Normal VWF Antigen Level Does Not Rule Out Type 2 von Willebrand Disease
No, a Von Willebrand antigen level of 1.33 does not rule out type 2 von Willebrand disease, as type 2 VWD is characterized by qualitative defects in VWF function that can occur with normal antigen levels. 1
Diagnostic Criteria for Type 2 VWD
Type 2 VWD is characterized by qualitative defects in von Willebrand factor (VWF) rather than simply reduced levels. The key laboratory findings include:
- Disproportionately low VWF activity (VWF:RCo) relative to VWF antigen (VWF:Ag)
- VWF:RCo/VWF:Ag ratio <0.5-0.7 is the hallmark of type 2 VWD 1
- VWF:Ag levels are typically in the 30-200 IU/dL range (which includes normal values) 1
- VWF:RCo is typically <30 IU/dL 1
Type 2 VWD Subtypes and Their Laboratory Profiles
Each subtype of type 2 VWD has distinct laboratory findings:
Type 2A
- VWF:RCo <30 IU/dL
- VWF:Ag 30-200 IU/dL (can be normal)
- VWF:RCo/VWF:Ag <0.5-0.7
- Loss of high & intermediate molecular weight multimers 1, 2
Type 2B
- VWF:RCo <30 IU/dL
- VWF:Ag 30-200 IU/dL (can be normal)
- VWF:RCo/VWF:Ag <0.5-0.7
- Loss of high molecular weight multimers
- Enhanced ristocetin-induced platelet aggregation (RIPA) at low concentrations
- Often associated with thrombocytopenia 1, 2
Type 2M
- VWF:RCo <30 IU/dL
- VWF:Ag 30-200 IU/dL (can be normal)
- VWF:RCo/VWF:Ag <0.5-0.7
- Normal multimer pattern 1, 3
Type 2N
- Normal VWF:RCo and VWF:Ag (can be completely normal)
- Low FVIII:C
- Normal VWF:RCo/VWF:Ag ratio
- Reduced VWF:FVIII binding 1, 4
Critical Diagnostic Considerations
Multiple tests are required: Relying on a single test for VWD diagnosis is insufficient. A comprehensive panel including VWF:Ag, VWF:RCo, and FVIII is essential 1.
Activity-to-antigen ratio is key: The ratio of VWF activity (VWF:RCo) to VWF antigen (VWF:Ag) is the most important diagnostic indicator for type 2 VWD, not the absolute values 1, 2.
Multimer analysis may be necessary: For definitive subtyping, multimer analysis is often required, particularly to distinguish between type 2A, 2B, and 2M variants 1, 2.
Type 2N requires specific testing: Type 2N VWD specifically requires VWF:FVIII binding assay (VWF:FVIIIB) for diagnosis, as routine VWF tests may be completely normal 4.
Common Pitfalls to Avoid
Relying solely on VWF antigen levels: A normal or even elevated VWF:Ag level does not exclude type 2 VWD 1, 5.
Failing to calculate activity-to-antigen ratio: Without calculating the VWF:RCo/VWF:Ag ratio, type 2 VWD may be missed 1.
Not considering preanalytical variables: VWF levels can be affected by stress, exercise, pregnancy, and inflammation, potentially masking underlying defects 1.
Overlooking type 2N VWD: This subtype can present with normal VWF:Ag and VWF:RCo levels but reduced FVIII levels, resembling mild hemophilia A 1, 4.
Recommended Diagnostic Approach
- Measure VWF:Ag, VWF:RCo, and FVIII levels
- Calculate VWF:RCo/VWF:Ag ratio (key diagnostic indicator)
- If ratio is <0.5-0.7, proceed with additional testing:
- Multimer analysis
- RIPA (for type 2B)
- VWF:FVIIIB assay (for type 2N)
- Consider genetic testing for definitive diagnosis and subtyping 1, 3
In conclusion, a normal or elevated VWF antigen level (such as 1.33) does not rule out type 2 VWD, which is defined by qualitative defects that may exist despite normal antigen levels.