Model illustrating a hypothetical shift of the Mpl-Tpo equilibrium in Yall;Mpl^−/− mice. (A) In wild-type mice, both platelets in the periphery and megakaryocytes in the bone marrow act as negative regulators of Tpo through absorption via surface Mpl, restricting the expansion of the megakaryocytic lineage. (B) In Yall;Mpl^−/− mice, platelets are almost devoid of surface Mpl, thus having a reduced capacity to absorb Tpo (dashed blunt arrow). Consequently, the megakaryocytic lineage expands until the combined amount of Mpl on megakaryocytes and platelets is sufficiently high to reduce Tpo concentration to normal levels. In this new equilibrium, the increased megakaryocyte mass has a more pronounced role in Tpo absorption than in the wild-type equilibrium (large blunt arrow).