Yu Cui, Xin-Hong Wang, Yong Zhao, Shao-Yuan Chen, Bao-Ying Sheng, Li-Hua Wang, Hui-Sheng Chen
Abstract
Early neurologic improvement (ENI) after intravenous thrombolysis is associated with favorable outcome, but associated serum biomarkers were not fully determined. We aimed to investigate the issue based on a prospective cohort.
Introduction
Stroke is the second leading cause of disability and mortality worldwide, which prevalence increased annually in China [1]. Intravenous alteplase is recommended as the most effective treatment for acute ischemic stroke within 4.5 hours of symptom onset [2]. Early neurologic improvement (ENI) after intravenous thrombolysis is associated with vessel recanalization and predicts functional outcome at 90 days [3,4]. Exploring predictors of ENI is critical for identifying potential patients who can benefit from intravenous thrombolysis.
Methods
From August 2018 to July 2019, patients receiving intravenous thrombolysis within 4.5 hours were consecutively screened to collect blood samples before thrombolysis from five selected hospitals participating in the INTRECIS study. The registry study is nationwide, multicenter, and prospective, which enrolled consecutive adult patients who were eligible for intravenous thrombolysis within 4.5 hours. Details of the trial design and primary outcomes analyses have been previously reported [14]. Briefly, the consecutive patients who received standard dose of alteplase (0.9 mg/kg, maximum 90 mg; manufacturer: Boehringer Ingelheim) within 4.5 hours after symptoms onset were enrolled. The exclusion criteria were as follows: (1) patients received urokinase or non-standard dose of alteplase, (2) patients received any endovascular treatment, (3) lacked complete baseline data, (4) blood samples were not collected before intravenous alteplase.
Results
Overall, 358 thrombolytic patients were consecutively screened in the current study and 234 patients were excluded due to the following reasons: 135 patients with urokinase and 25 patients with non-standard dose of alteplase, 10 patients with endovascular treatment, 3 patients with incomplete baseline data, and 61 patients without blood samples collection. Finally, 124 patients were included into the study, including 19 patients with ENI, and 105 patients without ENI.
Discussion
Up to date, only a few biomarkers, such as ADAMTS13 activity, Aquaporin-4, leukocyte count, and neutrophil to lymphocyte ratio, were found to be associated with post-thrombolytic ENI in stroke [10–13]. The nine biomarkers identified in the present study were previously reported in ischemic stroke which involved the process of inhibiting development of atherosclerotic plaques, vascular remodeling, neural regeneration, and inflammatory response [16–25]. For example, IGFBP-6 and IL-5 were reported to be associated with inhibiting development of atherosclerotic plaques [26–29], LYVE-1 and PDGF-AA were beneficial to vascular remodeling and neural regeneration, respectively [16–18], while CCL-23, CXCL-12, ST-2, and TNF-α were reported to promote and worsen the inflammatory response: CCL-23, CXCL-12, and TNF-α played pro-inflammatory role [19–21], while ST-2 prevented anti-inflammatory effect of IL-33 [22,23].
Conclusion
For the first time, we found that higher serum levels of CCL-23, CXCL-12, IGFBP-6, IL-5, LYVE-1, PAI-1, PDGF-AA, ST-2, and TNF-α at admission were associated with post-thrombolytic ENI in ischemic stroke. The value of these newly identified biomarkers warrants further investigation.
Citation: Cui Y, Wang X-H, Zhao Y, Chen S-Y, Sheng B-Y, Wang L-H, et al. (2022) Association of serum biomarkers with early neurologic improvement after intravenous thrombolysis in ischemic stroke. PLoS ONE 17(10): e0277020. https://doi.org/10.1371/journal.pone.0277020
Editor: Wen-Jun Tu, Chinese Academy of Medical Sciences and Peking Union Medical College, CHINA
Received: July 23, 2022; Accepted: October 17, 2022; Published: October 31, 2022
Copyright: © 2022 Cui et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: The raw datasets used in the study can be found in the Zenodo online repository (https://doi.org/10.5281/zenodo.7059085).
Funding: The study was funded by grants from National Key R&D Program of China (2017YFC1308203), and the Project on Research and Application of Effective Intervention Techniques for Chinese Stroke Guidelines from the National Health and Family Planning Commission in China (GN-2016R0008). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
