title: Quinine-induced thrombocytopenia: drug-dependent GPIb/IX antibodies inhibit megakaryocyte and proplatelet production in vitro.
abstract: The development of immune cytopenias is a well-recognized side effect of many drugs. Quinine- and quinidine-dependent antibodies are classic examples of drug-induced effects that cause severe, life-threatening thrombocytopenia. Whereas the effects of drug-dependent antibodies on platelets have been well documented, their effects on megakaryocyte (Mk) biology are still unclear. We analyzed sera from several quinine-induced thrombocytopenia (QITP) patients on highly pure Mks (98% glycoprotein IIb-positive [GPIIb(+)]; 92% GPIX(+)) derived from human CD34(+) cells cultured with human thrombopoietin. We demonstrate by flow cytometry and confocal microscopy that QITP IgGs bind Mks efficiently in the presence of quinine. Incubation of day-4 Mks with QITP sera or purified IgG resulted in induction of apoptosis, a significant decrease in cell viability, and an increase in cell death. Furthermore, QITP sera preferentially reduced the number of late GPIX(+)/GPIbα(+) Mks and the number of receptors per cell in the surviving population. Ploidy distribution, lobularity, and average cell size of Mks remained unchanged after treatment. In addition, treated Mks showed a marked decrease in their proplatelet production capacity, suggesting that drug-dependent antibodies hinder platelet production. Therefore, QITP antibodies considerably reduce the proplatelet production capabilities of Mks despite undetectable effects on DNA content, morphology, and cell size.
authors.affiliation: Department of Medicine, St George Clinical School, University of New South Wales, Gray Street, Kogarah, Australia.
authors.forename: José
authors.initials: J
authors.lastname: Perdomo
authors.forename: Feng
authors.initials: F
authors.lastname: Yan
authors.forename: Zohra
authors.initials: Z
authors.lastname: Ahmadi
authors.forename: Xing-Mai
authors.initials: XM
authors.lastname: Jiang
authors.forename: Roland
authors.initials: R
authors.lastname: Stocker
authors.forename: Beng H
authors.initials: BH
authors.lastname: Chong
mesh_terms: D000328:Adult; D000368:Aged; D000962:Antimalarials / Q000009:adverse effects*; D017209:Apoptosis; D001323:Autoantibodies / Q000276:immunology*; D001792:Blood Platelets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008533:Megakaryocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D008875:Middle Aged; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000276:immunology*; D011803:Quinine / Q000009:adverse effects*; D013921:Thrombocytopenia / Q000139:chemically induced* / Q000276:immunology; D013926:Thrombopoietin / Q000378:metabolism; D055815:Young Adult
chemical_list: D000962:Antimalarials; D001323:Autoantibodies; D019038:Platelet Glycoprotein GPIb-IX Complex; D013926:Thrombopoietin; D011803:Quinine