Leukocytes in Cerebral Thrombus Respond to Large-Vessel Occlusion in a Time-Dependent Manner and the Association of NETs With Collateral Flow.

Xi Chen,Qu Liu,Meiling Jiang,Hao Tian,Zhenhua Zhou,Xianhua Hou,Li Wang,Wenying Ju,Lin Lin,Min Wu,Wen Zeng,Zhaojing Ba,Lu Liu,Lin Chen,Guangjian Li

doi:10.3389/fimmu.2022.834562

Abstract

Thrombus components are dynamically influenced by local blood flow and blood immune cells. After a large-vessel occlusion stroke, changes in the cerebral thrombus are unclear. Here we assessed a total of 206 cerebral thrombi from patients with ischemic stroke undergoing endovascular thrombectomy. The thrombi were categorized by time to reperfusion of <4 h (T4), 4–8 h (T4–8), and >8 h (T8). The cellular compositions in thrombus were analyzed, and relevant clinical features were compared. Both white blood cells and neutrophils were increased and then decreased in thrombus with time to reperfusion, which were positively correlated with those in peripheral blood. The neutrophil extracellular trap (NET) content in thrombus was correlated with the degree of neurological impairment of patients. Moreover, with prolonged time to reperfusion, the patients showed a trend of better collateral grade, which was associated with a lower NET content in the thrombus. In conclusion, the present results reveal the relationship between time-related endovascular immune response and clinical symptoms post-stroke from the perspective of thrombus and peripheral blood. The time-related pathological changes of cerebral thrombus may not be the direct cause for the difficulty in thrombolysis and thrombectomy. A low NET content in thrombi indicates excellent collateral flow, which suggests that treatments targeting NETs in thrombi might be beneficial for early neurological protection.

Highlights

Thrombus-based cerebrovascular occlusion is the main cause of acute ischemic stroke (AIS), which has a high rate of death and disability worldwide [1]
The results showed that the neutrophils were rapidly recruited to the thrombus and were observable at T4, remained high at T4–8 (P = 0.003), and decreased at T8 (P = 0.001), which was consistent with the WBC findings (Figures 2A, B)
Since WBC-mediated immune responses in both thrombi and peripheral blood may affect neurological function via an impaired blood–brain barrier, we found that neutrophil extracellular trap (NET) in thrombi were positively related to the National Institutes of Health Stroke Scale (NIHSS) score (r = 0.4024, P = 0.003; Figure 3C) and NIHSS score (r = 0.2745, P = 0.047; Figure 3D)

Summary

Introduction

Thrombus-based cerebrovascular occlusion is the main cause of acute ischemic stroke (AIS), which has a high rate of death and disability worldwide [1]. The consensus is that reducing the occlusion time of cerebral vessels promotes a successful endovascular recanalization and favorable neurological outcomes in ischemic stroke [5, 6]. The sudden interruption of cerebral blood flow contributes to local blood cell traps, adhesion of platelets and leukocytes, and activation of the coagulation cascade [8]. Given these facts, the quantification of thrombus components under different times of occlusion and different statuses of collateral flow would help clinicians better understand the dynamic pathological changes in thrombi after stroke onset, guide individualized recurrence prevention, and provide more evidence for revealing the mechanism of time-dependent thrombolysis resistance [9]

Methods

Results

Conclusion