Mechanism of Action of Eltrombopag
Eltrombopag is a thrombopoietin receptor agonist that binds to the transmembrane domain of the TPO receptor (cMpl) and activates intracellular signaling cascades—specifically the JAK/STAT pathway—leading to proliferation and differentiation of megakaryocytes and ultimately increased platelet production. 1
Molecular Mechanism
Eltrombopag selectively binds to the transmembrane domain of the human thrombopoietin receptor on platelets, megakaryocytes, and megakaryocyte precursor cells 2
The binding site differs from endogenous thrombopoietin, meaning eltrombopag does not compete with native TPO for receptor binding and can act additively with endogenous TPO to increase platelet production 3, 4
Upon receptor binding, eltrombopag initiates signaling through the Janus Kinase 2 (JAK2) and Signal Transducer and Activator of Transcription (STAT) 5 pathways, which are the same pathways activated by endogenous thrombopoietin 5, 3
Cellular Effects
The activated JAK/STAT signaling stimulates proliferation and differentiation of primary human CD34+ bone marrow progenitor cells into CD41+ megakaryocytes, ultimately leading to increased platelet production 5, 4
Eltrombopag demonstrates species-specific activity, activating STAT pathways only in human and chimpanzee platelets, which explains why preclinical testing required chimpanzee models 3, 4
Clinical Pharmacodynamics
Treatment with eltrombopag produces dose-dependent increases in platelet counts following repeated daily dosing 1
The increase in platelet counts reaches maximum approximately two weeks after initiation of dosing, and platelet counts return to baseline within approximately two weeks after discontinuation 1
Initial clinical responses are typically observed within 1-2 weeks of treatment in patients with immune thrombocytopenia 2
Structural Characteristics
The chemical structure of eltrombopag differs fundamentally from recombinant human thrombopoietin, which provides improved activity on the thrombopoietin receptor and a remarkably reduced incidence of severe thrombocytopenia compared to earlier TPO mimetics 2
This structural difference eliminates the risk of developing neutralizing anti-TPO antibodies, which was a major limitation of earlier recombinant TPO therapies that caused severe thrombocytopenia 2
Potential Immunomodulatory Effects
Beyond direct effects on megakaryocytes, emerging evidence suggests eltrombopag may have MPL-mediated effects on other immune cells, potentially involving interferon-gamma, transforming growth factor-beta, and regulatory T-cell pathways 6
Some patients achieve sustained remissions off treatment, with approximately 30% maintaining platelet counts after discontinuation, suggesting possible disease-modifying immunomodulatory activity beyond simple platelet production 2