title: Impaired proplatelet formation in immune thrombocytopenia: a novel mechanism contributing to decreased platelet count.
abstract: The pathophysiological mechanisms contributing to the decreased platelet count in immune thrombocytopenia (ITP) are not entirely understood. Here, we investigated the key step of proplatelet formation (PPF) by studying the effect of ITP plasma in thrombopoiesis. Normal cord blood-derived mature megakaryocytes were cultured in the presence of recalcified plasma from ITP patients, and PPF was evaluated by microscopic analysis. Patient samples induced a dose-dependent inhibition in PPF, as well as decreased complexity of proplatelet architecture. Although slightly increased, plasma-induced megakaryocyte apoptosis was not related to PPF impairment. Purified IgG reproduced the inhibitory effect, while platelet-adsorbed plasma induced its reversion, suggesting the involvement of auto-antibodies in the inhibition of thrombopoiesis. Impaired PPF, induced by ITP plasmas bearing anti-GPIIb-IIIa antibodies, was related to their ability to interfere with the normal function of this integrin, as assessed by megakaryocyte PAC-1 binding and β3 integrin phosphorylation while the presence of anti-glycoprotein Ia-IIa auto-antibodies was associated with loss of normal inhibition of PPF induced by type I collagen. In conclusion, abnormal thrombopoiesis comprising decreased PPF and morphological changes in proplatelet structure are induced by patient samples, unveiling new mechanisms contributing to decreased platelet count in ITP.
authors.affiliation: Departamento de Hematología Investigación, Instituto de Investigaciones Médicas Alfredo Lanari, Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina.
authors.forename: Paola R
authors.initials: PR
authors.lastname: Lev
authors.forename: Matías
authors.initials: M
authors.lastname: Grodzielski
authors.forename: Nora P
authors.initials: NP
authors.lastname: Goette
authors.forename: Ana C
authors.initials: AC
authors.lastname: Glembotsky
authors.forename: Yesica R
authors.initials: YR
authors.lastname: Espasandin
authors.forename: Marta S
authors.initials: MS
authors.lastname: Pierdominici
authors.forename: Geraldine
authors.initials: G
authors.lastname: Contrufo
authors.forename: Verónica S
authors.initials: VS
authors.lastname: Montero
authors.forename: Luciana
authors.initials: L
authors.lastname: Ferrari
authors.forename: Felisa C
authors.initials: FC
authors.lastname: Molinas
authors.forename: Paula G
authors.initials: PG
authors.lastname: Heller
authors.forename: Rosana F
authors.initials: RF
authors.lastname: Marta
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000918:Antibody Specificity / Q000276:immunology; D017209:Apoptosis / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology; D001792:Blood Platelets / Q000166:cytology; D006801:Humans; D016023:Integrins / Q000276:immunology; D008533:Megakaryocytes / Q000166:cytology / Q000276:immunology; D008875:Middle Aged; D010976:Platelet Count; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000276:immunology; D010980:Platelet Membrane Glycoproteins / Q000276:immunology; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000097:blood* / Q000276:immunology*; D034061:Thrombopoiesis / Q000276:immunology; D055815:Young Adult
chemical_list: D001323:Autoantibodies; D016023:Integrins; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D010980:Platelet Membrane Glycoproteins
keywords: auto-antibodies; immune thrombocytopenia; platelets; proplatelets; thrombopoiesis