Our study found that stroke patients had significantly higher mean levels of fibulin-5 and IMA in the acute phase in comparison to the control group, and this increase was higher in hemorrhagic than ischemic stroke in case of fibulin-5 contrary to ischemia-modified albumin which showed higher levels in ischemic than hemorrhagic stroke.
In agreement with our results, all the previous studies [6, 11, 22,23,24] done to measure these two biomarkers in acute stroke, whether ischemic or hemorrhagic, found that their level is increased in cases than control group. And also as regard to differentiation between ischemic and hemorrhagic stroke, Hu et al.  found that serum fibulin-5 concentration had increased in ICH patients, and the studies of Gunduz et al. , Jena et al. , and Ertekin et al.  showed elevated IMA levels with a diagnosis of ischemic stroke. Also, Gad et al.  found that IMA was significantly higher in the infarction group than the hemorrhage group.
As for ischemia-modified albumin, many studies explained the association of IMA with ischemic brain injury by increasing ischemia following acute stroke, there occurs anaerobic metabolism of glucose leading to excess production of lactic acid causing acidosis, which may also lead to IMA formation . Also in case of cerebral hemorrhage, cerebral blood flow and cerebral metabolic rate of oxygen decreased adjacent to hematoma after bleeding resulting in oxygen fraction reduction  with relative ischemia leading also to IMA formation but to lesser extent than in ischemic stroke.
In case of fibulin-5, it was found that hypoxic stress, in case of ischemic stroke or relative ischemia that occurs in case of hemorrhage due to oxygen fraction reduction secondary to decreased blood flow around the hematoma , induces fibulin (FBLN5) expression in vascular endothelial cells through hypoxia-inducible factor-1 (HIF-1) as a part of the adaptive response of endothelial cells to survive to hypoxia . The effects of fibulin-5 on brain injury following ischemia/reperfusion have been reported by Guo et al. . In this study, they examined the effect of overexpressed fibulin-5 on reactive oxygen species (ROS) production. Fibulin-5 overexpression attenuated ROS expression, which in turn decreased apoptosis and blood–brain barrier (BBB) permeability following MCAO and reperfusion. Fibulin-5 also improved neurological deficits but had no effect on infarction volume. T2-weighted MRI and electron microscopy further confirmed brain edema reduction and decreased BBB disruption in fibulin-5 overexpression recombinant adenovirus (Ad-FBLN) treated rats. In addition, tight junction protein occludin was significantly degraded, and matrix metalloproteinase 9 (MMP-9) immunoreactivity was significantly increased. Fibulin-5-mediated ROS decrease was not due to increased total superoxide dismutase levels but was instead correlated with the activation of Rac-1 pathway. The findings highlight the importance of antioxidant mechanism underlying cerebral ischemia/reperfusion. Furthermore, FBLN5 favors endothelial cell attachment to the ECM, contributing to preserve structural and functional characteristics of the endothelial cell monolayer . Furthermore, FBLN5 cooperates with FBLN2 to maintain the integrity of the adult vessel wall after injury and to avoid abnormal remodeling .
Regarding relation between biomarkers and different vascular risk factors, fibulin-5 has significantly higher mean levels in patients with smoking, diabetes mellitus (DM), and AF, while IMA has significant positive correlation with DM, BMI and cholesterol, TG, HDL, and LDL. This came in agree with the study Han et al. , in which serum IMA levels were positively correlated with patients’ total cholesterol (TC), triglycerides (TG), and low density lipoproteins (LDL) levels, but negatively correlated with high-density lipoproteins (HDL), and this did not come in agree with our study. Also, in disagreement with our study, Jena et al.  demonstrated a significant negative correlation between serum IMA with serum uric acid and albumin, which supports the fact that imbalance in oxidant and antioxidant status plays an important role in pathophysiology and generation of IMA in ischemic brain injury. Few years before, Cherubini et al.  also demonstrated that majority of antioxidants including uric acid were reduced immediately after an acute ischemic stroke.
In our study, there were significant positive correlations between serum fibulin-5 and IMA levels with lesion volume. Hu et al.  showed that the mean concentration of serum fibulin-5 in ICH patients was mainly influenced by hemorrhage volume and extension to ventricles. The larger the hemorrhage volume is, the more severe the disease is, and the higher the serum fibulin-5 concentration is in compensation. When hematomas extend to ventricles, the inflammatory reaction spread out into the central nervous system, and BBB permeability was disrupted more seriously. Koivunen  also stated that both hematoma volume and expansion of intraventricular hemorrhage are powerful and independent predictors of ultimate outcomes in the case of ICH. As for ischemia, several biomarkers have been associated with infarct volume, including S-100B, matrix metalloproteinase (MMP), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), intracellular adhesion molecule-1 (ICAM-1), and glutamate. These could be useful to predict clinical outcome in patients with ischemic stroke. However, it should be emphasized that lesion size may not correlate with neurologic outcome, as even small lesions can cause devastating neurological outcomes when they occur in certain anatomical regions such as the brainstem .
Regarding severity, our study showed significant positive correlations between fibulin-5 and IMA levels with NIHSS in stroke patients; whereas there were significant negative correlations with GCS. This means that the fibulin-5 and IMA can be regarded as biomarkers for evaluating disease severity. This agreed with Hu et al.  and Abboud et al. .
Regarding the outcome, many candidate markers have been studied, and higher levels of biomarkers of most pathophysiological processes involved with stroke are associated with worse outcome after stroke . On applying Modified Rankin Scale (MRS) 3 months after stroke, our study showed that there were positive correlation between MRS and fibulin-5 levels, but not with IMA, suggesting that fibulin-5 could be used as prognostic biomarker for acute cerebrovascular diseases, but more studies needed to confirm this results. This comes in agreement with Hu et al. , who concluded that serum fibulin-5 can be regarded as prognostic biomarker in ICH patients.