How to manage a patient with a strong family history of type 2B von Willebrand disease, normal VWF level, and a VWF activity to antigen ratio of 1.0?

Management of a Patient with Strong Family History of Type 2B von Willebrand Disease with Normal VWF Level and Activity/Antigen Ratio of 1.0

A single normal VWF level and activity/antigen ratio of 1.0 is insufficient to rule out type 2B von Willebrand disease (VWD) in a patient with strong family history, and specialized testing including multimer analysis and RIPA testing is required for accurate diagnosis. 1

Diagnostic Approach

Initial Considerations

• VWF is an acute phase reactant and levels can be falsely elevated due to stress, inflammation, or pregnancy 1
• A single normal test does not exclude type 2B VWD, especially with strong family history 1
• Type 2B VWD accounts for <5% of all VWD cases but requires specific management approaches 2

Required Additional Testing

1. Repeat standard testing (up to 3 times) 1:

   • VWF antigen (VWF:Ag)
   • VWF activity (VWF:RCo or other platelet binding assay)
   • Factor VIII coagulant activity (FVIII:C)
   • VWF:RCo/VWF:Ag ratio calculation

2. Specialized testing (essential for type 2B diagnosis) 1:

   • VWF multimer analysis (to detect loss of high molecular weight multimers)
   • Ristocetin-induced platelet aggregation (RIPA) at low concentrations
   • VWF:CB (collagen binding) assays

3. Genetic testing for mutations in the A1 domain of the VWF gene 3

   • Common mutations include p.V1316M, p.R1308C, and p.S1310F 4

Diagnostic Pitfalls to Avoid

• A normal VWF:RCo/VWF:Ag ratio does not rule out type 2B VWD 4
  • In one study, patients with p.S1310F mutation had normal VWF:RCo/VWF:Ag ratios 4
• Negative RIPA at 0.5 mg/mL does not exclude type 2B VWD 4
  • 75% of patients with p.R1308C mutation showed absence of RIPA at this concentration 4
• Consider acquired von Willebrand syndrome (AVWS) that can mimic type 2B VWD 5
  • Especially important in patients with atypical history for inherited disease

Management Recommendations

Immediate Steps

1. Refer to a hematologist for comprehensive evaluation 1
2. Use a standardized bleeding assessment tool (BAT) to objectively quantify bleeding history 1
3. Screen family members as type 2B VWD has complete penetrance but variable expressivity 4

Treatment Options Based on Bleeding Risk

For Minor Bleeding or Procedures

• VWF-containing factor concentrates are recommended as first-line treatment 1, 2
• Desmopressin (DDAVP) is controversial in type 2B VWD:
  • May cause transient decrease in platelet count increasing bleeding risk 2
  • Sometimes used for minor bleeding in practice, but requires careful monitoring 6
  • Should be used with caution and after testing patient's response in a controlled setting

For Major Bleeding or Surgery

• VWF-containing factor concentrates are the mainstay of therapy 1, 2, 6
• Monitor VWF:RCo and FVIII:C levels at 12-24 hours post-surgery 1
• Maintain VWF:RCo >50 IU/dL for at least 72 hours after major surgery 1
• Consider platelet transfusions if thrombocytopenia is severe, but be aware that:
  • Transfused platelets may be aggregated by the patient's abnormal VWF 2
  • Target platelet count ≥50,000/μL for procedures with significant bleeding risk 1

Special Considerations

• Pregnancy management requires close monitoring:
  • Thrombocytopenia may worsen during pregnancy 3, 6
  • Target VWF:RCo ≥50 IU/dL for vaginal delivery and ≥80 IU/dL for cesarean section 1
• Minimize stress factors that can exacerbate thrombocytopenia 3
• Avoid concomitant use of aspirin or other platelet antiaggregants 1
• Document response to interventions to guide future management 1

Follow-up Plan

• Regular monitoring of platelet counts and VWF parameters
• Genetic counseling for family members
• Patient education about bleeding precautions and when to seek medical attention