Platelet and liver TPO production feedback loop. (A) At steady state, completely sialylated platelets (purple circles) circulate through the hepatic sinusoids. Aged platelets with heightened terminal Gal and GalNAc residues (yellow circles) are cleared in the liver, initiating hepatic TPO production. (B) The hepatic AMR directly recognizes desialylated platelets, activating the JAK2-STAT3 pathway to elicit TPO production. Various lectins on liver macrophages (Kupffer cells), including the integrin αMβ2, the macrophage Gal lectin (MGL), and Clec4f bind desialylated platelets. Platelet binding to macrophage lectins could trigger cytokine release, including IL-6, and induce IL-6 receptor (IL-6R) responses to stimulate TPO production further.