Advances in von Willebrand disease diagnosis
image: Structure of the LBD-A1 complex. LBD of GPIbα is shown in green, and the A1 domain of VWF in blue. The contact sites between LBD and A1 are marked with yellow dashed boxes.
Credit: E.G. Huizinga, S. Tsuji, R.A. Romijn.
Overview: von Willebrand disease (VWD) is the most common inherited bleeding disorder, caused by defects in von Willebrand factor (VWF). Diagnosis remains challenging due to disease heterogeneity and limitations in current assays. Recent advances in understanding VWF structure and function have led to improved diagnostic tools and updated guidelines.
Classification Updates:
- Type 1 (quantitative deficiency): Diagnostic threshold revised to VWF:Ag <30 IU/dL (VWF:Act/VWF:Ag >0.7), eliminating the "Low VWF" category for levels 30–50 IU/dL with bleeding history.
- Type 2 (qualitative defects): Subtypes (2A, 2B, 2M, 2N) require functional assays. A VWF:Act/VWF:Ag ratio <0.7 is now recommended for diagnosis.
- Type 3 (severe deficiency): Near-absent VWF:Ag (<3 IU/dL).
- Type 1C (accelerated clearance): Diagnosed via desmopressin trial (post-infusion VWF:Ag drop >30%) rather than VWFpp/VWF:Ag ratio.
Novel Diagnostic Assays:
- VWF:GPibM: Uses gain-of-function GPIbα fragment, offering high precision (CV 5.6%) and insensitivity to common polymorphisms.
- VWF:GPibNab: Employs VWF-activating nanobodies, showing superior sensitivity to high-molecular-weight multimers (HMWMs).
- VWF:GPibR: Recombinant GPIbα with ristocetin, improving lower detection limits (LOD 0.5 IU/dL).
- These assays outperform traditional VWF:RCo (high variability, CV 20–40%) and VWF:Ab (misses some variants).
Clinical Algorithms:
- Initial testing includes VWF:Ag, VWF:Act, and FVIII:C.
- Additional tests (e.g., VWF:CB, RIPA, multimer analysis, genetic testing) refine subtype diagnosis.
- Bleeding assessment tools (BATs) help identify patients needing lab work (e.g., ISTH-BAT scores ≥4 for males, ≥6 for females).
Challenges:
- Assay variability and low sensitivity for mild cases.
- Genetic testing is most useful for Type 2/3 VWD; Type 1 often lacks clear VWF mutations.
- Limited access to specialized tests in some regions.
Future Directions:
- Broader adoption of automated assays (e.g., Hydrasys 2 scan for multimer analysis).
- Integration of nanobody-based assays into clinical practice.
- Continued research into non-VWF genetic contributors (e.g., ABO blood group, clearance receptors).
Key Takeaway:
Recent advancements in VWF activity assays and updated diagnostic guidelines are transforming VWD diagnosis, enabling more accurate classification and personalized care. However, global standardization and accessibility remain critical goals.