Biophysical alterations of less-deformable and sRBCs directly induce endothelial inflammation via margination and increased RBC-endothelial interactions. Cartoon representation of our new paradigm of SCD vasculopathy, showing that when RBC suspensions are not uniform, such as in SCD, a subpopulation of the smallest and least-deformable sRBCs will tend to enter the CFL and marginate closer to vessel walls. These marginating RBCs not only come into direct contact (ie, RBC-EC collisions) with the endothelium but also create altered local wall shear stress, simply from coming into close proximity to the vessel wall, inducing endothelial inflammation via mechanobiological mechanisms. Furthermore, as these less-deformable and sRBCs flow into smaller areas of more complex geometries, such as at bifurcations, additional brief, collision-like events will occur secondary to their altered flow patterns, causing further exposure to increased mechanical forces. Finally, as sRBCs squeeze into the capillaries, ECs are exposed to pathologically increased compressive mechanical forces, which again induce a proinflammatory phenotype via mechanotransduction.