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Page 8 of 11 Ghosh et al. Neuroimmunol Neuroinflammation 2018;5:38 I http://dx.doi.org/10.20517/2347-8659.2018.28

per 10 mmHg change in SBP. In our study too, the higher MABP at admission was significantly associated
[27]
with the stroke severity, the unfavorable outcome, and mortality. Bruno et al. described that in all strokes
combined (P = 0.03) and in non-LSs (P = 0.02), higher admission blood glucose levels were associated with
the worse outcomes at 3 months according to multivariate logistic regression analysis adjusted for stroke se-
verity, diabetes mellitus, and other vascular risks, thereby, corroborating with our findings.

Discussion on the role of thrombolysis
Our study demonstrated that thrombolysis significantly reduced the incidence of the unfavorable outcome,
which is evidenced by the fact that only 20% of thrombolysed patients and 70% of non-thrombolysed pa-
[28]
tients had the unfavorable outcome. Mehta et al. reported 67.1% good outcome and 32.9% unfavorable out-
come post thrombolysis; diabetes, dyslipidemia, NIHSS at admission > 15, blood sugar > 250 mg/dL, dense
cerebral artery sign and occlusion of large artery being significant predictors of the poor outcomes on mul-
[29]
tivariate analysis. Liu et al. reported that age ≥ 70 years, NIHSS score > 20, serum glucose on admission >
9.0 mmol/L and cardioembolism were independent predictors of hemorrhage after thrombolysis in Chinese
patients with acute ischemic stroke. Thirty percent patients in our study had post-thrombolysis hemorrhage.
Blood glucose, MABP, higher mean NIHSS score and serum fibrinogen level at admission correlated signifi-
cantly with post-thrombolysis hemorrhage. Higher NIHSS score increases the risk of hemorrhages since se-
vere ischemic stroke is reflected by large areas of injured brain tissue, including injured blood vessels, which
[30]
are prone to bleeding after rtPA treatment .
Discussion on the role of biomarkers
Our study demonstrated that the mean values of all the 4 biomarkers-CRP, fibrinogen, D-dimer, and NSE
were significantly higher among patients with severe stroke. Fibrinogen level decreased and D-dimer level
increased significantly following thrombolysis. Fibrinogen was the only biomarker, whose elevated levels
[31]
could significantly predict post-thrombolysis hemorrhage. Results of a meta-analysis indicated a signifi-
cant association between the elevated baseline CRP and unfavorable long-term functional outcome. Al-
though our study is based on the CRP values at admission, interestingly, two studies of the meta-analysis [32,33]
showed a stronger association of poor outcome with hs-CRP measurements at 24-48 h and 7 days reflecting
impairment of the recovery process due to prolonged inflammation after ischemic stroke.

[34]
Rothwell et al. described that fibrinogen predicted ischemic stroke, with the association tending to be
stronger in patients with nonlacunar than lacunar syndromes. Moreover, fibrinogen levels were found to
[35]
be an independent predictor of early neurological deterioration among diabetic patients . The Alteplase-
Tenecteplase Trial Evaluation for Stroke Thrombolysis study demonstrated that alteplase was associated with
prolongation of prothrombin time, reduced fibrinogen and plasminogen, elevated fibrin degradation prod-
[36]
ucts and d-dimer level . Following ischemic stroke, tissue responds with mitochondrial dysfunction and
increased nitric oxide (NO) production which vasodilates and maintains blood perfusion. In turn this leads
to a burst in free radical production and the generation of peroxynitrite, which irreversibly nitrates proteins.
Fibrinogen’s up-regulation as an acute-phase reactive protein and increased permeability of the blood-brain
barrier during ischemic stroke allowing extravasation of different plasma proteins into the brain parenchy-
ma further potentiates fibrinogen nitrotyrosination. At early stages nitro-fibrinogen delays clot formation,
but in the long term, it becomes harmful due to the production of fibrinolysis resistant clots and the induc-
[37]
tion of neuronal damage . Hence, possibly more elevation in the fibrinogen level produces more cellular
and local vascular damage, resulting in a higher chance of post-thrombolysis hemorrhage.

Previous studies demonstrated that acute ischemic stroke patients had significantly higher plasma median
[38]
D-dimer levels as compared to healthy controls . D-dimer levels increased with increasing severity of
stroke and infarct volume and the positive trends existed even after correcting for possible confounding
[38]
factors . Thus, D-dimer concentrations may be considered a direct consequence of marked cerebral infarc-