A breakthrough discovery of a new blood protein will finally help doctors identify patients whose immune systems react violently against nearly all blood transfusions.
For over half a century, a set of rare but devastating complications from simple blood transfusions have been linked to the elusive absence of a key immune-system triggering ‘antigen’ molecule, known as the AnWj blood group antigen.
But now a team of researchers in the UK have identified which compound found in 99.9 percent of human blood carries this AnWj antigen. They call it the ‘Mal’ protein.Â
This 50-year-old cold case was cracked by blood detectives with the UK’s National Health Service Blood and Transplant (NHSBT) group — who are routinely tasked with these kinds of medical mysteries by healthcare providers across the globe.
‘Often if the labs cannot resolve it we have to do a lot more work,’ Nicole Thornton of the NHSBT’s red blood cell lab said. ‘That is where the interesting cases come from.’
A team of researchers in the UK have identified which compound found in 99.9 percent of human blood carries the AnWj antigen, which they call the Mal protein. The breakthrough will help doctors finally identify patients whose bodies react violently against blood transfusions
The four major blood types, and their positive or negative variations, are all defined by the presence or absence of two key antigens, A and B, alongside another protein called the Rh factor, whose presence equates to the so-called positive blood types.
‘Since some antigens can trigger a patient’s immune system to attack the transfused blood, safe blood transfusions depend on careful blood typing and cross-matching,’ as the American Red Cross notes in their explainer on the issue.
While the new discovery will likely be much too obscure to merit common use alongside the eight most common blood types (A+, A-, B+, B-, O+, O-, AB+ and AB-), its identification could help save hundreds of lives each year, researchers estimated.
Thornton, the head of NHSBT’s International Blood Group Reference Laboratory ‘Red Cell Reference,’ her team and scientists with the University of Bristol worked with a variety of blood samples and tools to finally identify where the AnWj antigens reside.
Their work even included a 2015 sample given by the anonymous woman who was the first person to have ever been discovered to be ‘AnWj negative’ in the 1970s.
‘Mal is a very small protein with some interesting properties which made it difficult to identify,’ said Dr Tim Satchwell, who assisted the investigation while he was a Research Fellow at the University of Bristol.
‘We needed to pursue multiple lines of investigation to accumulate the proof we needed to establish this blood group system,’ Dr Satchwell told reporters in a press statement.Â
The decisive factor proved to be a method called ‘whole exome sequencing,’ a more cost effective and tailored form of whole genome sequencing that focuses solely on the DNA from a given patient that encodes or creates proteins.Â
This process helped the team lock-in on the rare genetic cases whereby DNA sequence deletions in the MAL gene prevented encoding of the Mal protein.
‘We would not have achieved this without exome sequencing,’Â Louise Tilley, a senior research scientist with NHSBT’s Red Cell Reference said in a statement.
‘The gene we identified wasn’t an obvious candidate and little is known about Mal protein in red cells,’ she noted.Â
The MAL gene that was deleted in these rare cases gets its names from the ‘Myelin and lymphocyte’ (Mal) protein it encodes.Â
Mal proteins — ‘multi-pass membrane proteolipids’ coated in fatty lipid molecules — appear to play an essential role in the movement of cells through the blood stream as well as the stability of cell membranes.
Above, two men donating blood this July at the West End Donor Centre in London, England
‘AnWj-positive individuals were shown to express full-length Mal on their red cell membranes, which was not present on the membranes of AnWj-negative individuals,’ the team noted in their new study for the journal Blood.
‘The genetic background of AnWj has been a mystery for more than 50 years, and one which I personally have been trying to resolve for almost 20 years of my career,’ Tilley told reporters.
‘It represents a huge achievement,’Â she added, ‘and the culmination of a long team effort to finally establish this new blood group system and be able to offer the best care to rare, but important, patients.’
As Tilley emphasized to the BBC, it is ‘quite difficult to a put a number’ to just how many people will benefit from the newly identified Mal protein.Â
But, she noted that — every year — the NHSBT is typically the last hope for as many as 400 patients from across the world.
In their new study, Tilley and her colleagues reported that ‘the most common reason for being AnWj-negative is due to suffering from a hematological disorder or some types of cancer which suppress antigen expression.’
Hematologic diseases, which afflict millions of Americans, include rare genetic disorders, sickle cell disease, conditions related to HIV, and complications from treatments like chemotherapy or blood transfusions.
‘Only a very small number of people are AnWj-negative due to a genetic cause,’ the team noted. Among them: ‘five genetically AnWj negative individuals in the study including a family of Arab-Israelis.’
It’s these genetically AnWj-negative patients who will benefit most from Mal’s discovery — as new lab tests will be devised to help pair them with the correct blood for any needed transfusions.
NHSBT’s International Blood Group Reference Laboratory ‘Red Cell Reference’ head Nicole Thornton holds a vile of the blood used to crack the 50-year-old AnWj mystery
‘Resolving the genetic basis for AnWj has been one of our most challenging projects,’Â Thornton said.
‘Now genotyping tests can be designed to identify genetically AnWj-negative patients and donors. Such tests can be added to the existing genotyping platforms.’
One staffer at Thornton’s ‘Red Cell Reference,’ Philip Brown, explained that he himself had been diagnosed with a form of leukemia about 20 years ago that required life-saving blood transfusions and a bone marrow transplant.
 ‘Anything we can do to make our blood much safer and a better match for patients is a definite step in the right direction,’ Brown said.
