What is the sensitivity of the RIPA (Ristocetin-Induced Platelet Aggregation) test in patients with type 2 von Willebrand disease?

Sensitivity of RIPA Test in Type 2 von Willebrand Disease

The Ristocetin-Induced Platelet Aggregation (RIPA) test has limited sensitivity for diagnosing Type 2 von Willebrand Disease, with false normal results occurring in up to 30% of cases, making it inadequate as a standalone diagnostic test.

Understanding RIPA Test Limitations

RIPA testing measures the ability of von Willebrand Factor (VWF) to bind to platelets in the presence of ristocetin. However, its diagnostic accuracy in Type 2 VWD varies significantly by subtype:

• Type 2A: May show normal RIPA results at low-dose ristocetin despite having qualitative VWF defects 1
• Type 2B: Usually shows enhanced RIPA at low-dose ristocetin (characteristic finding), but can occasionally be normal 1
• Type 2M: Often shows normal RIPA results despite functional VWF defects 1

Diagnostic Performance of RIPA

The sensitivity of RIPA testing varies across studies and VWD subtypes:

• In a prospective study of 641 children with bleeding disorders, RIPA at low-dose ristocetin (0.5 mg/ml) identified only 6 patients (0.93%) with Type 2B VWD 2
• Another study found that RIPA was decreased in only 13 of 18 patients (72%) with VWD who had decreased plasma levels of VWF, with 5 patients (28%) showing normal RIPA despite having mild VWD 3
• When using whole blood RIPA with the Multiplate platform, sensitivity ranged from 76% to 95% depending on the cutoff value used, with >90% of Type 2 VWD patients correctly identified 4

Why RIPA Has Limited Sensitivity

Several factors contribute to the limited sensitivity of RIPA in Type 2 VWD:

1. Pre-analytical variables affecting sample quality
2. Variations in testing methodology across laboratories
3. Normal platelet count can mask VWF defects
4. Borderline phenotypic expression of the disease 1
5. Ristocetin itself is not a physiological activator of VWF, creating an artificial testing environment 5

Recommended Diagnostic Approach

Due to RIPA's limitations, a more comprehensive approach is needed:

1. Calculate VWF:RCo/VWF:Ag ratio: A ratio <0.5-0.7 strongly suggests Type 2 VWD, regardless of RIPA results 1
2. Perform VWF multimer analysis: Essential for proper subtyping of Type 2 VWD variants 1
3. Consider flow cytometric analysis: Flow cytometry-based assays measuring ristocetin-induced VWF binding to platelets have shown good correlation with other VWD diagnostic tests 6
4. Newer assay alternatives: Consider VWF:GPIbR or VWF:GPIbM assays which have improved sensitivity and precision compared to traditional RIPA 5

Laboratory Profile for Type 2 VWD Diagnosis

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

The limited sensitivity of RIPA has important clinical implications:

• Normal RIPA does not rule out Type 2 VWD: Patients with normal RIPA results may still have Type 2 VWD, particularly Types 2A and 2M 1
• Treatment decisions require accurate subtyping: Different subtypes respond differently to desmopressin (DDAVP), making accurate diagnosis critical for proper management 1
• False reassurance risk: Relying solely on RIPA may lead to missed diagnoses and inadequate treatment of bleeding disorders

Emerging Alternatives

The International Society on Thrombosis and Haemostasis (ISTH) now recognizes several newer assays with improved performance:

• VWF:GPIbR: Uses recombinant GPIb fragments with ristocetin, showing excellent correlation with classic VWF:RCo but with improved precision 5
• VWF:GPIbM: Uses gain-of-function mutant GPIb fragments without ristocetin, offering higher precision and sensitivity 5
• VWF:Ab: Uses monoclonal antibodies against VWF epitopes involved in GPIb binding, showing good correlation with VWF:RCo but with limitations in detecting certain mutations 5

In conclusion, while RIPA testing has historically been important in VWD diagnosis, its limited sensitivity in Type 2 VWD necessitates a more comprehensive diagnostic approach including VWF:RCo/VWF:Ag ratio calculation and multimer analysis for accurate diagnosis and appropriate clinical management.