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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.

SUBMITTER: Lozano ML

PROVIDER: S-EPMC8269123 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Immune thrombocytopenia (ITP) is an autoimmune disorder that induces a decrease in the number of circulating platelets due to spleen destruction and inability of megakaryocytes to restore normal counts. Immunosuppressive therapy with glucocorticoid drugs constitutes the first line of treatment. However, lack of response to these agents is not uncommon, and the management of refractory patients is a matter of controversy. In fact, day-to-day clinical practice shows that, in spite of the current guidelines, splenectomy, which is currently considered a suitable second-choice therapy, is being replaced by treatment with thrombopoietin receptor agonists. These boost platelet production by megakaryocytes. The use of one of these, namely eltrombopag, has been permitted for ITP patients refractory to first-line drugs or splenectomy, for the last 10 years. This review summarizes the experience reported using eltrombopag in ITP, paying attention to efficacy and safety. Results from clinical trials will be discussed, and studies performed in the course of daily clinical practice will also be reviewed, as these are useful to assess the potential of the drug in real-world settings. The management of adverse events and the use of eltrombopag in particular situations will also be covered. The experience reported so far permits us to suggest that eltrombopag efficiently induces recovery of platelet counts. Furthermore, recent papers have demonstrated that a sustained response after discontinuation, initially thought to be problematic, may be possible in a nonnegligible number of cases. The safety profile is satisfactory, although patients presenting with thromboembolism risk factors should be treated with caution until the eltrombopag-associated prothrombotic risk is fully established. In summary, although larger studies are still needed to clarify some issues, eltrombopag may be a useful alternative tool for ITP patients refractory to conventional medical management or splenectomy.

Project description:Primary immune thrombocytopenia (ITP) is a cause of severe thrombocytopenia in dogs. Immunosuppressive corticosteroid drugs are frequently used in the management of ITP, but treatment failure may occur. Immunomodulatory and non-corticosteroid immunosuppressive drugs might improve outcomes from therapy either alone or in combination with corticosteroids. The objectives of this scoping review were (1) to evaluate the current evidence relating to immunomodulatory and immunosuppressive drug protocols in the treatment of canine ITP, and (2) to answer the clinical question, whether or not therapy with immunomodulatory or non-corticosteroid immunosuppressive drugs alone or in combination with corticosteroids could improve outcome, compared to therapy with corticosteroids alone. A literature search was performed in the electronic databases of Agricola, CAB Abstracts, Embase, Medline and Web of Science for publications in November 2019 and again February 1, 2021. Selection criteria were relatively strict and included peer-reviewed research papers reporting outcome measures from immunomodulatory and immunosuppressive drug protocols in the treatment of canine ITP with a pre-therapeutic mean or median platelet count < 50,000/µL as a strict criterion for inclusion. Studies were evaluated if they had an appropriate diagnostic work up to exclude underlying conditions. Outcome measures and adverse events were compared between drug protocols both within studies and between studies. The search identified 456 studies, with six studies being eligible for inclusion. The studies were mostly case series while two were randomized controlled trials. Level of evidence varied with an overall uncertain subject enrollment, small groups, inadequate description and variable use of drug protocols or outcome measures. For outcomes such as platelet recovery time and duration of hospitalization, an improvement was observed using adjunctive therapy (human intravenous immunoglobulin) compared to therapy with corticosteroids alone. For outcomes of complete platelet recovery time, survival (6-month), mortality and relapse, no improvement was observed using adjunctive drugs compared to corticosteroids alone. Specifically, therapy with mycophenolate mofetil alone and adjunctive azathioprine were associated with more severe adverse events compared to other drug protocols. Evidence relating to immunomodulatory and immunosuppressive drug protocols in the treatment of canine ITP was of variable quality. Future larger case-controlled trials are required for determination of optimal treatment protocols in canine ITP.

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

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