A national research team is working to improve care for adolescent females with heavy menstrual bleeding tied to low levels of von Willebrand factor (VWF), a protein essential for proper hemostasis.
While low VWF in women is well-recognized for its link to heavy menstrual bleeding, the research team was focused on adolescents, specifically. Their analysis revealed that 90 percent of adolescent females with low VWF experience severe bleeding during menstruation, with surgical bleeding, anemia and iron deficiency noted as additional complications of their bleeding disorder.
The researchers recently completed the first whole-exome analysis of adolescent females with low VWF-associated heavy menstrual bleeding as a way to help improve the basis for projecting risk stratification and patient outcomes. The study found an excess of rare pathogenic and nonsynonymous variants in the genes involved in anemia and bleeding disorders.
“Because of the normalcy of menstruation, I think that we forget how it can connect with pathology. But menstrual periods are often the first bleeding challenge that a pediatric patient will experience.”
According to Allison P. Wheeler, M.D., a hematologist at Vanderbilt University Medical Center involved in the work, better awareness and earlier diagnosis could minimize complications and improve patient well-being.
“Because of the normalcy of menstruation, I think that we forget how it can connect with pathology. But menstrual periods are often the first bleeding challenge that a pediatric patient will experience,” Wheeler said. “These aren’t usually patients who are going to have spontaneous intracranial bleeding or intra-abdominal bleeding, but we do want to identify them and provide hemostatic support.”
New Understanding, Updated Guidelines
Diagnosis of low VWF and the associated bleeding disorder, von Willebrand disease, has posed a consistent challenge for clinicians.
“While some patients with low VWF can have a severe bleeding disorder, the vast majority will have a more mild or moderate phenotype that may go unnoticed for years,” Wheeler said.
“The updated guidelines for the diagnosis of von Willebrand disease reflect the new understanding that patients with levels of VWF greater than 30 IU/dL can still experience a bleeding phenotype.”
Von Willebrand disease is the most common inherited bleeding disorder. In the past, patients received a diagnosis only if they had a VWF level of less than 30 IU/dL, Wheeler explained, however patients with levels of 30-50 IU/dL were often followed by hematologists with a diagnosis of low VWF. Then, in 2021, the diagnostic criteria expanded to include patients with abnormal bleeding and a VWF level of less than 50 IU/dL.
“The updated guidelines for the diagnosis of von Willebrand disease reflect the new understanding that patients with levels of VWF greater than 30 IU/dL can still experience a bleeding phenotype,” Wheeler explained.
The challenge now lies in identifying those VWF patients with the highest risk of bleeding disorder symptoms.
Genetic Links
Wheeler and colleagues undertook and completed a whole-exome sequencing of 86 postmenarchal females under age 21, each of whom had a VWF level of between 30-50 IU/dL and HMB. The results were compared to a large dataset of 660 control exomes.
In total, pathogenic variants were identified in eight genes associated with varying types of anemias, while gene burden analysis revealed that the two genes harboring the largest number of rare variants, CFB and DNASE2, were also directly linked to anemia.
Further analysis found four rare nonsynonymous mutations in genes known to cause severe bleeding disorders.
“It was exciting to see these variants identified,” Wheeler said. “Some of these hits I may have predicted, but others are more esoteric. It really speaks to the complexity of the hemostatic system.”
Clues for Further Care
The study authors speculate that while the patients lack the full disorder associated with the identified gene variants, it is possible that having incomplete penetrance or haploinsufficiency causes a milder version.
Wheeler also stresses that heavy menstrual bleeding should be a cue to promptly screen for a bleeding disorder, as addressing the symptoms will not only minimize risk but lessen any social or emotional stress commonly caused by abnormal menstruation.
“Young adolescents with heavy menstrual bleeding are easily identifiable as patients who are at increased risk of other bleeding symptoms,” Wheeler said. “Our goal is to understand these patients better, pay more attention to them, and be more helpful to them as physicians.”
