Study Could Explain Why Some Fetuses With Different Antigens to Mother Suffer Brain Bleeds

A newly discovered bodily process in mice may explain why some human fetuses who have different antigens than their mothers suffer life-threatening brain bleeds, according to a new study.

“Antigens are like the body’s national flag. They’re planted on each cell in the body and tell the immune system whether something in the body, such as a bacteria or virus, is foreign,” said Dr. Heyu Ni, a scientist in the Keenan Research Centre for Biomedical Science of St. Michael’s Hospital. “Because each parent’s DNA is different, a fetus can have different antigens, or flags, on some cells than his or her mom. When a mom’s immune system identifies those cells as foreign to the body it attacks them, which can cause brain bleeds and result in neurological impairment or even death.”

The condition where mothers and fetuses have different antigens is called fetal and neonatal alloimmune thrombocytopenia, or FNAIT. It affects about one in 1,000 live births. Fetuses experience bleeding in the brain in about 10 to 20 per cent of FNAIT cases. The disease can also cause miscarriages, although that has not been well studied.

Platelets–cells in the blood that help form blood clots and stop bleeding–are one of the cell types that commonly have different antigens. Because they are often different in the mother and fetus, they can be targeted by the mother’s immune system. Until now, low amounts of platelets were considered the cause of brain bleeds in fetuses and newborns.

Images shows a pregnant woman looking out of a window.

The condition where mothers and fetuses have different antigens is called fetal and neonatal alloimmune thrombocytopenia, or FNAIT. It affects about one in 1,000 live births. This image is for illustrative purposes only. Image credit: harael.

“Our research challenges the idea that low platelet counts are responsible for fetal brain bleeds and instead shows that the immune system’s attack on the new blood vessel cells in the brain are more likely responsible,” said Dr. Ni, who is also a Canadian Blood Services scientist. “An antigen, called beta 3 integrin, is found both on platelets and on the cells responsible for developing blood vessel in fetuses.”

Newborn platelet levels are tested at birth since it’s believed a lower platelet count signifies the newborn lacks the ability to stop bleeding. A safe level of platelets for newborns is between 150 million and 450 million cells per ml of blood. Babies with low platelet counts (less than 150 million cells per ml of blood) are usually treated right away with platelet transfusions.

“What we’ve discovered means that platelet transfusions are necessary to control bleeding after birth but may not be an effective therapy for brain bleeds in fetuses since platelets may be not essential to stop fetal bleeding,” said Dr. Ni. “We should consider different therapies to prevent brain bleeds and ensure blood vessels in the brain are developed properly before birth.”

Dr. Ni’s research team also looked at the potential treatment of intravenous immunoglobulin transfusions. He said IVIG–made of plasma from donated blood–may be an effective therapy to control this devastating disease, although more research is needed to confirm this.

The study was published in the Journal of Clinical Investigation.

About this neurobiology research

The project was supported by Canadian Institutes of Health Research, the Canadian Foundation for Innovation and Canadian Blood Services.

Contact: Melissa Di Costanzo – St. Michael’s Hospital
Source: St. Michael’s Hospital press release
Image Source: The image is credited to harael and is in the public domain
Original Research: Full open access research for “Maternal anti-platelet β3 integrins impair angiogenesis and cause intracranial hemorrhage” by 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, and Heyu Ni in Journal of Clinical Investigation. Published online March 16 2015 doi:10.1172/JCI77820

Open Access Neuroscience Abstract

Maternal anti-platelet β3 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 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.

“Maternal anti-platelet β3 integrins impair angiogenesis and cause intracranial hemorrhage” by 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, and Heyu Ni in Journal of Clinical Investigation. doi:10.1172/JCI77820.

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