Von Willebrand Factor Antigen to Activity Ratio in Type 2B von Willebrand Disease
Type 2B von Willebrand Disease (VWD) typically presents with a VWF:RCo/VWF:Ag ratio of less than 0.5-0.7, but atypical cases can have ratios greater than 0.75, particularly with certain mutations outside the A1 domain. 1, 2
Laboratory Characteristics of Type 2B VWD
- Type 2B VWD is characterized by increased VWF affinity for platelet GP Ib, often with decreased platelet numbers, VWF:RCo typically <30 IU/dL, VWF:Ag between 30-200 IU/dL, and a VWF:RCo/VWF:Ag ratio that is usually <0.5-0.7 1
- Laboratory testing for VWD has relatively high coefficients of variation (10-30%), especially for the VWF:RCo assay, which can impact diagnostic accuracy and interpretation of ratios 1, 3
- The recommended VWF:RCo/VWF:Ag ratio cutoff to distinguish Type 1 from Type 2 VWD variants (including 2B) ranges from 0.5 to 0.7 according to different guidelines 4
Atypical Type 2B VWD Presentations
- Atypical cases of Type 2B VWD have been documented with normal VWF:RCo/VWF:Ag ratios (>0.75) 5, 6
- In a study of genotypically confirmed Type 2B VWD patients, those with the p.S1310F mutation had VWF:RCo/VWF:Ag ratios that were not reduced below 0.6, demonstrating that some Type 2B variants can maintain normal activity-to-antigen ratios 5
- Noncanonical Type 2B VWD associated with mutations outside the typical A1 domain (such as in D'D3 and D4 domains) can present with Type 2B clinical and laboratory features despite atypical genetic findings 6
Diagnostic Considerations for Mild/Atypical Type 2B VWD
- Enhanced ristocetin-induced platelet aggregation (RIPA) at low concentrations of ristocetin is traditionally considered a key diagnostic test for Type 2B VWD, but some atypical cases may not show this characteristic finding 2, 5
- VWF multimer analysis showing the characteristic loss of high molecular weight multimers is crucial for diagnosis, especially in cases with normal VWF:RCo/VWF:Ag ratios 2, 7
- Genetic testing should be considered when laboratory findings are inconclusive but clinical bleeding symptoms are significant, as some Type 2B variants may have atypical laboratory presentations 3, 2
Potential Pitfalls in Diagnosis
- Relying solely on VWF:RCo/VWF:Ag ratio without considering family history, clinical symptoms, or other specialized testing can lead to misdiagnosis 3, 7
- Pre-analytical variables can significantly affect test results, including sample processing and storage conditions, potentially leading to falsely normal ratios 1, 2
- VWF is an acute phase reactant, and levels can vary in response to clinical status, potentially resulting in falsely elevated results and misleading ratios 3
- Some patients with p.R1308C mutations (a known Type 2B variant) may show absence of RIPA at standard concentrations and very low VWF:RCo levels, which could lead to misclassification 5
Diagnostic Algorithm for Suspected Type 2B VWD
- Initial laboratory evaluation should include VWF:RCo, VWF:Ag, FVIII levels, and calculation of VWF:RCo/VWF:Ag ratio 3, 7
- If initial testing shows normal ratios but clinical suspicion remains high, consider repeat testing up to 3 times due to variability in VWF levels 3
- Perform RIPA testing to assess for enhanced platelet aggregation at low ristocetin concentrations 2
- Conduct VWF multimer analysis to assess for the characteristic loss of high molecular weight multimers 2, 7
- Consider genetic testing for definitive diagnosis, particularly when laboratory findings are inconsistent with clinical presentation 3, 2