What are the diagnostic criteria for Von Willebrand disease (VWD)?

Diagnostic Criteria for Von Willebrand Disease

The diagnosis of von Willebrand disease (VWD) requires a combination of clinical assessment (personal and family history of bleeding) and specific laboratory testing, with no single test being sufficient for diagnosis. 1

Clinical Evaluation

• Initial screening involves asking key questions about bleeding history, which if positive, should lead to more detailed bleeding assessment 1
• Three initial screening questions should be asked to determine if further evaluation is needed:
  • History of prolonged bleeding after surgery or dental procedures
  • History of bruising with minimal trauma
  • History of spontaneous bleeding 1
• If any of these are positive, a more detailed set of nine questions specific for VWD should be asked to assess bleeding symptoms 1

Laboratory Testing Algorithm

Initial Laboratory Tests

• Complete blood count (CBC) and platelet count 1
• Partial thromboplastin time (PTT) 1
• Fibrinogen or thrombin time (optional) 1

Initial VWD-Specific Assays

• VWF antigen (VWF:Ag) - measures the quantity of VWF protein 1
• VWF ristocetin cofactor activity (VWF:RCo) - measures VWF binding to platelets 1, 2
• Factor VIII activity (FVIII) - often decreased in VWD due to reduced VWF carrier function 1, 2

Specialized Testing (if initial tests are abnormal)

• VWF multimer analysis - to determine distribution of VWF multimers (not recommended for initial screening) 1, 3
• VWF:RCo to VWF:Ag ratio - ratio below 0.5-0.7 suggests qualitative VWF defects 1, 4
• VWF collagen binding assay (VWF:CB) - helps reduce misdiagnosis and can decrease need for multimer analysis 5, 4
• Ristocetin-induced platelet aggregation (RIPA) - particularly useful for Type 2B VWD 1, 3
• VWF-FVIII binding assay - for Type 2N VWD 1, 6
• DNA sequencing of VWF gene - for definitive typing in complex cases 1, 3

Diagnostic Criteria by VWD Type

• Type 1 VWD (partial quantitative deficiency):

  • Decreased VWF:Ag and VWF:RCo (typically 30-50 IU/dL)
  • Normal VWF:RCo/VWF:Ag ratio (>0.7)
  • Normal multimer pattern 1, 4

• Type 2 VWD (qualitative defects):

  • Type 2A: Decreased VWF:RCo/VWF:Ag ratio (<0.7) with absence of high and intermediate molecular weight multimers 3, 4
  • Type 2B: Decreased VWF:RCo/VWF:Ag ratio, often with thrombocytopenia and enhanced RIPA 1, 4
  • Type 2M: Decreased VWF:RCo/VWF:Ag ratio with normal multimer pattern 3, 4
  • Type 2N: Normal VWF:Ag and VWF:RCo but decreased FVIII due to defective FVIII binding 4, 6

• Type 3 VWD (complete deficiency):

  • Severely decreased or undetectable VWF:Ag and VWF:RCo
  • Severely decreased FVIII (typically <10 IU/dL) 1, 4

Important Considerations for Testing

• Blood samples should be collected atraumatically at room temperature to prevent cryoprecipitation of VWF 1
• Patient stress, exercise, pregnancy, inflammation, and estrogen therapy can falsely elevate VWF levels 1
• Blood group O individuals have 25% lower VWF levels than other blood groups 1, 4
• African-Americans have higher baseline VWF levels than Caucasians 1, 4
• Plasma samples should be processed promptly at room temperature and thoroughly centrifuged to remove platelets 1
• If not tested within 2 hours, samples should be frozen at or below -40°C 1, 4
• Bleeding time and PFA-100 tests have limited sensitivity and specificity and are not recommended as screening tests 1

When to Refer to a Hematologist

• Abnormal initial VWD assays requiring specialized testing 1, 7
• Significant bleeding history despite normal initial test results 1, 7
• Need for VWF multimer analysis or other specialized VWD studies 1, 7
• Isolated prolonged PTT that corrects on 1:1 mixing study 1, 7