Acute Ischemic Stroke (AIS) is a major cause of death and disability worldwide. Mechanical thrombectomy to remove clots from cerebral vasculature represents a unique opportunity to study characteristics and biological patterns of stroke pathophysiology. There is marked heterogeneity in clots and great interest in etiological biomarkers for novel therapeutic approaches/stroke prevention strategies. We investigated expression of prototypic marker of inflammation C-reactive protein (CRP) and coagulation factor thrombin in AIS clots of different etiologies. Clots from Clotbase International registry of 500 stroke cases were used. 3 μm-sections were stained with Martius Scarlet Blue for quantification of main clot components (red and white blood cells, fibrin, platelets, collagen). CRP and thrombin immunohistochemistry was performed using Leica Bond III autostainer. Whole slides were scanned, components quantified via Orbit Image Analysis software and correlated with etiology. Data expressed as mean±SD; non-parametric statistical tests used. Red blood cell% in large artery atherosclerotic clots (LAA) (45±21%) was higher than cardioembolic (CE) (37±21%) and cryptogenic (40±21%) (p=0.08; H=5.02, df2), which were similar. 38% cardioembolic (CE), 28% cryptogenic and 21% LAA clots expressed substantial levels of CRP, mainly in females (62%). Thrombin expression was significantly higher in cryptogenic (55±23%), CE (43±23%) than LAA (30±20%) (p= 0.0001,H=23,df2). Cryptogenic clots are more similar in composition to CE clots than LAA, suggesting cardiac origin. Our observation that CRP and thrombin expression is higher in CE and cryptogenic cases suggests that inflammation may promote platelet activation and the formation of AIS clots in the heart.