Immune thrombocytopenia: antiplatelet autoantibodies inhibit proplatelet formation by megakaryocytes and impair platelet production in vitro

Iraqi, Muna; Perdomo, José; Feng, Yuping; Choi, Philip Young-Ill; Chong, Beng H.

doi:10.3324/haematol.2014.115634

Cited by 91 publications

(77 citation statements)

References 48 publications

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“…The percentage of mature MK (CD41 + /CD42a + ) also increased after treatment with hetrombopag (Figure D). Proplatelet formation and platelet release could be a consequence of increased MK proliferation and maturation . As expected, hetrombopag stimulated MK proplatelet formation from human CB‐CD34 + cells in vitro (Figure E).…”

Section: Resultssupporting

confidence: 71%

“…Proplatelet formation and platelet release could be a consequence of increased MK proliferation and maturation. 21 As expected, hetrombopag stimulated MK proplatelet formation from human CB-CD34 + cells in vitro ( Figure 2E). Corresponding to its MKstimulating activity, hetrombopag induced a concentration-dependent increase in the phosphorylation of STAT3, STAT5 and ERK1/2 in human CB CD34 + cells, exerting a much stronger effect than eltrombopag ( Figure 2F).…”

Section: Hetrombopag Is a Nonpeptide Agonist Of Human Tporsupporting

confidence: 80%

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Pharmacological characterization of hetrombopag, a novel orally active human thrombopoietin receptor agonist

Xie

Zhao

Bao

et al. 2018

J Cellular Molecular Medi

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Nonpeptide thrombopoietin receptor (TPOR/MPL) agonists, such as eltrombopag, have been used to treat thrombocytopenia of various aetiologies. Here, we investigated the pharmacological properties of hetrombopag, a new orally active small‐molecule TPOR agonist, in preclinical models. Hetrombopag specifically stimulated proliferation and/or differentiation of human TPOR‐expressing cells, including 32D‐MPL and human hematopoietic stem cells, with low nanomolar EC 50 values through stimulation of STAT, PI3K and ERK signalling pathways. Notably, hetrombopag effectively up‐regulated G1‐phase–related proteins, including p‐RB, Cyclin D1 and CDK4/6, normalized progression of the cell cycle, and prevented apoptosis by modulating BCL‐XL/BAK expression in 32D‐MPL cells. Moreover, hetrombopag and TPO acted additively in stimulating TPOR‐dependent signalling, promoting cell viability, and preventing apoptosis. Orally administered hetrombopag specifically promoted the viability and growth of 32D‐MPL cells in hollow fibres implanted into nude mice with much higher potency than that of the well‐known TPOR agonist, eltrombopag, in association with activation of TPOR‐dependent signal transduction in vivo. Taken together, our findings indicate that, given its favourable pharmacological characteristics, hetrombopag may represent a new, orally active, small‐molecule TPOR agonist for patients with thrombocytopenia.

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Section: Resultssupporting

confidence: 71%

Section: Hetrombopag Is a Nonpeptide Agonist Of Human Tporsupporting

confidence: 80%

Pharmacological characterization of hetrombopag, a novel orally active human thrombopoietin receptor agonist

Xie

Zhao

Bao

et al. 2018

J Cellular Molecular Medi

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“…202 Finally, the therapeutic armamentarium has been enriched with new, targeted drugs interfering specifically with the pathogenic mechanisms of diseases and promising to modify their natural history. 199,[203][204][205] Thus, platelet disorders have truly entered the era of personalized medicine, and European researchers have played a key role in achieving this goal.…”

Section: The Eha Roadmap For European Hematology Researchmentioning

confidence: 99%

The European Hematology Association Roadmap for European Hematology Research: a consensus document

et al. 2016

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T he European Hematology Association (EHA) Roadmap for European Hematology Research highlights major achievements in diagnosis and treatment of blood disorders and identifies the greatest unmet clinical and scientific needs in those areas to enable better funded, more focused European hematology research. Initiated by the EHA, around 300 experts contributed to the consensus document, which will help European policy makers, research funders, research organizations, researchers, and patient groups make better informed decisions on hematology research. It also aims to raise public awareness of the burden of blood disorders on European society, which purely in economic terms is estimated at €23 billion per year, a level of cost that is not matched in current European hematology research funding. In recent decades, hematology research has improved our fundamental understanding of the biology of blood disorders, and has improved diagnostics and treatments, sometimes in revolutionary ways. This progress highlights the potential of focused basic research programs such as this EHA Roadmap. The EHA Roadmap identifies nine 'sections' in hematology: normal hematopoiesis, malignant lymphoid and myeloid diseases, anemias and related diseases, platelet disorders, blood coagulation and hemostatic disorders, transfusion medicine, infections in hematology, and hematopoietic stem cell transplantation. These sections span 60 smaller groups of diseases or disorders. The EHA Roadmap identifies priorities and needs across the field of hematology, including those to develop targeted therapies based on genomic profiling and chemical biology, to eradicate minimal residual malignant disease, and to develop cellular immunotherapies, combination treatments, gene therapies, hematopoietic stem cell treatments, and treatments that are better tolerated by elderly patients.

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“…Although the trigger for initiating the autoantibody response is unknown, autoreactive T helper cells that interact with antibody-producing B cells are believed to play a key role. 3 In addition, platelet maturation may be inhibited, and their destruction accelerated, by autoantibodies that bind to megakaryocytes. Thrombopoietin (TPO), a liver-derived glycoprotein hormone that drives thrombopoiesis, is not able to normalize platelet levels: it has been found that even 60% of patients with ITP present with normal or decreased TPO plasma levels, indicating that a functional deficit of TPO may also contribute to the pathophysiology of the disease.…”

Section: Introductionmentioning

confidence: 99%

Autoimmune thrombocytopenia: Current treatment options in adults with a focus on novel drugs

Witkowski

Witkowska

Robak

2019

European J of Haematology

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Immune thrombocytopenia (ITP) is an autoimmune disease characterized by platelet destruction and reduced platelet production resulting in decreased platelet level and an increased risk of bleeding. Based on the immunologic mechanism of ITP, frontline standard therapy consists of corticosteroids and intravenous immunoglobulins (IVIG). If patients do not respond to the first-line treatment, or if continuous therapy is required, the disorder is called refractory ITP, and second-line therapy is indicated.This treatment may consist of rituximab, thrombopoietin receptor agonists, splenectomy, or cytotoxic drugs. Despite significant advances, many patients do not respond to any the treatments listed below, and new treatment options need to be developed for this relapsed and refractory group. Recent clinical studies have indicated promising outcomes for novel drugs, either as single agents or in combination with traditional drugs. This review discusses the latest and the most promising novel drugs for ITP in adults. K E Y W O R D Savatrombopag, eltrombopag, immune thrombocytopenia, indirubin, receptor antagonist, rituximab, romiplostim, rozanolixizumab, rozrolimupab, thrombopoietin

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Immune thrombocytopenia: antiplatelet autoantibodies inhibit proplatelet formation by megakaryocytes and impair platelet production in vitro

Cited by 91 publications

References 48 publications

Pharmacological characterization of hetrombopag, a novel orally active human thrombopoietin receptor agonist

Pharmacological characterization of hetrombopag, a novel orally active human thrombopoietin receptor agonist

The European Hematology Association Roadmap for European Hematology Research: a consensus document

Autoimmune thrombocytopenia: Current treatment options in adults with a focus on novel drugs

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