Background and objectives <p>In stroke thrombi, neutrophil extracellular traps (NETs) have been hypothesized to promote thrombogenic processes that enhance stability and decrease amenability to thrombolysis and endovascular removal. Here, we examined the relationship between NET enrichment and clot structure and mechanical properties.</p> Methods <p>Platelet-rich plasma and red blood cells (RBCs) were isolated from human blood and mixed with concentrated white blood cells to produce no-RBC and high-RBC clot analogs (0% and 40%, respectively). Lipopolysaccharide (LPS) was added at 3 different concentrations to enrich clots with varying amounts of NETs. Clots were analyzed mechanically using a uniaxial stretch tester. Clots were also imaged by microCT, and histology was used to investigate biologic structure and composition, as well as NET enrichment. Statistical analysis was completed to assess stiffness, radiomic, and histological features among clots of various NET enrichment. Clustering was performed on radiomic and histological image features to identify feature signatures unique to NET-enriched clots, and correlation was performed to identify radiomics and histomics related to NET enrichment.</p> Results <p>LPS enriched clots with NETs in a dose-dependent manner, and NETs were associated with greater microstructural complexity. For fibrin-platelet rich clots (0% RBCs), NET enrichment produced a significant increase in mechanical stiffness as measured by Young’s Modulus, as well as in breaking strength. For each percent composition, radiomic and histomic profiling clustered clot analogs well by NET-enrichment, with NET-enriched clots demonstrating radiomic and histological texture feature correlations distinct from clots without NETs.</p> Conclusion <p>NET enrichment produces mechanically stiffer stroke clot analogs with distinct microstructure, radiomic, and histological profiles.</p>