Effects of Eltrombopag on In Vitro Macrophage Polarization in Pediatric Immune Thrombocytopenia

Paola, Alessandra Di; Palumbo, Giuseppe; Merli, Pietro; Argenziano, Maura; Tortora, Chiara; Strocchio, Luisa; Roberti, Domenico; Santoro, Claudia; Perrotta, Silverio

doi:10.3390/ijms22010097

Cited by 31 publications

(51 citation statements)

References 33 publications

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“…Eltrombopag license for chronic immune thrombocytopenia (ITP) treatment in both pediatric and adult patients when the rst-line therapy or splenectomy fail [20]. Eltrombopag improves T and B regulatory cells functions, suppresses T-cells activity, and inhibits monocytes activation in pediatric patients with immune thrombocytopenia (ITP) [21]. The combination of eltrombopag with an oral immunosuppressant and an androgen in patients with refractory severe aplastic anemia is feasible and could restore multi-lineage hematopoiesis [22].…”

Section: Discussionmentioning

confidence: 99%

Treatment of Severe Refractory Thrombocytopenia in Brucellosis With Eltrombopag

Zhang

Ren

Sang

et al. 2021

Preprint

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Background: Brucellosis is a common zoonotic illness in the world. Brucellosis is often characterized by hematologic abnormalities, including mild anemia, leukopenia, thrombocytopenia, or pancytopenia. However, severe refractory thrombocytopenia in brucellosis is very rare and easily misdiagnosed.Case presentation: The patient was a 5-year-old girl with brucellosis who developed severe refractory thrombocytopenia (platelet count: 3×109/L) with complaints of epistaxis, skin petechiae and purpura. Most conventional treatments including glucocorticoids and intravenous immunoglobulin (IVIg) did not elevate her platelets, but eltrombopag worked well and her platelet count recovered rapidly. One week later, the patient's symptoms improved and the platelet count returned to normal.Conclusions:Patients with severe refractory thrombocytopenia, particularly resistant to IVIg and steroid treatment should be considered for second-line drugs such as eltrombopag. Our results also increase the application experience of eltrombopag in Chinese patients with severe refractory thrombocytopenia in brucellosis. To the best of our knowledge, this case is the first reported case of the successful treatment of severe refractory thrombocytopenia in brucellosis with eltrombopag.

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Section: Discussionmentioning

confidence: 99%

Treatment of Severe Refractory Thrombocytopenia in Brucellosis With Eltrombopag

Zhang

Ren

Sang

et al. 2021

Preprint

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“…Also in ITP, it has been observed a prevalence of M1 macrophages, responsible for an increased release of pro-inflammatory cytokines [63,64]. Accordingly, the switch from the M1 pro-inflammatory phenotype to the M2 anti-inflammatory type in ITP pediatric patients is correlated to a reduction of the inflammatory state and to a restoration of the immune system function [65]. In accordance with these findings, Pereira et al demonstrated that acute iron deprivation in human macrophages causes anti-inflammatory responses.…”

Section: Iron and Inflammationmentioning

confidence: 99%

“…M1 macrophages are characterized by an elevated iron content which is responsible for inducing inflammation and inhibiting pathogen growth. They show anti-microbial, pro-inflammatory and anti-tumor properties, by releasing high levels of pro-inflammatory cytokines, such as IL-6, TNF-α, IL-1β and Nitric Oxide Synthase (iNOS) [65,132]. In contrast, M2 macrophages release high quantity of iron, thus contributing to cell proliferation.…”

Section: Metabolism and Tumor Microenvironmentmentioning

confidence: 99%

“…In contrast, M2 macrophages release high quantity of iron, thus contributing to cell proliferation. They have both anti-inflammatory and immunosuppressive functions, by releasing anti-inflammatory cytokines, such as IL-10 and Transforming Growth Factor-β (TGF-β), and also pro-angiogenic and pro-fibrotic properties, contributing to tumor progression [65,132]. Therefore, while pro-inflammatory M1 macrophages are responsible for iron uptake and storage with a consequent iron retention; anti-inflammatory M2 phenotype is involved in iron release in the extracellular space [103,132].…”

Section: Metabolism and Tumor Microenvironmentmentioning

confidence: 99%

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Iron Metabolism: From Inflammation to Cancer

A¹,

Tortora²,

Argenziano³

et al. 2021

annhematoloncol

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Iron is a trace element essential for several physiological cell functions and any alteration in its metabolism could be associated to the onset of several disorders. Cells normally avoid any dysregulation, activating fine molecular mechanisms to balance iron uptake, utilization, recycling, storage and export. The main “actors” in this event are hepcidin, ferroportin, ferritin and transferrin, both at cell and systemic level. Dysregulation in iron homeostasis is closely related to inflammation onset and perpetuation, osteoporosis and cancer progression. During inflammation, it has been observed a reduction in circulating iron as direct consequence of increase in ferritin levels, aimed to contain inflammatory processes and in many cases to restore the immune response. Iron overload directly promotes bone resorption and inhibits bone formation inducing osteoporosis. Moreover, iron cellular accumulation is responsible for ROS production with consequent DNA damage and neoplastic transformation of cells. In conclusion, even though many molecular mechanisms have to be clarified, targeting iron and also the mediators of its metabolism could be useful to manage a great variety of disorders, such inflammation, immune diseases, osteoporosis and cancer.

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“…The pharmacological effect of EPAG interactions with TPO-R results in an increase of differentiation and proliferation rate of the megakaryocytoblastic cellular line and its precursors. Alongside this effect on platelet count, recent evidence also suggests an immune-modulating and iron chelating property of EPAG ( Argenziano et al, 2021 ; Di Paola et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic Evaluation of Eltrombopag in ITP Pediatric Patients

et al. 2021

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Background: Eltrombopag (EPAG) is an oral thrombopoietin receptor agonist, approved for refractory primary immune thrombocytopenia (ITP) in pediatric patients. In two pediatric RCTs, EPAG led to an improvement of platelet counts and a reduction in bleeding severity. However, a significant number of pediatric patients did not achieve the primary endpoints. We performed a pharmacokinetic evaluation of EPAG in pediatric patients with refractory ITP.Methods: Outpatients aged from 1 to 17 y, affected by refractory ITP to first-line treatment, were enrolled for a pharmacokinetic assessment. The analysis of drug plasma concentration was performed by the LC-MS/MS platform. Non-compartmental and statistical subgroup analyses were carried out using the R package ncappc.Results: Among 36 patients eligible for PK analysis, the median dose of EPAG given once daily was 50 mg. The EPAG peak occurs between 2 and 4 h with a population Cmax and AUC 0–24 geo-mean of 23, 38 μg/ml, and 275, 4 µg*h/mL, respectively. The pharmacokinetic profile of EPAG did not show a dose proportionality. Female patients showed a statistically significant increase of dose-normalized exposure parameters, increasing by 110 and 123% for Cmax and AUC 0–24, respectively, when compared to male patients. Patients aged 1–5 y showed values increased by more than 100% considering both exposure parameters, compared to older children. Furthermore, patients presenting complete response (83%), showed augmented EPAG exposure parameters compared to subjects with partial or no response.Conclusion: These data highlight the need to further explore the variability of EPAG exposure and its pharmacokinetic/pharmacodynamic profile in pediatric patients also in a real-life setting.

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Effects of Eltrombopag on In Vitro Macrophage Polarization in Pediatric Immune Thrombocytopenia

Cited by 31 publications

References 33 publications

Treatment of Severe Refractory Thrombocytopenia in Brucellosis With Eltrombopag

Treatment of Severe Refractory Thrombocytopenia in Brucellosis With Eltrombopag

Iron Metabolism: From Inflammation to Cancer

Pharmacokinetic Evaluation of Eltrombopag in ITP Pediatric Patients

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