. Brain imaging (either CT or MRI) was performed routinely
within 24 hours after admission. An AIS was defined according to
the World Health Organization criteria [16]. We excluded
patients with intracranial hemorrhage, malignancy, febrile disor-
ders, acute or chronic inflammatory disease at study enrollment,
coma or epileptic seizure activity, and patients who were
anticoagulated before admission were also excluded. The onset
time was defined as the time patients were last known to be
without ischemic symptoms.
One hundred healthy people matched for age and gender were
assigned to the healthy control group. Records of potential
controls were reviewed by a neurologist (not an author) to exclude
the presence of stroke, other types of diseases. This study was
approved by the Institutional Review Board of The Xin Qiao
Hospital, Third Military Medical University and informed written
consent was obtained from each patient, family, or legal guardian.
Clinical Variables
At baseline, demographic data (age and sex) and history of
conventional vascular risk factors: hypertension, diabetes mellitus,
dyslipidemia, other cardiac diseases (including acute myocardial
infarction and angina), and cigarette smoking were obtained.
Routine blood and biochemical tests, ECG, and a baseline brain
CT/MRI scan were performed in all patients at admission. Stroke
severity was assessed on admission using the National Institutes of
Health Stroke Scale (NIHSS, the NIHSS score ranges from 0 to 34
and higher values reflect more severe neurological damage)[17] by
a neurologist. Stroke subtype was classified according to TOAST
(Trial of Org 10172 in Acute Stroke Treatment) criteria [18],
which distinguished large-artery arteriosclerosis, small-artery
occlusion, cardioembolism, other causative factor, and undeter-
mined causative factor. The clinical stroke syndrome was
determined by applying the criteria of the Oxfordshire Commu-
nity Stroke Project: total anterior circulation syndrome (TACS);
partial anterior circulation syndrome (PACS); lacunar syndrome
(LACS); and posterior circulation syndrome (POCS) [19].
Neuroimaging
MRI with diffusion-weighted imaging (DWI) was available in
183 stroke patients (76.3%). In those patients, DWI lesion volumes
were determined by one experienced neurologist unaware of the
clinical and laboratory results. The infarct volume was calculated
by using the formula 0.56a6b6c (where a is the maximal
longitudinal diameter, b is the maximal transverse diameter
perpendicular to a and c is the number of 10-mm slices containing
infarct) [2021].
Blood Collection and Quantification
Blood samples of patients and controls were obtained at 7:00
AM in the next morning of the day of admission (within 06
[n =131], 612 [n =62], 1224 [n =26], and 2448 [n =21]
hours from symptom onset). Patients blood samples were collected
in the ward bedside in 5-ml vacuum tubes containing 0.5 ml
buffered sodium citrate. Plasma aliquots were collected within one
hour after randomization and centrifuged at 4000 g for 10 min at
ambient room temperature. Plasma was then frozen at 270C until
assayed.
D-dimer concentration was measured with a particle-enhanced,
immunoturbidimetric assay in a calibrated SYSMEX7000 ana-
lyzer (Sysmex Corporation, Hyogo, Japan). The normal range of
morning plasma D-dimer concentration in our hospital laboratory
is 00.55 mg/L, which is slightly higher than other laboratory
(0.25 mg/L [6]). The detection limit was 0.05 mg/L, and the
dynamic range was from 0.07 to 35.2 mg/L. The intra-assay
coefficient of variation [CV] and inter-assay CV were 1.53.4%,
2.6%4.5%, respectively. Plasma levels of glucose, C-reactive
protein (CRP), leucocyte count, prothrombin time (PT), activated
partial thromboplastin time (APTT), thrombin time (TT) and
fibrinogen (FBG) were also tested by standard method. For all
measurements, levels that were not detectable were considered to
have a value equal to the lower limit of detection of the assay.
Statistical Analysis
Results are expressed as percentages for categorical variables
and as medians (interquartile ranges, IQRs) for the continuous
variables. Proportions were compared using the x2 test, and the
MannWhitney test or one-way analysis of variance (ANOVA) to
compare continuous variables among groups. The relationship
between serum D-dimer and others factors were determined using
Spearman critical value rankings. Associations between NIHSS
score and D-dimer were assessed using ordered logistic regression
models in multivariate adjustment with possible confounders; ie,
age, gender, stroke syndrome, stroke etiology, vascular risk factors
and plasma levels of CRP, PT, APTT, TT and FBG. Associations
between infarct volume and plasma D-dimer levels were also
assessed using linear regression models in multivariate adjustment
with the above confounders. Results were expressed as adjusted
OR (odds ratios) with the corresponding 95% confidence interval
(CI). Receiver operating characteristic (ROC) curves were utilized
to evaluate the accuracy of D-dimer to predict AIS. Area under
the curve (AUC) was calculated as measurements of the accuracy
of the test. Two-sided P values of less than 0.05 were regarded as
significant. All statistical analysis was performed with SPSS for
Windows, version 18.0 (SPSS Inc., Chicago, IL, USA).
Results
Baseline Characteristics of Study Samples
During the inclusion period, 240 patients with AIS were
included. The baseline characteristics of the 240 patients
presenting with AIS are described in Table 1. Overall, in the
study population, 166 (69.2%) were male and median age was 67
years (IQR, 5376). The median NIHSS score on admission was 8
points (IQR, 5 to 11). The median time from symptom recognition
to admission to hospital was 4.8 hours (IQR 2.210.1), and 199
patients (82.9%) were admitted within 12 hours of symptom
recognition.
Plasma D-dimer Levels and Stroke Characteristics
The results indicated that the Plasma D-dimer levels were
significantly (P=0.000) higher in AIS as compared to healthy
controls (0.88; IQR, 0.282.11 mg/L and 0.31; IQR, 0.17
0.74 mg/L, respectively; Figure 1.). There were modest correla-
tion that linked the plasma D-dimer levels to age(r =0.212,
p =0.000), sex (r =0.352, p =0.000). PT and APTT were also
correlated with the Plasma D-dimer levels (r =0.211 and r =0.205;
P=0.000, respectively).
Plasma D-Dimer Levels in Stroke
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Plasma D-dimer levels increased with increasing severity of
stroke as defined by the NIHSS score. There were positive
correlation that linked the levels of D-dimer to the NIHSS (r
=0.179, p =0.005; Figure 2a.), FBG (r =0.346, p =0.000;
Figure 2b.) and CRP levels (r =0.261, P=0.000; Figure 2c.).
There was still a significant positive trend between plasma D-
dimer levels and NIHSS score (P=0.012), using ordered logistic
regression after multivariate adjustment for possible confounders:
age, gender, time to admission, stroke syndrome, stroke etiology,
vascular risk factors and plasma levels of CRP, PT, APTT, TT
and FBG.
In patients for whom MRI data were available (n =183), there
was a positive correlation between levels of D-dimer and the
infarct volume (r =0.425, P=0.000; Figure 2d.). There was still
Table 1. Baseline characteristics of acute ischemic stroke patients and normal cases.
Characteristics
All
(n=240) Normal cases (n=100) p
a
Male sex (%) 166(69.2) 70(70.0) NS
Age (years), median(IQR) 67(5376) 66(5277) NS
Stroke severity, median NIHSS score (IQR) 8(511)
Infarct volume(mL, IQR; n =183) 10(722)
Vascular risk factors no. (%)
Diabetes mellitus 54(22.5)
Hypertension 172(71.7)
Coronary heart disease 61(25.4)
Atrial fibrillation 55(22.9)
Hypercholesterolemia 66(27.5)
Family history for stroke 52(21.7)
Smoking habit 49(20.4)
Clinical findings median(IQR)
Temperature (uC) 37.0(36.437.4) 36.5(36.336.8) ,0.01
BMI (kg m
22
) 24.8(23.227.4) 24.7(23.327.2) NS
Heart rate (beats min
21
) 82(7291) 79(6787) NS
Systolic blood pressure(mmHg) 158(144175) 127(112134) ,0.001
Diastolic blood pressure(mmHg) 94(8099) 80(7586) ,0.01
Laboratory findings (median, IQR)
Glucose(mmol L
21
) 5.99(5.526.68) 5.45(4.765.93) ,0.001
C-reactive protein (mgL
21
) 5.5(3.39.3) 3.2(2.56.6) ,0.01
Leucocyte count (610
3
m L
21
) 8.2(6.39.4) 8.1(6.29.3) NS
PT(second) 12.3(11.21.3.1) 11.1(10.611.6) ,0.01
APTT(second) 28.3(25.930.2) 26.9(24.528.6) ,0.01
TT(second) 18.3(17.719.1) 18.1(17.618.9) NS
FBG(g L
21
) 3.54(3.053.99) 2.93(2.343.66) ,0.01
D-dimer(mg L
21
) 0.88(0.282.11) 0.31(0.170.74) ,0.001
Stroke syndrome no. (%)
TACS 31(12.9)
PACS 95(39.6)
LACS 55(22.9)
POCS 59(24.6)
Stroke etiology no. (%)
Small-vessel occlusive 47(19.6)
Large-vessel occlusive 49(20.4)
Cardioembolic 98(40.8)
Other 22(9.2)
Unknown 24(10.0)
IQR, interquartile range; TACS, total anterior circulation syndrome; LACS, lacunar syndrome; PACS, partial anterior circulation syndrome; POCS, posterior circulation
syndrome; NIHSS, National Institutes of Health Stroke Scale; CRP, C-reactive protein; PT, prothrombin time; APTT, activated partial thromboplastin time; TT, thrombin
time; FBG, fibrinogen.
a
p value was assessed using Mann-Whitney U test or x2 test.
doi:10.1371/journal.pone.0086465.t001
Plasma D-Dimer Levels in Stroke
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persists a significant positive trend between plasma D-dimer levels
and infarct volume (P=0.000), after adjustment for the same
above covariates. In addition, D-dimer levels were significantly
lower in patients with LACS 0.55 mg/L (IQR 0.211.56 mg/L)
compared with patients with PACS 0.92 mg/L (IQR 0.322.06,
p,0.001), POCS 0.88 mg/L (IQR 0.292.16, p,0.001) or TACS
0.90 mg/L (IQR 0.282.08, P,0.01).
Plasma D-dimer Levels and Stroke Etiology
Significant stroke etiology differences in plasma D-dimer levels
were observed ((analysis of variance [ANOVA]: p =0.000); See the
Figure. 3). D-dimer levels in patients with cardioembolic stroke
(2.17 mg/L (IQR, 1.243.48)) were significantly higher as
compared with small-vessel occlusive stroke (0.59 mg/L (IQR,
0.250.96)), large-vessel occlusive stroke (0.56 mg/L (IQR, 0.22
0.95)), other stroke (0.25 mg/L (IQR, 0.140.41)) and unknown
stroke (0.29 mg/L (IQR, 0.180.68)); P=0.000, respectively. A
multiple regression model also demonstrated a significant corre-
lation between stroke category and D-dimer levels (P=0.006).
D-dimer (medians) were higher in patients with cardioembolic
strokes than in those with other etiologies (2.17 vs. 0.47 mg/L,
P =0.000). Based on the ROC curve, the optimal cut-off value of
plasma D-dimer levels as an indicator for diagnosis of cardioem-
bolic strokes was projected to be 0.91 mg/L, which yielded a
sensitivity of 83.7% and a specificity of 81.5%, the area under the
curve was 0.862(95%CI, 0.811 0.912). See the figure 4. In this
process, the positive predictive value was 83.9%, and the negative
predictive value was 87.8%.
Discussions
In our study, we reported that plasma D -dimer levels were
significantly increased in cases of first AIS compared to age and
gender matched healthy controls. Our main findings were that D-
dimer levels were in correlation with stroke subtypes and could be
seen as an indicator for diagnosis of cardioembolic stroke.
Furthermore, we found that the D-dimer levels increased with
increasing severity of stroke as defined by the NIHSS score and
infarct volume. Those positive trends still existed even after
correcting for possible confounding factors.
Our findings were consistent with results of previous prospective
studies showing that D-dimer levels were elevated in the acute
phase of AIS compared with the healthy control population [22
23]. Smith et al [24] reported that D-dimer could predict incident
stroke in the general population, even though no significant
association was seen in the Three-City French cohort study [25].
In addition, a sex and age-related increase in D-dimer levels were
noted between stroke patients and controls [26], which was in
accordance with our work. In another study [27], elevated D-
dimer was related to stroke severity on admission and poor
outcome at discharge. We also found that D-dimer was related to
stroke severity.
D-dimer levels have been shown to be associated with
cardioembolic strokes [2829], yet their significance in acute
stroke remains to be determined. Overall, our data provided a
detailed description of plasma D-dimer levels in correlation with
stroke subtypes, and D-dimer levels were significantly higher in
cardioembolic patients than in noncardioembolic AIS patients or
healthy control subjects, which was in accordance with prior works
[26]. Furthermore, Dougu et al [30] have also reported that D-
dimer level of .1.6 mg/L may indicate a high possibility of
cardioembolic. Takano et al [31] reported a D-dimer cut-off point
of 300 ng/mL for distinguishing cardioembolic stroke from
atherothrombotic infarction (ATI) and lacunar infarction (LI),
yielding a sensitivity of 80% and a specificity of 77%. Another
study proposed that the optimal D-dimer cut-off point for
discriminating between the presence and absence of a cardioem-
bolic source be 2.00 mg/mL to yield a specificity of 93%, a
sensitivity of 59%, a positive predictive value of 73%, and a
negative predictive value of 88% [32]. In our study, the optimal
cut-off value of plasma D-dimer levels as an indicator for diagnosis
of cardioembolic strokes was projected to be 0.91 mg/L, which
Figure 1. Plasma D-dimer levels in acute ischemic stroke patients and control group. MannWhitney U-test. All data are medians and
interquartile ranges (IQR). Significantly higher in stroke patients as compared to those in normal cases (p=0.000).
doi:10.1371/journal.pone.0086465.g001
Plasma D-Dimer Levels in Stroke
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yielded a sensitivity of 83.7%and a specificity of 81.5%, the area
under the curve was 0.862(95%CI, 0.811 - 0.912). These reports
appeared to suggest that assay of D-dimer levels in the acute stage
of AIS can be useful in distinguishing cardioembolic strokes.
Increased D-dimer level is hypothesized to be indicative of
thrombus formation within the left Atrium and is the key factor of
cardiac embolism onset [33].
This study showed that elevated levels of D-dimer in the 24-
hour after AIS were associated with brain infarct volume
independent of other clinical and laboratory variables. These
results were in accordance with the results from other studies
showing that D-dimer were associated with brain infarct [34], and
had a statistical correlation to infarct volume [3536].
There are several plausible mechanisms through which D-dimer
levels could be closely related to stroke. Firstly, increased D-dimer
levels may reflect ongoing thrombus formation within cerebral
vessels or may be a marker of systemic hypercoagulability[37].
Furthermore, thrombi formed in hypercoagulable states such as
high D-dimer levels may be resistant to the endogenous fibrinolytic
system [38]. Secondly, some markers of hemostatic function are
acute-phase reactants; D-dimer is one of these markers. There is,
in fact, some evidence that fibrin degradation products, including
D-dimer, may act to stimulate the inflammatory process [39], and
this might provide a further pathological mechanism through
which D-dimer is linked to progressing stroke [40]. There is some
evidence that D-dimer itself stimulates monocyte synthesis and
release of proinflammatory cytokines such as interleukin- 6[41].
Elevated systemic inflammation reflected by high D-dimer levels
could also contribute to the stroke severity [42]. Activated
inflammation and activated coagulation, in concert with each
other, may contribute to the development of stroke. Thirdly,
because D-dimer is one of the acute phase reactants, it is possible
that elevated D-dimer levels in patients with stroke may be the
result rather than the cause of stroke. Although D-dimer was
significantly correlated with baseline infarct volume, D-dimer was
associated with severity independently of infarct volume. Thus, we
consider that it is less likely that elevated D-dimer is merely an
epiphenomenon of development of stroke.
Some limitations of this observational study merit consideration.
Firstly, without serial measurement of the circulating D-dimer
Figure 2. Correlation between plasma D-dimer levels and others predictors. (a) Correlation between plasma D-dimer levels and the
National Institutes of Health Stroke Scale (NIHSS) score; (b) Correlation between the plasma D-dimer levels and fibrinogen levels; (c) Correlation
between plasma D-dimer levels and CRP; (d) Correlation between plasma D-dimer levels and infract volume.
doi:10.1371/journal.pone.0086465.g002
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Figure 3. Plasma D-dimer levels in different etiology of acute ischemic stroke patients. Significant differences in plasma D-dimer levels
were observed (analysis of variance [ANOVA]: p=0.000).
doi:10.1371/journal.pone.0086465.g003
Figure 4. Receiver operating characteristic (ROC) curves were utilized to evaluate the accuracy of D-dimer levels to predict
cardioembolic strokes.
doi:10.1371/journal.pone.0086465.g004
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levels, this study yielded no data regarding how long after the
initiation of clot formation D-dimer levels become elevated or for
how long they remain elevated in circulation. Secondly, follow-up
data are lacking. Welsh et al [42] have reported that D -dimer
were independently associated with poor outcome in acute
ischemic stroke, and Barber et al [37] suggested that other
potentially important factors were taken into consideration, fibrin
D-dimer levels independently predicted progressing stroke. Fur-
ther studies are needed to determine whether elevated D-dimer
predicts outcomes after a stroke in our population. Thirdly, a
number of different commercial D-dimer assays are available, and
so our results may not necessarily be generalized to all assays.
Furthermore, D-Dimer level is very rarely elevated in healthy
individuals, however, may increase in many illnesses and
physiological conditions associated with thrombosis and throm-
bolysis [43]. These patients may have had widespread vascular
disease before stroke onset and are, therefore, likely to have
increased pre-event levels when compared with population
controls. We cannot exclude the possibility that plasma D -dimer
increased under those state.
In conclusion, we have shown that plasma D-dimer levels
increased with increasing severity of stroke as defined by the
NIHSS score and infarct volume and these associations were
independent of inflammation and other possible variables. In
addition, cardioembolic strokes can be distinguished from other
stroke etiologies by measuring plasma D-dimer levels very early
(048hours from stroke symptom onset).
Acknowledgments
Disclaimer: All authors have contributed significantly, and that all authors
are in agreement with the content of the manuscript. We are grateful to the
Department of Neurology; the nurses, physicians, and patients who
participated in our study; and the staff of the central laboratory of the
Hospital.
Author Contributions
Conceived and designed the experiments: WZ JS. Performed the
experiments: WZ JS. Analyzed the data: WZ JS. Contributed reagents/
materials/analysis tools: WZ JS. Wrote the paper: WZ JS.
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