If the RIPA (Ristocetin-Induced Platelet Aggregation) test is normal, does that rule out Type 2B Von Willebrand Disease (VWD)?

Normal RIPA Does Not Rule Out Type 2B Von Willebrand Disease

A normal Ristocetin-Induced Platelet Aggregation (RIPA) test does not definitively rule out Type 2B von Willebrand Disease (VWD), as some Type 2B VWD patients can present with normal RIPA results. 1

Diagnostic Considerations for Type 2B VWD

Type 2B VWD is characterized by several laboratory findings:

• VWF:RCo <30 IU/dL
• VWF:Ag 30-200 IU/dL
• VWF:RCo/VWF:Ag ratio <0.5-0.7
• Loss of high molecular weight multimers
• RIPA that is usually enhanced at low-dose ristocetin, but can be normal 1

The key point is that while enhanced RIPA at low ristocetin concentrations is typical of Type 2B VWD, normal RIPA results can still occur in patients with this subtype.

Diagnostic Algorithm for Type 2B VWD

1. Initial laboratory testing:

   • Complete blood count (CBC) with platelet count
   • VWF antigen (VWF:Ag)
   • VWF ristocetin cofactor activity (VWF:RCo)
   • Factor VIII coagulant activity (FVIII:C)
   • Calculate VWF:RCo/VWF:Ag ratio

2. Additional testing if Type 2 VWD is suspected:

   • VWF multimer analysis (essential for subtyping)
   • RIPA at both standard and low-dose ristocetin
   • Genetic testing of VWF gene (particularly exon 28)

3. Specific findings that suggest Type 2B despite normal RIPA:

   • Mild thrombocytopenia
   • Characteristic loss of high molecular weight multimers
   • VWF:RCo/VWF:Ag ratio <0.5-0.7
   • Genetic testing showing mutations in the A1 domain of VWF

Limitations of RIPA Testing

RIPA has several limitations that can affect its reliability:

• The International Society on Thrombosis and Haemostasis (ISTH) notes that relying on a single test for VWD diagnosis is insufficient 1
• RIPA results can be variable and may not always reflect the true VWF content of platelets 2
• Heterogeneity within the same family has been observed, where different phenotypic patterns can occur despite the same genetic mutation 3

Alternative Diagnostic Approaches

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

• DDAVP (desmopressin) challenge can be useful to unmask Type 2B phenotype, as demonstrated in cases where basal RIPA was normal or reduced 3
• Newer assays such as VWF:GPIbR, VWF:GPIbM, and VWF:Ab offer improved performance for diagnosing VWD 1
• Genetic testing of exon 28 of the VWF gene can identify mutations associated with Type 2B VWD 4

Clinical Implications

The heterogeneity of Type 2B VWD presentations has important clinical implications:

• Treatment approaches differ significantly among VWD subtypes
• Type 2B VWD requires VWF-containing concentrates rather than desmopressin (which can worsen thrombocytopenia) 1
• Misdiagnosis can lead to inappropriate treatment and increased bleeding risk

Common Pitfalls to Avoid

• Relying solely on RIPA for Type 2B VWD diagnosis
• Failing to perform VWF multimer analysis, which is essential for proper subtyping
• Not considering the possibility of Type 2B VWD when RIPA is normal but other findings are suggestive
• Overlooking the need for genetic testing when laboratory findings are inconclusive

In conclusion, while enhanced RIPA at low ristocetin concentrations is characteristic of Type 2B VWD, a normal RIPA result does not exclude this diagnosis. Comprehensive evaluation including multimer analysis and genetic testing is necessary for accurate diagnosis.