This study, to the best of our knowledge, is the first to analyze the relationships between the NPR and HE in spontaneous ICH patients. The present study found that a high NPR was related to HE after spontaneous ICH.
The occurrence of HE could be detected within 3 h of symptom onset in approximately 73% of ICH patients, and clinically obvious expansion was present in 35% of patients [11,12,13]. Accumulating evidence suggests that inflammation caused by HE accelerates brain injury in patients with ICH [4, 14,15,16]. Although the relationship between WBC count and outcome in ICH patients has been well demonstrated [3, 17], the correlation between early HE and leukocyte subsets remains disputed [4, 16, 18, 19]. In our study, the univariate analysis showed significant associations between HE and ANC, ALC, AMC and NPR, and multivariate logistic regression analysis showed that all those biomarkers mentioned above could not independently predict early HE, except for the NPR. However, the exact underlying mechanism of the associations between routine blood variables and HE remains unclear and needs further study.
Neutrophils play a basic defensive role in both infection-related diseases and aseptic inflammation, which are indicators of inflammation and immune response . Neutrophils appear first in the hematoma , delivering pro-inflammatory factors, oxygen free radicals and proteases, which could have an effect on blood–brain barrier (BBB) disruption and brain damage [22, 23]. Previous studies have reported that neutrophils are the primary cellular source of metalloproteinases (MMPs), specifically MMP-9, working on the BBB . Moreover, it has been shown that in ischemia–reperfusion injury, the increase in BBB permeability induced by WBC-derived MMP-9 is associated with peak neutrophil infiltration . Furthermore, accumulating studies have reported that HE is associated with changes in the basal membrane of the BBB induced by MMP [4, 26, 27]. Therefore, it is reasonable to believe that neutrophils are associated with HE.
Several studies have reported the relationship between neutrophil count and hematoma size. Neutrophil count at admission was positively associated with intracerebral hemorrhage volume , and it was found in another study that the inhibition of neutrophil recruitment could reduce the amount of bleeding . One study reported that neutrophil count was negatively related to an increased risk of HE during the hyperacute phase of ICH . One possible explanation for this paradoxical finding is that the injury to blood vessels caused by neutrophils may be mediated by platelets, and neutrophil-platelet interactions may play different roles in vascular inflammation at different stages of ICH . Despite activated neutrophils having a procoagulant role , the mutual relationship between neutrophils and platelets could increase the formation of reactive oxygen species and aggravate vascular damage . In addition, platelets, as a considerable contributor to some pro-inflammatory factors, could enhance the aggregation of activated neutrophils [30, 33].
In a review of neutrophil-platelet interplay, activated platelets were found to be connected with the release of inflammatory mediators, the accumulation of neutrophils, and increased vascular permeability . By locally releasing soluble vascular protective factors, platelet-endothelial interplay may prevent or treat neutrophil-induced vascular damage . The hemostatic role of platelets depends on embolization and coagulation at the location of vascular injury , which contributes to the preservation the integrity of the BBB . Systemic inflammation is often accompanied by thrombocytopenia, which may be attributed to the immune response in the blood circulation . According to the above, it can be speculated that in patients with ICH, the higher the NPR, the more serious the BBB damage may be, resulting in the higher occurrence of HE.
The NPR may be more stable as a ratio than individual blood parameters, such as neutrophils or thrombocytes, because of the mutual relationship between neutrophils and platelets. Recent studies have shown a correlation between the NPR and other diseases, such as ischemic stroke [8, 37,38,39,40], ST-elevation myocardial infarction  and infective endocarditis . For example, a high NPR was related to an increased risk of hemorrhagic transformation in acute ischemic stroke patients ; the platelet-to-neutrophil ratio (PNR) was found to be an independent protective predictor of 90-day prognosis in patients with acute ischemic stroke . Moreover, the PNR on admission could independently predict poor functional prognosis in ischemic stroke patients undergoing intravenous thrombolysis . Consistent with these findings, we found a significant association between the NPR and ICH, and a high NPR on admission was an independent predictor of HE in ICH patients.
In addition, previous studies have reported that a larger baseline ICH volume and lower GCS score on admission were associated with HE [43, 44]. In our study, the initial hematoma volume and GCS score on admission were predictors of HE in both univariate analysis and multivariate regression analysis. The results were consistent with Zhang’s study  and Li’s study . On the other hand, an onset-to-first-CT time of less than 6 h was independently associated with HE [19, 46]. However, in our study, the median onset-to-first-CT time was 7 h and the median for the group with HE was 8 h. One possible explanation may be that West China Hospital of Sichuan University is an upper-level hospital in Southwest China, and many patients request to be transferred to our hospital for treatment from lower-level hospitals in this region or other regions. Therefore, the median onset-to-first-CT time in our study was longer.
Given HE being the independent risk factor for disability and death in ICH patients, it is crucial to timely identify HE [2, 13]. In this case, NPR has its clinical implications. Firstly, in clinical practice, as a routine indicator of blood test, it is easy and convenient to obtain NPR. Moreover, the predictability of NPR here can help clinicians initially estimate the risk of HE in ICH patients, and then conduct appropriate treatment and follow-up CT for that population. In addition, since single predictor for HE has its limitation, there are currently a variety of prediction scores containing several predictors . Similarly, the combination of NPR and other predictive factors can form new prediction scores with higher specificity and sensitivity. However, the potential clinical implications of NPR should be further investigated.
Several limitations should be noted in this study. First, the data were recorded in a single center, and the sample size was limited. Second, although the results of this retrospective study may be influenced by confounding factors, multivariate analysis was used to address this problem. Third, given the complex role of inflammation in HE, more studies that record more inflammatory biomarkers are necessary in future studies.