Does a normal RIPA (Ristocetin-Induced Platelet Aggregation) test conclusively eliminate type 2B von Willebrand's disease from the differential diagnosis?

RIPA Test in Type 2B von Willebrand Disease Diagnosis

A normal Ristocetin-Induced Platelet Aggregation (RIPA) test does not conclusively eliminate type 2B von Willebrand disease from the differential diagnosis, as some variants of type 2B VWD can present with normal RIPA results. 1

Understanding RIPA in Type 2B VWD Diagnosis

• RIPA testing is traditionally considered a key diagnostic test for type 2B von Willebrand disease, which typically shows enhanced ristocetin-induced platelet aggregation at low concentrations of ristocetin 2
• Type 2B VWD is characterized by increased VWF affinity for platelet GP Ib, which often results in thrombocytopenia and absence of high molecular weight multimers 2
• While enhanced RIPA is characteristic of most type 2B VWD cases, research has identified specific mutations that present with normal or negative RIPA results 1

Evidence of Type 2B VWD with Normal RIPA

• In a 2017 study of genotypically confirmed type 2B VWD patients, 75% of patients with the p.R1308C mutation showed absence of RIPA at 0.5 mg/mL, despite genetic confirmation of type 2B VWD 1
• The same study concluded that "a negative RIPA at 0.5 mg/mL does not necessarily rule out a diagnosis of VWD2B" 1
• Some type 2B VWD variants present with atypical laboratory findings that do not match the classic type 2B profile, including normal RIPA results 1, 3

Comprehensive Diagnostic Approach for Type 2B VWD

When RIPA results are normal but type 2B VWD is still suspected:

• Evaluate VWF:RCo/VWF:Ag ratio - typically reduced (<0.5-0.7) in type 2B VWD, but may be normal in some variants 2
• Check for thrombocytopenia, which is often present in type 2B VWD 2
• Perform VWF multimer analysis to assess for the characteristic loss of high molecular weight multimers 2
• Consider VWF collagen binding (VWF:CB) assays, which may help differentiate between VWD subtypes 4, 5
• Genetic testing of the VWF gene remains the gold standard for definitive diagnosis of type 2B VWD when laboratory findings are inconclusive 2, 1

Potential Pitfalls in RIPA Testing

• Pre-analytical variables can significantly affect RIPA test results, including:
  • Sample processing and storage conditions 2
  • Patient stress levels, which may elevate VWF levels 2
  • Recent exercise, which can also increase VWF levels 2
  • Inflammatory conditions that may elevate VWF 2
• Technical variations in RIPA testing methodology between laboratories can lead to inconsistent results 2
• The VWF:RCo assay has a high coefficient of variation (10-30%), which may affect interpretation of results 2

Clinical Implications

• Relying solely on RIPA testing to rule out type 2B VWD may lead to misdiagnosis in patients with atypical variants 1, 3
• A comprehensive diagnostic approach is essential, particularly when clinical suspicion for type 2B VWD remains high despite normal RIPA results 2, 1
• Genetic testing should be considered when laboratory findings are inconclusive but clinical bleeding symptoms are significant 2, 1
• The 2008 NHLBI/NIH guidelines recommend a strategic algorithmic approach to VWD diagnosis rather than reliance on any single test 2