Intracranial hemorrhage development in fetal and neonatal alloimmune thrombocytopenia

Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a life-threatening condition that results from the development of maternal antibodies that target and destroy fetal platelets.  Intracranial hemorrhage (ICH) is the most serious complication of FNAIT and is thought to be the result of severe thrombocytopenia. In this episode, Heyu Ni and colleagues present evidence that the development of ICH in FNAIT specifically occurs as the result of maternal anti-platelet β3 integrins and not as the result of maternal antibodies against other platelet factors. In a murine model of anti–β3 integrin–mediated FNAIT, ICH was the result of impaired angiogenesis and was prevented by administration of intravenous immunoglobulin. The results of this study suggest that current platelet transfusion therapies for FNAIT should be reexamined and intravenous immunoglobulin be further explored to treat this disease. 

Published April 23, 2015, by The JCI

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Citation Information: J Clin Invest. 2015;125(4):1545-1556. https://doi.org/10.1172/JCI77820.
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Research Article Vascular biology

Maternal anti-platelet β3 integrins impair angiogenesis and cause intracranial hemorrhage

Abstract

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 β3 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–β3 integrin–mediated, but not anti-GPIbα–mediated, FNAIT, despite similar thrombocytopenia in both groups. Only anti–β3 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–β3 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–β3 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.

Authors

Issaka Yougbaré, Sean Lang, Hong Yang, Pingguo Chen, Xu Zhao, Wei-She Tai, Darko Zdravic, Brian Vadasz, Conglei Li, Siavash Piran, Alexandra Marshall, Guangheng Zhu, Heidi Tiller, Mette Kjaer Killie, Shelley Boyd, Howard Leong-Poi, Xiao-Yan Wen, Bjorn Skogen, S. Lee Adamson, John Freedman, Heyu Ni

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