Possible pathways of PS exposure in red blood cells (RBCs). PS is represented by blue circles. Starting from the upper left, in normal and sickle reticulocytes, plasma membrane internalization creates inside-out endocytic vesicles. These can merge with autophagic vacuoles in 2 ways: (1) their membranes can fuse to create a hybrid vacuole. Egress of this structure intact from the cell would require an autophagy-like event (as depicted) or a novel process. In the former case, breakdown of the limiting membrane (dashed line) would expose PS; and (2) alternatively, the plasma membrane-derived vesicle could provide a source of isolation membrane and merge (but not fuse) with the autophagic vacuole. In this case, loss of membrane asymmetry would be required for PS exposure. As applies to older cells, and shown at the top, sickling-dependent processes lead to changes in aminophospholipid translocase and phospholipid scramblase activities, and PS exposure diffusely in the plasma membrane.