Platelet clearance mechanisms. (1) Glycan-lectin mediated clearance: platelets lose Sia as they age, leading to their clearance by the C-type lectin AMR on hepatocytes. Stored platelets additionally lose Gal leading to exposure of GlcNAc and their clearance by the αMβ2 integrin on hepatic macrophages (Kupffer cells). (2) Autoantibody Fc receptor and lectin-mediated clearance: platelet clearance is mediated by autoreactive antibodies toward the integrin αIIbβ3 and the GP GPIbα as part of the von Willebrand receptor complex (GPIb-IX). Platelets are cleared via Fc receptors on macrophages and CD8⁺ cytotoxic T lymphocytes. Specific anti-GPIbα but not anti-αIIbβ3 antibodies induce platelet desialylation, thereby diverging platelet clearance to hepatic AMRs. (3) Programmed cell death (apoptosis) mediated clearance: platelet survival also depends on the interplay between prosurvival and proapoptotic members of the Bcl-2 family, which are critical regulators of the intrinsic apoptotic pathway. Platelet clearance via scavenger receptors is accelerated in mice lacking the prosurvival proteins Bcl-2, Bcl-xL, and Mcl-1. It is unclear if the apoptotic and glycan-lectin–mediated clearance converge at a certain stage of platelet “death” to induce platelet clearance. Gal, galactose; Sia, sialic acid.