To study plasma D-dimer levels in acute ischemic stroke and their correlation with the National Institute of Health Stroke Scale

INTRODUCTION

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

Atherosclerosis is central in the pathogenesis of stroke. Inflammation plays a key role in the initiation, progression, and complications of atherosclerosis by facilitating every stage of atheroma development. Thrombosis, platelet activation, and inflammation are essential in the pathophysiology of AIS.

Hemostasis is the property of circulation where blood retains fluidity within the vasculature, while the system simultaneously prevents excessive blood loss upon injury.⁴ When the vascular injury occurs, clotting reactions are initiated, creating an insoluble fibrin-platelet plug at the site of the vessel wall defect, arresting blood loss, and finally restoring the vascular integrity.⁵ The activation releases many substances required in platelet aggregation and initiates the coagulation cascade, leading to the formation of cross-linked fibrin, creating a clot at the injury site. During the fibrinolysis process, plasmin cleaves fibrinogen and soluble fibrin. The resulting smallest oligomer is D-dimer.⁶ The value of the measurement helps to predict the presence of thrombosis. The normal plasma D-dimer level is 0 to 500 ng/mL. The D-dimer assay depends on the interaction between the monoclonal antibody and the D-dimer fragment. The level of D-dimer correlates with the clot burden. D-dimer levels have certain advantages over other measures of thrombin generation, because it is resistant to ex vivo activation, relatively stable, and have a long half-life. Additionally, plasma D-dimer levels can be tested economically and easily with standard laboratory equipment. Increased D-dimer levels are frequently found in patients with AIS. Several studies indicated that high D-dimer levels are not only associated with high risk of poor outcome and mortality^7,8 but also infarct volume⁹ and progressing ischemic stroke.¹⁰ Therefore, the purpose of this study is to determine the level of D-dimer and correlate its levels with National Institute of Health Stroke Scale (NIHSS) in AIS patients.

MATERIAL AND METHODS

After obtaining approval from the institutional ethical committee, a hospital-based, prospective, and observational study was conducted on 200 patients with AIS, admitted under the Department of Medicine, Govt. Medical College and Associated M.B.S. Hospital, Kota, from 2021 to 2022. This group was compared with 200 age and sex matched controls. All AIS patients with symptom onset within 7 days were included in our study, having provided written informed consent. Whereas, patients <18 years, having hemorrhagic stroke, active cancer, prior myocardial infarction, pulmonary embolism, deep vein thrombosis, pregnancy, puerperium upto 2 weeks, head injury in the last 3 months, history of stroke or transient ischemic attack, venous stroke, stroke due to tumors, or systemic acute, chronic inflammatory, autoimmune, infectious, or connective tissue disease, and patients refusing to give informed consent for the study were excluded. The diagnosis of acute stroke was made based on the temporal profile of clinical syndrome, clinical examination, and CT scan/MRI of the brain. Ischemic stroke risk factors (modifiable and non-modifiable) were identified by considering detailed history, clinical examination, and routine lab investigations. Severity of stroke was determined with the NIHSS in all patients at initial presentation and discharge. Stroke severity was grouped in minor stroke (1-4), moderate stroke (5-15), moderate to severe stroke (16-20), and severe stroke (21-42). Immediately after admission, 2 mL of a peripheral venous sample was drawn following all aseptic precautions before starting any treatment. The samples were processed immediately. Blood (9vol) was collected in 3.2% trisodium citrate anticoagulant (1vol) [Light blue top vial] and sent for D-dimer. The D-dimer test is a latex-enhanced immunoturbidimetric test for the quantitative determination of cross-linked fibrin degradation products in human plasma. This level of D-dimer was then compared with the reference value calculated from the control group of the same age and sex and with the NIHSS severity score (calculated at the time of admission and discharge).

RESULTS

In our study, the mean age was 62.04±9.54 years, which was comparable with the mean age of the control group (62.42±9.01 years). Both groups had maximum subjects in the range of 50-69 years, i.e., 148 and 146, respectively. Males (57%) outnumbered females (43%) with a ratio of 1.3:1. Table 1 depicts the age and sex distribution of subjects in the case and control groups. Isolated left hemiparesis was the most common focal neurological deficit observed in 31% of the patients, as compared with isolated right hemiparesis (28%). Features of posterior circulatory stroke, like vertigo, blurring of vision, incoordination, etc., without weakness, were present in only 6% of the patients. Patients had left hemiparesis with cranial nerve palsy and right hemiparesis with cranial nerve palsy were 14% and 21%. Partial anterior circulation strokes were maximum at 54% and 14% of patients had total anterior circulation stroke. Patients with lacunar and posterior circulation strokes were 23% and 9%, respectively, as per the trial of ORG 10172 in acute stroke treatment classification.

Distribution of AIS patients in different NIHSS scores shows that maximum cases were present in NIHSS score group 5-15 (moderate stroke), both at the time of admission and discharge, i.e., 122 and 98, respectively [Table 2]. The mean NIHSS score in AIS patients at admission was 11.96±5.72 as compared with 9.16±7.12 at discharge. In our study, hypertension was the most common risk factor (53%), followed by smoking (50%), dyslipidemia (33%), diabetes mellitus (40%), and alcoholism (37%), as shown in [Table 3]. Biochemical and hematological profiles of both case and control groups show that the value of random blood sugar, urea, creatinine, total cholesterol, triglyceride, hemoglobin, and platelet count was significantly higher (P<0.05) in the study group as compared to the control group [Table 4].

It was observed that the D-dimer levels were significantly higher in patients with AIS (1042.9±624.75 ng/mL) as compared to the control group (250±113.96 ng/mL) with a p-value of 0.0001. Moreover, D-dimer did not change significantly with sex and presence of risk factors like hypertension, smoking, alcoholism, diabetes, and dyslipidemia (p>0.05). The value of D-dimer was higher in patients with total anterior circulation stroke (1485±583.68 ng/mL) followed by partial anterior circulation stroke (1075.18 ± 626.85 ng/mL), lacunar stroke (876.52±541.92 ng/mL), and posterior circulation stroke (586.66±450.30 ng/mL) [Table 5]. On comparing D-dimer with patients of different NIHSS score, it was found to be lowest in NIHSS score group 1-4 (395.45±184.46 ng/mL), which increased to (857.70±455.66 ng/mL) in the NIHSS score group 5-15 (1633.68±551.25 ng/mL) in the NIHSS score group 16-20, and was highest in the NIHSS score group of 21-42 at 1842.22±401.30 ng/mL [Table 6]. This showed a positive, moderately strong, and statistically significant correlation between D-dimer and NIHSS score at the time of admission [Correlation coefficient (r)=0.7787] [Figures 1 to 2]. Table 7 shows the distribution of AIS patients according to clinical status in different NIHSS score groups, as assessed on day 7 or at discharge. From this table, we found that out of 200 patients, 138 improved, 32 deteriorated, and 30 remained static. Comparison of D-dimer levels according to clinical status in AIS patients showed that D-dimer in deteriorated patients was 1556.25 ±614.30 ng/mL at admission. On the other hand, the mean D-dimer in improved patients was 911.74±561.56 ng/mL at admission, whereas the value of D-dimer was 1098.67±659.35 ng/mL in patients who remained static [Table 7].

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Figure 1:

Comparison of D-Dimer according to NIHSS score at the time of admission and hospital stay. NIHSS: National Institutes of Health Stroke Scale.

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Figure 2:

Correlation between D-Dimer of patients suffering from AIS with NIHSS at the time of admission. Blue dots show distribution and blue lines show correlation. AIS: Acute ischemic stroke, NIHSS: National Institutes of Health Stroke Scale.

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DISCUSSION

Our study included 200 patients of AIS and 200 age and sex-matched control subjects. Although the control subjects were free from AIS, some of them had risk factors for ischemic stroke. Our study had a male preponderance with a male-to-female ratio of 1.3:1, which was similar to all other studies done by Melake MS et al.¹¹ (2016), Bruno Zecca et al.¹² (2014), Liu Y et al.^,13 (2020), where 51%, 55.3%, and 64.4% males, respectively. The mean age of our study group was 62.04±9.54 years, with the maximum cases in the age range of 50 to 69 years. This is in accordance with various other studies done by Glickman et al.¹⁴ (2011), Kim et al¹⁵., 2010 Altès et al.¹⁶, (1995)¹ and Takano et al.¹⁷ (1990) In our study, hypertension was the most common risk factor detected in 53% of the patients, followed by smoking (50%), dyslipidemia (33%), diabetes mellitus (40%), and alcoholism (37%). This is similar to the recent studies by Yao T et al.¹⁸ (2019), Wang J et al.¹⁹ (2020), Wang J et al.²⁰ (2016) and Abd Elhamid et al.²¹ (2016). In the present study, we determined the level of D-dimer in patients with AIS and observed that the mean D-dimer in AIS patients was 1042.9±624.75 ng/mL, significantly higher than that in the control group (250±113.96 ng/mL) with a p value of 0.0001. In our study, we found a high negative predictive value (85%), positive predictive value (60%), and a sensitivity and specificity of 80% and 65%, respectively. These measures of test accuracy were comparable to a study by Barber M et al.²² (2006) and Ye N et al.²³ (2020). In our study positive, moderately strong, and statistically significant correlation was found between D-dimer and NIHSS score at the time of admission, such that plasma D-dimer level increased proportionately with the increasing NIHSS score. (p=0.0001) and (r=0.7787). Our study is similar to the studies done by YLiu Y et al.¹³ (2020) and Wang J et al.¹⁹ (2020) in which there was a positive correlation between D-dimer and NIHSS score at the time of admission. In our study, of the 200 patients, 138 improved, 32 deteriorated, and 30 remained static. It was observed that mean D-dimer in patients who improved, deteriorated, and were static was 911.14±561.56, 1556.25±614.30, and 1096.67±659.35 ng/mL, respectively, and this was found to be statistically significant (p= 0.0006) by one-way Analysis of Variance (ANOVA).

This highlighted that the patients who deteriorated had higher D-dimer levels than those who remained static or improved. Our study supports the finding by Barber M et al.²² (2006) and Wang J et al.¹⁹ (2020), which demonstrated that AIS patients with higher D-dimer had poor outcomes as compared to patients with lower plasma D-dimer levels.

CONCLUSION

D-dimer is a simple, cost-effective marker that may help in the diagnosis of ischemic stroke, predicting the severity of disease and prognosis in terms of functional outcomes, as evidenced by its increased value in patients of AIS as well as its linear positive correlation with NIHSS score.