{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T17:05:01Z","timestamp":1778605501057,"version":"3.51.4"},"reference-count":104,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2021,6,27]],"date-time":"2021-06-27T00:00:00Z","timestamp":1624752000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/ijms22136907","type":"journal-article","created":{"date-parts":[[2021,6,27]],"date-time":"2021-06-27T22:24:57Z","timestamp":1624832697000},"page":"6907","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Elucidating the Mechanism of Action of the Attributed Immunomodulatory Role of Eltrombopag in Primary Immune Thrombocytopenia: An In Silico Approach"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3148-7037","authenticated-orcid":false,"given":"Maria L.","family":"Lozano","sequence":"first","affiliation":[{"name":"Hospital General Universitario Morales Meseguer, Centro Regional de Hemodonaci\u00f3n, Universidad de Murcia, IMIB-Arrixaca, CB15\/00055-CIBERER, 30007 Murcia, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cristina","family":"Seg\u00fa-Verg\u00e9s","sequence":"additional","affiliation":[{"name":"Anaxomics Biotech S.L., Diputaci\u00f3 237, 1\u00b0, 1<sup>a<\/sup>, 08007 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mireia","family":"Coma","sequence":"additional","affiliation":[{"name":"Anaxomics Biotech S.L., Diputaci\u00f3 237, 1\u00b0, 1<sup>a<\/sup>, 08007 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u00eda T.","family":"\u00c1lvarez-Roman","sequence":"additional","affiliation":[{"name":"Unidad de Trombosis y Hemostasia, Servicio de Hematolog\u00eda, Hospital Universitario La Paz, Instituto de Investigaci\u00f3n Hospital Universitario La Paz (IdiPAZ), Paseo de la Castellana 261, 28046 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jos\u00e9 R.","family":"Gonz\u00e1lez-Porras","sequence":"additional","affiliation":[{"name":"Unidad de Hemostasia y Trombosis, Servicio de Hematolog\u00eda, Hospital Universitario de Salamanca, Instituto de Investigaci\u00f3n Biom\u00e9dica de Salamanca (IBSAL), Paseo de San Vicente, 58-182, 37007 Salamanca, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8443-900X","authenticated-orcid":false,"given":"Laura","family":"Guti\u00e9rrez","sequence":"additional","affiliation":[{"name":"Grupo de Investigaci\u00f3n en Plaquetas, Instituto de Investigaci\u00f3n Sanitaria del Principado de Asturias (ISPA), Departamento de Medicina, Universidad de Oviedo, 33071 Oviedo, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Valc\u00e1rcel","sequence":"additional","affiliation":[{"name":"Servicio Hematolog\u00eda, Vall d\u00b4Hebron Insitute of Oncology (VHIO), Hospital Univesitario Vall d\u2019Hebron, Universitat Aut\u00f2noma de Barcelona, Centro Cellex, Natzaret, 115-117, 08035 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4601-7150","authenticated-orcid":false,"given":"Nora","family":"Butta","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n HospitaUniversitario La Paz (IdiPAZ), Paseo de la Castellana 261, 28046 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3829","DOI":"10.1182\/bloodadvances.2019000966","article-title":"American Society of Hematology 2019 guidelines for immune thrombocytopenia","volume":"3","author":"Neunert","year":"2019","journal-title":"Blood Adv."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2386","DOI":"10.1182\/blood-2008-07-162503","article-title":"Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: Report from an international working group","volume":"113","author":"Rodeghiero","year":"2009","journal-title":"Blood"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1080\/10245332.2016.1219497","article-title":"Advances in the pathophysiology of primary immune thrombocytopenia","volume":"22","author":"Perera","year":"2017","journal-title":"Hematology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1177\/2042098618769587","article-title":"Eltrombopag in immune thrombocytopenia: Efficacy review and update on drug safety","volume":"9","author":"Bastida","year":"2018","journal-title":"Adv. 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