What is the likely diagnosis for three generations of women with von Willebrand antigen activity ratios between 0.70 and 0.75?

Type 1 von Willebrand Disease: Likely Diagnosis for Three Generations with VWF Antigen Activity Ratios of 0.70-0.75

Based on the VWF:RCo/VWF:Ag ratios between 0.70 and 0.75 across three generations of women, the most likely diagnosis is Type 1 von Willebrand Disease (VWD), which is characterized by a partial quantitative deficiency of von Willebrand factor with preserved function.

Diagnostic Rationale

The diagnostic process for VWD relies on specific laboratory parameters:

• VWF:RCo/VWF:Ag ratio: According to the 2008 NHLBI/NIH guidelines, a ratio >0.5-0.7 is consistent with Type 1 VWD, while ratios <0.5-0.7 suggest Type 2 variants 1
• Family pattern: The autosomal dominant inheritance pattern observed across three generations (grandmother, mother, daughter) strongly supports Type 1 VWD, which is predominantly inherited in this manner 2
• Consistency of values: The similar ratios (0.70-0.75) across all three family members further supports a hereditary condition with stable expression

Distinguishing Type 1 from Other VWD Types

Type 1 VWD can be differentiated from other types based on the following:

• Type 2 variants (A, B, M): These typically show VWF:RCo/VWF:Ag ratios <0.5-0.7, indicating qualitative defects 1
• Type 2N: While this type also shows ratios >0.5-0.7, it is characterized by markedly decreased VWF binding affinity for FVIII, which would present differently clinically 1
• Type 3: This is characterized by virtually complete deficiency of VWF with levels <3 IU/dL, which would result in much more severe clinical manifestations 1

Clinical Implications

The diagnosis of Type 1 VWD has important implications for these women:

• Bleeding risk: Patients may experience mucocutaneous bleeding including nosebleeds, easy bruising, gingival bleeding, and bleeding from small wounds 2
• Women-specific concerns: Menorrhagia and postpartum bleeding are common in women with VWD 2, 3
• Treatment approach: Desmopressin (DDAVP) is typically the treatment of choice for Type 1 VWD as it often corrects factor VIII/VWF levels 4, 5

Important Considerations

• Laboratory variability: VWF testing has high coefficients of variation (10-30%), especially the VWF:RCo assay, so repeat testing may be necessary to confirm the diagnosis 1
• Physiologic modifiers: Blood group, exercise, thyroid hormones, estrogens, and aging can all affect VWF levels and should be considered when interpreting results 6
• Clinical correlation: Laboratory data should always be interpreted in the context of personal and family bleeding history 7

Management Approach

For these three women with likely Type 1 VWD:

1. Confirm diagnosis with comprehensive VWF testing including VWF:Ag, VWF:RCo, and FVIII levels
2. Assess bleeding history to determine clinical significance
3. Consider DDAVP trial to evaluate response for future bleeding episodes
4. For women with menorrhagia: Consider hormonal contraceptives as first-line therapy 3
5. For surgical procedures: DDAVP may be sufficient for minor procedures, but major surgery may require VWF/FVIII concentrates 2, 7

The consistent VWF:RCo/VWF:Ag ratios between 0.70-0.75 across three generations strongly points to Type 1 VWD, the most common inherited bleeding disorder, affecting approximately 1% of the general population 4, 6.