Maternal anti-platelet ß3 integrins impair angiogenesis and cause intracranial hemorrhage.

Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a life-threatening disease in which intracranial hemorrhage (ICH) is the major risk. Although thrombocytopenia, which is caused by maternal antibodies against ß3 integrin and occasionally by maternal antibodies against other platelet antigens, such as glycoprotein GPIbα, has long been assumed to be the cause of bleeding, the mechanism of ICH has not been adequately explored. Utilizing murine models of FNAIT and a high-frequency ultrasound imaging system, we found that ICH only occurred in fetuses and neonates with anti-ß3 integrin-mediated, but not anti-GPIbα-mediated, FNAIT, despite similar thrombocytopenia in both groups. Only anti-ß3 integrin-mediated FNAIT reduced brain and retina vessel density, impaired angiogenic signaling, and increased endothelial cell apoptosis, all of which were abrogated by maternal administration of intravenous immunoglobulin (IVIG). ICH and impairment of retinal angiogenesis were further reproduced in neonates by injection of anti-ß3 integrin, but not anti-GPIbα antisera. Utilizing cultured human endothelial cells, we found that cell proliferation, network formation, and AKT phosphorylation were inhibited only by murine anti-ß3 integrin antisera and human anti-HPA-1a IgG purified from mothers with FNAIT children. Our data suggest that fetal hemostasis is distinct and that impairment of angiogenesis rather than thrombocytopenia likely causes FNAIT-associated ICH. Additionally, our results indicate that maternal IVIG therapy can effectively prevent this devastating disorder.

Platelet antibodies and fetal growth: maternal antibodies against fetal platelet antigen 1a are strongly associated with reduced birthweight in boys.

OBJECTIVE: To assess whether maternal HPA 1a alloimmunization is associated with birthweight. DESIGN: A retrospective observational cohort study. SETTING: The national reference laboratory for clinical platelet immunology at a university hospital. POPULATION: 165 HPA 1a incompatible pregnancies identified from a recent screening study of 100 448 women (124 pregnancies) and the national reference laboratory for clinical platelet immunology (41 pregnancies). METHODS: A linear mixed model analysis was used to assess whether maternal anti-HPA 1a antibodies were associated with birthweight. A generalized linear model was used to assess maternal anti-HPA 1a antibodies as risk factor for small-for-gestational age neonates. Both models were adjusted for gestational age at time of delivery, maternal age, parity, smoking habits during pregnancy, preeclampsia, diabetes mellitus and fetal sex. MAIN OUTCOME MEASURES. Maternal anti-HPA 1a antibody as risk factor of reduced birthweight and small-for-gestational age neonates. RESULTS: The level of maternal anti-HPA 1a antibodies was significantly associated with birthweight and risk of small-for-gestational age neonates after correcting for confounding variables (p<0.001). However, this association was only significant for boys. When the mother had high levels of anti-HPA 1a antibodies during pregnancy, the adjusted mean birthweight in boys was 530g lower compared with anti-HPA 1a antibody negative pregnancies (p<0.001). CONCLUSIONS: A linear relation between maternal anti-HPA 1a antibody levels and reduced birthweight in boys was demonstrated. Reduced birthweight should be considered a possible complication of fetal and neonatal alloimmune thrombocytopenia.