In this study, we found that the increase in SIRI-GPR score in patients with AIS after IVT was closely related to poor stroke outcome and was an independent predictor of prognosis at 3 months in patients with AIS who underwent intravenous thrombolysis at the first time. In addition, a nomogram model combining the SIRI-GPR score and other conventional risk factors was more favorable in its ability to discriminate the poor prognosis of IVT for AIS.
The pathogenesis of AIS usually involves inflammation and immunity. The infiltration of inflammatory cells is the beginning of inflammatory response, and inflammation plays a key role in vascular injury. SIRI is a novel integrated immune-inflammatory index that relies on absolute values of peripheral blood neutrophil counts, monocyte counts, and lymphocyte counts. In the early stages of AIS, peripheral circulating neutrophils are first activated, resulting in the release of antimicrobial enzymes and chemicals.23, 24Some studies have also shown that the increase of neutrophil counts is related to the increase of infarct size, so the increase of neutrophil counts level may aggravate the blood-brain barrier injury by promoting the overexpression of matrix metalloproteinase-9.25, 26 In addition, after AIS, monocytes are another important class of inflammatory cells, which can infiltrate the infarct site and aggravate brain damage.27-29In contrast to neutrophils and monocytes, some lymphocytes play a protective role during post-AIS inflammation and play a key role in controlling and alleviating local inflammation.30 Compared to other blood cell ratios, such as neutrophil/lymphocyte ratio (NLR), lymphocyte/monocyte ratio (LMR), and platelet/lymphocyte ratio (PLR), SIRI symbolize different pathways related to inflammation and immunity in the body, and may provide a more comprehensive response to the body's inflammatory state. As such, the SIRI can accurately indicate adaptive immune responses and inflammatory responses, with the potential to serve as a reliable prognostic indicator. 31Therefore, it is speculated that the level of SIRI may better reflect the severity of neuroinflammation in patients with AIS after IVT, which in turn reflects the severity of the patients' condition. The results of our study showed that there was a statistically significant difference in SIRI between the good prognosis group and the poor prognosis group. The SIRI of the poor prognosis group was significantly higher than that of the good prognosis group, which was also similar to the results of Min Chu et al. 13
In addition to inflammation and immune response in AIS its important role, the stress response also plays an important role. M.J. Brown and J. Brown first suggested a strong link between the renin-angiotensin-aldosterone system (RAAS) and stroke in 1986. 32 In the brain, the RAAS has an autocrine function that maintains cerebral dynamic homeostasis and blood flow regulation. Angiotensin II (Ang II) acts by stimulating angiotensin receptor subtype 1, leading to disruption of cerebral blood flow and tissue ischemia. 33 In the setting of an AIS, these effects of Ang II will further damage regions of the cerebral ischemic hemidiaphragm in areas where cells are still viable and will amplify the cerebral damage and loss of brain volume. 34-36 Subsequent studies have also found that stroke patients' neuronal damage may be associated with increased activity of angiotensin receptor subtype 1 in the brain-specific RAAS. 37, 38 Other possible mechanisms by which Ang II contributes to brain damage include induction of inflammation and production of reactive oxygen species, leading to brain damage and apoptosis. 39
In the context of acute disease, blood glucose may reflect the interaction of hormones involved in the stress response with concomitant insulin resistance, blood glucose is a major contributor to brain damage. Previous studies have confirmed that hyperglycemia may lead to increased oxidative stress, inflammatory responses, and endothelial dysfunction, resulting in brain tissue reperfusion injury. 40-44 It has also been found that IVT has a poorer prognosis in patients with AIS with electrolyte disturbances. 45, 46 Previously, Cheng et al. demonstrated that minor deviations of serum K+ levels from the normal range may lead to severe muscle dysfunction, palpitations, arrhythmias, and deterioration of neurological function. 47-49 Multiple meta-analyses have reported that K+ inhibits the formation of free radicals and prevents endothelial dysfunction. 50-52 In addition, blood potassium levels are mainly regulated by the ATP-Na+/K+ pump on the cell surface regulation, there is an important relationship with glycemic changes. In the case of AIS stress, increased adrenergic hormones upregulate this pump, thereby decreasing K+ levels. 53, 54 Stress-induced increases in insulin secretion and catecholamines due to intracellular K+ uptake, and further hyperglycemia, will have clinical consequences. In addition, it has also been shown that lower blood potassium levels may be a marker of enhanced activity of the RAAS and may potentiate the adverse effects of other risk factors.32, 55 The results of this study showed that there was a statistically significant difference in GPR between the good and poor prognosis groups, with the GPR in the poor prognosis group being significantly higher than that in the good prognosis group, and Yuzhao Lu et al. also previously found that GPR was positively correlated with 30-day mortality in patients with AIS, and that the two had a linear relationship. 21 Therefore, the GPR at the time of admission may be a promising predictor of short-term prognosis for patients with AIS.
There are many clinical indicators related to the poor prognosis of patients with AIS after IVT for 3 months. It is now considered that the causes affecting the prognosis of IVT in stroke are diverse and complex and need to be evaluated comprehensively. In our study, Large artery occlusion, NIHSS score within 24h after thrombolysis and SIRI-GPR score after thrombolysis were found to be independently associated with poor prognosis at 3 months after IVT in AIS. Large artery occlusion is the cause of irreversibility, SIRI and GPR are both reversible causes, and are easy to obtain laboratory indicators. Among these indicators, the OR value of SIRI-GPR score is the highest, indicating that SIRI-GPR score plays the most important role in predicting the poor 3-month prognosis of AIS after IVT. Here, through the nomogram model to show the relationship between the independent risk factors of each outcome index, it is proved that SIRI-GPR score has a better correlation in predicting poor 3-month prognosis after IVT in AIS.
Given that inflammatory and immune responses have been shown to play an important role in the prognosis of thrombolysis in AIS, and that the GPR can respond to the stress state of the organism, reflecting the activity of the RAAS, and that lymphoid organs are directly innervated by nerves, catecholamines are released from the nerve endings during stress in the organism, and stress hormones are regulated through adrenergic receptors and glucocorticoid receptors immune cell function56, and thus influence the immune response after thrombolysis in AIS. In our present study, GPR was used for the first time in a 3-month prognostic prediction study of IVT in AIS, and the results showed a statistically significant difference in GPR between the good prognosis and poor prognosis groups. The final results demonstrated that the SIRI-GPR score was a good predictor of 3-month prognosis in AIS after IVT, and thus, we hypothesized whether it is possible to intervene in the prognosis of IVT in AIS by decreasing the SIR-GPR score and thus provide timely intervention to enable the patients with AIS to have a good functional prognosis from IVT.
There are several defects that need to be considered in depth. First of all, this study lacks a prospective design and does not further compare the dynamic changes of hematological inflammatory markers. Secondly, we did not collect the ASPECTS score and TOAST classification into our study. Thirdly, this study is a single-center study with relatively small sample size and short follow-up time, so there may be some bias and variation. Therefore, these factors may lead to our outcome SIRI and GPR have no independent predictive significance for 3-month functional prognosis. Finally, given that the samples are collected from only one city in China, the results may not be generalized. This also provides a research direction for the future: to collect dynamic blood biochemical data before and after IVT for accurate comparative study to see whether dynamic SIRI-GPR score has different effects on prognosis, and to study the specific effects of dynamic SIRI-GPR score on the prognosis of IVT in AIS, such as early prognosis (early neurological deterioration and bleeding transformation) and collect the ASPECTS score and TOAST classification into study. We also need further large-scale prospective studies and multicenter collaborative studies to verify our conclusions.