Leiden researchers have found clues to why a rare pregnancy disorder is mild in some babies but life-threatening in others. Their discovery opens the door to a test that could identify severe cases during pregnancy. Fortunately, a treatment already exists.
Why does one baby barely get sick while another suffers a life-threatening brain haemorrhage even before birth, when the same mechanism is involved? That was the question researchers Coert Margadant and Wendy Stam set out to answer in their study of the pregnancy disorder FNAIT. Their findings completely overturn existing ideas.
What is FNAIT?
Foetal and Neonatal Alloimmune Thrombocytopenia (FNAIT) develops when a pregnant woman's immune system produces antibodies against her baby's platelets. This happens when mother and father differ in a small piece of genetic material. FNAIT occurs in about 1 in 1,000 pregnancies - meaning thousands of cases each year in Europe and North America.
Why prediction is so difficult
Doctors can prevent the disease during pregnancy, but only if they know about the risk in time. At present, the condition is often only diagnosed after birth. 'The real problem is that we can't predict which pregnancies are dangerous. Yet early treatment can save lives,' says Stam.
A stubborn theory overturned: no antibodies attack blood vessels alone
Until now, scientists believed severity depended on which cells the antibodies attacked. The idea was that the most dangerous antibodies mainly damaged blood vessel cells.
The Leiden researchers have shown this is not the case. They collected blood samples from more than 80 patients, including 20 children who had suffered brain haemorrhages. 'In our study we see that all antibodies bind both to platelets and to blood vessel cells. There are no antibodies that attack only the blood vessels,' Stam explains.
The real culprit: the shape of the protein
The difference lies in the shape of the protein targeted by the antibodies: integrin β3. This protein can be in a 'closed' or an 'open' state. Only in the open state is the integrin active. On platelets, the integrins are usually closed; on blood vessel cells, more often open.
The researchers discovered that antibodies mainly recognise the closed form - the state in which platelets normally remain inactive. By binding to them, the antibodies lock the integrins and prevent platelets from doing their job, which leads to bleeding. 'Some antibodies block this process very strongly, others much less. That likely explains why the disease is sometimes mild and sometimes life-threatening,' says Stam.
'Sommige antistoffen blokkeren dat proces heel sterk, andere veel minder. Dat verklaart waarschijnlijk waarom de ziekte soms mild en soms levensbedreigend is,' vertelt Stam.
We're grateful to all the parents and doctors who contributed
Collaboration and unique samples
The research was made possible through close collaboration with doctors and the Sanquin blood bank (Janita Oosterhoff, Gestur Vidarsson and Ellen van der Schoot). 'Sometimes we had just two millilitres of blood to work with - really very little. We're grateful to all the parents and doctors who contributed,' says Margadant.
Using flow cytometry, the researchers measured how many antibodies bound to each cell and whether the integrins were activated or blocked. With cryo-electron microscopy, they are now capturing high-resolution images of exactly how the antibodies grip onto the integrin.
Step towards a test
These findings mark a turning point in how FNAIT is understood. Where researchers previously searched for differences between types of antibodies, this study highlights the role of integrin blockade. 'This finally gives us a starting point for a diagnostic test,' Margadant explains. 'We hope that in future we'll be able to predict during pregnancy which babies are truly at risk, so we can treat them in time and prevent brain haemorrhages.'
