Correlation between Serum D-Dimer Level and Volume in Acute Ischemic Stroke

Abstract

Objective

D-dimer is a breakdown product of fibrin mesh after factor XIII stabilization. Previously, many authors have demonstrated a relationship between D-dimer level and stroke progression or type. This study aimed to investigate the relationship between D-dimer level and stroke volume.

Methods

Between January 2008 and December 2009, we analyzed the D-dimer levels of 59 acute ischemic stroke patients in our neurosurgical department both upon admission and after seven days of initial treatment. Each patient's National Institute of Health Stroke Scale score, modified Rankin Scales score, Glasgow outcome score, and infarction volume were also evaluated.

Results

Mean D-dimer level at admission was 626.6 µg/L (range, 77-4,752 µg/L) and the mean level measured after seven days of treatment was 238.3 µg/L (range, 50-924 µg/L). Mean D-dimer level at admission was 215.3 µg/L in patients with focal infarctions, 385.7 µg/L in patients with multiple embolic infarctions, 566.2 µg/L in those with 1-19 cc infarctions, 668.8 µg/L in 20-49 cc infarctions, 702.5 µg/L in 50-199 cc infarctions, and 844.0 µg/L in >200 cc infarctions (p=0.044). On the 7th day of treatment, the D-dimer levels had fallen to 201.0 µg/L, 293.2 µg/L, 272.0 µg/L, 232.8 µg/L, 336.6 µg/L, and 180.0 µg/L, respectively (p=0.530).

Conclusion

Our study shows that D-dimer level has the positive correlation with infarction volume and can be use to predict infarction-volume.

INTRODUCTION

Acute ischemic stroke (AIS) has recently become a common cause of death and disability in the world^29,36). Diagnosis of acute ischemic stroke is difficult because computed tomography (CT) results may appear normal in the early stage or in patients with minor symptoms, and magnetic resonance imaging (MRI) is not always possible in golden time of treatment. Thus, many eligible cases experience delays in receiving intravenous thrombolysis treatment. Rapid diagnosis in patients with suspected AIS is critical for the patient's treatment and prognosis⁴⁵⁾.

Many studies have shown elevated D-dimer levels during the acute phase of stroke, which eventually fall^14,26,30,34). However, previous studies have demonstrated only that plasma D-dimer levels predict a progressing ischemic stroke^4,5).

We studied the relationship between D-dimer level and infarction volume and the relationship between D-dimer change and clinical outcome in AIS.

MATERIALS AND METHODS

Patient selection and evaluation

Between January 2008 and December 2009, we studied 59 patients out of 125 patients admitted to our department of neurosurgery due to acute ischemic stroke. Patients who were receiving anticoagulation therapy (due to atrial fibrillation, valvular heart disease, deep venous thrombosis, pulmonary embolism, severe hepatic disease, renal disease, malignancy, or drug use) were excluded. We evaluated risk factors : age, sex, hypertension, diabetes mellitus, dyslipidemia, other cardiac diseases (including acute myocardial infarction and angina), and cigarette smoking³⁷⁾. There were 32 male and 27 female patients, ranging from 19 to 82 years in age (mean, 65.3 years).

At emergency room we took each patient's history and performed a physical examination, neurologic examination using the National Institutes of Health Stroke Scale (NIHSS), serologic evaluation, and radiological evaluation [brain CT, brain MRI, and magnetic resonance angiography (MRA)]. We classified our patients into two groups according to treatment modality. One group received treatment with recombinant tissue plasminogen activator (rt-PA) and/or intra-arterial thrombolysis (the thrombolysis group), and the others received treatment with intravenous argatroban (the argatroban group). We graded their outcomes using the modified Rankin Scale (mRS) and modified Glasgow Outcome Scale (GOS), which places the scores in reverse order. To analyze the initial NIHSS results, we divided the patients into three categories according to this baseline NIHSS score : mild (0-6), moderate (7-15), and severe (16 and above)^1,38).

D-dimer analysis

D-dimer levels of patients with AIS were evaluated at admission and after seven days of treatment. The D-dimer test is a latex-enhanced immunoturbidimetric test for quantitative determination of cross-linked fibrin degradation products in human plasma. The D-dimer value is considered abnormal when in excess of 250 µg/L (normal range, 63.8-246.4 µg/L).

Volumetric analysis of infacrted areas

We obtained CT and MRI scans and performed volumetric analyses using DWI. MRI studies used a Siemens Vision 3.0T MR scanner (Magnetom Verio, Siemens, Erlangen, Germany). The imaging protocol comprised DWI, T2-weighted, fluid-attenuated inversion recovery, conventional spin-echo T1- and T2-weighted images, and MRA.

We measured infarction volume using DWI. To calculate the infarction volume, we employed the following 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. One senior experienced neuroradiologist, performed the volumetric analyses.

The criteria used in the analysis of infarction volume have been previously reported⁴²⁾. We classified patients into 6 subgroups by infarction volume : focal (volume estimation was difficult), multiple embolic (focal multiple lesions in both hemispheres where volumetric calculation was difficult), 1-19 mL, 20-49 mL, 50-199 mL, and >200 mL.

Treatment

AIS patients received intravenous rt-PA treatment (0.9 mg/kg) if they reached the hospital within 4.5 hours after ictus⁴³⁾. For patients with persistent arterial occlusion without signs of early recanalization immediately after IV thrombolysis and for patients visiting the hospital more than 4.5 hours after symptom onset but within 6 hours, we administered combined (IV and IA) thrombolysis therapy, for early recanalization^{11,12,17,24,25,46)}. The patients who visited the hospital between 6 and 48 hours after symptom onset underwent treatment with IV direct thrombin inhibitor (argatroban) for 7 days. During the first 2 days the argatroban 120 mg (60 mg/day) was administered continuously. And, then during the subsequent 5 days 10 mg of argatroban was injected per 12 hours²⁰⁾.

Brain CTs were checked immediately after thrombolysis, upon any neurological deterioration associated with an NIHSS increase of 2 points over baseline, and at a conscious level of arm, leg, or eye movement⁷⁾.

Statistical analysis

Relationships between plasma D-dimer level, changes in D-dimer, treatment modality, and NIHSS, mRS, and GOS scores were evaluated using the Mann-Whitney test for comparisons between two subgroups. The Mann-Whitney test, Kruskal-Wallis test, and Pearson correlation were used to evaluate correlations between plasma D-dimer level, change of D-dimer level, infarction volume, and NIHSS, mRS, and GOS scores.

RESULTS

Patients

Table 1 presents the patients' profiles. Via the NIHSS, we diagnosed mild stroke in 29 patients (49%), moderate stroke in 23 (40%), and severe stroke in 7 (11%). After 7 days of treatment, NIHSS scores showed 42 (71%) with mild, 15 (26%) with moderate, and 2 (3%) with severe strokes. Modified Rankin scale scores of these patients ranged from 0 to 5 (mean, 1.75±1.38). The thrombolysis group showd a significantly higher mean mRS scale score than the argatroban group had (3.0 vs. 1.5, p=0.005). The mean modified GOS of all patients in this study was 1.68±0.84.

Table 1.

Patients' profiles

D-dimer and treatment modality

Table 2 shows the plasma D-dimer levels at admission and after seven days of stroke therapy, by treatment modality. Patients treated with rt-PA or intra-arterial thrombolysis showed higher D-dimer levels at admission than patients receiving intravenous argatroban did (922.3 µg/L vs. 573.4 µg/L, p=0.016). The thrombolysis group showed significantly greater changes in D-dimer levels compared to the argatroban group (p=0.019).

Table 2.

Plasma D-dimer levels at admission and after the 7th day of stroke therapy

D-dimer and volume of infarcted area

Fig. 1 presents the D-dimer and stroke volume data, describing a statistically positive correlation between initial D-dimer value and D-dimer value change (p<0.05). Mean D-dimer level at admission was 215.3 µg/L (77-497 µg/L) in patients with focal infarctions, 385.7 µg/L (161-819 µg/L) in patients with multiple embolic infarctions, 566.2 µg/L (96-2,098 µg/L) in those with 1-19 cc infarctions, 668.8 µg/L (161-4,752 µg/L) in 20-49 cc infarctions, 702.5 µg/L (248-1,991 µg/L) in 50-199 cc infarctions, and 844.0 µg/L in >200 cc infarctions (p=0.044). On the 7th day of treatment, the D-dimer levels had fallen to 201.0 µg/L (50-456 µg/L), 293.2 µg/L (103-528 µg/L), 272.0 µg/L (91-924 µg/L), 232.8 µg/L (97-535 µg/L), 336.6 µg/L (122-421 µg/L), and 180.0 µg/L respectively (p=0.530).

Fig. 1.

The positive relationship between intial D-dimer and stroke volume.

D-dimer value did not correlate statistically with stroke volume at the 7th day after stroke (p>0.05). D-dimer levels were higher in the large infarction volume subgroups than in the small volume subgroups, and the D-dimer changes were significantly larger for large infarction volumes than for small infarction volumes (Fig. 2).

Fig. 2.

The changes of D-dimer level each stroke volume group.

D-dimer and neurological outcome

Table 3 shows D-dimer level comparisons between the two groups with regard to the outcome index (mRS, modified GOS, and NIHSS scores). Forty-two patients belonged to the good mRS score (0-2) group and 17 patients to the poor mRS score (3-6) group. The favorable modified GOS (1-2) group had 47 patients, and the unfavorable modified GOS (3-5) group had 12 patients. When we analyzed the final NIHSS scores, 42 patients were in the mild category (71%), 15 in the moderate category (26%), and 2 in the severe (3%). We found no correlation between the D-dimer of the groups and the clinical outcome groups (p>0.05).

Table 3.

D-dimer (µg/L) levels according to each outcome group

mRS : modified Rankin Scale, GOS : Glasgow Outcome Scale, NIHSS : National Institutes of Health Stroke Scale

DISCUSSION

Although most diagnostic approaches to the evaluation of acute stroke rely on neuroimaging techniques, an alternative strategy could be the evaluation of blood-borne biochemical markers of tissue injury. This approach has precedents in the triage and early management of other urgent medical conditions. For example, biomarkers such as troponin, CK-MB, D-dimer, and B-type natriuretic peptide play important roles in the evaluation of myocardial ischemia, pulmonary embolism, and congestive heart failure^13,32). In the correct clinical context, such a rapid, noninvasive test would help identify a patient population at risk for cerebral ischemia, who need rapid evaluation and triage. Furthermore, it could provide adjunctive diagnostic information for patients for whom physicians are contemplating acute intervention.

D-dimer can be elevated in any case with deep venous thrombosis, pulmonary thromboembolism, myocardial infarction, disseminated intravascular coagulation, surgery, trauma, or stroke^{2,9,16,33,41)}. D-dimer, a marker of plasmin-mediated fibrin degradation, is cross-linked to fibrin degradation products (FDP) and indicates vessel occlusion. Plasmin splits the fibrin into FDP and D-dimers when the coagulation and fibrinolytic system is activated. A number of studies have shown that D-dimer, C-reactive protein, and other markers of hemostatic activation associate with a stroke diagnosis^{5,18,19,21-23,28,31,35,39)} and with progression and death in acute ischemic stroke^{5,6,10,30,44)}. The report by Laskowitz et al.²²⁾ 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. Laskowitz et al.²²⁾ also demonstrated that, for the evaluation of early ischemia, a strategy incorporating the current biomarker test in conjunction with noncontrast CT has significantly greater sensitivity than CT alone possesses. They have demonstrated the usefulness of some serologic markers, such as D-dimer, brain natriuretic peptide, matrix metalloproteinase-9, and protein S100-beta, for detecting cerebral ischemic stroke.

Skoloudík et al.⁴⁰⁾ found that the D-dimer levels increase within 6 hours after stroke onset is greater in patients with large artery occlusion and in patients with cardioembolic stroke than it is in patients with lacunar stroke or in patients without arterial occlusion. Barber et al.⁵⁾ showed D-dimer can help physicians target interventions for preventing early neurological deterioration after acute ischemic stroke. However, some studies postulated that D-dimer assessment cannot be used as an AIS index, with the exception of the cardioembolic subtype^15,41). In this study, D-dimer had a statistical correlation to infarct volume, and D-dimer value changes during stroke therapy appeared greater in patients receiving intravenous rt-PA (with or without intra-arterial thrombolysis) than in those receiving intravenous argatroban therapy.

Lövblad et al.²⁷⁾ provided evidence that infarction volume may be predictive of clinical severity and outcome. Also, infarction volume has shown significant correlations with NIHSS and brain injury scores^3,8,27). Our study assessed the relationship between clinical outcome and infarction volume in AIS patients. Compared to previous studies, our results showed similar correlations between infarction volume and mRS, GOS, and NIHSS scores. Infarct volume increase correlated with poor outcomes on the mRS and NIHSS (p<0.05) but showed weaker correlation with the modified GOS (p=0.077).

Baird et al.³⁾ reported a high correlation between volume change and change in NIHSS score. Our study used DWI to check infarction volume change, comparing the volumes at the acute infarction onset and after 7 days. Only 24 (40%) of 59 patients showed reduced infarction volume on MRI during the follow-up period. Eighteen patients (30%) showed no change, 6 (10%) patients had an increased infarction volume, and 6 (10%) had a decreased volume. Hemorrhagic transformation of the infarcted area occurred in 5 patients (8%). Infarcted volume after seven days of treatment could not predict neurological outcome in our results. However, we found that patients with higher D-dimer levels were more likely to have high NIHSS scores upon admission (p=0.040) and after 7 days (p=0.015).

According to previous studies in the literature, such as the Trial of Org 10172 in Acute Stroke Treatment¹⁾, the stroke subtype categories are atherothrombotic, cardioembolic, small-vessel occlusion or lacunar stroke of undetermined etiology, and stroke of other undetermined etiology. Moreover, Montaner et al.²⁹⁾ have confirmed the usefulness of a unique biomarker in the etiologic diagnosis of a stroke, especially a cardioembolic stroke. We did not analyze by etiologic stroke diagnosis, as previous studies did, but rather categorized patients into 6 groups by infarction volume. The 6 groups comprised patients with focal, multiple embolic, 1-19 mL, 20-49 mL, 50-199 mL, and >200 mL infarctions, whose D-dimer levels were 215.3 µg/L, 385.7 µg/L, 566.2 µg/L, 668.8 µg/L, 702.5 µg/L, and 844.0 µg/L, respectively (p<0.05), at admission. Average D-dimer levels after 7 days were 201.0 µg/L, 293.2 µg/L, 272.0 µg/L, 232.8 µg/L, 336.6 µg/L, and 180.0 µg/L, respectively (p>0.05). This is the first study assessing the relationship between the D-dimer levels and stroke volume in ischemic stroke patients. Although we did not consider stroke etiology, our results show that knowing the D-dimer level is helpful for predicting infarction volume.

This study has several limitations. First, explaining the measurable variables in volume by our volumetric analysis, particularly in the focal and multiple embolic subgroups, was difficult. Though relationships among the other subgroups in our study correlate positively with D-dimer level and AIS lesion volume, D-dimer level in the focal and multiple embolic subgroups trended toward lower values. Second, we did not take account of potential confounding variables, such as age, gender, and co-morbid medical condition (pneumonia, acute renal failure, GI bleeding). Although many factors can influence an AIS patient's outcome, D-dimer level showed less correlation with patient outcome in our results. However, our data supports a correlation between D-dimer level and infarction volume in acute ischemic strokes. In spite of the confounding factors, D-dimer level revealed a positive correlation with infarction volume in our results. Third, our patient group was relatively small and heterogenous in age and therapeutic modality. Patients with various stroke therapies and various risk factors were included in this one study.

CONCLUSION

This study shows that D-dimer level significantly increases after the onset of an acute ischemic stroke and that the D-dimer level correlates positively with acute ischemic volume. D-dimer can be considered as a valuable marker for predicting infarction volume in acute ischemic strokes and treatment response.