Should there be a concern for Bryn having von Willebrand disease (VWD) given his family history of low von Willebrand factor (VWF) activity?

Concern for Von Willebrand Disease in Bryn Based on Family History

Yes, there should be significant concern for Bryn having von Willebrand disease (VWD) given his family history of two first-degree relatives with von Willebrand's antigen activity ratios of 0.7, which is considered abnormal according to current guidelines. 1

Understanding the Significance of VWF Activity Ratios

The von Willebrand factor (VWF) activity to antigen ratio is a critical diagnostic parameter:

• A VWF activity to antigen ratio <0.7 is considered abnormal by the American Society of Hematology, indicating a qualitative defect in VWF 1
• A ratio of 0.7 (as seen in Bryn's sister and niece) is considered borderline abnormal 1
• This ratio helps distinguish between quantitative defects (Type 1 VWD) and qualitative defects (Type 2 VWD)

Importance of Family History in VWD Diagnosis

Family history is particularly significant in VWD diagnosis:

• VWD is a hereditary bleeding disorder with variable penetrance and expressivity
• The Centers for Disease Control and Prevention recommends screening all first-degree relatives of patients with VWD 1
• The probability of having a specific bleeding disorder increases significantly in the setting of a family history of that specific named bleeding disorder 2

Diagnostic Approach for Bryn

Given the family history, Bryn should undergo the following diagnostic workup:

1. Comprehensive bleeding assessment using a standardized bleeding assessment tool (BAT) to document any bleeding symptoms 1

2. Laboratory testing:

   • Complete blood count (CBC) and platelet count
   • Prothrombin time (PT) and activated partial thromboplastin time (aPTT)
   • VWF screening panel:
     • VWF antigen (VWF:Ag)
     • VWF ristocetin cofactor activity (VWF:RCo)
     • Factor VIII coagulant activity (FVIII:C)
     • VWF:RCo/VWF:Ag ratio calculation 1

3. If initial testing suggests VWD:

   • VWF multimer analysis to confirm diagnosis and classify subtype
   • Ristocetin-Induced Platelet Aggregation (RIPA) test may help distinguish Type 2B from other subtypes 1

Important Considerations

• Test variability: VWF levels can be affected by various conditions including stress, exercise, pregnancy, and inflammation 1
• Repeat testing: Testing may need to be repeated up to 3 times to ensure reliable results, as VWF is an acute phase reactant 2
• Borderline cases: Even patients with mildly decreased VWF (30-50% or IU/dL) should be evaluated if family history is present 1

Management Implications

If Bryn is diagnosed with VWD, treatment options would depend on the specific subtype:

• Type 1 VWD: May respond to desmopressin (DDAVP) at 0.3 mcg/kg 3
• Type 2 VWD: Response to desmopressin varies by subtype; VWF-containing concentrates may be needed 1
• Type 3 VWD: Typically requires VWF-containing concentrates 1

Pitfalls to Avoid

• Single testing: Relying on a single test for VWD diagnosis is insufficient; multiple tests and clinical correlation are required 1
• Overlooking borderline results: A ratio of 0.7 is considered borderline abnormal and should not be dismissed, especially with positive family history 1
• Failure to consult specialists: Consultation with a hematologist is recommended when clinical suspicion remains high or interpretation of borderline test results is required 1

Given the family history of two first-degree relatives with abnormal VWF activity ratios, Bryn should be evaluated for VWD even if he has not experienced significant bleeding symptoms, as VWD can have variable expressivity and may only become clinically apparent during hemostatic challenges.