Some patients with lupus who possess specific antibodies are at a higher risk of thrombotic events such as a blood clot, stroke or heart attack, a new study led by Johns Hopkins Medicine researchers shows. The finding might help clinicians determine which patients may need early treatment and clinical monitoring for thrombotic events.

Normally, antibodies help protect the body by fighting infections and tumours, but in autoimmune conditions such as lupus, antibodies may attack healthy tissues and molecules. In this study, researchers looked at anti-transcription factor A, mitochondrial (or anti-TFAM) antibodies, which attack an essential protein (called TFAM) that is crucial for maintaining the health and genetics of mitochondria, the powerhouses of cells.

Damage to this protein and to mitochondria has previously been implicated in the development of lupus. Now, researchers expand on this idea in the full report, published in the Annals of the Rheumatic Diseases. Their work not only definitively identifies that the mitochondrial protein TFAM may act as a trigger for the immune system in lupus, but also reveals that the antibodies that attack TFAM are significantly associated with thrombotic events in patients with lupus.

"The results of this work are very surprising and exciting," says first author Eduardo Gómez-Bañuelos, M.D., Ph.D., assistant professor of medicine at the Johns Hopkins University School of Medicine. "We originally were looking at these antibodies' involvement in lupus nephritis. Instead, we saw a different clinical manifestation with our analysis—a strong association between anti-TFAM antibodies and thrombotic events in lupus patients that can be very serious."

The team began by looking at blood samples from a group of 98 healthy controls and 158 people with lupus from the Lupus Hopkins Cohort, a study led by Michelle Petri, M.D., M.P.H. Around one-third of participants tested positive for anti-TFAM antibodies.

Researchers then conducted statistical analysis on patients who tested positive for anti-TFAM antibodies and also had a range of clinical, laboratory and molecular features found in lupus. The team found that those with anti-TFAM antibodies were between 2.8 and 3.3 times more likely to experience a thrombotic event, even when they accounted for other conditions and biomarkers that could contribute to blood clots, such as smoking and other autoantibodies previously linked to thrombosis, known as anti-phospholipid antibodies.

"When we discovered the anti-TFAM antibodies, we had no idea how crucial they were. Access to samples from the Lupus Hopkins Cohort, as well as support from an exploratory/developmental research grant, were vital in defining the importance of anti-TFAM antibodies in lupus," says corresponding author Felipe Andrade, M.D., Ph.D., associate professor of medicine at the Johns Hopkins University School of Medicine.

"Our study adds a new idea to the pathogenesis of thrombosis in lupus: that anti-TFAM antibodies are associated with thrombotic events independently of other factors and other autoantibodies," Andrade adds.

Both Gómez-Bañuelos and Andrade add that the work illustrates how anti-TFAM antibodies could act as a biomarker for patients with lupus to help determine if an individual is at an elevated risk for blood clots, stroke, heart attack or another thrombosis disorder seen in lupus called antiphospholipid syndrome.

The team also plans to investigate the role of anti-TFAM antibodies in such thrombotic events. Specifically, they hope to determine if these antibodies contribute to the development of blood clots in lupus or if their role is largely that of a biomarker.

"This is a new and exciting topic for our lab and others interested in this area of lupus, thanks largely to federal grants that were critical for this study," says Andrade. "We plan to see what this role of anti-TFAM is in lupus and in mitochondria—maybe even in other conditions associated with thrombosis."