Comparative analyses of the small molecule thrombopoietin receptor agonist eltrombopag and thrombopoietin on in vitro platelet function

Erhardt, Joseph A.; Erickson‐Miller, Connie L.; Aivado, Manuel; Abboud, Melanie A; Pillarisetti, Kodandaram; Toomey, John R.

doi:10.1016/j.exphem.2009.06.011

Cited by 84 publications

(61 citation statements)

References 28 publications

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“…Eltrombopag lacks this effect [83]. Whether this is important clinically or not is unclear, but to date there has been no increased risk of thrombosis with this agent.…”

Section: Clinical Development Of Tpo Receptor Agonistsmentioning

confidence: 99%

“…• Eltrombopag activates signal transduction pathways differently than TPO or romiplostim [83]. Eltrombopag is a much weaker stimulator of JAK and STAT phosphorylation.…”

Section: Eltrombopagmentioning

confidence: 99%

“…• Eltrombopag does not potentiate platelet activation by platelet agonists such as ADP in standard aggregometry experiments, probably due to the altered signal transduction pathways mentioned above [83]. Although probably not clinically relevant, TPO and romiplostim both reduce by 50 % the concentration of agonist necessary to activate platelets [84].…”

Section: Eltrombopagmentioning

confidence: 99%

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The biology of thrombopoietin and thrombopoietin receptor agonists

2013

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Thrombopoietin (TPO) is the major physiological regulator of platelet production. TPO binds the TPO receptor, activates JAK and STAT pathways, thus stimulating megakaryocyte growth and platelet production. There is no ''sensor'' of the platelet count; rather TPO is produced in the liver at a constant rate and cleared by TPO receptors on platelets. TPO levels are inversely proportional to the rate of platelet production. Early recombinant TPO molecules were potent stimulators of platelet production and increased platelets in patients with immune thrombocytopenia, chemotherapy-induced thrombocytopenia, myelodysplastic syndromes and platelet apheresis donors. Neutralizing antibodies formed against one recombinant protein and ended their development. A second generation of TPO receptor agonists, romiplostim and eltrombopag, has been developed. Romiplostim is an IgG heavy chain into which four TPO agonist peptides have been inserted. Eltrombopag is an oral small molecule. These activate the TPO receptor by different mechanisms to increase megakaryocyte growth and platelet production. After administration of either to healthy volunteers, there is a delay of 5 days before the platelet count rises and subsequently reaches a peak after 12-14 days. Both have been highly effective in treating ITP and hepatitis C thrombocytopenia. Studies in a wide variety of other thrombocytopenic conditions are underway.

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“…Eltrombopag lacks this effect [83]. Whether this is important clinically or not is unclear, but to date there has been no increased risk of thrombosis with this agent.…”

Section: Clinical Development Of Tpo Receptor Agonistsmentioning

confidence: 99%

“…• Eltrombopag activates signal transduction pathways differently than TPO or romiplostim [83]. Eltrombopag is a much weaker stimulator of JAK and STAT phosphorylation.…”

Section: Eltrombopagmentioning

confidence: 99%

Section: Eltrombopagmentioning

confidence: 99%

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The biology of thrombopoietin and thrombopoietin receptor agonists

2013

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“…In vitro studies have shown that while treatment with hrTPO leads to a significant increase of both STAT3 and STAT5 phosphorylation, cells treated with eltrombopag respond with an increase in STAT5 phosphorylation only, while p-STAT3 levels remain consistent with levels observed in untreated controls [38]. In their signal transduction studies, Erhardt et al reported that eltrombopag induced the phosphorylation of STAT proteins, but not of Akt, whereas hrTPO induced the phosphorylation of Akt in addition to the STAT proteins [41]. These findings suggest that the effect of eltrombopag appears to be distinct from hrTPO or other TPO mimetics in some respects and may be explained by eltrombopag's unique binding site on the TPO receptor.…”

Section: Eltrombopagmentioning

confidence: 92%

“…Eltrombopag stimulates platelet production with little or no effect on platelet function. In vitro and ex vivo studies using platelet samples from healthy volunteers and patients with chronic ITP have shown that eltrombopag has no effect on platelet aggregation or activation [41,43] and that platelet function with eltrombopag is comparable to that with placebo [43]. The clinical relevance of these findings is unknown at present.…”

Section: Eltrombopagmentioning

confidence: 98%

Eltrombopag: an update on the novel, non-peptide thrombopoietin receptor agonist for the treatment of immune thrombocytopenia

Kühne

Imbach

2010

Ann Hematol

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Immune thrombocytopenia (ITP) is characterised by a transient or persistent decrease in platelets accompanied by an increased risk of bleeding, which can have a significant negative impact on patients' health-related quality of life. The condition has long been associated with an increased rate of immune-mediated platelet destruction, and traditional treatments have targeted the reduction in platelet destruction; however, some interventional drugs are limited by transient efficacy and side effects. Recent advances in our understanding of ITP pathogenesis have highlighted the role of impaired platelet production, which has led to the advent of a new generation of thrombopoietin (TPO)-receptor agonist therapies, including eltrombopag and romiplostim. The oral, non-peptide TPO-receptor agonist eltrombopag has shown considerable promise in both preclinical and clinical trials. Eltrombopag has a unique mechanism of action and binds to a transmembrane region of the TPO receptor that is distant from the TPO binding site. As such, eltrombopag may confer synergistic effects with endogenous TPO rather than competing for binding. Eltrombopag also induces activation of the TPO receptor and downstream signalling in a distinct manner to TPO and does not have a significant impact on platelet function. Clinical evidence demonstrates that eltrombopag produces a rapid and sustainable increase in platelet counts that significantly reduces bleeding and is well tolerated in patients with ITP. Eltrombopag therefore represents an important addition to the therapeutic armamentarium for ITP.

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Hematopoietic Agents

Pelus

Hoggatt

Singh

et al. 2010

Burger's Medicinal Chemistry and Drug Discovery

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Adult hematopoietic stem cells self‐renew, proliferate, and differentiate forming and maintaining appropriate levels of all the cellular components of blood as well as responding to increased demand. This lifelong process termed hematopoiesis is regulated in part by hematopoietic growth factors, interleukins, and chemokines. In an incredibly short period of time, since the discovery of culture systems and animal models that detected the growth of blood progenitor cells and identified the existence of hematopoietic stem cells in the 1960s, cytokines controlling their function have been identified, cloned, and brought into clinical practice. These agents have had a major impact on patient outcomes and the ability to treat disease. Clinicians now have the tools to modulate erythrocyte, neutrophil, and platelet production enabling treatment of congenital and iatrogenic conditions and harvest of hematopoietic stem and progenitor cells for curative hematopoietic transplantation. In this chapter, hematopoietic cytokines, mimetics, and other agents approved for use in humans are described. The fields of experimental hematology and cytokine research continue to expand and new interleukins continue to be identified. As our knowledge of hematopoietic cell function increases, so will our understanding of the cellular and molecular biology of cytokine actions, and the clinical use of these agents will be refined. The potential application of several newly defined cytokines is discussed as well as the potential for the future development of cytokines that directly regulate hematopoietic stem cell function.

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Comparative analyses of the small molecule thrombopoietin receptor agonist eltrombopag and thrombopoietin on in vitro platelet function

Cited by 84 publications

References 28 publications

The biology of thrombopoietin and thrombopoietin receptor agonists

The biology of thrombopoietin and thrombopoietin receptor agonists

Eltrombopag: an update on the novel, non-peptide thrombopoietin receptor agonist for the treatment of immune thrombocytopenia

Hematopoietic Agents

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