Published online before print March 5, 2009, doi: 10.1161/STROKEAHA.108.539429
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(Stroke. 2009;40:1653.)
© 2009 American Heart Association, Inc.
Original Contributions |
Inflammatory and Hemostatic Biomarkers Associated With Early Recurrent Ischemic Lesions in Acute Ischemic Stroke
From the Departments of Neurology (D.-W.K., S.-H.Y., K.-Y.K., S.U.K., J.-Y.K., J.S.K.) and Laboratory Medicine (S.C.), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Correspondence to Dong-Wha Kang, MD, PhD, Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Pungnap 2-dong, Songpa-gu, Seoul 138-736, Korea. E-mail dwkang{at}amc.seoul.kr
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Abstract |
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Background and Purpose— Early recurrent ischemic lesions (ERILs) on diffusion-weighted imaging after acute ischemic stroke have been suggested as a potential marker of early recurrent stroke. We hypothesized that biomarkers of inflammation or coagulation may be associated with the pathogenesis of ERILs and sought to investigate whether these biomarkers provide prognostic information on the risk of development of ERILs independently of clinical and imaging variables.
Methods— This prospective study enrolled 153 consecutive patients with acute ischemic stroke who underwent diffusion-weighted imaging within 24 hours and subsequently at 5 days after onset and whose plasma or serum for biomarkers (C-reactive protein, fibrinogen, D-dimer, tissue plasminogen activator, and plasminogen activator inhibitor-1) were collected within 24 hours of onset. Those receiving thrombolysis or interventional therapy were excluded. ERILs were defined as new ischemic lesions on 5-day diffusion-weighted imaging separate from the index stroke lesions, which were not accompanied by subsequent recanalization.
Results— ERILs were observed in 37 patients (24.2%). In univariate analysis, shorter time from onset to initial MRI (P=0.013), initial acute multiple infarcts (P<0.001), initial larger infarct volume (P=0.005), stroke subtype (P<0.001), elevated D-dimer (P=0.028), and anticoagulation after admission (P=0.001) were associated with ERILs. In multivariate analysis, initial acute multiple infarcts (OR, 16.60; 95% CI, 5.73 to 48.08), large artery atherosclerosis (OR, 4.62; 95% CI, 1.51 to 14.11), and log D-dimer (OR, 3.20; 95% CI, 1.14 to 9.00) remained independent predictors of ERILs.
Conclusion— These data suggest that elevated D-dimer level reflecting increase of thrombin generation and fibrin turnover may be an independent factor predicting ERILs.
Key Words: acute ischemic stroke • D-dimer • diffusion-weighted imaging • recurrence
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Introduction |
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Recurrent stroke is a major cause of morbidity and mortality among stroke survivors. Because the risk of recurrent stroke is highest in the first few months after stroke, the identification of factors associated with early recurrence is of great importance to establish effective treatments for the secondary stroke prevention.1,2 Previous studies have shown that the evidence of early recurrence on MRI is much more frequent than clinical recurrent stroke within the first week3 and up to 1 to 3 months after an index stroke.4,5 Recurrence on MRI, although mostly clinically silent, has been suggested as a potential surrogate marker for clinical recurrent stroke, because these silent lesions were associated with subsequent clinical recurrent ischemic stroke.6
According to the previous studies, patients with acute multiple infarcts at baseline diffusion-weighted imaging (DWI) were at an increased risk for early recurrent ischemic lesions (ERILs).3,4 In another study, patients with multiple DWI lesions of varying ages (reduced and normalized apparent diffusion coefficient) were at a higher risk of new infarcts on the 30-day MRI compared with those having lesions of the same age.7 These data suggest that there might be a prolonged risk of stroke over the first few weeks after onset. Because atherosclerosis is partly an inflammatory disease, inflammation or hypercoagulability may contribute to the pathogenesis of ERILs. This speculation is supported by the fact that patients with acute multiple infarcts in multiple cerebral circulations had higher C-reactive protein, fibrinogen, and hematocrit than those without.8,9
Based on these observations, we hypothesized that biomarkers of inflammation or coagulation may be associated with the pathogenesis of ERILs and sought to investigate whether these biomarkers provide prognostic information on the risk of development of ERILs independently of clinical and imaging variables.
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Methods |
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Patients
This was a prospective study performed in a tertiary university hospital in Seoul, South Korea, between December 8, 2004, and March 20, 2006. We screened consecutive patients (1) who had acute ischemic stroke confirmed by initial DWI performed within 24 hours of onset; and (2) in whom plasma or serum for the assay of biomarkers (high-sensitivity C-reactive protein, fibrinogen, D-dimer, tissue plasminogen activator, and plasminogen activator inhibitor-1) could be collected within 24 hours of symptom onset. Follow-up DWI scan was performed at 5 days after symptom onset. We excluded patients who (1) received intravenous or intra-arterial thrombolysis; or (2) underwent diagnostic or therapeutic neurointerventional procedures that potentially cause ERILs (eg, diagnostic cerebral angiography, angioplasty, or stenting) between initial and follow-up DWI scans. The onset time was defined as the time patients were last known to be without ischemic symptoms. This study was approved by the Institutional Review Board of the Asan Medical Center, and informed written consent was obtained from each patient, family, or legal guardian.
Stroke severity was assessed using the National Institutes of Health Stroke Scale score at admission. Clinical stroke recurrence within the first week was identified by another investigator (S.-H.Y.) blinded to the MRI data as "any recurrent stroke occurring >24 hours after onset of the index stroke, irrespective of vascular territory."10 Systemic causes of clinical deterioration after an initial stroke (eg, infection) or worsening of initial symptoms because of the progression or hemorrhagic transformation of the initial stroke were not classified as clinical recurrences. The stroke subtypes were determined according to the modified Trial of ORG 10172 in Acute Stroke Treatment classification.11 Diagnosis of stroke subtype was made by the consensus of 3 stroke neurologists (D.-W.K., S.U.K., and J.S.K.) blinded to ERIL results. During the 1-week study period, all patients received secondary stroke prevention therapy (eg, antiplatelet agents, anticoagulants, and/or statins) as standardized by our center’s stroke care pathway. According to the pathway, patients with acute ischemic stroke are supposed to receive antiplatelet therapy. However, heparin anticoagulation during the acute stage may be indicated in patients with (1) high risk of cardioembolic sources (eg, atrial fibrillation, prosthetic cardiac valve); (2) known coagulopathies (eg, protein C, S deficiency, antiphospholipid antibody syndrome); or (3) territorial infarcts and normal intracranial and extracranial arteries on magnetic resonance angiography (MRA), suggesting the possibility of cardioembolism.
Image Analysis
Acute stroke MRI protocol included DWI, gradient echo T2*-weighted imaging, fluid-attenuated inversion recovery image, 3-dimensional time-of-flight MRA, and 3-dimensional contrast-enhanced MRA. Follow-up MRI protocol at 5 days after onset included DWI, gradient echo T2*-weighted imaging, and fluid-attenuated inversion recovery image in all patients and MRA in selected patients who had steno-occlusive arterial lesions on baseline MRA. The detailed MRI protocol has been previously described.12
Ischemic lesions on DWI were analyzed by an investigator (D.-W.K.) blinded to clinical data and stroke subtypes, except initial neurological symptoms. ERILs were defined as new lesions on follow-up DWI outside the region of the acutely symptomatic (index) lesion and which was not detected on initial DWI. Enlargement of an initial DWI lesion was not considered ERIL. Furthermore, new ischemic lesions in the same vascular territory of index stroke accompanied by significant (residual stenosis less than 50% on follow-up MRA) or complete recanalization were not considered ERILs, because they might represent fragmentation of initial embolus rather than recurrent ischemic events. However, if arterial stenosis or occlusion were persistent on follow-up MRA, new ischemic lesions in the same vascular territory of index stroke were regarded as ERILs. The presence of ERILs was determined by slice-to-slice comparison of initial and follow-up DWIs. Ischemic lesion volume was measured by another investigator (K.-Y.K.) blinded to clinical and other imaging information, as infarct volume (mL)=the sum of infarct area on each DWI slicex(slice thickness+interslice gap). Infarct volume measurements were performed using the inherent program of Picture Archiving and Communication System of our hospital.
Laboratory Analysis
For biomarker assay, BD Vacutainer CTAD tubes (Becton Dickinson Biosciences, Rutherford, NJ) and VACUETTE serum tubes (Greiner Bio-One GmbH, Kremsmunster, Austria) were used to collect blood. Blood was withdrawn before the initiation of any oral, enteral, or parenteral feeding or medications. Plasma or serum was immediately separated by centrifugation at 1500 g for 15 minutes. Samples were analyzed within 4 hours or stored at –70°C until analysis. Biomarkers were measured with the following methods: high-sensitivity C-reactive protein with turbidimetry (COBAS INTEGRA 700; Roche GmbH, Mannheim, Germany), fibrinogen with Clauss method (STA fibrinogen; Diagnostica STAGO, Asnières, France), D-dimer with turbidimetry (STA Liatest D-Di; Diagnostica STAGO) on the STAgo compact analyzer (Diagnostica STAGO), and tissue plasminogen activator and plasminogen activator inhibitor-1 with enzyme-linked immunosorbent assay (TintElize tissue plasminogen activator and TintElize plasminogen activator inhibitor-1; Biopool AB, Ventura, Calif). There was no change in the instrumentation or control results during the study period. The coefficients of variation of high-sensitivity C-reactive protein, fibrinogen, D-dimer, tissue plasminogen activator, and plasminogen activator inhibitor-1 were 3.3% to 4.0%, 2.2% to 4.0%, 6.5% to 13.4%, 4.9% to 8.3%, and 5.8% to 9.6%, respectively.
Data Analysis
Baseline demographics, conventional risk factors, statin medication before index stroke, baseline National Institutes of Health Stroke Scale scores, time-to-MRI scans, stroke subtypes, infarct volume on baseline DWI, the presence of acute multiple infarcts on baseline DWI, antithrombotics (antiplatelets versus anticoagulants), and various laboratory data, including biomarkers, were compared between the patients with ERILs and those without (Table 1). For univariate analysis of categorical variables, Fisher exact test was used. For univariate analysis of continuous variables, Student t test was used for normally distributed variables, and Mann-Whitney U test was used for nonnormally distributed variables. Multiple logistic regression analysis was used to determine independent predictors of ERILs. Variables were selected for entry into the multivariate model based on the results of univariate analyses (P<0.1). Parameters that did not fit a normal distribution (eg, values of biomarkers) were transformed into their logarithmic (Log) values for multivariate analysis. The ORs and 95% CIs were calculated. The Hosmer-Lemeshow goodness-of-fit test was used to assess how well the model accounted for outcomes. All statistical analyses were performed using SPSS for Windows (version 12.0; SPSS Inc).
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Results |
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During the study period, we screened 321 patients who had acute infarcts on initial DWI within 24 hours of onset, but 168 were excluded: 104 for unavailable plasma or serum collection mostly due to the admission during the night or weekends, 44 for thrombolysis, 11 for diagnostic or therapeutic intervention, and 9 for refusal of consent or withdrawal. There were no differences in demographics, risk factors, and stroke subtypes between included (n=153) and excluded (n=168) patients, except that baseline National Institutes of Health Stroke Scale scores were higher in excluded (median, 6; range, 0 to 30) than in included (median, 4; range, 0 to 23) patients (P=0.002). However, baseline characteristics, including National Institutes of Health Stroke Scale, were comparable between included (n=153) and those with unavailable plasma or serum collection (n=104).
Of the 153 patients enrolled in this study, 99 were men and 54 were women. Their mean age was 64.6 years (± 10.8 years; range, 39 to 93 years). The median time from onset to initial DWI scan was 11.3 hours (range, 1.2 to 24.0 hours) and the median time from onset to follow-up DWI was 4.4 days (range, 2.4 to 8.9 days). Stroke subtype was large artery atherosclerosis in 43 patients (28.1%), cardioembolism in 33 (21.6%), small vessel occlusion in 54 (35.3%), and other or undetermined etiologies in 23 (15.0%). During the first week after stroke onset, 44 (28.8%) patients received anticoagulant therapy and 108 (70.6%) received antiplatelet therapy, and one (0.7%) received none due to gastrointestinal bleeding.
ERILs were observed in 37 (24.2%) patients and clinical recurrence was identified in 2 (1.3%) of the total 153 patients. In univariate analysis, shorter time from onset to initial DWI, larger baseline infarct volume, presence of multiple infarcts on baseline DWI, stroke subtypes, anticoagulant therapy, and elevated D-dimer were significantly associated with the development of ERILs. Large artery atherosclerosis was the most common stroke subtype associated with ERILs. When we categorized D-dimer levels by median value (470 ng/mL) or 90th percentile value (1876 ng/mL), they were also associated with ERILs (P=0.014 for median value and P=0.052 for 90th percentile value). However, demographics, conventional risk factors, time from onset to follow-up DWI, and other laboratory results except D-dimer did not differ between patients with and without ERILs (Table 1).
Of biomarkers included in this study, D-dimer (r=0.27, P=0.001) and fibrinogen (r=0.18, P=0.033) were positively correlated with the baseline infarct volume (Spearman’s correlation). The level of D-dimer was different according to the stroke subtypes (P=0.004); it was highest in other or undetermined etiology (median, 850 ng/mL; interquartile range [IQR], 320 to 1070 ng/mL) and cardioembolism (median, 820 ng/mL; IQR, 320 to 1480 ng/mL) followed by large artery atherosclerosis (median, 470 ng/mL; IQR, 220 to 960 ng/mL) and small vessel occlusion (median, 300 ng/mL; IQR, 220 to 660 ng/mL). The level of D-dimer tended to be higher in patients with multiple infarcts on baseline DWI (median, 710 ng/mL; IQR, 320 to 1115 ng/mL) than in those without (median, 440 ng/mL; IQR, 220 to 960 ng/mL; P=0.069). On the contrary, the level of D-dimer was not different between patients treated with anticoagulation (median, 585 ng/mL; IQR, 265 to 1133 ng/mL) and those treated otherwise (median, 440 ng/mL; IQR, 220 to 1020 ng/mL; P=0.17).
Multiple logistic regression analysis showed that acute multiple infarcts on baseline DWI, large artery atherosclerosis, and Log D-dimer were independently associated with ERILs (Table 2). The higher level of D-dimer than the 90th percentile (versus lower) was also independently associated with ERILs (OR, 6.04; 95% CI, 1.28 to 28.44; P=0.023). D-dimer more than 470 ng/mL (versus 
470 ng/mL) was associated with ERILs with borderline significance (OR, 2.70; 95% CI, 0.94 to 7.74; P=0.064). When adjusted for baseline infarct volume alone, Log D-dimer still remained independent predictor of ERILs (OR, 2.92; 95% CI, 1.29 to 6.62; P=0.010).
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Discussion |
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This study shows that elevated levels of D-dimer in the 24-hour window after acute ischemic stroke are associated with early recurrence of silent brain infarcts independent of other clinical, imaging, and laboratory variables. Initial multiple acute DWI lesions and large artery atherosclerosis independently predicted the ERILs, whereas conventional risk factors were not associated with ERILs, which is in accordance with prior works.3,4
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 crosslinked fibrin by plasmin.13,14 Highly elevated D-dimer values are observed in various disorders in which the coagulation system is excessively activated such as acute venous thromboembolism.15 In healthy populations, D-dimer is a risk factor for the first venous thrombosis,16 and after a venous thrombosis, it predicts recurrent events.17 It has been suggested that modestly elevated circulating D-dimer values reflect minor increases in blood coagulation, thrombin formation, and turnover of crosslinked intravascular fibrin (which is partly intra-arterial in origin) and that these increases may be associated with coronary heart disease.14 D-dimer is known to be positively associated with coronary heart disease incidence18,19 and its recurrence,20 which is largely independent of conventional risk factors.21 D-dimer has also been shown to predict early clinical progression in ischemic stroke22,23 and poor functional outcome after acute spontaneous intracerebral hemorrhage24 and subarachnoid hemorrhage.25
There are several plausible mechanisms through which D-dimer levels could be closely related to ERILs. First, increased D-dimer levels may reflect ongoing thrombus formation within cerebral vessels or may be a marker of systemic hypercoagulability.22 Second, D-dimer may stimulate the inflammatory process. There is some evidence that D-dimer itself stimulates monocyte synthesis and release of proinflammatory cytokines such as interleukin-6.26 This might provide a further pathomechanism through which D-dimer is linked to ERILs. However, other biomarkers related to inflammation and coagulation were not associated with ERILs in this study. The reason for stronger association of D-dimer with ERILs is not clear. Activated inflammation and activated coagulation, in concert with each other, may contribute to the development of ERILs. Alternatively, the sample size in this study may not be sufficient to detect the difference in other biomarkers than D-dimer. Third, because D-dimer is one of the acute phase reactants, it is possible that elevated D-dimer levels in patients with ERILs may be the result rather than the cause of ERILs. However, other acute phase reactants such as C-reactive protein, fibrinogen, or leukocytes were not related to ERILs in this study. Moreover, we adjusted other confounding variables such as baseline infarct volume, which potentially alter biological markers in our analysis. Although D-dimer was significantly correlated with baseline infarct volume, D-dimer was associated with ERILs independently of infarct volume. Thus, we consider that it is less likely that elevated D-dimer is merely an epiphenomenon of development of ERILs.
The temporal relationship between elevated D-dimer and ERILs is not certain. Although we tried to collect samples soon after initial MRI and always within 24 hours of onset, we cannot exclude the possibility that actual occurrence of ERILs predated time of blood collection. Conversely, there is a possibility that elevated D-dimer predated the event of acute ischemic stroke, particularly in patients who are likely to have increased prestroke D-dimer levels.
The frequency of ERILs in this study is somewhat lower than that of previous studies,3,5,6 partly because the proportion of patients with small vessel occlusion is relatively high in this sample and partly because we did not regard new ischemic lesions accompanied with subsequent recanalization as ERILs. We excluded these lesions from ERILs because we consider that new lesions accompanied with recanalization or reperfusion may be a fragmentation of initial embolus rather than recurrent ischemic events. Nevertheless, some ERILs occurring with recanalization or reperfusion might be caused by true recurrent ischemic events. On the contrary, some ERILs without apparent recanalization might occur with reperfusion, because MRA has a limitation in the evaluation of distal arterial branches and thus might miss small cortical perfusion defect. In these regard, imaging-defined recurrence might under- or overestimate the true incidence of early recurrence. Further studies are needed to elucidate the underlying pathomechanism of ERILs.
In this study, patients receiving anticoagulant therapy were more likely to develop ERILs; this association may be confounded by stroke subtypes. Antiplatelet treatment group included patients with small vessel occlusion who rarely develop ERILs (Table 1). Thus, antithrombotic treatment modality did not remain as an independent predictor by multivariate analysis.
The therapeutic implication of the findings in this study is not certain. Although this study suggests that acute interventions such as heparin that potentially modify hemostatic function may be beneficial for the prevention of early recurrence, previous several clinical trials have failed to show such a benefit.27–29
Several limitations of this study should be noted. First, not all patients with acute ischemic stroke were enrolled, which resulted in including patients with relatively milder stroke in this study, thus limiting generalization of our results to all patients with stroke. Second, long-term MRI and clinical follow-up data are lacking. Further studies are needed to determine whether elevated D-dimer predicts subsequent clinical recurrence after an index stroke.
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Acknowledgments |
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We thank the patients for their consent to participate in this study.
Sources of Funding
This study was supported by grants of the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (A050586 and A060171) and a grant from Brain Research Center of the 21st Century Frontier Research Program funded by the Ministry of Science and Technology of Korea (M103KV010010 06K2201 01010).
Disclosures
None.
Received October 5, 2008; accepted October 27, 2008.
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