Can a Ristocetin-Induced Platelet Aggregation (RIPA) test yield false normal results in a patient with suspected type 2 von Willebrand disease on low-dose ristocetin with a normal platelet count?

False Normal RIPA Test in Type 2 von Willebrand Disease

Yes, a Ristocetin-Induced Platelet Aggregation (RIPA) test can give a false normal result at low-dose ristocetin in a patient with suspected type 2 von Willebrand disease, even with a normal platelet count of 155. 1

Diagnostic Limitations of RIPA Testing

RIPA testing has several limitations in diagnosing type 2 von Willebrand disease (VWD):

1. VWF:RCo/VWF:Ag Ratio is More Reliable:

   • A VWF:RCo/VWF:Ag ratio <0.5-0.7 is the preferred diagnostic indicator for Type 2 VWD, as it can identify qualitative VWF defects even when RIPA results are normal 1
   • This ratio calculation is essential for definitive diagnosis, particularly for Type 2B VWD 1

2. False Normal Results Can Occur Due To:

   • Normal platelet count (155 is within normal range)
   • Variations in testing methodology
   • Pre-analytical variables affecting sample quality 2
   • Borderline phenotypic expression of the disease 3

Proper Diagnostic Approach for Type 2 VWD

When Type 2 VWD is suspected despite normal RIPA:

1. Calculate VWF:RCo/VWF:Ag Ratio:

   • A ratio <0.5-0.7 strongly suggests Type 2 VWD regardless of RIPA results 2, 1
   • This ratio is critical for distinguishing Type 1 from Type 2 variants 2

2. Perform VWF Multimer Analysis:

   • Essential for confirming Type 2 VWD, especially with borderline or normal RIPA results 1
   • Can detect qualitative defects in VWF structure not identified by RIPA 1

3. Consider Phenotypic Heterogeneity:

   • Even within the same family with identical mutations, phenotypic expression can vary significantly 3
   • Some patients may present with typical Type 2B features while others show patterns closer to Type 2A 3

Type 2 VWD Subtypes and 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

Clinical Implications and Recommendations

1. Don't Rule Out Type 2 VWD Based on Normal RIPA Alone:

   • A normal RIPA test with abnormal bleeding suggests a possible qualitative defect in VWF that would only be detected through multimer analysis 1

2. Comprehensive Testing Is Required:

   • When clinical suspicion is high, perform complete VWD panel including VWF:RCo/VWF:Ag ratio and multimer analysis 1
   • Consider DDAVP challenge testing which may unmask Type 2B phenotype in ambiguous cases 3

3. Consider Specialized Testing:

   • RIPA-based mixing studies can help differentiate between Type 2B VWD and Platelet-Type VWD when enhanced RIPA is present 4
   • Genetic testing of VWF gene (particularly exon 28) may be necessary for definitive diagnosis 3

In conclusion, while RIPA testing is part of the diagnostic workup for VWD, it should not be used in isolation to rule out Type 2 VWD, as false normal results can occur even with normal platelet counts. The VWF:RCo/VWF:Ag ratio and multimer analysis are more reliable diagnostic tools.