People with Fabry may be at higher risk of blood clots, study shows
Patients found more likely to generate protein that's key to clot formation
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People with Fabry disease appear to have an increased capacity to generate thrombin — a key protein involved in blood clot formation — and higher levels of several other clotting-related factors, potentially putting them at a greater risk of developing a blood clot in a blood vessel or the heart.
Those are the key findings from a small study in Poland that showed that, compared with healthy individuals, people with Fabry had a 17.6% higher endogenous thrombin potential (ETP), which is a measure of the total amount of thrombin the blood can generate. Fabry patients also had a 9.8% higher thrombin peak than the study’s healthy controls, the data showed.
According to the researchers, people with Fabry “exhibit an unfavorable altered thrombin generation profile, suggesting an increased risk of thrombosis,” which occurs when one or more blood clots form in the heart or blood vessels and block the flow of blood.
Thrombin abnormalities were especially evident in men with Fabry, the scientists found. Further, individuals on enzyme replacement therapy (ERT) — a standard treatment — had thrombin generation similar to that of patients not on ERT. The team noted that “ERT had no impact on our results.”
“To the best of our knowledge, this study is the first to show that [Fabry disease] patients exhibit an enhanced [blood-related] thrombin generation capacity,” the researchers wrote.
The study, “Enhanced thrombin generation potential in male and female patients with Fabry disease: a single-center observational study,” was published in the journal Scientific Reports.
Fabry is a rare inherited disease caused by mutations in the GLA gene, which results in deficient activity of alpha-galactosidase A (alpha Gal-A), an enzyme needed to break down certain fatty molecules. Without sufficient levels of the enzyme, molecules such as globotriaosylceramide (Gb3) and lyso-Gb3 gradually accumulate inside cells throughout the body.
That buildup can damage the blood vessels, kidneys, heart, and nervous system, leading to an array of symptoms. People with Fabry have an increased risk of cardiovascular and thromboembolic events, in which a blood clot blocks a blood vessel. Among such events are stroke, heart attack, deep vein thrombosis — when a blood clot forms in a deep vein inside the body — and pulmonary embolism, which occurs when a clot blocks a lung artery.
Testing if blood in Fabry patients has greater tendency to clot
Exactly why the disease increases the likelihood of such events is not fully understood. Researchers have proposed that glycosphingolipid accumulation — the buildup of a type of fat molecule that has a sugar attached to it — may damage blood vessels and alter components of the clotting system. Inflammation and oxidative stress, an imbalance between molecules, also may promote clot formation.
Now, a research team from Krakow sought to determine whether the blood of people with Fabry shows an increased tendency toward clotting by measuring thrombin generation and examining the clinical and laboratory factors associated with it.
The single-center study involved 34 adults with genetically confirmed Fabry, split about equally by sex, and 34 healthy people who served as controls. The patients had a median age of 40. Of them, 25 had classic Fabry disease, four had a late-onset form, and five were women with few symptoms. None had a history of venous thromboembolism, or a clot in a deep vein, and there was no history of heart attack or stroke; people using anticoagulant or antiplatelet medications were excluded. Seven patients (21%) were receiving ERT.
The researchers used a laboratory test called a calibrated automated thrombogram to assess how much thrombin participants’ plasma could produce and how quickly it was generated. Plasma is the liquid part of blood.
ETP and peak thrombin generation were significantly higher in the Fabry group than in controls, the data showed. Those with Fabry were also about 6.7 times more likely to have an ETP above the cutoff established by the researchers.
However, the time before thrombin production began and the time required to reach peak thrombin levels did not differ significantly between the groups. According to the researchers, this suggests Fabry may affect the amount, rather than the speed, of thrombin generation.
Those with Fabry also had significantly higher platelet counts, factor VIII activity, and fibrinogen, all key elements involved in blood clotting. Platelet counts were 20.1% higher, factor VIII activity was 50.6% higher, and levels of fibrinogen were 20% higher. Higher platelet counts, inflammation, and fibrinogen independently contributed to increased ETP.
Finding support a ‘prothrombotic phenotype’ in Fabry
Thrombin generation did not differ significantly between men and women with Fabry when the two groups were directly compared. However, comparisons against sex-matched controls showed increased thrombin generation only among the men. Women with Fabry disease instead had higher platelet counts and fibrinogen than female controls, while factor VIII activity was elevated in both sexes.
The researchers also found no significant differences in thrombin generation between the seven patients receiving ERT and the 27 who were not. The team cautioned, however, that the treated group was too small to establish whether ERT influences clotting abnormalities.
Because the study measured laboratory markers rather than following patients for cardiovascular events, it cannot show whether increased thrombin generation actually predicts future blood clots, the researchers stressed.
Still, the findings support the presence of what the team called a “prothrombotic phenotype” in Fabry and provide a possible biological contributor to patients’ known vascular risks, according to the scientists.
Further prospective studies are needed to determine whether these clotting abnormalities can identify Fabry patients at greater risk of thromboembolic or cardiovascular events, the researchers concluded. The team added that “it seems crucial to carefully assess and manage traditional cardiovascular risk factors in patients with Fabry disease.”
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