A novel murine model of fetal and neonatal alloimmune thrombocytopenia: response to intravenous IgG therapy

Fetal and neonatal alloimmune thrombo-cytopenia (FNAITP) is a life-threatening bleeding disorder caused by maternal antibodies directed against fetal platelet antigens. The immunoreactive epitopes in FNAITP are primarily located in the extracellular regions of the platelet glycoprotein IIIa (beta(3) integrin). Here we have established a novel animal model of FNAITP using beta(3) integrin-deficient (beta(-/-)(3)) mice. We demonstrated first that these mice are immunoresponsive to beta 3 integrin; beta(-/-)(3) mice transfused with wild-type platelets generated specific anti-beta(3) antibodies which were able to induce thrombocytopenia in wild-type mice. Subsequently, beta(-/-)(3) female mice (both naive and immunized) were bred with wild-type male mice to recapitulate the features of FNAITP. The titer of generated maternal antibodies correlated with the severity of FNAITP. High titer maternal anti-beta(3) antibodies caused severe fetal thrombocytopenia, intracranial hemorrhage, and even miscarriage. Furthermore, maternal administration of intravenous immunoglobulin G(IgG) ameliorated FNAITP and downregulated pathogenic antibodies in both the maternal and fetal circulations.