Effect of thrombopoietin receptor agonists on the apoptotic profile of platelets in patients with chronic immune thrombocytopenia
- Mitchell, WB; Pinheiro, MP; Boulad, N; Kaplan, D; Edison, MN; Psaila, B; Karpoff, M; White, MJ; Josefsson, EC; Kile, BT; Bussel, JB;
Publication Year 2014-08-16, Volume 89, Issue #12, Page E228-E234
- Journal Title
- Am J Hematol
- Publication Type
- Journal Article
- 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. Am. J. Hematol., 2014. (c) 2014 Wiley Periodicals, Inc.
- WEHI Research Division(s)
- Chemical Biology; Cancer And Haematology
- Publisher's Version
- Rights Notice
- Copyright © 2014 Wiley Periodicals, Inc.
Creation Date: 2014-11-14 01:50:09Last Modified: 2014-11-28 08:38:01