Effect of thrombopoietin receptor agonists on the apoptotic profile of platelets in patients with chronic immune thrombocytopenia

William Beau Mitchell, Mariana P. Pinheiro, Nayla Boulad, David Kaplan, Michele N. Edison, Bethan Psaila, Marissa Karpoff, Michael J. White, Emma C Josefsson, Benjamin T. Kile, James B. Bussel

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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 languageEnglish
Pages (from-to)E228-E234
Number of pages7
JournalAmerican Journal of Hematology
Volume89
Issue number12
DOIs
Publication statusPublished - Dec 2014
Externally publishedYes

Cite this

Mitchell, W. B., Pinheiro, M. P., Boulad, N., Kaplan, D., Edison, M. N., Psaila, B., ... Bussel, J. B. (2014). Effect of thrombopoietin receptor agonists on the apoptotic profile of platelets in patients with chronic immune thrombocytopenia. American Journal of Hematology, 89(12), E228-E234. https://doi.org/10.1002/ajh.23832
Mitchell, William Beau ; Pinheiro, Mariana P. ; Boulad, Nayla ; Kaplan, David ; Edison, Michele N. ; Psaila, Bethan ; Karpoff, Marissa ; White, Michael J. ; Josefsson, Emma C ; Kile, Benjamin T. ; Bussel, James B. / Effect of thrombopoietin receptor agonists on the apoptotic profile of platelets in patients with chronic immune thrombocytopenia. In: American Journal of Hematology. 2014 ; Vol. 89, No. 12. pp. E228-E234.
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abstract = "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.",
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Mitchell, WB, Pinheiro, MP, Boulad, N, Kaplan, D, Edison, MN, Psaila, B, Karpoff, M, White, MJ, Josefsson, EC, Kile, BT & Bussel, JB 2014, 'Effect of thrombopoietin receptor agonists on the apoptotic profile of platelets in patients with chronic immune thrombocytopenia' American Journal of Hematology, vol. 89, no. 12, pp. E228-E234. https://doi.org/10.1002/ajh.23832

Effect of thrombopoietin receptor agonists on the apoptotic profile of platelets in patients with chronic immune thrombocytopenia. / Mitchell, William Beau; Pinheiro, Mariana P. ; Boulad, Nayla; Kaplan, David; Edison, Michele N.; Psaila, Bethan; Karpoff, Marissa; White, Michael J.; Josefsson, Emma C; Kile, Benjamin T.; Bussel, James B.

In: American Journal of Hematology, Vol. 89, No. 12, 12.2014, p. E228-E234.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Effect of thrombopoietin receptor agonists on the apoptotic profile of platelets in patients with chronic immune thrombocytopenia

AU - Mitchell, William Beau

AU - Pinheiro, Mariana P.

AU - Boulad, Nayla

AU - Kaplan, David

AU - Edison, Michele N.

AU - Psaila, Bethan

AU - Karpoff, Marissa

AU - White, Michael J.

AU - Josefsson, Emma C

AU - Kile, Benjamin T.

AU - Bussel, James B.

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