How does Type 2 von Willebrand disease (VWD) manifest differently among family members with varying levels of von Willebrand factor (VWF) antigen and activity?

Type 2 von Willebrand Disease Manifestations Among Family Members

Type 2 von Willebrand disease (VWD) can manifest differently among family members due to variable expressivity of the same genetic mutation, with some individuals showing low VWF:RCo/VWF:Ag ratios (<0.5-0.7) while others may have borderline or low-normal von Willebrand factor levels despite carrying the same mutation. 1, 2

Laboratory Variations in Type 2 VWD

Type 2 VWD is characterized by qualitative defects in von Willebrand factor (VWF) function rather than simply reduced VWF levels. Key laboratory findings include:

• Type 2A, 2B, and 2M: VWF:RCo typically <30 IU/dL with VWF:Ag levels ranging from 30-200 IU/dL 1
• VWF:RCo/VWF:Ag ratio: Usually <0.5-0.7 in type 2 variants 1
• Multimer patterns: Vary by subtype (normal in 2M, loss of high molecular weight multimers in 2A and 2B) 2

Family Variability Factors

Several factors contribute to the variable presentation within families:

1. Penetrance and expressivity: The same mutation can produce different phenotypic severity
2. ABO blood group influence: Blood type O is associated with approximately 25% lower VWF levels 1
3. Age-related changes: VWF levels typically increase with age
4. Environmental factors: Stress, exercise, pregnancy, and inflammation can temporarily increase VWF levels

Specific Type 2 VWD Subtype Variations

Type 2M VWD

• Family members may show borderline or low VWF antigen levels with disproportionately low ristocetin cofactor activity 3, 4
• Normal VWF multimer patterns despite functional defects 3
• Some family members may have significant bleeding symptoms while others with the same mutation may be asymptomatic 4

Type 2B VWD

• Characterized by increased affinity of VWF for platelet glycoprotein Ib 5
• Family members may show variable degrees of thrombocytopenia
• Some relatives may have all VWF multimers present while others show loss of high molecular weight multimers 5

Diagnostic Challenges in Families

1. Misdiagnosis risk: Type 2M VWD is frequently misdiagnosed as type 1 or 2A VWD 4
2. Laboratory artifacts: Some sequence variations (like P1467S) can affect ristocetin binding without causing true VWF dysfunction, leading to false diagnoses 6
3. Test limitations: The ristocetin cofactor assay has high coefficient of variation (10-30%), which may contribute to inconsistent results among family members 1

Clinical Implications

• Bleeding symptoms may vary significantly among family members with the same VWD type
• Some family members may have significant bleeding despite borderline laboratory values
• Others may have abnormal laboratory values but minimal bleeding symptoms

Recommended Approach for Evaluating Families

1. Test all first-degree relatives of individuals with diagnosed type 2 VWD
2. Use standardized bleeding assessment tools to objectively quantify bleeding history 2
3. Perform comprehensive laboratory testing including:
   • VWF antigen (VWF:Ag)
   • VWF ristocetin cofactor activity (VWF:RCo)
   • Factor VIII coagulant activity (FVIII)
   • VWF multimer analysis
4. Consider genetic testing to confirm specific mutations in the VWF gene, particularly in the A1 domain for type 2M and 2B variants 3, 7

Important Caveats

• A normal VWF antigen level does not rule out type 2 VWD, as these subtypes are characterized by qualitative defects 2
• The VWF:RCo/VWF:Ag ratio is critical for distinguishing between type 1 and type 2 variants 1
• Laboratory samples must be properly handled (processed at room temperature and promptly frozen) to avoid artifactual lowering of VWF activity 1