In ITP, antibody-coated platelets are rapidly cleared from the circulation by the reticuloendothelial system, primarily by splenic macrophages (A). Polyclonal platelet autoantibodies produced in the spleen also inhibit megakaryocyte maturation (B) and affect platelet production. Romiplostim binds directly to the thrombopoietin receptor (C), acting as a TPO agonist by stimulating downstream signaling via the JAK-STAT pathway. The result is megakaryocyte maturation (D) and marked increase in marrow platelet production and release of platelets. Although romiplostim does not interfere with antibody production or binding to platelets, there are more platelets available in the peripheral circulation than can be rapidly cleared, resulting in an increased circulating platelet count (E). Professional illustration by Debra Dartez.