Cracking the code of antibodies in newly identified blood-clotting disorder

A team of researchers have cracked the code behind lethal blood antibodies that mediate a recently identified chronic blood clotting disorder that can persist, despite treatment with maximum doses of blood thinners.

Collaborators Dr Jing Jing Wang, co-first author, and Professor Tom Gordon alongside colleagues from Flinders University, Adelaide, South Australia, joined a study led Professor Ted Warkentin of McMaster University, Ontario, Canada.

They found this new type of blood clotting disorder had similarities to vaccine-induced immune thrombocytopenia and thrombosis (VITT) – which is a rare but aggressive clotting disorder that was associated with some now discontinued COVID-19 vaccines.

The research revealed that some patients can develop the severe blood clotting disorder because of antibodies that closely resemble those that cause VITT, even in the absence of known antibody triggers such as blood thinners, like heparin, or a prior vaccination.

The newly identified disorder has been termed VITT-like monoclonal gammopathy of thrombotic significance (MGTS).

The team’s findings are expected to influence how doctors test for unusual or recurrent blood clotting with the potential to improve patient outcomes.

“Low-level serum M (monoclonal) proteins are often identified in patients who have VITT-like MGTS,” said research team leader Dr Wang, from the College of Medicine and Public Health and Flinders Health and Medical Research Institute (FHMRI).

“By using our proteomic approach developed at Flinders Proteomics Facility, we have proven that the M proteins are the VITT-like, pathological antibodies.

“Despite these M proteins being in relatively low concentrations, they are highly pathological VITT-like proteins, which explains the severity of symptoms,” she said.

“This is a new disorder identified by researchers at McMasters University and is of considerable importance to all physicians,” says clinical team leader Professor Gordon, from the College of Medicine and Public Health and South Australia Pathology.

Vaccine-induced thrombotic thrombocytopenia (VITT) was linked to Vaxzevria – the  AstraZeneca COVID-19 vaccine which has now been widely withdrawn from market authorisation – in early 2021 which led some governments restricting its provision for populations that were perceived to be potentially vulnerable.

“We all remember those difficult times during the pandemic when some vaccines were linked to the rare, sometimes lethal clotting complication called vaccine-induced immune thrombocytopenia and thrombosis or ‘VITT’,” said Professor Gordon.

“This was initially thought to be self-limiting over days and weeks.

“The major jump in knowledge coming from this new study is that a highly similar chronic condition – over months and years – can occur with patients presenting with intermittent clotting episodes,” he says.

Flinders University researchers played the key role in analysing the specific antibodies that are involved in VITT-like MGTS.

“We examined the antibodies to see how they are constructed by our immune system and what makes this new disorder different from the classic VITT cases [that] we saw during the [COVID-19] pandemic. And to improve our overall understanding of this condition,” said Dr Wang.

“Our findings indicate that chronic anti-PF4 disorders, such as VITT-like MGTS, have distinct immunological features and require tailored diagnostic and therapeutic approaches.

“The chronic nature of these disorders often leads to severe clinical outcomes, necessitating comprehensive management strategies,” she said.

“By understanding how to diagnose VITT-like MGTS, we can develop more effective treatment strategies that go beyond traditional anticoagulation,” said Professor Ted Warkentin, co-first author and professor emeritus in the Department of Pathology and Molecular Medicine at McMaster University.

Researchers performed a detailed analysis of cases exhibiting unusual blood-clotting despite patients being on full-dose blood thinners, focusing on five patients who had unexplained VITT-like antibodies that were detectable for a year or more.

The analyses identified the presence of M (monoclonal) proteins – which typically indicated plasma cell disorders – and together with the persisting VITT-like reactivities over at least 12 months, which is highly unusual for most anti-PF4 antibodies. This pointed to an ongoing pathological process rather than a short-term anomaly.

A remarkable observation was that each of the patients had failed blood thinning treatment, but they showed some benefit with unusual treatments, such as high-dose intravenous immunoglobulin (IVIG), Bruton tyrosine kinase inhibitors (ibrutinib) and plasma cell–targeted myeloma therapy.

The existence of this novel blood clotting disorder has important implications for how health care providers will evaluate patients who develop unusual or difficult to treat blood clots in the future.

The study included a multinational collaboration, with data collected from patients treated at institutions in Canada, New Zealand, France, Spain and Germany.

For further reading please visit: https://ashpublications.org/blood/article/140/15/1738/485465/Vaccine-induced-immune-thrombotic-thrombocytopenia