Schematic presentation showing different mechanisms of platelet clearance in 2 mouse models of antibody-induced thrombocytopenia. (A) In the acute platelet-depletion model (left), high-dose antibody causes platelet activation, aggregation, and desialylation. Aggregates and desialylated platelets are stuck in the microvasculature of the liver by binding to AMR. Opsonized platelets are also cleared by splenic macrophages via Fc receptor. Excess antibody is accumulated in MK in BM, which induces internalization of GPIbα. In the chronic thrombocytopenia model (right), 5A7 accumulates in MK in the BM and surface expression of GPIbα of newly produced platelets is decreased by shedding and internalization. Antibody concentration in plasma is not high enough to induce platelet aggregation, and thus, opsonized platelets are primarily cleared by splenic macrophages. (B) In the spleen, the antibody-bound platelets or platelet aggregates are cleared by macrophages via Fc receptor in both models. (C) In the acute platelet-depletion model, platelets are desialylated and aggregated. These platelets interact with hepatocytes through fenestrations in liver sinusoidal endothelial cells, transduce signal through AMR to upregulate TPO mRNA expression. Trapped desialylated platelets and aggregates are cooperatively cleared via hepatocyte capture and Kupffer cell phagocytosis. C-type lectins expressed on Kupffer cells, such as CLEC4F and macrophage galactose-type lectin,^23,24  which have high affinity for desialylated glycoproteins, may contribute to this process.