Should a patient with normal von Willebrand (vW) antigen levels and a normal vW factor ratio undergo genetic testing for type 2B von Willebrand's disease if they have a family history of the condition?

Genetic Testing for Type 2B von Willebrand Disease with Normal VWF Levels

Normal von Willebrand factor (VWF) antigen levels and a normal VWF:RCo/VWF:Ag ratio do not definitively exclude type 2B von Willebrand disease (VWD), and genetic testing should still be considered in patients with affected family members, as exceptions to typical laboratory patterns occur.

Laboratory Values in Type 2B VWD

• Type 2B VWD is typically characterized by VWF:RCo <30 IU/dL, VWF:Ag between 30-200 IU/dL, and a VWF:RCo/VWF:Ag ratio usually <0.5-0.7 1
• However, these values represent prototypical cases, and exceptions occur that may require repeat testing 1
• Some patients with genetically confirmed type 2B VWD can present with normal VWF:RCo/VWF:Ag ratios, particularly those with certain mutations 2

Limitations of Standard Laboratory Testing

• Laboratory testing for VWD has relatively high coefficients of variation (10-30%), especially for the VWF:RCo assay 1
• Quality of laboratory testing varies considerably among laboratories (high interlaboratory CV) 1
• In some type 2B VWD cases, a negative ristocetin-induced platelet aggregation (RIPA) test at 0.5 mg/mL does not rule out the diagnosis 2
• VWF is an acute phase reactant, and levels can vary in response to clinical status, potentially resulting in falsely elevated results 1

Role of Genetic Testing in VWD Diagnosis

• Molecular screening can confirm phenotypic diagnosis and is important for tracking VWF defects within families 3
• With next-generation sequencing technologies, genetic diagnosis has substantially improved in accuracy 4
• Genetic testing can be used to confirm or differentiate a VWD diagnosis, as well as provide genetic counseling 4
• The penetrance of mutations in type 2B VWD is complete, making it mandatory to study entire family sets to complete diagnostic profiles 2

Diagnostic Algorithm for Suspected VWD with Family History

1. Initial laboratory evaluation should include VWF:RCo, VWF:Ag, and FVIII levels 1, 5
2. Calculate the VWF:RCo/VWF:Ag ratio to distinguish between type 1 and type 2 VWD 5
3. If initial testing is normal but family history is positive for type 2B VWD:
   • Consider repeat testing up to 3 times due to variability in VWF levels 1, 5
   • Perform specialized tests including RIPA and VWF multimer analysis 1, 6
   • Proceed with genetic testing to identify known type 2B VWD mutations 2, 4

Common Pitfalls in VWD Diagnosis

• Relying solely on VWF:RCo/VWF:Ag ratio without considering family history 5
• Failing to repeat testing when initial results are normal but clinical suspicion is high 1
• Not considering that some type 2B VWD mutations may present with atypical laboratory findings 2
• Overlooking the need for genetic testing in families with known VWD mutations 2, 4

Conclusion

For a patient with normal VWF antigen levels (0.8) and normal ratio (0.9) but with family members diagnosed with type 2B VWD, genetic testing is still warranted as laboratory values represent prototypical cases and exceptions occur. The complete penetrance of type 2B VWD mutations and the limitations of standard laboratory testing make genetic analysis an important diagnostic tool in this scenario.