How can someone who has a low factor VIII level of around 40% be considered to possibly have type 2N VWD?

Answer: Since type 2N VWD follows a recessive inheritance pattern, a clinical diagnosis requires a homozygous or compound heterozygous state. Therefore someone who is a carrier may seem to have mild hemophilia when it is type 2N.

Type 2N arises from D'-D3 domain variants that impair VWF binding to FVIII. In the German type 2 VWD cohort, genotype sorted the phenotype into tiers. FVIII:C/VWF:Ag ratio is what separates them:

• Homozygous / compound heterozygous for two 2N variants (e.g. p.Arg854Gln, p.Arg816Trp): FVIII:C 2–25%, VWF:Ag 50–166%, ratio 0.01–0.4. The classic severe picture.
• 2N variant compound heterozygous with a quantitative VWF variant (nonsense, small deletion, splice site, or the type 1 clearance variant p.Tyr1584Cys): FVIII:C 10–50%, VWF:Ag 29–74%, ratio 0.2–1.3.
• Heterozygous carriers (8 with p.Arg854Gln, 2 with p.Cys1225Gly): a carrier state, not a 2N diagnosis. Notably they had a normal average FVIII:C/VWF:Ag ratio. Diagnosis of suspected 2N should be confirmed by DNA testing, per the ISTH-SSC VWF guidelines.

Source: Yadegari H et al. Landscape and spectrum of VWF variants in type 2 von Willebrand disease: insights from a German patient cohort. Thromb Haemost. 2025;126(2):156–178. doi:10.1055/a-2616-5161 — primary-literature