Effects of romiplostim in WT and G6b-B–deficient mice. Romiplostim is a thrombopoietin receptor agonist clinically used to treat chronic ITP. It mimics thrombopoietin binding to its receptor, Mpl, therefore driving differentiation and maturation of MKs. In this study, we demonstrate that (A) treatment of WT mice with romiplostim leads to an 8-fold increase in platelet counts to supraphysiological levels. It also reduces GPVI and α2β1 expression in WT mice. We hypothesize that romiplostim drives a cell intrinsic negative feedback pathway that autoregulates platelet reactivity to collagen depending, suppressing their thrombotic capacity. (B) Romiplostim successfully rescued thrombocytopenia in G6b KO mice, with an increase in the platelet counts to physiological levels. It also partially rescued GPVI expression and platelet reactivity to collagen in G6b KO mice, suggesting a loss of negative feedback. Romiplostim proved to be the most effective therapy tested for rescuing the platelet phenotype in G6b KO mice.