Thrombopoiesis regulation. A simplified summary of the major mechanisms in thrombopoiesis regulation based on the currently available evidence is illustrated. TPO, produced primarily in the liver and released into blood, binds to its receptor c-Mpl (MPL protein, TPO-R) expressed on hematopoietic cells, activates JAK/STAT pathways, and stimulates MK growth/maturation. In the presence of oxidative stress, the defective redox coupling in heme degradation pathway results in increased accumulation of ROS, which leads to accelerated terminal megakaryocytopoiesis and possibly enhanced proplatelet formation. Platelets in circulation, also with c-Mpl expression on the cell surface, can bind to and internalize TPO. The desialylated platelets (eg, from senescence or cold storage) can be removed through the AMR-mediated pathway. The hepatocyte AMRs, upon binding to desialylated platelets, activate downstream JAK2-STAT3 pathways, leading to elevated THPO messenger RNA expression and translation. TPO is then released to stimulate thrombopoiesis. HSC, hematopoietic stem cells. Professional illustration by Patrick Lane, ScEYEnce Studios.