Can a normal Seaton induced platelet aggregation test result be a false normal in patients with suspected type 2 von Willebrand disease (VWD) and a normal platelet count?

False Normal Results in Ristocetin-Induced Platelet Aggregation Tests for Type 2 von Willebrand Disease

False normal results can occur in ristocetin-induced platelet aggregation (RIPA) tests in patients with Type 2 von Willebrand disease (VWD), even with a normal platelet count of 155. 1 This is particularly relevant for Type 2M VWD, where qualitative defects in von Willebrand factor (VWF) function exist despite normal multimer distribution.

Reasons for False Normal RIPA Results

• Type 2 VWD Subtypes: Different subtypes of Type 2 VWD can present with variable RIPA results:

  • Type 2M VWD: Often shows normal RIPA at low ristocetin doses despite having platelet-binding defects 2
  • Type 2A VWD: May show normal RIPA at low doses despite missing high and intermediate molecular weight multimers 1
  • Type 2B VWD: Usually shows enhanced RIPA at low doses but can occasionally present with normal results 1

• VWF as an Acute Phase Reactant: VWF levels can be falsely elevated in response to clinical status, masking underlying defects 3

• Test Variability: The American Academy of Pediatrics notes that VWF testing may need to be repeated up to 3 times to ensure reliable results 3

Diagnostic Approach for Suspected Type 2 VWD

1. Core Initial Testing:

   • VWF antigen (VWF:Ag)
   • VWF ristocetin cofactor activity (VWF:RCo)
   • Factor VIII coagulant activity (FVIII:C) 1

2. Calculate VWF:RCo to VWF:Ag ratio:

   • A ratio below 0.5-0.7 suggests qualitative VWD (Type 2) even if individual values appear normal 3, 1

3. Additional Testing When Initial Results Are Normal but Clinical Suspicion Remains High:

   • VWF multimer analysis - not recommended for initial screening but valuable when clinical suspicion is high 3
   • Repeat testing during non-stress periods (VWF is an acute phase reactant) 3
   • Consider specialized testing such as flow cytometry with fixed platelets or ELISA with recombinant glycoprotein Ibα 2

Important Clinical Considerations

• A comprehensive re-evaluation study found that 90% of previously diagnosed Type 2 VWD patients met current diagnostic criteria, confirming that Type 2 VWD is generally diagnosed accurately 4

• Platelet-type VWD (PT-VWD) can mimic Type 2B VWD with similar laboratory features and can be misdiagnosed, requiring specialized testing to differentiate 5

• Normal platelet count (155) does not rule out Type 2 VWD, as thrombocytopenia is primarily associated with Type 2B VWD and PT-VWD, not other Type 2 subtypes 1, 5

Common Pitfalls to Avoid

• Single Testing: Relying on a single RIPA test can lead to misdiagnosis. The American Academy of Pediatrics recommends repeating testing up to 3 times 3

• Overlooking Ratio Analysis: Normal individual values of VWF:RCo and VWF:Ag may mask Type 2 VWD if the ratio is not calculated 3, 1

• Ignoring Clinical History: Strong bleeding history should prompt additional testing even when initial tests are normal 1

• Failure to Consider Test Limitations: RIPA testing has inherent variabilities that can affect results, including conditions of the patient, blood sample handling, and laboratory methodology 3

In conclusion, a normal RIPA test in a patient with a platelet count of 155 does not definitively rule out Type 2 VWD. Additional testing, particularly calculation of the VWF:RCo/VWF:Ag ratio and possibly VWF multimer analysis, should be considered when clinical suspicion remains high.