期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 121, 期 11, 页码 4537-4547出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI57850
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资金
- Canadian Institutes of Health Research
- St. Michael's Hospital
- Canadian Blood Services
- Canada Foundation for Innovation
- NIH [HL-42846]
- Connaught Scholarship
- University of Toronto
- Ontario Graduate Scholarship
- Heart and Stroke Foundation of Canada (Ontario)
- Heart and Stroke Foundation of Canada/Ontario Graduate Scholarship in Science and Technology
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.
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