Abstract
INTRODUCTION: Recent literature has demonstrated remarkable heterogeneity in the composition of acute ischemic stroke (AIS) emboli from different etiologies, which may directly impact their susceptibility to current standard-of-care therapies. METHODS: The full proteomic composition of retrieved thromboembolic material from 24 patients with AIS was evaluated by mass spectrometry. Of the 1797 total proteins identified, 88 known marker proteins were sorted into groups representing broad classes of embolus components: RBCs, PLTs, PMNs, histones, complement proteins, and other clotting-associated proteins (e.g., fibrinogen). The abundance of individual proteins in patients with AF was compared to that of patients without AF using Mann-Whitney U-tests, with significant differences described by the fold change (FC) in abundance. Functional implications of identified differences were explored using the Gene Ontology (GO) enRIchment anaLysis and visuaLizAtion tool (GOrilla). RESULTS: There were no significant differences in protein abundance in the RBC, complement, or clotting-associated protein groups. One out of the 11 PLT group proteins (p = 0.042, FC = 2.46), eight out of the 15 PMN group proteins (p < 0.05, FC > 2), and four out of the 14 histone proteins were significantly enriched in emboli from patients with AF (p < 0.05, FC > 2). The most significantly represented functional GO pathways in patients with AF involved PMN activation and degranulation (p < 10-7). CONCLUSIONS: The enrichment of PMN proteins and histones, as well as pathways culminating in PMN activation and degranulation, suggests the presence of neutrophil extracellular traps (NETs) in emboli of stroke patients with AF. NETs are a significant though understudied structural component of clots, and so this work hints at not only significant pathological immunothrombosis in patients with AF, but also at potential therapeutic targets for AIS in this population.
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