Von Willebrand's Antigen Activity Ratio of 0.75 and Type 2 von Willebrand Disease
A von Willebrand antigen activity ratio of 0.75 does not definitively rule out type 2 von Willebrand disease (VWD), as the recommended cutoff ratio for distinguishing between type 1 and type 2 VWD varies from 0.5 to 0.7 according to different guidelines. 1
Diagnostic Ratios for Type 2 VWD
The VWF:RCo/VWF:Ag ratio is a critical parameter for classifying VWD subtypes:
- Current guidelines suggest that a ratio of <0.5-0.7 is typically seen in qualitative defects (type 2 VWD) 2
- A ratio of 0.75 falls just above this commonly used cutoff range
- The International Society on Thrombosis and Haemostasis (ISTH) notes that the VWF:RCo/VWF:Ag ratio is critical for current classification, but the test has limitations including high coefficient of variation that may lead to false diagnoses 3
Limitations of VWF:RCo Testing
Several factors affect the reliability of VWF:RCo testing:
- Poor sensitivity that prevents measuring VWF activity <10 IU/dL 3
- High coefficient of variation that may lead to false diagnoses 3
- Instability and batch-to-batch variability of ristocetin or platelet reagents 3
- Genetic polymorphisms (p.P1467S and p.D1472H) can cause spuriously decreased VWF:RCo levels without correlation to bleeding symptoms 3
Alternative Testing Methods
Due to limitations of traditional VWF:RCo assays, newer methods have been developed:
- Ristocetin-triggered GPIb binding (VWF:GPIbR) assays with improved limits of detection and coefficient of variation 3
- Gain-of-function mutant GPIb binding (VWF:GPIbM) assays that don't require ristocetin 3
- Monoclonal antibody binding-based VWF activity (VWF:Ab) assays 3
Comprehensive Diagnostic Approach
A single ratio value should not be used in isolation to rule out type 2 VWD:
Consider the full laboratory panel including:
- VWF antigen (VWF:Ag)
- VWF ristocetin cofactor activity (VWF:RCo)
- Factor VIII coagulant activity (FVIII:C)
- VWF:RCo/VWF:Ag ratio 2
Additional specialized testing may be necessary:
- Multimeric analysis of VWF (critical for type 2 diagnosis)
- Ristocetin-induced platelet aggregation (RIPA)
- Response to desmopressin (DDAVP) 4
Type 2 VWD Subtypes and Laboratory Findings
Different type 2 VWD subtypes have characteristic laboratory findings:
| Subtype | Key Laboratory Findings | RIPA Characteristics |
|---|---|---|
| Type 2A | • VWF:RCo <30 IU/dL • VWF:Ag 30-200 IU/dL • VWF:RCo/VWF:Ag <0.5-0.7 • Loss of high & intermediate MW multimers |
May be normal at low-dose |
| Type 2B | • VWF:RCo <30 IU/dL • VWF:Ag 30-200 IU/dL • VWF:RCo/VWF:Ag <0.5-0.7 • Loss of high MW multimers |
Usually enhanced at low-dose, but can be normal |
| Type 2M | • VWF:RCo <30 IU/dL • VWF:Ag 30-200 IU/dL • VWF:RCo/VWF:Ag <0.5-0.7 • Normal multimer pattern |
Often normal at low-dose |
| Type 2N | • Normal VWF:RCo and VWF:Ag • Low FVIII:C • Normal VWF:RCo/VWF:Ag ratio • Reduced VWF:FVIII binding |
Resembles mild hemophilia A |
Clinical Implications
When evaluating a patient with a VWF:RCo/VWF:Ag ratio of 0.75:
- Consider the analytical variability of the VWF:RCo assay
- Evaluate the multimer pattern, which is crucial for distinguishing type 2 from type 1 VWD
- Remember that some type 2 variants may have borderline ratios
- Genetic testing may be necessary in cases with borderline laboratory results
Pitfalls to Avoid
- Relying solely on the VWF:RCo/VWF:Ag ratio for diagnosis
- Failing to perform multimer analysis in cases with borderline ratios
- Not considering the high coefficient of variation of the VWF:RCo assay
- Overlooking the possibility of genetic polymorphisms affecting test results
- Ignoring clinical bleeding history in the diagnostic process
In conclusion, while a VWF:RCo/VWF:Ag ratio of 0.75 is above the commonly used cutoff for type 2 VWD, it does not definitively rule out this diagnosis due to test limitations and variability. A comprehensive approach including multimer analysis and possibly genetic testing is necessary for accurate diagnosis.