Does a normal result on the low-dose Ristocetin-Induced Platelet Aggregation (RIPA) test at 0.5 mg/mL definitively rule out Type 2B von Willebrand disease (VWD)?

Low-Dose RIPA Testing in Type 2B von Willebrand Disease

A normal result on the low-dose Ristocetin-Induced Platelet Aggregation (RIPA) test at 0.5 mg/mL does not definitively rule out Type 2B von Willebrand disease (VWD), and further testing is necessary for a complete diagnosis.

Diagnostic Limitations of Low-Dose RIPA Testing

The low-dose RIPA test at 0.5 mg/mL is an important screening tool for Type 2B VWD, but it has several limitations:

• While enhanced RIPA at low concentrations (0.5 mg/mL) is characteristic of Type 2B VWD, some variants may show normal results on this initial test 1

• According to the American Society of Hematology guidelines, VWF multimer analysis is necessary for proper subtyping of VWD, particularly for Type 2 variants, even when initial screening tests appear normal 1

• Some Type 2B VWD variants have been reported with normal RIPA results but still demonstrate the clinical and molecular features of the disorder 2

Comprehensive Diagnostic Approach

When Type 2B VWD is suspected despite a normal low-dose RIPA test, the following additional tests should be performed:

1. VWF Multimer Analysis

• Essential for definitive diagnosis of Type 2B VWD
• Typically shows absence of high molecular weight multimers, but some variants may show normal multimer patterns 3, 2

2. VWF:RCo/VWF:Ag Ratio

• A ratio <0.5-0.7 suggests Type 2 VWD (including Type 2B) 4, 1
• Even with normal RIPA, this ratio can identify qualitative VWF defects

3. Advanced Laboratory Testing

• Binding assays measuring VWF binding to recombinant fragments of glycoprotein Ibα (rfGPIbα) 5
• ELISA-based methods that can detect enhanced VWF-GPIb binding even when traditional RIPA is normal 5

4. Genetic Testing

• Molecular analysis of the VWF gene, particularly the A1 domain where Type 2B mutations typically cluster
• Can identify known Type 2B mutations even when phenotypic tests are inconclusive 6

Atypical Type 2B VWD Variants

Several variant forms of Type 2B VWD have been described that may not show the classic laboratory findings:

• Type 2B Hiroshima: characterized by chronic thrombocytopenia but with the presence of all VWF multimers in plasma 3

• Type I New York: shows increased RIPA but with a full range of VWF multimers, combining features of both Type 1 and Type 2B VWD 2

Clinical Implications

The diagnosis of Type 2B VWD has important treatment implications:

• Desmopressin (DDAVP) is generally contraindicated in Type 2B VWD as it may exacerbate thrombocytopenia 6

• VWF replacement therapy is the mainstay of treatment for Type 2B VWD 6

• Proper diagnosis ensures appropriate management during high-risk periods such as surgery or pregnancy 1, 6

Recommendation for Next Steps

If clinical suspicion for Type 2B VWD remains despite a normal low-dose RIPA test at 0.5 mg/mL, proceed with:

1. VWF multimer analysis
2. VWF:RCo/VWF:Ag ratio calculation
3. Advanced binding assays if available
4. Genetic testing for Type 2B VWD mutations
5. Evaluation of family members if appropriate

This comprehensive approach will help ensure an accurate diagnosis and appropriate management of potential Type 2B VWD, even when initial screening tests appear normal.