The Hemoglobin, Albumin, Lymphocytes and Platelets (HALP) Predicts Long-term Survival in Posterior Circulation Ischemic Stroke

The survival of posterior circulation ischemic stroke (PCIS) patients is worse. The hemoglobin, albumin, lymphocyte, and platelet (HALP) score is a novel combined index reecting nutritional and inammation status. We aimed to evaluate the impact of the HALP score on the prognosis of PCIS. The Kaplan-Meier method with log-rank test was used to draw the survival curves. Cox proportional hazard regression model were performed to determine the independent prognostic factors. The predictive power was evaluated by assessing the area under the receiver operating characteristic (ROC) curve. A total of 238 PCIS patients were retrospectively enrolled, and the median follow-up time was 4.3 years. Based on the Kaplan–Meier curve analysis, it was noticed that a low HALP value was signicantly associated with a worse overall survival (P < 0.001). Multivariate Cox analysis showed that age, National Institutes of Health Stroke Scale (NIHSS), and HALP score were independent risk factors for overall survival (HR 1.059, 1.26 and 0.354). Furthermore, the combination of the HALP and NIHSS score improved the prediction performance (AUC 0.888) and appeared to has the ability to accurately identify high-risk patients with poor prognosis. Data were presented as mean ± standard deviation, median (interquartile range), or n (%). NIHSS, the National Institute of Health Scale Score; pc-ASPECTS, posterior circulation Alberta Stroke Program Early Computed Tomography Score; PLR, platelet-to-lymphocyte ratio; NLR, neutrophil-to-lymphocyte ratio; HALP, hemoglobin, albumin, lymphocyte, and platelet score VA, vertebral artery; BA, basilar artery; PCA, posterior cerebral artery.


Introduction
Posterior circulation ischemic stroke (PCIS) accounts for 20-25% of all acute ischemic strokes and its prognosis is worse, with higher disability and higher mortality 1 . However, in comparison with patients with anterior circulation ischemic stroke, patients with PCIS have not been studied extensively. Exploring new predictors of long-term prognosis may help in early identi cation of high-risk patients with poor outcome and contribute to more effective prevention.
Nutritional status such as anemia and hypoalbuminemia are related to functional outcomes of stroke 2,3 . Immune-in ammation index such as neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) are also associated with the prognosis 4 . Recent studies have identi ed a new index called HALP, comprised of hemoglobin, albumin, lymphocytes, and platelets, which has proven to be a good prognostic indicator [5][6][7] . Anemia is common and independently predicts mortality of acute ischemic stroke 8, 9 . Serum albumin is a multifunctional protein that plays neuroprotective roles in ischemic stroke 10 . Hypoalbuminemia is associated signi cantly with poor outcome 11,12 . As systemic in ammatory markers, white blood cells and their subtypes such as lymphocytes, are known to mediate the response during cerebrovascular diseases. Studies have shown that lower lymphocyte counts were associated with a poor functional outcome 13,14 . Platelet hyperactivity increases the risk of thromboembolism and atherosclerotic lesions 15 . The HALP score is a combination of nutritional status and in ammatory responses. Thus, we sought to assess the association between HALP and the long-term survival of PCIS patients.

Baseline characteristics
A total of 238 PCIS patients were enrolled in the current study. The median age was 64.3 ± 11.6 years and 171 (71.8%) patients were male. The median NIHSS score and pc-ASPECTS were 3 (2-6) and 8 (8-9).  Association of HALP score with clinical characteristics We performed ROC analysis and found that the area under the curve (AUC) of HALP score was 0.76, indicating that it was signi cant for predicting 5-year overall survival (p < 0.001, Fig. 1a). The optimal cutoff value was 42.89. Subsequently, PCIS patients were divided into low-HALP (n = 118, 49.6%) and high-HALP (n = 120, 50.4%) groups (Table 2). Patients with low levels of HALP tended to have a higher NIHSS, a lower pc-ASPECES and a higher recurrence rate (all p < 0.05). A low level of HALP was more likely to be present in higher age and in female patients (all p < 0.001). Low levels of HALP were signi cantly associated with high NLR and PLR levels (all p < 0.001).  Table 3). Kaplan-Meier analysis also showed that low HALP score predicted a worse overall survival (p < 0.001, Fig. 1b).

Creation of the HALPN value as a new prognostic model index
According to the multivariate Cox regression analysis, NIHSS was identi ed as an important predictor, in addition to the HALP score. The AUC of NIHSS was 0.825, and the optimal cutoff value was 4.5 (Fig. 2a, p < 0.001). Kaplan-Meier analysis showed that the high NIHSS score was associated with increased mortality ( (Fig. 2b,  Kaplan-Meier analysis showed that a higher HALPN score predicted poor overall survival (Fig. 3a, p < 0.001) in PCIS patients. As age at diagnosis was an independent factor for overall survival, we performed further strati cation analysis for the PCIS patients according to age. It showed that patients with a higher HALPN score had a worse overall survival with age ≤ 60 and age > 60 ( Fig. 3b and 3c, all p < 0.01)

Discussion
This study assessed the value of the novel index HALP for predicting the long-term survival of PCIS patients. It was observed that a low level of HALP score at admission was signi cantly associated with a poor survival rate. Moreover, the combination of HALP and NIHSS score enabled us to create a new index, HALPN, which was observed to be an independent risk factor. HALP combined with NIHSS offered a powerful prediction effect for long-term overall survival of PCIS patients.
Increased HALP score has previously been correlated with a decreased risk of recurrent stroke and death within 90 days and 1 year in patients with acute ischemic stroke 16 . Consistent with previous ndings, this study showed that HALP score was an independent factor for long-term overall survival and represented a clinically valuable prognostic tool for PCIS patients. The HALP score is a new index combined with hemoglobin, albumin, lymphocyte, and platelet. The relationship between low hemoglobin concentration and poor outcomes in patients with ischemic stroke has been well established 9,17 20 . Serum albumin is an indicator of the nutritional status. Recent studies have shown that decreased serum albumin levels were independently associated with poor prognosis in ischemic stroke 21,22 . The role of albumin as a neuroprotectant has been assessed in the ALIAS (albumin in acute stroke) trial. However, the Phase III clinical trial con rmed that high-dose albumin treatment was not associated with improved outcome at 90 days in acute ischemic stroke patients 23 . Immune cells contribute to acute ischemic injury and is associated with outcomes 24 . NLR is signi cantly higher at admission in patients with poor 3-month outcome 25 . However, we did not observe an association between NLR, PLR and long-term mortality risk. Further studies are needed to clarify this issue.
NIHSS score was also identi ed as a predictor for long-term overall survival in this study. The association is easy to understand because NIHSS is the most commonly used scale to evaluate the neurologic de cit in stroke patients. Numerous studies have also con rmed the predictive effect of NIHSS on prognosis of PCIS and basilar artery occlusion patients [26][27][28][29] . In the present study, besides the NIHSS score, we also examined the predictive value of pc-ASPECTS, which has been widely studied in PCIS patients. The BASILAR study revealed that pc-ASPECTS was important for predicting mortality within 90 days in patients with acute basilar artery occlusion 30 . pc-ASPECTS ≤ 6 was independently associated with poor outcome in patients with symptomatic basilar artery stenosis 31 . However, by multivariate analysis, this study identi ed that it had no statistically signi cant association with long-term survival of PCIS patients.
Accordingly, another study also failed to detect a signi cant association after adjusting for related confounders 8 . These discrepancies may be due to the differences in patient characteristics, treatment options among these studies.
By combining NIHSS with the HALP score, we created a new index, HALPN. The HALPN was further strati ed and was found that a higher HALPN score was signi cantly associated with poor overall survival. The prediction power of the combination of these two factors had a better t than both HALP and NIHSS used alone. To the best of our knowledge, this study is the rst to investigate the value of HALP and NIHSS score combination. The combined scoring process is concise and would be critical in areas where resources are limited.
In conclusion, The HALP score are associated with NIHSS, pc-ASPECES, recurrence rate, age at diagnose, and NLR and PLR levels. Age, NIHSS score, and the HALP score were signi cantly associated with the long-term overall survival of PCIS patients. The combination of the HALP and NIHSS score, appeared to has the ability to accurately identify high-risk patients with poor prognosis.

Patients
We conducted a retrospective study with consecutive patients who diagnosed PCIS from January 1, 2016 to May 1, 2017 in the Stroke Center, Beijing Youyi Hospital Capital Medical University. PCIS was de ned as a symptomatic infarct in the territory of the vertebral, basilar, or posterior cerebral artery, which was con rmed by magnetic resonance imaging. Inclusion criteria were as follows: 1) Age ≥ 18, 2) Clinical diagnosis of PCIS, 3) CT angiography (CTA) or Digital subtraction angiography (DSA) was performed to identify the location of the stenosis artery. Exclusion criteria were as follows: 1) Chronic/acute in ammatory disease, 2) Neoplastic hematologic disorders or using immunosuppressant drugs, 3) Lack of HALP parameters; 4) Lost to follow-up.
Clinical and imaging characteristics Patient clinical characteristics included: age, gender, smoking, alcohol-drinking, history of hypertension, history of diabetes, history of coronary heart disease, history of atrial brillation, history of peripheral artery disease, National Institutes of Health Stroke Scale (NIHSS) score at admission, pathogenesis, blood cell counts, and serum albumin levels.
Imaging characteristics included: location of the affected artery, posterior circulation Alberta Stroke Program Early Computed Tomography Score (pc-ASPECTS) on diffusion-weighted imaging (DWI). All the neuroimaging data were analyzed independently by two experienced neuro-radiologists not knowing the clinical information. For cases with disagreement, the nal evaluation outcome was reached by consensus.
Calculation of HALP score The HALP score was calculated according to the following formula: hemoglobin (g/L) × albumin (g/L) × lymphocytes count (/L) / platelets count (/L). All of these blood parameters were obtained within 24 h of admission.

Follow-up
The overall survival time was the interval from the time of diagnosis to death or the last follow-up.
Patients were followed up during face-to-face interviews or via telephone calls by trained research doctors unaware of the study group assignments. Patients were followed up at 3 months for the rst time. Then, follow-up was conducted once a year. The last follow-up was performed in January 2021.

Statistical Analysis
Baseline characteristics were reported. Normally distributed continuous variables were presented by mean and standard deviation, while non-normally distributed continuous variables were presented by median and interquartile range. Categorical variables were presented by number and percentage. The cutoff value and prediction e ciency were calculated by the receiver operating characteristic (ROC) curve analysis. The association between the clinical features and the HALP score were analyzed using the