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 Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 53  |  Issue : 3  |  Page : 146-150

Prognostic value of D-dimer measurement in patients with acute ischemic stroke


Department of Neurology, Ain Shams University, Cairo, Egypt

Date of Submission05-Jul-2015
Date of Acceptance23-Aug-2015
Date of Web Publication27-Oct-2016

Correspondence Address:
Yousry A Abd-Elhamid
Department of Neurology and Psychiatry, Faculty of Medicine, Ain Shams University, Cairo
Egypt
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Source of Support: None, Conflict of Interest: None


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  Abstract 

Background D-dimer, a marker of plasmin-mediated fibrin degradation, is cross-linked to fibrin degradation products and indicates vessel occlusion.
Objectives The purpose of this study was to evaluate the role of D-dimer serum level as a serological marker in the diagnosis and prognosis of acute ischemic stroke in Egyptian population.
Patients and methods This prospective observational case–control study was conducted on 50 patients with acute ischemic stroke. Ten healthy age-matched and sex-matched individuals were taken as controls. The patient and control groups were subjected to detailed history taking, examination, and D-dimer level assessment. Neurologic examination using the National Institutes of Health Stroke Scale was carried out at admission and on discharge after treatment. Serum D-dimer level was evaluated within the first 24 h of admission. The outcome of the patients was graded using the modified Rankin scale on admission and 1 month of treatment.
Results The mean D-dimer level was significantly higher in the patient group than in the control group (P < 0.001). There was a positive correlation between the levels of D-dimer and the National Institutes of Health Stroke Scale scores (P = 0.002) and the initial infarct volume in MRI of the brain (P = 0.000). The mean D-dimer level was significantly higher in patients with unfavorable outcome than in patients with favorable outcome, measured using the modified Rankin scale (P = 0.029).
Conclusion Plasma D-dimer levels were significantly higher in patients with acute ischemic stroke than in controls. D-dimer levels increased with increasing severity of stroke and with increasing infarction volume. Moreover, D-dimer level could predict stroke outcome.

Keywords: acute stroke, D-dimer, outcome, stroke severity, stroke volume


How to cite this article:
Abd-Elhamid YA, Tork MA, Abdulghani MO. Prognostic value of D-dimer measurement in patients with acute ischemic stroke. Egypt J Neurol Psychiatry Neurosurg 2016;53:146-50

How to cite this URL:
Abd-Elhamid YA, Tork MA, Abdulghani MO. Prognostic value of D-dimer measurement in patients with acute ischemic stroke. Egypt J Neurol Psychiatry Neurosurg [serial online] 2016 [cited 2021 May 15];53:146-50. Available from: http://www.ejnpn.eg.net/text.asp?2016/53/3/146/193090


  Introduction Top


Stroke is the second leading cause of death and one of the most frequent causes of disability worldwide [1]. Ischemic stroke represents about 87% of all strokes [2]. Diagnosis of acute ischemic stroke is sometimes difficult because computed tomography results may appear normal in the early stage and MRI is not always possible in golden time of treatment. Thus, many eligible cases experience delay in receiving intravenous thrombolytic treatment. Rapid diagnosis in patients with suspected acute ischemic stroke is critical for the patient’s treatment and prognosis [3].

D-dimer is a fibrin degradation product released into the blood stream by fibrinolysis of cross-linked fibrin and indicates the presence of active thrombus formation and lysis [4]. The measurement of plasma or whole-blood D-dimer is a very useful test for the diagnosis of conditions that result from blood clots.

Many studies have shown elevated D-dimer levels during the acute phase of stroke [5],[6]. D-dimer also seems to have a role in prognosis following a stroke [7]. D-dimer assays have good sensitivity but poor specificity because elevated D-dimer may be due to various other causes.


  Aim of the work Top


The aim of this study was to evaluate the role of D-dimer serum level as a serological marker for infarction size, and clinical outcome in acute ischemic stroke.


  Patients and methods Top


This prospective observational case–control study was conducted on 50 patients admitted to the Stroke Unit of Ain Shams Specialized Hospital with first-ever acute ischemic stroke within 24 h of onset of symptoms. Acute ischemic stroke was defined according to the WHO criteria [8]. Ten healthy age-matched and sex-matched individuals were taken as controls. Patients receiving anticoagulation therapy due to any cause and patients older than 70 years (because D-dimer increases with age) [9] were excluded. Patients with severe hepatic disease, renal disease, malignancy, drug use, epileptic seizure activity before admission, collagen diseases, sepsis, rheumatoid disease, and patients with previous history of stroke were also excluded [4]. Informed written consent was obtained from each patient, family, or legal guardian and controls.

All patients were subjected to full detailed neurological history, and general and neurological examination. Stroke severity was assessed using the National Institutes of Health Stroke Scale (NIHSS), a tool used to objectively quantify the impairment caused by a stroke at admission and on discharge after treatment. We divided the patients according to NIHSS results into three groups: mild (0–6), moderate (7–15), and severe (≥16) [10]. Routine blood and biochemical tests, ECG, and echocardiography were carried out to exclude any other hidden causes that may elevate D-dimer level. Serum D-dimer level was evaluated within the first 24 h of admission. Radiological evaluation included brain computed tomography (CT) (General Electric CT-scanner 9800 Little Chalfont, UK), to exclude intracranial hemorrhage. Brain MRI studies were carried out using a Siemens Vision 1.5-T MR scanner (Magnetom Verio; Siemens, Erlangen, Germany). MRI stroke protocol comprised T1-weighted and T2-weighted images in the axial, sagittal, and coronal views, fluid-attenuated inversion recovery, diffusion-weighted image (DWI), and magnetic resonance angiography to assess the site and volume of infarction. We measured infarction volume in DWI using the formula [A × B × C/2], where A is the largest diameter and B is the perpendicular diameter of the ischemic lesion, as measured, and C is the sum of the thicknesses of the slices where the lesion was visible. The criteria used in the analysis of infarction volume have been previously reported [8]. The outcome of the patients was graded using the modified Rankin scale (mRS) at admission, discharge, and 1 month of treatment. Patients with no impairment or symptoms receive the best score of 0, whereas patients with severe disability who are bedridden, incontinent, and require constant nursing care and attention received the worst score of 5; death can be rated 6 in the mRS [7].

The blood sample was taken within the first 24 h of the symptom onset. The technician who studied D-dimer levels in the blood samples was blinded to the diagnosis of the patient and the control group. The D-dimer test is a latex-enhanced immunoturbidimetric test for the quantitative determination of cross-linked fibrin degradation products in human plasma. The D-dimer value is considered abnormal when in excess of 490 ng/ml (0.49 mg/l) fibrinogen equivalent unit.

Stroke subtype was classified blindly according to TOAST (Trial of Org 10172 in Acute Stroke Treatment) criteria [11], which distinguished large-artery arteriosclerosis, small-artery occlusion, cardioembolism, other causative factor, and undetermined causative factor.

Statistical analysis

Statistical presentation and analysis of the present study was carried out using mean, SD, unpaired Student’s t-test, the Wilcoxon tests, linear correlation coefficient, analysis of variance tests, paired t-test, and the χ2-test. All statistical analyses were performed using SPSS 11.0J for Windows (IBM Corp., Chicago, Illinois, USA). The results were considered as significant if P value was less than 0.05 and as highly significant if P value was less than 0.01.


  Results Top


This study included 50 patients, 26 male (52%) and 24 female (48%), with acute ischemic stroke admitted within 24 h of the onset of symptoms. Their ages ranged from 26 to 70 years, with a mean age of 53.1 ± 12.42. The control group included 10 healthy individuals, five male (50%) and five female (50%), matched with the age and sex. Their ages ranged between 30 and 65 years, with a mean of 52.5 ± 10.5. There were 37 (74%) patients with hypertension, 30 (60%) patients with diabetes mellitus, 28 (56%) patients with dyslipidemia, 28 (56%) patients with ischemic heart disease, 14 (28%) patients with atrial fibrillation, and 21 (42%) smokers [Table 1]. The mean D-dimer level was significantly higher in patients (1035.6 ± 565.6 ng/ml) than in controls (305 ± 121 ng/ml) (P < 0.001) [Table 1].
Table 1: The patient and control groups as regards age, sex, and mean D-dimer level at the time of admission

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In the patient group, plasma D-dimer levels increased with increasing severity of stroke as defined by the NIHSS score. There was a positive correlation between the levels of D-dimer and the NIHSS scores (P = 0.002) [Figure 1].
Figure 1: Correlation between D-dimer and stroke severity (NIHSS score) on admission. NIHSS, National Institutes of Health Stroke Scale.

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In our study, with regard to the volume of infracted area, there was a statistically positive correlation between initial D-dimer levels and the initial infarct volume in MRI of the brain (P < 0.000). D-dimer level increases as the initial infarction volume in MRI of the brain (DWI) increases on admission.

Our patients were divided into two groups according to the estimated volume of the infracted area in relation to the cerebral hemisphere: the first group included patients with infarction volume larger than one-third of the cerebral hemisphere, and the second group included patients with infarction volume less than one-third of the cerebral hemisphere. The mean D-dimer level was significantly higher in the first group (1525 ± 541.822 ng/ml) than that in the second group (942.38 ± 525.8 ng/ml) (P = 0.006).

In this study, with regard to the volume of infarction area, the best cutoff limit for D-dimer level was 1190 ng/ml using recover operator characteristic analysis (ROC) curves, with a sensitivity of 75% and a specificity of 66.7%.

With regard to ischemic stroke subtype, D-dimer levels in patients with cardioembolic stroke was statistically significantly higher than that in patients with other ischemic stroke subtypes [LAA (880.8 ± 449 ng/ml), SAA (703 ± 286.6 ng/ml), and unknown etiology (1010 ± 888.7 ng/ml), respectively] (P < 0.01) [Table 2]. Using ROC curve, it was found that the best cutoff limit of D-dimer levels evaluated in patients early after admission within the first 24 h predicting cardioembolic stroke was 1090 ng/ml, which achieves 87.5% sensitivity and 76.5% specificity.
Table 2: Comparison between different acute ischemic stroke subtypes as regards mean D-dimer level

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Patients were followed up prospectively for 1 month for the clinical outcome as measured using the mRS. There was a significant correlation between the D-dimer levels and the mRS scores of the patients (P = 0.004). Patients were grouped on the basis of clinical outcome as follows: patients with favorable outcome (mRS 0–2) and patients with unfavorable outcome (mRS 3–6). The mean D-dimer level was significantly higher in patients with unfavorable outcome (1122.3 ± 561.6 ng/ml) than in patients with favorable outcome (9689 ± 456.4 ng/ml) (P = 0.029).

Using ROC analysis curves, it was found that the best cutoff limit of D-dimer levels evaluated in patients early after admission (within the first 24 h) in predicting poor outcome was 650 ng/ml, which achieves 80% sensitivity and 60% specificity.


  Discussion Top


Although most diagnostic approaches for the evaluation of acute stroke rely on neuroimaging techniques, an alternative strategy could be the evaluation of blood-borne biochemical markers of tissue injury [11],[12]. The study by Laskowitz et al. [13] suggests that a biomarker panel may add valuable and time-sensitive diagnostic information to early stroke evaluation and rapid identification of patients with suspected stroke, which would expand the availability of time-limited treatment strategies. They also reported that biomarker test in conjunction with noncontrast CT has a significantly greater sensitivity compared with CT alone.

In this study, we found that D-dimer levels are significantly elevated in patients with acute ischemic stroke when compared with the healthy control population. This is in agreement with some studies [14],[15],[16]. However, other studies concluded that normal D-dimer levels do not exclude brain infarction and elevated D-dimer levels do not substitute clinical or radiological examinations [17].

Serum D-dimer level when measured within 24 h of stroke onset was correlated significantly with the stroke severity according to the NIHSS score on admission. Plasma D-dimer level increased with increasing severity of stroke as defined by the NIHSS score. This result is in agreement with other studies [11],[16]. In addition, Zi and Shuai [17] added that this association was independent of other possible variables. In contrast, Ageno et al. [18] found no significant correlation between D-dimer levels and stroke severity. Other studies postulated that D-dimer assessment cannot be used as an acute ischemic stroke index, with the exception of the cardioembolic subtype [5],[15]. This difference could be attributed to methodological variability and heterogeneity of the study group.

Our study showed that the serum D-dimer level correlated positively with the initial infarction volume (P = 0.000). D-dimer level increases as the initial infarction volume in MRI of the brain (DWI) increases on admission. This is in agreement with other studies [16],[19].

Moreover, the mean D-dimer level in our study was significantly higher in a group of patients with initial stroke volume more than one-third of the cerebral hemisphere (P = 0.006). These results are similar to the results by Barber et al. [11], who reported that D-dimer serum level and an increased rate of intracerebral bleeding in stroke patients undergoing systemic thrombolysis were higher in patients with brain DWI lesions size at least one-third of the middle cerebral artery territory.

Moreover, in our study, with regard to the volume of infarction area, the best cutoff limit for D-dimer level was 1190 ng/ml, with a sensitivity of 75% and a specificity of 66.7%. Above the cutoff limit, the volume of the infracted area is most likely larger than one-third of the cerebral hemisphere, and might be helpful to refrain from using intravenous thrombolysis in the hyperacute phase of stroke [17].

Current study also showed that there was a significant positive correlation between the stroke severity measured using the NIHSS and the initial infarction volume on admission (P = 0.000). Severe stroke measured using the NIHSS on admission associated with large initial infarction volume (more than one-third of the cerebral hemisphere). Many other studies that are in agreement with this result [13],[17],[20].

D-dimer levels were significantly different among stroke subtypes after an acute ischemic event. Patients with cardioembolic events had significantly higher levels compared with patients with different etiologic factors. These findings are in agreement with other different studies [16],[18]. Classification of ischemic stroke as cardioembolic requires identification of a commonly accepted cardiac source, usually atrial fibrillation. Atrial fibrillation leads to the activation of coagulation in the left atrium, thereby leading to the formation of a thrombus [8]. This may explain elevated D-dimer level in cardioembolic stroke.

On the basis of the ROC curve, the optimal cutoff value for plasma D-dimer levels as an indicator for the diagnosis of cardioembolic strokes was projected to be 1090 ng/ml, which yielded 87.5% sensitivity and 76.5% specificity. D-dimer below 1090 ng/ml (1.09 mg/l) makes a cardioembolic stroke unlikely. This may be useful to guide further investigations. Ageno et al. [18] similarly reported that the optimal D-dimer cutoff point for discriminating between the presence and absence of a cardioembolic source was 2000 ng/ml to yield a specificity of 93%, a sensitivity of 59.3%, a positive predictive value of 72.7%, and a negative predictive value of 88%. Doufekias et al. [21] have also reported that D-dimer level of more than 1.6 mg/l may indicate a high possibility of cardioembolic stroke. Zi and Shuai [17] concluded that the optimal cutoff value for plasma D-dimer levels as an indicator for the 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%. Differences in cutoff value may be attributed to the fact that specificity of the same assay type can vary from 24 to 82%. Thus, some investigators suggest setting a critical cutoff value for each individual assay, based on the test performances established in clinical studies [8].

Our results also showed that patients with high levels of plasma D-dimer were associated with poor clinical outcome as measured with the mRS when followed prospectively after 1 month in comparison with patients with good outcome. Similarly, other studies concluded that, after adjusting for all other significant outcome predictors, D-dimer level remained an independent predictor for unfavorable functional outcome and mortality in patients with acute ischemic infarction [7],[22].


  Conclusion Top


We had shown that plasma D-dimer levels were statistically significantly higher in patients with acute ischemic stroke than in controls. D-dimer level increased with increasing severity of stroke as defined by the NIHSS score and infarct volume, and might be helpful marker in selecting patients for intravenous thrombectomy. In addition, cardioembolic strokes can be distinguished from other stroke etiologies by measuring plasma D-dimer levels very early (within the first 24 h from stroke symptom onset). Moreover, D-dimer circulating level could predict unfavorable outcome when measured early in acute stroke.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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