Peri-Stenotic Stagnation Associates With Red Blood Cell-Rich Thrombi, Linked to Stroke Recurrence and Lesion Volume

BACKGROUND: Despite antiplatelet therapy, plaque-induced strokes recur frequently. This recurrence may reflect thrombus heterogeneity driven by peri-stenotic stagnation and red blood cell (RBC) entrapment. The clinical implications of such variations for stroke outcomes remain unclear. We investigated whether plaque-derived RBC-rich thrombi, indicated by the clot sign, were associated with recurrence, lesion volume, and stenosis-related hemodynamics. METHODS: Because asymptomatic plaque rupture limits direct evaluation of hemodynamics and thrombus compositions, we performed a hybrid human-animal study. In humans, we conducted a retrospective case-control study across 2 tertiary stroke centers in the Republic of Korea between April 2017 and March 2024, evaluating stroke recurrence and lesion volume by clot sign, using inverse probability of treatment weighting. We included artery-to-artery embolization confirmed by diffusion weighted imaging, excluding other etiologies. In animals, thrombus compositions were histologically analyzed in an FeCl 3 -induced stenosis model across 3 segments (ascent, peak, and descent). Peri-stenotic hemodynamics, including wall shear stress and relative residence time, were assessed using ultrafast ultrasound imaging to evaluate whether RBC entrapment correlated with elevated relative residence time. RESULTS: In humans, clot sign-positive patients exhibited higher recurrence risk (hazard ratio, 2.76 [95% CI, 1.32–5.74]; P =0.007), and larger lesion (mean difference, 16.14 [95% CI, 5.03–27.25]; P =0.005). In animals, RBCs proportion was increased in the descent (ascent, 23.89±15.91%; peak, 12.33±11.19%; descent, 59.58±35.09%; P =0.019), correlating with a 3-fold higher relative residence time in the descent than the other regions (ascent, 1.25±0.75 au; peak, 1.55±0.55 au; descent, 4.50±2.74 au; P =0.001) CONCLUSIONS: Peri-stenotic stagnation was associated with RBC-rich thrombi formation under both clinical and experimental conditions, providing mechanistic insight into stroke recurrence and larger lesion volumes. Identifying peri-stenotic stagnation using ultrafast ultrasound imaging may help stratify high-risk patients; however, its therapeutic implications require validation in prospective randomized studies.