What are the steps to diagnose von Willebrand disease?

How to Diagnose von Willebrand Disease

Diagnose von Willebrand disease using a structured algorithmic approach that begins with a validated bleeding history questionnaire, followed by three mandatory initial laboratory tests (VWF:Ag, VWF:RCo, and FVIII), and then specialized testing based on the pattern of abnormalities. 1, 2, 3

Step 1: Clinical Screening with Structured Bleeding History

Use a validated bleeding assessment tool to systematically evaluate bleeding symptoms, as 80% of specialists rely on these instruments to guide testing decisions. 4 The NHLBI guidelines recommend asking three initial screening questions for asymptomatic patients undergoing surgery, and if any are positive, proceed to a detailed nine-question assessment specifically designed for VWD sensitivity and specificity. 1, 2

Key Bleeding Symptoms to Identify:

• Mucocutaneous bleeding patterns: epistaxis requiring medical intervention, menorrhagia, easy bruising, prolonged bleeding from minor cuts, gingival bleeding 1, 5, 6
• Surgical/procedural bleeding: excessive bleeding during dental extractions, tonsillectomy, or other invasive procedures 2, 7
• Family history of bleeding disorders or similar symptoms 1, 2
• NSAID use in conjunction with bleeding symptoms 2

Physical Examination Findings:

• Ecchymoses, hematomas, petechiae, or active bleeding sites 1
• Signs suggesting alternative diagnoses: jaundice or splenomegaly (liver disease), joint/skin laxity (Ehlers-Danlos), telangiectasias (hereditary hemorrhagic telangiectasia) 1

Step 2: Initial Laboratory Testing

First-Tier Screening Tests:

Order these tests if bleeding disorder is suspected, though they do not diagnose VWD specifically: 1, 3, 4

• Complete blood count (CBC) with platelet count and peripheral smear 1, 4
• Prothrombin time (PT) 1, 4
• Activated partial thromboplastin time (aPTT) 1, 4

Critical caveat: PT and aPTT alone will miss VWD entirely and should never be relied upon to exclude bleeding disorders. 2, 4 The aPTT may be prolonged in severe VWD due to low FVIII, but is often normal in mild-moderate cases. 1

Mandatory Initial VWD Assays (Grade B Recommendation):

All three tests must be ordered simultaneously for patients with strong mucocutaneous bleeding history: 1, 3

1. VWF antigen (VWF:Ag): Measures the quantity of VWF protein 1, 3, 8
2. VWF ristocetin cofactor activity (VWF:RCo): Measures VWF functional activity in platelet binding 1, 3, 8
3. Factor VIII coagulant activity (FVIII): Measures FVIII levels, which are often reduced in VWD 1, 3, 8

Normal reference ranges: 50-200 IU/dL for all three tests 3

Critical Pre-Analytical Considerations:

Sample collection and handling significantly affect results—improper technique leads to false negatives or positives: 1, 3

• Atraumatic blood draw at room temperature to prevent tissue factor activation 1
• Minimize patient stress: anxiety, crying, or recent exercise falsely elevate VWF and FVIII levels 1, 3
• Avoid testing during: acute illness, pregnancy, estrogen/oral contraceptive use—all elevate VWF levels 1, 3
• Transport samples at room temperature, separate plasma promptly, centrifuge thoroughly to remove platelets 1, 3
• If testing delayed >2 hours: freeze at ≤-40°C immediately and thaw at 37°C before assay 1, 3
• Document ABO blood type: Type O individuals have VWF levels 25% lower than other blood groups; African-Americans have higher baseline VWF than Caucasians 1, 3

Step 3: Interpretation of Initial Results

Diagnostic Thresholds:

• VWF:RCo <30 IU/dL: Definitive diagnosis of VWD 3
• VWF:RCo 30-50 IU/dL with supportive clinical/family history: Likely VWD, requires repeat testing 3
• VWF:RCo/VWF:Ag ratio <0.5-0.7: Suggests Type 2 (qualitative) VWD rather than Type 1 (quantitative deficiency) 1, 3, 4

Important limitation: VWF:RCo has high coefficient of variation (10-30%), so repeat testing is often necessary to confirm abnormal results. 1, 3

If All Initial Tests Are Normal But Bleeding History Remains Strong:

• Repeat testing on a separate occasion, ensuring optimal pre-analytical conditions 1, 3
• Consider referral to hemostasis specialist for further evaluation 1

Step 4: Specialized Testing for Subtyping

Order these tests when initial VWD assays show abnormalities or when VWF:RCo/VWF:Ag ratio is <0.5-0.7: 1, 3, 4

VWF Multimer Analysis:

• Not for initial screening—technically complex, qualitatively interpreted, used only for subtyping 1, 3, 4
• Visualizes distribution of VWF multimers to distinguish Type 2A, 2B, 2M subtypes 1, 5, 6
• Should be performed in specialized laboratories with expertise 1, 6

Additional Specialized Assays:

• VWF collagen binding (VWF:CB): Alternative functional assay, particularly useful for Type 2 variants 4, 5, 8
• Ristocetin-induced platelet aggregation (RIPA): Distinguishes Type 2B (increased sensitivity) from other types 1, 7
• FVIII binding assay: Identifies Type 2N (defective FVIII binding) 1
• VWF propeptide measurement: Helps identify increased VWF clearance mechanisms 5
• Genetic sequencing of VWF gene: Confirms diagnosis and guides treatment selection 1, 5

Step 5: Consider Acquired von Willebrand Syndrome (AVWS)

Suspect AVWS if: abnormal VWF results with bleeding symptoms but no personal or family history consistent with hereditary VWD 2

Associated conditions: aortic stenosis (high shear stress causes VWF proteolysis), lymphoproliferative disorders, autoimmune diseases 1

Testing approach: VWF multimer analysis may show isolated loss of high molecular weight multimers even when VWF:RCo is only mildly reduced 1

Common Diagnostic Pitfalls to Avoid

• Relying on single test results: VWF:RCo assay variability (CV 10-30%) mandates repeat testing for borderline values 1, 3
• Testing during acute stress or illness: Inflammatory states, pregnancy, and estrogen use falsely normalize VWF levels, masking diagnosis 1, 3
• Ignoring ABO blood type: Failure to adjust interpretation for Type O patients (naturally lower VWF) leads to overdiagnosis 1, 3
• Improper sample handling: Room temperature transport and proper centrifugation are non-negotiable—frozen samples must remain frozen until analysis 1, 3
• Using PT/aPTT to exclude VWD: These tests miss VWD entirely and provide false reassurance 2, 4
• Ordering VWF multimer analysis as initial test: This specialized test is for subtyping only, not screening 1, 3

When to Refer to Hemostasis Specialist

Immediate referral indicated for: 1

• Abnormal initial VWD assay results requiring subtyping
• Strong bleeding history with repeatedly normal tests
• Suspected AVWS
• Guidance on repeat testing interpretation
• Access to specialized assays (multimer analysis, RIPA, genetic testing)