What are the diagnostic criteria and management options for type 2B von Willebrand's disease (VWD)?

Diagnosis of Type 2B von Willebrand Disease

Type 2B von Willebrand Disease (VWD) is diagnosed through specific laboratory findings including enhanced ristocetin-induced platelet aggregation (RIPA) at low concentrations, loss of high molecular weight multimers, and genetic testing confirming gain-of-function mutations in the VWF gene. 1

Clinical Presentation and Initial Evaluation

Type 2B VWD is characterized by:

• Mucocutaneous bleeding (epistaxis, bruising, gingival bleeding)
• Potential thrombocytopenia, which may be intermittent or persistent
• Bleeding following surgery, invasive procedures, or childbirth
• Autosomal dominant inheritance pattern 2, 3

Key clinical evaluation points:

• Document frequency and severity of bleeding episodes
• Assess for thrombocytopenia, which is common in Type 2B VWD and can be exacerbated by physiologic stressors like pregnancy 4
• Review family history for bleeding disorders consistent with autosomal dominant inheritance
• Note any conditions that might cause acquired von Willebrand syndrome 2

Laboratory Diagnosis

First-line Tests

• Complete blood count (CBC) - to assess for thrombocytopenia
• VWF antigen (VWF:Ag)
• VWF ristocetin cofactor activity (VWF:RCo)
• Factor VIII coagulant activity (FVIII:C)
• Calculate VWF:RCo to VWF:Ag ratio (ratio <0.5-0.7 suggests Type 2 VWD) 1

Specialized Tests for Type 2B VWD

1. Ristocetin-Induced Platelet Aggregation (RIPA):

   • Enhanced aggregation at low ristocetin concentrations is the hallmark finding
   • This distinguishes Type 2B from other VWD subtypes 1, 5

2. VWF Multimer Analysis:

   • Shows characteristic loss of high molecular weight multimers 1

3. Genetic Testing:

   • Confirms gain-of-function mutations in the VWF gene
   • Mutations typically cluster in the A1 domain of VWF
   • Common variants include p.Arg1306Trp and p.Arg1308Cys 4, 6

Diagnostic Criteria for Type 2B VWD

• VWF:RCo <30 IU/dL
• VWF:Ag typically 30-200 IU/dL
• VWF:RCo/VWF:Ag ratio <0.5-0.7
• Loss of high molecular weight multimers
• Enhanced RIPA at low ristocetin concentrations
• Genetic confirmation of causative VWF mutation 1

Differential Diagnosis

The most important differential diagnosis is platelet-type VWD (pseudo-VWD):

• Clinically similar to Type 2B VWD
• Distinguished by genetic testing showing mutations in GP1BA gene rather than VWF gene
• Critical distinction as treatment approaches differ 5

Other conditions to consider:

• Other VWD subtypes (particularly Type 2A)
• Acquired von Willebrand syndrome
• Immune thrombocytopenia 2, 1

Management Considerations

Treatment of Type 2B VWD requires special consideration:

• VWF replacement therapy is the mainstay of treatment
• Desmopressin (DDAVP) is contraindicated in most cases due to risk of worsening thrombocytopenia and potential thrombosis 7
• The FDA label specifically warns about increased risk of thrombosis in patients with Type 2B VWD when using desmopressin 7
• Antifibrinolytic agents can be used as adjunctive therapy 3

Special Considerations

Pregnancy

• Thrombocytopenia may worsen during pregnancy, particularly in the third trimester
• Sharp decrease in platelet count often occurs in the week before delivery
• High risk of postpartum hemorrhage despite prophylactic treatment with VWF concentrates 4
• Close monitoring of platelet counts throughout pregnancy is essential

Genetic Variants and Clinical Phenotype

• Strong association between specific genetic variants and severity of thrombocytopenia
• p.Arg1306Trp variant is associated with more severe and persistent thrombocytopenia compared to p.Arg1308Cys 4
• Genotype information can help predict clinical course and guide management

Pitfalls in Diagnosis

• Intermittent thrombocytopenia may be missed with single platelet count measurement
• RIPA testing can be technically challenging and requires specialized expertise
• Repeat testing may be necessary as VWF levels can vary 1
• Failure to distinguish from platelet-type VWD can lead to inappropriate treatment decisions 5