Cracking the code of lethal antibodies in a new blood-clotting disorder

A team of researchers have made a new discovery in the field of hematology, providing an explanation for spontaneous and unusual blood-clotting that continues to occur despite treatment with full-dose blood thinners.

Collaborators Dr Jing Jing Wang (co-first author), Professor Tom Gordon, and colleagues from Flinders University played a key role in cracking the code of lethal blood antibodies mediating the new chronic blood clotting disorder.

The new study led by Professor Ted Warkentin from McMaster University in Canada was published in the leading international medical journal, The New England Journal of Medicine.

The findings are expected to influence how doctors test for, and treat patients with, unusual or recurrent blood clotting, with the potential to improve patient outcomes.

Researchers found this new blood clotting disorder to have certain similarities to vaccine-induced immune thrombocytopenia and thrombosis (VITT)—a rare but aggressive clotting disorder that was caused by certain discontinued COVID-19 vaccines.

The research reveals that certain patients can develop severe blood clotting due to antibodies that closely resemble those that cause VITT, even in the absence of known triggers for such antibodies, such as blood thinners (heparin) or prior vaccination.

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

“Low-level serum M (monoclonal) protein are often identified in patients who have VITT-like MGTS,” says 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 pathological VITT-like antibodies.

“Despite these M proteins being in relatively low concentrations, they are highly pathological VITT-like proteins, which explain the patients’ severe symptoms,” she says.

“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 SA Pathology.

Vaccine-induced thrombotic thrombocytopenia (VITT) was linked to the AstraZeneca COVID-19 vaccine in early 2021, leading the Australian government to restrict its rollout to those aged over 65. It is also associated with the Johnson & Johnson vaccine Janssen, although the vaccine is not currently included in Australia’s vaccination program.

“We all remember those difficult times during the pandemic when the vaccine was linked to the rare, sometimes lethal clotting complication called vaccine-induced immune thrombocytopenia and thrombosis or "VITT",” says 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 a 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 we saw during the pandemic and to improve our overall understanding of this condition,” says 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 says.

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

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 indicate 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), thus pointing 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 five patients treated at institutions in Canada, New Zealand, France, Spain, and Germany.

‘VITT-like Monoclonal Gammopathy of Thrombotic Significance’ by Jing Jing Wang, Theodore E. Warkentin, Linda Schönborn, Matthew B. Wheeler, M.D., William H. Geerts, Nathalie Costedoat-Chalumeau, Nicolas Gendron, Gabriela Ene, Miquel Lozano, Florian Langer, Edelgard Lindhoff-Last, Kathrin Budde,Tim Chataway, Alexander Troelnikov, Jo-Ann I. Sheppard, Donald M. Arnold, Tom P. Gordon, Thomas Thiele and Andreas Greinacher, has been published in The New England Journal of Medicine journal. DOI: 10.1101/2022.03.28.22272975.

See also, ‘Vaccine-induced immune thrombotic thrombocytopenia (VITT) is mediated by a stereotyped clonotypic antibody’ by Jing Jing Wang, Bridie Armour, Tim Chataway, Alexander Troelnikov, Alex Colella, Olivia Yacoub, Simon Hockley, Chee Wee Tan and Tom Paul Gordon. DOI: 10.1101/2022.03.28.22272975.

‘Antibody fingerprints linking adenoviral anti-PF4 disorders’ by Jing Jing Wang, Linda Schönborn, Ted Warkentin, Tim Chataway, Leonie Grosse, Paolo Simioni, Stephan Moll, Andreas Greinacher, Tom Gordon. The New England Journal of Medicine journal. 2024 May 16;390(19):1827-1829.  DOI: 10.1056/NEJMc2402592.