New gene study highlights clot risk factor in people living with PNH
MUC4 mutations associated with higher thrombosis rates
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Mutations in the MUC4 gene may be linked to a higher risk of dangerous blood clots in people with paroxysmal nocturnal hemoglobinuria (PNH), a study has found.
Researchers believe the mutations may be associated with increased activity in part of the immune system called the complement system. In mouse experiments, preventive treatment with the blood thinner heparin reduced clot formation, suggesting it could be a potential strategy that warrants further study.
The study, “MUC4 mutations promote a thrombotic phenotype in patients with paroxysmal nocturnal haemoglobinuria by increasing the deposition of terminal complement,” was published in Clinical and Translational Medicine by researchers in China.
Why blood clots are a serious concern in PNH
In PNH, red blood cells are destroyed by an overactive complement system, a group of proteins that normally help the immune system clear debris and fight infection. Symptoms of PNH include thrombosis, a condition in which blood clots form inside blood vessels.
Not all patients develop blood clots, so preventing thrombosis in everyone is debated. Preventive treatment with anticoagulants (blood thinners) can reduce clot risk but also raises the chance of bleeding. For this reason, doctors need better ways to identify which patients are at the highest risk and would benefit most from preventive treatment.
This study focused on a gene called MUC4, which encodes a glycoprotein — a type of protein with bound sugars — that helps cells grow, stick to one another, and communicate. In earlier studies, the researchers found that MUC4 mutations were nearly seven times more common in patients with PNH who had experienced thrombosis than in those without thrombosis.
To better understand the link between the MUC4 gene and thrombosis, the researchers compared data from 25 people with PNH, with and without thrombosis. The study also included 12 patients with acute thrombosis but no diagnosis of PNH and 12 healthy controls.
In addition to screening for MUC4 mutations, the researchers also measured C5b-9 levels in blood. C5b-9 is the final product of the complement cascade. It can form pores in a cell’s membrane — the outer layer of the cell — causing damage. High levels of C5b-9 have been linked to clot formation because they can make platelets, the cell fragments that help blood clot, more likely to stick together.
MUC4 mutations strongly linked to clot risk
Nearly half of the patients (48%) developed blood clots a median of three years after diagnosis of PNH. Five patients had repeat blood clots. The most common types were blood clots in the brain and deep vein thrombosis in the lower extremities, which occur in the deep veins in the legs.
Mutations in the MUC4 gene were significantly more common in patients with PNH than in those with thrombosis without PNH (36% vs. 16.7%). In PNH, they were also significantly more common in patients with thrombosis than in those without thrombosis (66.7% vs. 7.7%). Overall, carrying a MUC4 mutation was associated with 56.6 times higher odds of thrombosis.
Most patients with MUC4 mutations (89%) developed blood clots, compared with 25% of those without MUC4 mutations. “These results suggest that MUC4 mutations are closely related to [thrombotic events] and that MUC4 mutations increase the risk of [thrombotic events] in PNH,” the researchers wrote.
On average, C5b-9 levels in the blood were significantly higher in patients with PNH and thrombosis. Experiments showed that blood from these patients caused more C5b-9 to deposit on lab-grown cells than healthy blood, and that cells lacking MUC4 accumulated even more C5b-9 when exposed to the same blood from patients. These findings support the idea that increased complement activation may contribute to clot formation in PNH.
Lab and mouse studies explore how clots may form
To better understand this mechanism, the researchers used a mouse model of deep vein thrombosis with PNH. Mice with PNH developed more blood clots, and mice lacking MUC4, mimicking the effects of MUC4 mutation, developed even larger and more frequent blood clots. In these mouse experiments, preventive treatment with low-molecular-weight heparin, a common anticoagulant, significantly reduced both the number and the size of blood clots.
“In our current clinical practice, we are striving to expand mutation screening to more patients, aiming to identify PNH patients with high-risk thrombotic factors for the primary prevention of thrombosis,” the researchers wrote. “This approach seeks to reduce the incidence of TEs and improve long-term patient outcomes.”
