Significance The interendothelial slit (IES) is the narrowest circulatory pathway in the human spleen where aged and diseased red blood cells (RBCs) are filtered. We use a two-component RBC model to probe the dynamics of healthy and diseased RBCs traversing IES. Our simulations reveal that the spleen not only senses and clears RBCs with abnormal shapes and deformability but also alters the geometries of RBCs that contain protein defects arising from hereditary blood disorders. The framework presented here is sufficiently general to be extended to elucidate the pathophysiological roles of the spleen in other blood diseases.