title: Effect of thrombopoietin receptor agonists on the apoptotic profile of platelets in patients with chronic immune thrombocytopenia.
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.
authors.affiliation: Division of Pediatric Hematology/Oncology, Weill Cornell Medical College, New York, New York; Laboratory of Platelet Biology, New York Blood Center, New York, New York.
authors.forename: William Beau
authors.initials: WB
authors.lastname: Mitchell
authors.forename: Mariana P
authors.initials: MP
authors.lastname: Pinheiro
authors.forename: Nayla
authors.initials: N
authors.lastname: Boulad
authors.forename: David
authors.initials: D
authors.lastname: Kaplan
authors.forename: Michele N
authors.initials: MN
authors.lastname: Edison
authors.forename: Bethan
authors.initials: B
authors.lastname: Psaila
authors.forename: Marissa
authors.initials: M
authors.lastname: Karpoff
authors.forename: Michael J
authors.initials: MJ
authors.lastname: White
authors.forename: Emma C
authors.initials: EC
authors.lastname: Josefsson
authors.forename: Benjamin T
authors.initials: BT
authors.lastname: Kile
authors.forename: James B
authors.initials: JB
authors.lastname: Bussel
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001565:Benzoates / Q000627:therapeutic use*; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D002908:Chronic Disease; D005786:Gene Expression Regulation; D006801:Humans; D006834:Hydrazines / Q000627:therapeutic use*; D008533:Megakaryocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011720:Pyrazoles / Q000627:therapeutic use*; D011961:Receptors, Fc / Q000627:therapeutic use*; D053628:Receptors, Thrombopoietin / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D015398:Signal Transduction; D013926:Thrombopoietin / Q000627:therapeutic use*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C494772:BAK1 protein, human; C494826:BAX protein, human; C494811:BCL2L1 protein, human; D001565:Benzoates; D006834:Hydrazines; D011720:Pyrazoles; D011961:Receptors, Fc; D053628:Receptors, Thrombopoietin; D011993:Recombinant Fusion Proteins; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; C082218:MPL protein, human; D013926:Thrombopoietin; C488777:romiplostim; C520809:eltrombopag