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Platelet survival depends upon mediators of apoptosis e.g., Bcl-xL, Bax, and Bak, which are regulated by thrombopoietin (TPO)-mediated AKT signaling. Thrombopoietin receptor (TPO-R) signaling might decrease platelet and/or megakaryocyte apoptosis and increase the platelet count. This study therefore explored anti-apoptotic effects of TPO-R-agonists in vivo on platelets of patients with immune thrombocytopenia. Patients received eltrombopag or romiplostim for two weeks. Total, immature, and large platelet counts were assessed as were Bcl-xL inhibitor assay; Bcl-xL Western blot; and flow cytometric (FACS) analysis of the AKT-signaling pathway. Eight/ten patients had platelet responses to eltrombopag and all three to romiplostim. Platelet sensitivity to apoptosis by Bcl-xL inhibition was greater in pretreatment patients than controls. This sensitivity normalized after one week of therapy, but surprisingly returned to pretreatment levels at week two. FACS analysis revealed increased AKT-pathway signaling after one week, followed by a decrease at week two. Platelet counts correlated with the Bcl-xL /Bak ratio. Platelet survival may be enhanced by TPO-R-agonists as a transient decrease in platelet sensitivity to apoptosis was accompanied by transient activation of AKT. However, this mechanism has only a short-lived effect. Megakaryocytes and platelets already present at the start of TPO-R-agonist treatment appear to respond differently than those generated de novo.

Original publication

DOI

10.1002/ajh.23832

Type

Journal article

Journal

Am J Hematol

Publication Date

12/2014

Volume

89

Pages

E228 - E234

Keywords

Apoptosis, Benzoates, Blood Platelets, Case-Control Studies, Chronic Disease, Gene Expression Regulation, Humans, Hydrazines, Megakaryocytes, Purpura, Thrombocytopenic, Idiopathic, Pyrazoles, Receptors, Fc, Receptors, Thrombopoietin, Recombinant Fusion Proteins, Signal Transduction, Thrombopoietin, bcl-2 Homologous Antagonist-Killer Protein, bcl-2-Associated X Protein, bcl-X Protein