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Recent advent of endovascular thrombectomy (EVT) enables us to provide a new perspective on the use of tPA (tissue-type plasminogen activator) through histological analysis of retrieved thrombus. We investigated the responsiveness of intravenous thrombolysis (IVT) according to the thrombus composition in EVT-attempted patients with acute ischemic stroke.We reviewed 92 consecutive patients with anterior circulation stroke who received combined IVT and EVT for 2 years. IVT responsiveness is defined as any decrease in the clot burden from baseline computed tomographic angiography to digital subtraction angiography during EVT. We histologically analyzed the relative fractions of red blood cells (RBCs), congregated fibrin and platelets, and white blood cells in the retrieved thrombi using semiautomated color-based segmentation method. Clinical characteristics according to the RBC fraction were investigated, and associated factors with IVT responsiveness were explored.Fifty-two patients with histological analyses were stratified into lowest, middle, and highest tertiles of RBC fraction. Toward higher RBC fraction, there was more common susceptibility vessel signs on magnetic resonance imaging (50.0% versus 66.7% versus 91.7%; P=0.022) and prevalent IVT responsiveness (25.0% versus 41.7% versus 75.0%; P=0.010). IVT-responsive group (n=23) had higher RBC fraction (45.7±15.5% versus 35.9±12.2%; P=0.010), lower fibrin and platelet (50.4±14.0% versus 58.5±11.1%; P=0.027), and lower white blood cells fraction (3.9±2.1% versus 5.5±3.0%; P=0.027) than IVT-unresponsive group (n=29). After adjusting for potential variables, RBC fraction (odds ratio, 1.05; 95% confidence interval, 1.01–1.10) remained only independent determinant of IVT responsiveness.In EVT-attempted patients with acute ischemic stroke, IVT responsiveness would be closely associated with RBC fraction.