How do you rule out Type 2B von Willebrand disease, aren't multimer tests essential?

Ruling Out Type 2B von Willebrand Disease: The Role of Multimer Testing

Multimer testing is not essential for initial screening of Type 2B von Willebrand disease but is necessary for definitive subtyping after initial testing suggests VWD. 1

Diagnostic Algorithm for Type 2B VWD

Initial Testing Phase

The initial laboratory evaluation for von Willebrand disease should include three key tests:

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

These three tests are recommended as the first-line laboratory evaluation for all types of VWD, including Type 2B. 1

When to Suspect Type 2B VWD

Type 2B should be suspected when:

• VWF:RCo is decreased (<30 IU/dL)
• VWF:Ag is normal to decreased (30-200 IU/dL)
• VWF:RCo/VWF:Ag ratio is reduced (<0.5-0.7)
• Patient has thrombocytopenia (may be persistent or transient) 2, 3

Role of Multimer Testing

Multimer analysis becomes necessary only after the initial testing suggests VWD. It should be performed when:

1. Initial VWD testing identifies abnormal results (particularly low VWF:RCo or low VWF:RCo/VWF:Ag ratio)
2. Clinical information strongly suggests VWD despite normal initial testing 1

Distinctive Features of Type 2B VWD

Type 2B VWD is characterized by:

• Increased affinity of VWF for platelet glycoprotein Ib 2, 4
• Usually (but not always) absence of high molecular weight VWF multimers 3
• Thrombocytopenia that may be persistent or transient 3, 5
• Enhanced response to low-dose ristocetin in platelet aggregation studies 4

Important Clinical Caveat

There are two phenotypic variants of Type 2B VWD:

1. Classic Type 2B: Missing high molecular weight multimers with thrombocytopenia
2. Type 2B with normal multimers: Full range of multimers but still with thrombocytopenia 3, 6

This phenotypic heterogeneity makes multimer analysis crucial for proper classification but not necessarily for initial diagnosis. 3

Practical Diagnostic Approach

1. First step: Obtain VWF:Ag, VWF:RCo, and FVIII activity
2. Second step: Calculate VWF:RCo/VWF:Ag ratio
3. Third step: If ratio is <0.5-0.7 and/or thrombocytopenia is present, proceed with:
   • Ristocetin-induced platelet aggregation (RIPA) at low concentrations
   • VWF multimer analysis 1, 2

Common Pitfalls to Avoid

• Relying solely on platelet count: Some Type 2B patients may have normal platelet counts or only intermittent thrombocytopenia 5
• Assuming all Type 2B cases lack high molecular weight multimers: Some variants retain normal multimer patterns 3, 6
• Using bleeding time or PFA-100 as screening tests: These have inconsistent sensitivity and specificity for VWD 1
• Failing to consider pre-analytical variables: Sample collection, processing, and storage can significantly affect test results 1

In conclusion, while multimer analysis is not part of the initial screening for VWD, it is essential for proper subtyping and definitive diagnosis of Type 2B VWD, especially given the heterogeneity within this subtype. The diagnosis should follow a stepwise approach starting with the three basic VWF tests before proceeding to specialized testing including multimer analysis.