Fetal and neonatal alloimmune thrombocytopenia: Novel mechanisms of miscarriage learned from placental pathology in animal models

Fetal/neonatal alloimmune thrombocytopenia (FNAIT) is a life-threatening disease. Maternal alloimmune responses against fetal platelet antigens in FNAIT may lead to clinical complications including bleeding disorders, intrauterine growth restriction (IUGR) and in severe cases fetal death (miscarriage). It has been long suspected that thrombocytopenia may be the reason for bleeding disorders in FNAIT, recent studies from us and other groups, however, suggested that the anti-angiogenic effects of anti-platelet antibodies may play a key role in bleeding, particularly in intracranial hemorrhages. Our earlier studies using murine models also suggested that some anti-platelet antibodies can activate platelets and initiate thrombotic events in the placenta, which may contribute to miscarriage. Most recently, we found that maternal anti-β3 integrin antibodies can target fetal allogenic trophoblasts, form immune complexes, and generate binding sites for natural killer (NK) cell Fcγ receptors. Uterine NK cell activation through NKp46 and perforin release caused trophoblast apoptosis, impaired spiral artery remodeling, and ultimately lead to IUGR and/or fetal death. We found that NK cell-mediated placental pathologies are preventable by anti-NK antibody treatments, which may have translational importance. This mini-review mainly discussed the latest discoveries regarding activated uterine NK cells-mediated miscarriage. Future research on placental inflammation and remodeling should open new avenues for interventions in FNAIT-mediated pregnancy failures.