Significance The 3D opening of the interendothelial slit in human spleen creates a physical fitness test for red blood cells (RBCs) and clears them from circulation if their geometry and deformability are altered. We present a unique computational framework for the development of prognostic markers for diseases that alter RBC physical characteristics and identify quantitative limits for splenic slit clearance. Our work shows how the splenic slit determines distributions of size and shape of healthy RBCs. Our work lays the groundwork for systematic reconstruction of RBC navigation in the human spleen with consequences for a variety of acute and chronic medical conditions associated with hereditary alterations of RBCs, infectious diseases, and cancers.