von Willebrand disease

Diagnosis is established through clinical history and laboratory evaluation following the . Initial work-up comprises quantitative & functional assays: vWF antigen (VWF:Ag), platelet-dependent vWF activity assays (VWF:GPIbR, VWF:GPIbM, or VWF:RCo), and FVIII clotting activity (FVIII:C). Subtype discrimination is archived by multimer analysis, vWF-collagen-binding (VWF:CB), and vWF-factor VIII-binding (VWF:FVIIIB) assays. Of note, plasma vWF levels are significantly influenced by ABO blood type (individuals with blood group O have lower baseline vWF levels than non-O individuals), which must be considered when interpreting quantitative assays for type 1 VWD.

Main differential diagnoses include:

• Mild-to-moderate : reduced FVIII clotting activity (typically 2-40 IU/dL) with X-linked inheritance; phenotypically overlaps with type 2N VWD and is distinguished by molecular genetic testing (causative F8 variant identified in >98%) or by measurement of the factor VIII binding capacity of vWF (VWF:FVIIIB).
• Platelet-type VWD: A platelet disorder with a phenotype identical to type 2B VWD, including stress-induced thrombocytopenia. Caused by variants in GP1BA and distinguished from type 2B VWD by molecular genetic testing or RIPA mixing assays.
• Acquired VWD: non-hereditary vWF deficiency typically manifesting in adults >40 years without prior personal or family history. Secondary to underlying lymphoproliferative, autoimmune, myeloproliferative, or cardiovascular shear-stress disorders; germline VWF variants are absent.

Establishing a molecular genetic diagnosis confirms the clinical diagnosis, aids in precise subtype classification (especially distinguishing 2N from and 2B from platelet-type VWD), and supports cascade testing and reproductive counselling for families with high-penetrance variants. The likelihood of identifying causative variants in patients with a clinical diagnosis of VWD depends on the specific subtype:

• High yield in severe types: diagnostic yield of genetic testing approaches 90–95% for type 2 and type 3 VWD, where high-penetrance monogenic loss- or gain-of-function variants drive the distinct phenotype.
• Reduced yield in type 1 VWD: in contrast, standard sequencing of VWF fails to identify a single causative monogenic variant in 30% to 50% of individuals with type 1 VWD.

Type 1 VWD frequently behaves as a complex, multifactorial trait rather than a classical single-gene Mendelian disorder. Serum vWF concentrations are heavily influenced by common non-coding or promoter single nucleotide polymorphisms (SNPs) within VWF as well as by variants in genes associated with vWF secretion, clearance, or glycosylation (so-called “modifier genes”).

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