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

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 alpha IIb beta 3 integrin and GPIb alpha are the major antibody targets in immune thrombocytopenia, the reported incidence of anti-GPIb alpha-mediated FNIT is rare. Here, we developed mouse models of FNIT mediated by antibodies specific for GPIb alpha and beta 3 integrin and compared their pathogenesis. We found, unexpectedly, that miscarriage occurred in the majority of pregnancies in our model of anti-GPIb alpha-mediated FNIT, which was far more frequent than in anti-beta 3-mediated FNIT. Dams with anti-GPIb alpha antibodies exhibited extensive fibrin deposition and apoptosis/necrosis in their placentas, which severely impaired placental function. Furthermore, anti-GPIb alpha (but not anti-beta 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-GPIb alpha-mediated FNIT. Thus, the maternal immune response to fetal GPIb alpha 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-GPIb alpha-mediated FNIT, but also point to possible therapeutic interventions.