The maternal immune response to fetal platelet GPIbI? causes frequent miscarriage in mice that can be prevented by intravenous IgG and anti-FcRn therapies

Conglei Li, Siavash Piran, Pingguo Chen, Sean Lang, Alessandro Zarpellon, Joseph W Jin, Guangheng Zhu, Adili Reheman, Evertdina van der Wal, Elisa K Simpson, Ran Ni, Peter L Gross, Jerry Ware, Zaverio M Ruggeri, John Freedman, Heyu Ni

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Abstract

Fetal and neonatal immune thrombocytopenia (FNIT) is a severe bleeding disorder caused by maternal antibody-mediated destruction of fetal/neonatal platelets. It is the most common cause of severe thrombocytopenia in neonates, but the frequency of FNIT-related miscarriage is unknown, and the mechanism(s) underlying fetal mortality have not been explored. Furthermore, although platelet I?IIbI?3 integrin and GPIbI? are the major antibody targets in immune thrombocytopenia, the reported incidence of anti-GPIbI?-mediated FNIT is rare. Here, we developed mouse models of FNIT mediated by antibodies specific for GPIbI? and I?3 integrin and compared their pathogenesis. We found, unexpectedly, that miscarriage occurred in the majority of pregnancies in our model of anti-GPIbI?-mediated FNIT, which was far more frequent than in anti-I?3-mediated FNIT. Dams with anti-GPIbI? antibodies exhibited extensive fibrin deposition and apoptosis/necrosis in their placentas, which severely impaired placental function. Furthermore, anti-GPIbI? (but not anti-I?3) antiserum activated platelets and enhanced fibrin formation in vitro and thrombus formation in vivo. Importantly, treatment with either intravenous IgG or a monoclonal antibody specific for the neonatal Fc receptor efficiently prevented anti-GPIbI?-mediated FNIT. Thus, the maternal immune response to fetal GPIbI? causes what we believe to be a previously unidentified, nonclassical FNIT (i.e., spontaneous miscarriage but not neonatal bleeding) in mice. These results suggest that a similar pathology may have masked the severity and frequency of human anti-GPIbI?-mediated FNIT, but also point to possible therapeutic interventions.
Original languageEnglish
Pages (from-to)4537 - 4547
Number of pages11
JournalJournal of Clinical Investigation
Volume121
Issue number11
DOIs
Publication statusPublished - 2011

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