Proteomic approach identifies new blood-clotting disorder

Australian and international researchers have identified a new blood-clotting disorder that has been found 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.

Led by Professor Ted Warkentin — professor emeritus in the Department of Pathology & Molecular Medicine at McMaster University, Canada — the study demonstrates, in the words of clinical team leader Professor Tom Gordon from the College of Medicine and Public Health and SA Pathology: “This is a new disorder identified by researchers at McMasters University and is of considerable importance to all physicians.”

The newly identified disorder has been termed VITT-like monoclonal gammopathy of thrombotic significance (VITT-like MGTS) — the Warkentin-led study revealing 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 “major jump” of a VITT-like chronic condition

Linked to the AstraZeneca COVID-19 vaccine in early 2021 and leading the Australian Government to restrict its rollout to those aged over 65, VITT 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’,” Gordon said. “This was initially thought to be self-limiting over days and weeks.”

Gordon added: “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.”

“Proven” via a proteomic approach

The study included a detailed analysis of cases exhibiting unusual blood-clotting despite patients being on full-dose blood thinners. Including multinational collaboration, data was collected from five patients who had unexplained VITT-like antibodies that were detectable for a year or more and who were treated at institutions in Canada, France, Germany, Spain and New Zealand.

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

“Low-level serum M (monoclonal) protein are often identified in patients who have VITT-like MGTS,” said research team leader and co-first author Dr Jing Jing 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,” Wang said. That each of the patients had failed blood thinning treatment yet showed some benefit with unusual treatments — such as high-dose intravenous immunoglobulin (IVIG), Bruton tyrosine kinase inhibitors (ibrutinib), and plasma cell-targeted myeloma therapy — was a key observation.

Dr Jing Jing Wang and Professor Tom Gordon. Image: Flinders Foundation.

Developing more effective treatment strategies

For their part, Flinders 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,” Wang said.

“Our findings indicate that chronic anti-PF4 disorders, such as VITT-like MGTS, have distinct immunological features and require tailored diagnostic and therapeutic approaches,” Wang added. “The chronic nature of these disorders often leads to severe clinical outcomes, necessitating comprehensive management strategies.”

With the potential to improve patient outcomes and the expectation that their findings will influence how doctors test for and treat patients with unusual or recurrent blood clotting, it is believed that the existence of this novel blood clotting disorder will have important implications for how healthcare providers will evaluate patients who develop unusual or difficult-to-treat blood clots in the future.

In the words of co-first author Warkentin: “By understanding how to diagnose VITT-like MGTS, we can develop more effective treatment strategies that go beyond traditional anticoagulation.”

Top image credit: iStock.com/Alllex. Stock image used is for illustrative purposes only.