Many types of von Willebrand disease may be underdiagnosed: Study
Bleeding disorder likely more common globally than previously thought
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The many types of von Willebrand disease may be much more common globally than previously thought, a large study of more than 800,000 people found.
Given these results, the researchers say it’s likely that individuals with this bleeding disorder are underdiagnosed worldwide.
“These findings suggest that a substantial number of VWD [von Willebrand disease] patients remain undiagnosed, potentially leading to undertreatment,” the researchers wrote. “Our study reveals a significantly higher global prevalence of VWD than previously reported.”
The results of this new analysis were detailed in “Updated global prevalence and ethnic diversity of von Willebrand disease based on population genetics analysis,” a study published in the journal Scientific Reports.
In von Willebrand disease, the body cannot properly form blood clots, leading to abnormally heavy and prolonged bleeding. The condition is usually caused by mutations in the VWF gene that a person has inherited from their parents and is born with.
Although the disease is relatively common, doctors still do not know exactly how many people have it or how its different types are distributed worldwide.
Researchers turned to largest publicly available genetic database
To better estimate how common von Willebrand disease is, the researchers used genetic epidemiology. This is the study of how genetic changes are distributed in large populations. The team analyzed data from gnomAD, the largest publicly available genetic database, which contains DNA sequencing data from more than 800,000 people.
The dataset involved both exome sequencing, which looks only at protein-coding parts of genes, and whole-genome sequencing, which examines nearly all DNA. The population represented many ethnic groups, including African/African American, East Asian, South Asian, and non-Finnish European. This broad coverage made it possible to compare von Willebrand disease across populations.
The researchers focused on the VWF gene and identified more than 10,000 different genetic variants. A variant is a change in DNA sequence. From these, they selected only variants already known to cause von Willebrand disease, based on medical databases and published studies, and excluded variants considered harmless.
Some types of von Willebrand disease — types 1, 2A, 2B, and 2M — are autosomal dominant, meaning a person needs only one altered copy of the gene to have the disease. Types 2N and 3 are autosomal recessive, meaning two altered copies are required.
Using 321 disease-causing variants, the estimated global prevalence per 1,000 people was 10.6 for von Willebrand disease type 1. For type 2, the estimates were 1.3 for type 2A, 1.7 for type 2B, and 1.5 for type 2M. These numbers are higher than many earlier clinical estimates, the team noted.
For the recessive forms, the estimated prevalence was much lower. Type 2N affected about 33.9 people per million worldwide, while type 3 affected about 1.3 people per million. When large genetic changes that remove gene function were included, the estimate for type 3 rose slightly to 1.8 per million.
von Willebrand disease types found to differ among ethnic groups
The study also showed that the prevalence of von Willebrand disease, or how common it is, differs significantly among ethnic groups. This means genetic background plays an important role in how often the disease occurs and which types are more common.
[Overall,] these data suggest that [von Willebrand disease] is likely grossly underdiagnosed worldwide.
For instance, von Willebrand disease type 1 was most common in the European population, whereas type 2N was extremely rare in East Asian populations but more common in non-Finnish and Finnish European populations.
Overall, according to the researchers, “these data suggest that VWD is likely grossly underdiagnosed worldwide.”
The team noted that “the prevalence of genetic diseases has traditionally been determined through direct observation of the disease or using disease registries.” New resources have helped in better determining disease prevalence. However, other issues often contribute to underdiagnosis, the team noted.
Here, underestimates are likely “attributed to several factors, including the complexity of diagnosis, unavailability of all the diagnostic tools [in some regions], challenges in differentiating between normal and abnormal bleeding symptoms, [and] overlapping symptoms with other conditions,” the scientists wrote. They also noted “limited awareness of [this] disease among nonspecialist healthcare providers and patients.”
The team concluded, based on these genetic estimates, that von Willebrand disease is likely more frequently occurring than previously believed.
