title: Maternal anti-platelet β3 integrins impair angiogenesis and cause intracranial hemorrhage.
abstract: Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a life-threatening disease in which intracranial hemorrhage (ICH) is the major risk. Although thrombocytopenia, which is caused by maternal antibodies against β3 integrin and occasionally by maternal antibodies against other platelet antigens, such as glycoprotein GPIbα, has long been assumed to be the cause of bleeding, the mechanism of ICH has not been adequately explored. Utilizing murine models of FNAIT and a high-frequency ultrasound imaging system, we found that ICH only occurred in fetuses and neonates with anti-β3 integrin-mediated, but not anti-GPIbα-mediated, FNAIT, despite similar thrombocytopenia in both groups. Only anti-β3 integrin-mediated FNAIT reduced brain and retina vessel density, impaired angiogenic signaling, and increased endothelial cell apoptosis, all of which were abrogated by maternal administration of intravenous immunoglobulin (IVIG). ICH and impairment of retinal angiogenesis were further reproduced in neonates by injection of anti-β3 integrin, but not anti-GPIbα antisera. Utilizing cultured human endothelial cells, we found that cell proliferation, network formation, and AKT phosphorylation were inhibited only by murine anti-β3 integrin antisera and human anti-HPA-1a IgG purified from mothers with FNAIT children. Our data suggest that fetal hemostasis is distinct and that impairment of angiogenesis rather than thrombocytopenia likely causes FNAIT-associated ICH. Additionally, our results indicate that maternal IVIG therapy can effectively prevent this devastating disorder.
authors.forename: Issaka
authors.initials: I
authors.lastname: Yougbaré
authors.forename: Sean
authors.initials: S
authors.lastname: Lang
authors.forename: Hong
authors.initials: H
authors.lastname: Yang
authors.forename: Pingguo
authors.initials: P
authors.lastname: Chen
authors.forename: Xu
authors.initials: X
authors.lastname: Zhao
authors.forename: Wei-She
authors.initials: WS
authors.lastname: Tai
authors.forename: Darko
authors.initials: D
authors.lastname: Zdravic
authors.forename: Brian
authors.initials: B
authors.lastname: Vadasz
authors.forename: Conglei
authors.initials: C
authors.lastname: Li
authors.forename: Siavash
authors.initials: S
authors.lastname: Piran
authors.forename: Alexandra
authors.initials: A
authors.lastname: Marshall
authors.forename: Guangheng
authors.initials: G
authors.lastname: Zhu
authors.forename: Heidi
authors.initials: H
authors.lastname: Tiller
authors.forename: Mette Kjaer
authors.initials: MK
authors.lastname: Killie
authors.forename: Shelley
authors.initials: S
authors.lastname: Boyd
authors.forename: Howard
authors.initials: H
authors.lastname: Leong-Poi
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Wen
authors.forename: Bjorn
authors.initials: B
authors.lastname: Skogen
authors.forename: S Lee
authors.initials: SL
authors.lastname: Adamson
authors.forename: John
authors.initials: J
authors.lastname: Freedman
authors.forename: Heyu
authors.initials: H
authors.lastname: Ni
mesh_terms: D000818:Animals; D000918:Antibody Specificity; D016824:Antigens, Human Platelet / Q000276:immunology*; D017209:Apoptosis; D001324:Autoantigens / Q000276:immunology*; D001792:Blood Platelets / Q000276:immunology*; D001921:Brain / Q000098:blood supply / Q000196:embryology; D004195:Disease Models, Animal; D005260:Female; D005312:Fetal Blood / Q000276:immunology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007106:Immune Sera / Q000633:toxicity; D007112:Immunity, Maternally-Acquired; D007074:Immunoglobulin G / Q000276:immunology*; D016756:Immunoglobulins, Intravenous / Q000627:therapeutic use*; D039661:Integrin beta3 / Q000235:genetics / Q000276:immunology*; D020300:Intracranial Hemorrhages / Q000196:embryology / Q000209:etiology* / Q000276:immunology / Q000503:physiopathology; D008297:Male; D008431:Maternal-Fetal Exchange; D051379:Mice; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000209:etiology*; D018919:Neovascularization, Physiologic / Q000276:immunology; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000235:genetics / Q000276:immunology; D011247:Pregnancy; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D012171:Retinal Vessels / Q000196:embryology / Q000473:pathology; D054098:Thrombocytopenia, Neonatal Alloimmune / Q000196:embryology / Q000276:immunology* / Q000517:prevention & control
chemical_list: D016824:Antigens, Human Platelet; D001324:Autoantigens; C061248:ITGB3 protein, human; D007106:Immune Sera; D007074:Immunoglobulin G; D016756:Immunoglobulins, Intravenous; D039661:Integrin beta3; D019038:Platelet Glycoprotein GPIb-IX Complex; C094990:adhesion receptor; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt