Background: Stroke remains a leading cause of death worldwide. Acute treatments are limited to thrombolysis (alteplase or tenecteplase) and/or mechanical thrombectomy (MT), yet resistance to fibrinolysis is common in the setting of thromboinflammation. We hypothesized that scanning electron microscopy with advanced image processing of clots retrieved during MT could help elucidate mechanisms of fibrinolysis resistance in thromboinflammatory states and identify novel therapeutic targets to improve recovery. Methods: Formalin-preserved clots from 25 patients who underwent MT for acute large vessel occlusion stroke were analyzed. Twelve were from patients with thromboinflammation associated with acute SARS-CoV-2 infection, and 13 matched controls were from non-COVID patients. Importantly, all SARS-CoV-2–positive patients presented with acute stroke, then determined to be COVID-19 positive on admission. Ultrastructural analysis was performed using scanning electron microscopy with image processing to quantify clot features. Results: All clots from COVID-positive patients were long-segment occlusions including cervical internal carotid arteries, intracranial carotid the middle cerebral artery. Thrombi from non-COVID patients were mostly intracranial occlusions. Scanning electron microscopy demonstrated a distinct clot architecture between cohorts, with COVID-positive thrombi incorporating an abundance of red blood cells (RBCs) and displaying a more uniform fiber meshwork. COVID-19 thrombi contained a significantly higher number of RBCs per field compared to those from non-COVID patients (mean RBC count: 41.5 ±14.3 vs 2.5 ± 2.81, respectively; p=0.002) (Figure, Panel A). Sophisticated image processing analysis (Figure, Panel B) revealed a significant decrease in fiber density (quantified as fraction of fiber volume normalized to image area 0.55 ± 0.063 vs 0.66 ± 0.083, p=0.017) and a non-significant but trending difference in fiber branch diameter in COVID-positive versus non-COVID cthrombi (0.34 ± 0.09µm vs 0.39 ± 0.08µm p=0.27), Conclusions: Thrombi from patients with acute thromboinflammation demonstrate distinct architecture that may contribute to fibrinolysis resistance. COVID-associated clots serve as a model to uncover features relevant across other thromboinflammatory states. These findings highlight potential targets for improved thrombolysis and underscore the need for studies testing alternative agents in this high-risk population.
Mohamed et al. (Thu,) studied this question.