Effect of thrombopoietin receptor agonists on the apoptotic profile of platelets in patients with chronic immune thrombocytopenia |
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| Authors: | 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 |
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| Affiliation: | 1. Division of Pediatric Hematology/Oncology, Weill Cornell Medical College, New York, New York;2. Laboratory of Platelet Biology, New York Blood Center, New York, New York;3. Pathfinder Biotech, Cleveland, Ohio;4. Department of Haematology, Hammersmith Hospital, Imperial College London, London, United Kingdom;5. The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia |
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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. Am. J. Hematol. 89:E228–E234, 2014. © 2014 Wiley Periodicals, Inc. |
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