Can a person have von Willebrand disease (VWD) if their absolute antigen levels of von Willebrand factor (VWF) are normal?

Von Willebrand Disease with Normal VWF Antigen Levels

Yes, a person can have von Willebrand disease (VWD) even with normal absolute antigen levels of von Willebrand factor (VWF), particularly in Type 2 variants where the defect is qualitative rather than quantitative. 1

Types of VWD with Normal Antigen Levels

Type 2 VWD represents qualitative defects in VWF function that can occur despite normal antigen levels:

• Type 2M: Characterized by decreased VWF ristocetin cofactor activity (VWF:RCo) but normal VWF antigen (VWF:Ag) levels. The VWF:RCo/VWF:Ag ratio is typically <0.5-0.7, indicating dysfunctional VWF despite normal quantity. 1, 2

• Type 2N: Presents with normal VWF:RCo and VWF:Ag but reduced factor VIII binding capacity, resembling mild hemophilia A. 1

• Type 2A and 2B: While these often have reduced VWF:Ag levels, they can sometimes present with VWF:Ag in the normal range (30-200 IU/dL) but significantly reduced VWF:RCo. 1

Diagnostic Approach

When VWD is suspected despite normal VWF antigen levels:

1. Calculate VWF:RCo to VWF:Ag ratio

   • Ratio <0.5-0.7 suggests Type 2 VWD 1
   • This is a critical step that can identify functional defects despite normal antigen levels

2. Evaluate multimer pattern

   • Type 2M/2U: May show relative decreases in large VWF multimers with less resolved triplet structure 2
   • Type 2A: Loss of high and intermediate molecular weight multimers 1
   • Type 2B: Loss of high molecular weight multimers 1

3. Perform ristocetin-induced platelet aggregation (RIPA)

   • Type 2M: Often normal at low-dose ristocetin 1
   • Type 2B: Usually enhanced at low-dose ristocetin 1

4. Consider genetic testing

   • Type 2M/2U: Caused by loss-of-function mutations in the A1 domain of VWF gene 2, 3
   • Specific mutations like F606I and I662F have been identified in Type 2M with normal multimer patterns 3

Clinical Implications

• Patients with Type 2 VWD and normal antigen levels may still have significant bleeding symptoms 3
• Treatment approach differs from Type 1 VWD:
  • DDAVP (desmopressin) may be less effective in Type 2M VWD despite increasing VWF:Ag levels 2
  • VWF-containing factor concentrates are often needed for Type 2 variants 1

Common Pitfalls

• Relying solely on VWF:Ag levels: This will miss qualitative defects in VWF function
• Single testing: VWF levels can vary; repeat testing up to 3 times may be necessary 1
• Overlooking the VWF:RCo/VWF:Ag ratio: This ratio is crucial for identifying Type 2 VWD
• Incomplete laboratory evaluation: A comprehensive panel including VWF:Ag, VWF:RCo, FVIII activity, and multimer analysis is necessary for proper classification 1, 4

Remember that VWD is a heterogeneous disorder, and proper diagnosis requires assessment of both quantity and function of VWF. Normal antigen levels do not exclude VWD, particularly the qualitative Type 2 variants.