A novel type 2A von Willebrand factor mutation (V1499E) associated with variable clinical expression

Area of Science:

• Hematology
• Genetics
• Molecular Biology

Background:

• Type 2A von Willebrand disease (VWD) is a bleeding disorder characterized by deficient high-molecular-weight von Willebrand factor (VWF) multimers.
• Genetic mutations are the primary cause of VWD, leading to VWF dysfunction or deficiency.

Observation:

• A previously unreported mutation, V1499E, was identified in a family with type 2A VWD.
• Affected individuals exhibited variable VWF levels, multimer expression, and clinical symptoms, complicating diagnosis.
• The V1499E mutation was also found in patients at two other hospitals with similar presentations.

Findings:

• Recombinant V1499E-VWF demonstrated increased susceptibility to cleavage by ADAMTS13 compared to wild-type VWF.
• This increased cleavage suggests V1499E is the causative mutation for the observed type 2A VWD phenotype.
• The independent detection of V1499E across three institutions highlights its significance.

Implications:

• The V1499E mutation provides new insights into the molecular mechanisms of type 2A VWD.
• Establishing a central database for such mutations is crucial for accurate diagnosis and management.
• Understanding this mutation's variability can improve diagnostic strategies for von Willebrand disease.