Blood clotting factor XII may be marker of active AAV: Study

Researchers in China tested the blood of 127 patients with AAV diagnosis

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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A dropper is seen squirting blood alongside four half-filled vials of blood.

Factor XII (FXII), a protein involved in blood clotting, is found at significantly higher levels in the blood of people with active ANCA-associated vasculitis (AAV) relative to those in clinical remission, or whose symptoms have eased or disappeared.

That’s according to a study in China that also found that blood FXII levels were increased with worsened kidney tissue features, indicating a close association also with kidney-specific AAV activity.

These findings suggest that “elevated [blood] FXII levels reflect AAV clinical and [tissue] activity, and can serve as markers of active AAV,” the researchers wrote in “Elevated plasma FXII is associated with disease activity in ANCA-associated vasculitis: A Retrospective Cross-Sectional Study in Western China,” which was published in International Immunopharmacology.

AAV occurs when self-reactive antibodies, called ANCAs, abnormally target proteins in neutrophils, a type of white blood cell. This ultimately causes neutrophil overactivation, making them launch an attack against the walls of small blood vessels, which become inflamed.

Symptoms of AAV can occur anywhere in the body, but the kidneys are mostly affected.

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Mainly produced by the liver, FXII is a protein mainly known for its role in promoting blood clotting. However, FXII produced by neutrophils has been shown to have a different function, helping the cells move to sites of inflammation and form neutrophil extracellular traps (NETs) — a type of antimicrobial web that traps and kills microbes.

Among the many antimicrobial molecules present in NETs are proteinase 3 and myeloperoxidase (MPO) proteins, the most common targets of ANCAs.

While overactive neutrophils and their NETs are involved in AAV, it is unclear if FXII plays a role in AAV development, and whether its blood levels may serve as markers to diagnose and track active disease.

To know more, a team of researchers in China tested the blood of 127 patients with a diagnosis of AAV; 116 patients had microscopic polyangiitis (MPA) and 11 had granulomatosis with polyangiitis (GPA), the two most common types of AAV.

A total of 79 patients had new or worsening symptoms of AAV and a Birmingham Vasculitis Activity Score (BVAS) equal to or greater than 15 points — meeting the researchers’ criteria for active disease. The BVAS is a measure of disease activity, and higher scores mean worse disease.

The remaining 48 patients were considered to be in clinical remission, defined as a BVAS lower than 15 points, ongoing maintenance therapy with immunosuppressants, or a 50% reduction in the BVAS along with no new disease manifestations.

Higher FXII levels in patients with active AAV

Mean FXII levels in the blood were more than twice as high in patients with active disease than in those in clinical remission (35.5 vs. 14.8 micrograms per milliliter, or mcg/mL). Patients with active AAV also had significantly higher FXII levels relative to a group of 33 healthy people.

“FXII levels were significantly increased in patients with clinically active AAV compared to those in clinical remission and healthy individuals based on the BVAS,” the researchers wrote.

The higher the FXII levels, the higher those of creatinine, a marker of kidney damage, and the lower the estimated glomerular filtration rate, a measure of how well the kidneys are working.

Higher FXII levels also were significantly associated with elevated levels of ANCAs against MPO and a number of markers of inflammation, including white blood cells and C-reactive protein (CRP).

Statistical analyses accounting for potential influencing factors indicated FXII levels were independently linked to BVAS and elevated levels of FXII “were independently associated with increased clinically activity in AAV disease,” the researchers wrote.

When analyzing available kidney biopsies from 82 patients, the researchers found higher FXII levels were significantly associated with more tissue abnormalities indicative of worse damage.

In addition, patients with active disease had a higher number of FXII-producing neutrophils, and elevated FXII levels were linked to a greater buildup of MPO in the kidney tissue.

Further statistical analyses determined the optimal FXII cut-off level for predicting clinically active AAV was 24.5 mcg/mL, with 81% sensitivity (percentage of active AAV patients being correctly identified) and 82% specificity (percentage of remission cases being correctly ruled out).

Patients with FXII levels equal to or greater than 24.5 mcg/mL at diagnosis were significantly more likely to have active disease than those with FXII levels below the cut-off value (81% vs. 19%).

The ability of this FXII cut-off value to identify active AAV patients was superior to that of conventional blood markers, such as anti-MPO ANCAs and CRP levels.

“Taken together, these data suggest that FXII may participate in the [development] of AAV by promoting the release of MPO by neutrophils in both peripheral blood and [kidney] tissue,” and that blocking FXII “is a potential therapeutic strategy for AAV,” the team wrote.

Also, “the predictive value of [blood] FXII for assessing active AAV and its remission status was stronger than that of traditional biomarkers,” the researchers wrote. This less invasive marker, requiring only a blood draw, may work equally as well as kidney tissue analysis, “the gold standard for diagnosing the first AAV episode,” they added.