MPL receptor dimerization and the thrombopoietin pathway in primary immune thrombocytopenia: from molecular mechanisms to targeted therapies.

Primary immune thrombocytopenia (ITP) is characterized by the dual pathology of peripheral immune-mediated platelet clearance and restricted platelet production by megakaryocytes. The TPO-MPL axis is a central regulator of platelet homeostasis, and ligand-induced receptor activation is associated with downstream JAK2-STAT, MAPK, and PI3K-AKT signaling. This review summarizes the structural and functional features of TPO and MPL, the major immunopathogenic mechanisms of ITP, and the current clinical use of thrombopoietin receptor agonists (TPO-RAs) in ITP. Recent structural and functional studies suggest that TPO-RAs with distinct binding sites may not engage MPL in fully identical ways and may therefore be associated with differences in receptor conformation, dimer geometry, and downstream signaling output. Within this emerging structural and functional framework, these structural and signaling differences may help explain response heterogeneity and the clinical observation that some patients may still benefit after switching agents. However, direct experimental evidence linking switching outcomes to specific alterations in MPL dimer geometry remains lacking, and the available clinical evidence regarding switching comes mainly from retrospective and observational studies, with additional support from post hoc analyses. Overall, continued investigation of the TPO-MPL pathway and its structural basis may help refine our understanding of ITP pathogenesis, treatment-response heterogeneity, and the clinical observations associated with switching, although the proposed mechanistic links still require direct experimental validation.