Eltrombopag in paediatric immune thrombocytopenia: Iron metabolism modulation in mesenchymal stromal cells.
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ABSTRACT:
SUBMITTER: Di Paola A
PROVIDER: S-EPMC9303225 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Immune thrombocytopenia (ITP) is a bleeding disorder caused by a decrease in platelet count resulting from increased destruction and insufficient production of platelets. Although impaired regulatory T-lymphocyte activity plays a critical role in platelet destruction, many other immunologic abnormalities are also likely to be involved. Importantly, patients with ITP appear to have defects in a thrombopoietin-mediated physiological mechanism that compensates for a decrease in platelet count by increasing platelet production. Thus, simultaneous treatment of multiple pathogenic pathways involved in ITP could potentially result in synergistic efficacy. While conventional treatments for ITP suppress or modulate the immune system to reduce platelet destruction, a unique class of ITP therapy, namely thrombopoietin receptor agonists (TPO-RAs), improves platelet production by activating the thrombopoietin pathway. As hypothesized, preliminary studies show that combinations of eltrombopag, an oral TPO-RA, with conventional treatments improve outcomes in both newly diagnosed and refractory patients. In this review, the clinical experience with eltrombopag-based combinations in patients with ITP is summarized and the implications of the available data are discussed.
| S-EPMC6187430 | biostudies-literature
Project description:BackgroundEltrombopag (EP) is a small molecule that acts directly on hematopoietic stem cells (HSCs) and megakaryocytes to stimulate the hematopoietic process. Mesenchymal stem/stromal cells (MSCs) are key hematopoietic niche regulators.ObjectivesWe aimed to determine whether EP has any effect on MSC function and properties (especially on their hematopoietic-supporting ability) and if so, what changes (e.g. genome-wide transcriptomic alterations) are induced in MSC after EP treatment.Design/methodsMSCs were isolated from 12 healthy donors and treated with 15 µM and 50 µM of EP for 24 h. The toxicity of the drug on MSCs and their differentiation ability were analyzed, as well as the transcriptomic profile, reactive oxygen species (ROS) and DNA damage and the changes induced in the clonogenic capacity of HSCs.ResultsThe results show that EP also modifies MSC functions, decreasing their adipogenic differentiation, increasing the expression of genes involved in hypoxia and other pathways related to oxygen homeostasis, and enhancing their ability to support hematopoiesis in vitro.ConclusionOur findings support the use of EP in cases where hematopoiesis is defective, despite its well-known direct effects on hematopoietic cells. Our findings suggest that further studies on the effects of EP on MSCs from patients with aplastic anemia are warranted.
| S-EPMC9806379 | biostudies-literature
Project description:Immune thrombocytopenia (ITP) may occur in isolation (primary) or in association with a predisposing condition (secondary ITP [sITP]). Eltrombopag is a well-studied treatment for primary ITP, but evidence is scarce for sITP. We evaluated real-world use of eltrombopag for sITP using electronic health records. Eligible patients had diagnoses of ITP and a qualifying predisposing condition, and eltrombopag treatment. We described patient characteristics, treatment patterns, platelet counts, and thrombotic and bleeding events. We identified 242 eligible patients; the most common predisposing conditions were hepatitis C and systemic lupus erythematosus. Average duration of eltrombopag treatment was 6.1 months. Most (81.4%) patients achieved a platelet count ≥ 30,000/µL at a mean of 0.70 months, 70.2% reached ≥ 50,000/µL at a mean of 0.95 months, and 47.1% achieved a complete response of > 100,000/µL at a mean of 1.43 months after eltrombopag initiation. At eltrombopag discontinuation, 105 patients (43%) experienced a treatment-free period for a mean 3.3 months. Bleeding events occurred with similar frequency before and during eltrombopag treatment whereas thrombotic events were less frequent during eltrombopag treatment. Our results suggest similar rates of platelet response with eltrombopag in patients with sITP as compared with primary ITP. In addition, a treatment-free period is possible for a substantial minority of patients.
| S-EPMC8720735 | biostudies-literature
Project description:Eltrombopag is an orally administered, non-peptide, thrombopoietin receptor agonist which initiates thrombopoietin signaling and stimulates the production of normally functioning platelet. We aimed to do a systematic review and meta-analysis of currently available published data to verify whether eltrombopag treatment in patients with chronic immune-mediated thrombocytopenia can prolong survival. We searched for published, randomized, controlled trials in PubMed, Cochrane and Scopus databases using the following search strategy ("Eltrombopag" OR "Benzoates" OR "Hydrazines") AND ("Idiopathic Thrombocytopenic Purpura" OR "immune thrombocytopenia" OR "Idiopathic Thrombocytopenic Purpuras" OR "Immune Thrombocytopenia" OR "Autoimmune Thrombocytopenia" OR "Werlhof"). The pooled relative risk (RR) showed that eltrombopag group has significantly higher overall platelet response than placebo group (MD = 3.42, 95% CI [2.51, 4.65], P > .0001); pooled results were homogenous (P = .27, I2 = 22%). The pooled relative risk showed that eltrombopag group has lower incidence of any bleeding than placebo group (MD = 0.65, 95% CI [0.48, 0.87], P = .003); pooled results were heterogenous (P = .001, I2 = 75%) and the detected heterogeneity was best resolved after excluding Bussel et al (P = .10). Homogeneous results were still favored eltrombopag group (MD = 0.75, 95% CI [0.60, 0.93], P = .008).
| S-EPMC8060759 | biostudies-literature
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.
| S-EPMC5971401 | biostudies-literature
Project description:Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by antibody-mediated platelet destruction, with a complex and unclear pathogenesis. The impaired immunosuppressive capacity of mesenchymal stromal cells in ITP patients (ITP-MSCs) might play a role in the development of the disease. Correcting the MSC defects could represent an alternative therapeutic approach for ITP. High-dose dexamethasone (HD-Dexa) is the mainstay of the ITP therapeutic regimen, although it has several side effects. We previously demonstrated a role for cannabinoid receptor 2 (CB₂) as a mediator of anti-inflammatory and immunoregulatory properties of human MSCs. We analyzed the effects of CB₂ stimulation, with the selective agonist JWH-133, and of Dexa alone and in combination on ITP-MSC survival and immunosuppressive capacity. We provided new insights into the pathogenesis of ITP, suggesting CB₂ receptor involvement in the impairment of ITP-MSC function and confirming MSCs as responsive cellular targets of Dexa. Moreover, we demonstrated that CB₂ stimulation and Dexa attenuate apoptosis, via Bcl2 signaling, and restore the immune-modulatory properties of MSCs derived from ITP patients. These data suggest the possibility of using Dexa in combination with JWH-133 in ITP, reducing its dose and side effects but maintaining its therapeutic benefits.
| S-EPMC6429305 | biostudies-literature
Project description:Thrombopoietin receptor agonists (TPO-RAs) are used as effective alternative treatments in ITP patients unresponsive to first-/second-line therapies. TPO-RAs can also be used to normalize platelet count to safely perform invasive procedures and chemotherapy, in case of malignancies. In few responsive patients, TPO-RAs can be suspended maintaining a sustained response.
| S-EPMC5538052 | biostudies-other
Project description:The outbreak of coronavirus disease 2019 (COVID-19) pandemic is quickly spreading all over the world. This virus, which is called SARS-CoV-2, has infected tens of thousands of people. Based on symptoms, the pathogenesis of acute respiratory illness is responsible for highly homogenous coronaviruses as well as other pathogens. Evidence suggests that high inflammation rates, oxidation, and overwhelming immune response probably contribute to pathology of COVID-19. COVID-19 causes cytokine storm, which subsequently leads to acute respiratory distress syndrome (ARDS), often ending up in the death of patients. Mesenchymal stem cells (MSCs) are multipotential stem cells that are recognized via self-renewal capacity, generation of clonal populations, and multilineage differentiation. MSCs are present in nearly all tissues of the body, playing an essential role in repair and generation of tissues. Furthermore, MSCs have broad immunoregulatory properties through the interaction of immune cells in both innate and adaptive immune systems, leading to immunosuppression of many effector activities. MSCs can reduce the cytokine storm produced by coronavirus infection. In a number of studies, the administration of these cells has been beneficial for COVID-19 patients. Also, MSCs may be able to improve pulmonary fibrosis and lung function. In this review, we will review the newest research findings regarding MSC-based immunomodulation in patients with COVID-19.
| S-EPMC7499002 | biostudies-literature
Project description:Metabolism and mitochondrial biology have gained a prominent role as determinants of stem cell fate and function. In the context of regenerative medicine, innovative parameters predictive of therapeutic efficacy could be drawn from the association of metabolic or mitochondrial parameters to different degrees of stemness and differentiation potentials. Herein, this possibility was addressed in human mesenchymal stromal/stem cells (hMSC) previously shown to differ in lifespan and telomere length. First, these hMSC were shown to possess significantly distinct proliferation rate, senescence status and differentiation capacity. More potential hMSC were associated to higher mitochondrial (mt) DNA copy number and lower mtDNA methylation. In addition, they showed higher expression levels of oxidative phosphorylation subunits. Consistently, they exhibited higher coupled oxygen consumption rate and lower transcription of glycolysis-related genes, glucose consumption and lactate production. All these data pointed at oxidative phosphorylation-based central metabolism as a feature of higher stemness-associated hMSC phenotypes. Consistently, reduction of mitochondrial activity by complex I and III inhibitors in higher stemness-associated hMSC triggered senescence. Finally, functionally higher stemness-associated hMSC showed metabolic plasticity when challenged by glucose or glutamine shortage, which mimic bioenergetics switches that hMSC must undergo after transplantation or during self-renewal and differentiation. Altogether, these results hint at metabolic and mitochondrial parameters that could be implemented to identify stem cells endowed with superior growth and differentiation potential.
| S-EPMC6817850 | biostudies-other
Project description:BackgroundMesenchymal stromal cells (MSCs) are believed to be hypoimmunogeneic with potential use for allogeneic administration.MethodsBone marrow was harvested from Connemara (n = 1), Standardbred (n = 6), and Thoroughbred (n = 3) horses. MSCs were grouped by their level of expression of major histocompatibility factor II (MHC II). MSCs were then sub-grouped by those MSCs derived from universal blood donor horses. MSCs were isolated and cultured using media containing fetal bovine serum until adequate numbers were acquired. The MSCs were cultured in xenogen-free media for 48 h prior to use and during all assays. Autologous and allogeneic MSCs were then directly co-cultured with responder leukocytes from the Connemara horse in varying concentrations of MSCs to leukocytes (1:1, 1:10, and 1:100). MSCs were also cultured with complement present and heat-inactivated complement to determine whether complement alone would decrease MSC viability. MSCs underwent haplotyping of their equine leukocyte antigen (ELA) to determine whether the MHC factors were matched or mismatched between the donor MSCs and the responder leukocytes.ResultsAll allogeneic MSCs were found to be ELA mismatched with the responder leukocytes. MHC II-low and universal blood donor MSCs caused no peripheral blood mononuclear cell (PBMC) proliferation, no increase in B cells, and no activation of CD8 lymphocytes. Universal blood donor MSCs stimulated a significant increase in the number of T regulatory cells. Neutrophil interaction with MSCs showed that universal blood donor and MHC II-high allogeneic MSCs at the 6 h time point in co-culture caused greater neutrophil activation than the other co-culture groups. Complement-mediated cytotoxicity did not consistently cause MSC death in cultures with active complement as compared to those with inactivated complement. Gene expression assays revealed that the universal blood donor group and the MHC II-low MSCs were more metabolically active both in the anabolic and catabolic gene categories when cultured with allogeneic lymphocytes as compared to the other co-cultures. These upregulated genes included CD59, FGF-2, HGF, IDO, IL-10, IL-RA, IL-2, SOX2, TGF-β1, ADAMSTS-4, ADAMSTS-5, CCL2, CXCLB/IL-8, IFNγ, IL-1β, and TNFα.ConclusionsMHC II-low MSCs are the most appropriate type of allogeneic MSC to prevent activation of the innate and cell-mediated component of the adaptive immune systems and have increased gene expression as compared to other allogeneic MSCs.
| S-EPMC8588742 | biostudies-literature