Gene expression profiles of ischemic stroke clots retrieved by mechanical thrombectomy are associated with disease etiology.

Background: Determining stroke etiology is crucial for secondary prevention, but intensive workups fail to classify ~30% of strokes that are cryptogenic.
Objective: To examine the hypothesis that the transcriptomic profiles of clots retrieved during mechanical thrombectomy are unique to strokes of different subtypes.
Methods: We isolated RNA from the clots of 73 patients undergoing mechanical thrombectomy. Samples of sufficient quality were subjected to 100-cycle, paired-end RNAseq, and transcriptomes with less than 10 million unique reads were excluded from analysis. Significant differentially expressed genes (DEGs) between subtypes (defined by the Trial of Org 10 172 in Acute Stroke Treatment) were identified by expression analysis in edgeR. Gene ontology enrichment analysis was used to study the biologic differences between stroke etiologies.
Results: In all, 38 clot transcriptomes were analyzed; 6 from large artery atherosclerosis (LAA), 21 from cardioembolism (CE), 5 from strokes of other determined origin, and 6 from cryptogenic strokes. Among all comparisons, there were 816 unique DEGs, 174 of which were shared by at least two comparisons, and 20 of which were shared by all three. Gene ontology analysis showed that CE clots reflected high levels of inflammation, LAA clots had greater oxidoreduction and T-cell processes, and clots of other determined origin were enriched for aberrant platelet and hemoglobin-related processes. Principal component analysis indicated separation between these subtypes and showed cryptogenic samples clustered among several different groups.
Conclusions: Expression profiles of stroke clots were identified between stroke etiologies and reflected different biologic responses. Cryptogenic thrombi may be related to multiple etiologies.
Competing Interests: Competing interests: VMT: Financial Interest/Investor/Stock Options/Ownership: Neurovascular Diagnostics, Inc., QAS.ai, Inc. Grant Support: National Center for Advancing Translational Sciences of the National Institutes of Health under award number UL1TR001412 through the University at Buffalo, Cummings Foundation. SF: None. AC: None. TRP: None. AM: None. HHR: None. AAD: None. LDC: None. MW: None. EIL: None. KEP: None. AHS: Financial Interest/Investor/Stock Options/Ownership: Neurovascular Diagnostics, Inc., QAS.ai, Inc. Consultant/Advisory Board: Cerenovus, Penumbra, Q’Apel Medical, Inc., Stryker Neurovascular. National PI/Steering Committees: Cerenovus EXCELLENT and ARISE II Trial; Medtronic SWIFT PRIME, VANTAGE, EMBOLISE and SWIFT DIRECT Trials; MicroVention FRED Trial & CONFIDENCE Study; MUSC POSITIVE Trial; Penumbra 3D Separator Trial, COMPASS Trial; MIVI neuroscience EVAQ Trial. Board membership: Secretary, Society of NeuroInterventional Surgery (SNIS) Board of Directors. Grant Support: National Center for Advancing Translational Sciences of the National Institutes of Health under award number UL1TR001412 through the University at Buffalo. Cummings Foundation.
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