Elucidating the Mechanism of Action of the Attributed Immunomodulatory Role of Eltrombopag in Primary Immune Thrombocytopenia: An In Silico Approach

Abstract

Eltrombopag is a thrombopoietin receptor (MPL) agonist approved for the treatment of primary immune thrombocytopenia (ITP). Recent evidence shows that some patients may sustain platelet counts following eltrombopag discontinuation. The systemic immunomodulatory response that resolves ITP in some patients could result from an increase in platelet mass, caused either by the direct action of eltrombopag on megakaryocytes through MPL stimulation, or potential MPL-independent actions on other cell types. To uncover the possible mechanisms of action of eltrombopag, in silico analyses were performed, including a systems biology-based approach, a therapeutic performance mapping system, and structural analyses. Through manual curation of the available bibliography, 56 key proteins were identified and integrated into the ITP interactome analysis. Mathematical models (94.92% mean accuracy) were obtained to elucidate potential MPL-dependent pathways in non-megakaryocytic cell subtypes. In addition to the effects on megakaryocytes and platelet numbers, the results were consistent with MPL-mediated effects on other cells, which could involve interferon-gamma, transforming growth factor-beta, peroxisome proliferator-activated receptor-gamma, and forkhead box protein P3 pathways. Structural analyses indicated that effects on three apoptosis-related proteins (BCL2L1, BCL2, BAX) from the Bcl-2 family may be off-target effects of eltrombopag. In conclusion, this study proposes new hypotheses regarding the immunomodulatory functions of eltrombopag in patients with ITP.

Avatrombopag for the treatment of thrombocytopenia post hematopoietic stem-cell transplantation

“…We also concluded that the only independent factor for OR and CR was the number of MKs in the BM before the avatrombopag initiation, which was consistent with earlier studies on eltrombopag. 14,16–20 In vitro studies revealed that eltrombopag acted in multiple ways including immune regulation, 27 ferric chelation, 28 and rescue for the function of hematopoietic stem cells impaired by interferon-gamma in the inflammatory micro-environment. 29 Nonetheless, the basic pharmacological mechanism of TPO-RAs was mainly through a combination of TPO receptor c-MPL, leading to the activation of JAK-STAT, PI3K, and ERK pathways that regulated megakaryocytopoiesis.…”

Avatrombopag Treatment of Severe Aplastic Anemia With Liver Injury: a Case Report

“…TPO is usually produced by the liver, which regulates hematopoietic and megakaryocyte growth by binding to its receptor c-Mpl and triggering activation of the Janus kinase 2 (JAK2) / signal transducer and activator of transcription (STAT) pathway [3,4] . Many preclinical studies have con rmed the bene cial effect of TPO on the activation and maintenance of hematopoietic stem cells.…”

Exploring the Potential of Eltrombopag: Room for More?

“…The consistency of all these data is even more accentuated considering that RNA sequencing of blood cells subsets has revealed that TPO is expressed in immune cell subpopulations: T-regs, B lymphocytes, CD4 + and CD8 + T cells, monocytes, neutrophils, and NK cells ( Schmiedel et al, 2018 ; Monaco et al, 2019 ). Recently, an “in silico” approach has shown different pathways (upregulation of FOXP3 and PPARγ, attenuation of IFN-γ signaling) by which ELT may restore immune tolerance and reduce inflammation in the context of ITP ( Lozano et al, 2021 ). Interestingly, this model hypothesizes a potential pro-apoptotic BCL-2 mediated effect upon long term treatment with ELT, affecting the survival of platelets ( Lozano et al, 2021 ).…”

“…Recently, an “in silico” approach has shown different pathways (upregulation of FOXP3 and PPARγ, attenuation of IFN-γ signaling) by which ELT may restore immune tolerance and reduce inflammation in the context of ITP ( Lozano et al, 2021 ). Interestingly, this model hypothesizes a potential pro-apoptotic BCL-2 mediated effect upon long term treatment with ELT, affecting the survival of platelets ( Lozano et al, 2021 ). On the other hand, experimental data show that ELT could directly inhibit the pro-apoptotic factor Bax, thus contributing to the fine regulation of cell survival pathways ( Spitz et al, 2021 ).…”