Type 2M/2A von Willebrand disease: a shared phenotype between type 2M and 2A

Area of Science:

• Hematology
• Molecular Biology
• Structural Biology

Background:

• Von Willebrand disease (VWD) classification remains debated for several variants.
• Understanding the precise VWD classification of variants like p.R1315L, p.R1315C, p.R1374H, and p.R1374C is crucial for accurate diagnosis and management.

Purpose of the Study:

• To comprehensively investigate four debated VWD variants (p.R1315L, p.R1315C, p.R1374H, p.R1374C) using VWD tests, protein modeling, and structural biology.
• To elucidate the phenotypic characteristics and underlying disease mechanisms of these variants in comparison to established VWD types 2A and 2M.

Main Methods:

• Phenotypic assays and VWD tests were performed on patients carrying the variants.
• Deep protein modeling predictions and structural biology analyses were applied to understand variant effects.
• Comparative analysis with patients diagnosed with VWD types 2A and 2M.

Main Results:

• Variants p.R1315L, p.R1374H, and p.R1374C exhibited a common phenotype overlapping with VWD types 2M and 2A.
• Variant p.R1315C presented a distinct type 2M phenotype.
• Reduced VWF synthesis/secretion was observed in 2M and p.R1315L, p.R1374H, p.R1374C variants, while reduced VWF survival was noted in 2A, 2M, and all investigated variants.
• Structural analysis revealed these variants are located at the A1-A2 domain interface, influencing VWF structure and function.

Conclusions:

• A new classification of type 2M/2A is proposed for variants p.R1315L, p.R1374H, and p.R1374C based on their shared phenotype.
• The study highlights the distinct structural impacts of these variants on von Willebrand factor (VWF) and provides a basis for refined VWD classification.