Figure 1.

TPO levels are regulated by platelet mass. The liver constitutively produces TPO. Upon binding to Mpl receptors on platelets, TPO is internalized and removed from circulation. A smaller proportion of total TPO is produced by stromal cells in the bone marrow and their TPO mRNA production is sensitive to factors produced by platelets such as PF4 and thus also linked to platelet number. TPO then stimulates thrombopoiesis and HSC quiescence in the bone marrow. In the case of thrombocytosis, much TPO is removed from circulation, resulting in low levels of TPO signaling, while during thrombocytopenia, little TPO is cleared from circulation, resulting in high levels of TPO signaling. This feedback system allows thrombopoiesis to be regulated by the available platelet mass but also links HSC quiescence to platelet numbers.