What is the most likely diagnosis for a patient with a reduced von Willebrand (vW) antigen activity ratio and mild thrombocytopenia?

Diagnosis and Testing for Patient with von Willebrand's Antigen Activity Ratio of 0.7 and Intermittent Thrombocytopenia

The most likely diagnosis for a patient with a von Willebrand's antigen activity ratio of 0.7 and intermittent thrombocytopenia (120-150) is Type 2B von Willebrand Disease (VWD). 1

Diagnostic Reasoning

The key diagnostic findings in this case include:

1. VWF:RCo/VWF:Ag ratio of 0.7: This ratio is at the borderline cutoff for Type 2 VWD according to current guidelines. The American Journal of Hematology recommends further testing when this ratio is <0.5-0.7 1.

2. Intermittent thrombocytopenia (120-150): This is a critical finding that strongly points toward Type 2B VWD specifically, as this subtype is characterized by enhanced binding of abnormal VWF to platelets, leading to mild thrombocytopenia 1.

Required Additional Testing

To confirm the diagnosis of Type 2B VWD, the following tests should be performed:

1. Complete VWD panel including:

   • VWF antigen (VWF:Ag)
   • VWF ristocetin cofactor activity (VWF:RCo)
   • Factor VIII coagulant activity (FVIII:C) 1

2. VWF multimer analysis: Essential to demonstrate the characteristic loss of high molecular weight multimers seen in Type 2B VWD 1

3. Ristocetin-Induced Platelet Aggregation (RIPA): Type 2B VWD typically shows enhanced aggregation at low-dose ristocetin, which is a key distinguishing feature from Type 2A 1

4. Genetic testing: To identify mutations in the A1 domain of the VWF gene, which are characteristic of Type 2B VWD 1

Differential Diagnosis

The main differential diagnoses to consider:

• Type 2A VWD: Also shows decreased VWF:RCo/VWF:Ag ratio and loss of high molecular weight multimers, but typically does not cause thrombocytopenia 1

• Type 2M VWD: Shows decreased VWF:RCo/VWF:Ag ratio but normal multimer pattern and no thrombocytopenia 1

• Platelet-type (pseudo) VWD: Clinically resembles Type 2B VWD with thrombocytopenia, but the genetic defect is in the platelet GP1b receptor rather than in VWF 1

Clinical Considerations

• The combination of a borderline low VWF:RCo/VWF:Ag ratio (0.7) with intermittent thrombocytopenia strongly suggests Type 2B VWD, as this is the only VWD subtype that typically causes thrombocytopenia 1

• It's important to note that VWF levels can be affected by various conditions including stress, exercise, pregnancy, and inflammation. Testing should ideally be performed when the patient is in their baseline state 1

• The diagnosis of Type 2B VWD has important treatment implications, as desmopressin (DDAVP) is contraindicated in Type 2B VWD because it can worsen thrombocytopenia 1

Important Caveats

• A single VWF:RCo/VWF:Ag ratio measurement is insufficient for definitive diagnosis; repeat testing may be necessary 1, 2

• The diagnostic cutoff for VWF:RCo/VWF:Ag ratio varies between 0.5-0.7 according to different guidelines, with 0.7 being commonly recommended 2

• Screening of first-degree relatives is recommended due to the hereditary nature of VWD 1

• The diagnosis of Type 1 VWD can be particularly challenging when VWF levels are only mildly decreased (40-50 IU/dL), as these levels are weak risk factors for bleeding and may associate with bleeding symptoms by chance 3, 4