What is the appropriate workup and management for a patient with von Willebrand disease?

Workup of von Willebrand Disease

Clinical Assessment

Begin with a validated bleeding assessment tool to systematically document mucocutaneous bleeding patterns—epistaxis, menorrhagia, easy bruising, prolonged bleeding from minor cuts, and bleeding after dental procedures or surgery. 1

• Document family history of bleeding disorders or similar symptoms, as VWD follows autosomal inheritance patterns 1
• Identify bleeding after surgical or invasive procedures (dental extractions, tonsillectomy, childbirth) 1
• Examine for ecchymoses, hematomas, petechiae, or active mucosal bleeding sites 1
• Review medications that may exacerbate bleeding (NSAIDs, aspirin, anticoagulants, antiplatelet agents) 2

Initial Laboratory Testing

Order three mandatory VWD assays simultaneously: VWF antigen (VWF:Ag), VWF ristocetin cofactor activity (VWF:RCo), and Factor VIII coagulant activity (FVIII). 1

• Include CBC with platelet count and peripheral smear, PT, and aPTT to exclude other bleeding disorders 1
• Normal reference ranges are 50-200 IU/dL for VWF:Ag, VWF:RCo, and FVIII 1
• Blood type is essential—Type O individuals have 25-30% lower VWF levels physiologically 1

Critical Pre-Analytical Requirements

Ensure atraumatic blood draw with minimal tourniquet time, as stress and venipuncture trauma artificially elevate VWF levels. 1

• Transport samples at room temperature (never refrigerate) 3
• Separate plasma from blood cells promptly at room temperature 3
• If testing delayed beyond 2 hours, freeze samples at ≤-40°C 3
• Avoid testing during acute illness, pregnancy, inflammatory states, or within 48 hours of exercise, as these elevate VWF levels 1, 3
• Discontinue oral contraceptives 4-6 weeks before testing if clinically feasible 1

Interpretation of Initial Results

Diagnostic Thresholds

• VWF:RCo <30 IU/dL = definitive VWD diagnosis 1
• VWF:RCo 30-50 IU/dL with supportive clinical/family history = likely VWD 1
• VWF:RCo >50 IU/dL generally excludes VWD, though repeat testing may be needed given test variability (coefficient of variation 10-30%) 1

Type Classification

Calculate the VWF:RCo/VWF:Ag ratio to distinguish quantitative from qualitative defects. 1

• Ratio <0.5-0.7 suggests Type 2 (qualitative) VWD requiring specialized testing 1, 3
• Ratio ≥0.7 with proportionally decreased VWF:Ag, VWF:RCo, and FVIII suggests Type 1 (quantitative deficiency) 1
• Markedly low or absent VWF:Ag and VWF:RCo (<3 IU/dL) with very low FVIII suggests Type 3 1

Specialized Testing (When to Order)

Refer to hemostasis specialist for VWF multimer analysis if VWF:RCo/VWF:Ag ratio <0.7 or clinical suspicion remains high despite borderline results. 1

• VWF multimer analysis distinguishes Type 2A (loss of high molecular weight multimers), Type 2B (loss of high molecular weight multimers with thrombocytopenia), and Type 2M (normal multimer pattern with reduced function) 1
• Ristocetin-induced platelet aggregation (RIPA) identifies Type 2B (increased sensitivity to low-dose ristocetin) 1, 4
• VWF collagen binding (VWF:CB) and FVIII binding assay help characterize Type 2 variants 1, 5
• Genetic sequencing of VWF gene confirms diagnosis and aids family counseling 1

Indications for Immediate Hematology Referral

• Abnormal initial VWD assay results requiring subtyping 1
• Strong bleeding history with repeatedly normal tests (consider testing during active bleeding or after desmopressin challenge) 1
• Suspected acquired von Willebrand syndrome (AVWS)—particularly in patients with aortic stenosis, lymphoproliferative disorders, or monoclonal gammopathies 6, 1
• Guidance on repeat testing interpretation or access to specialized assays 1

Common Diagnostic Pitfalls

Never rely on a single test result—VWF levels fluctuate significantly, and the VWF:RCo assay has high variability (10-30% coefficient of variation). 1

• Failure to consider ABO blood type leads to overdiagnosis in Type O individuals 1
• Testing during stress, illness, pregnancy, or on oral contraceptives produces false-negative results 1, 3
• Improper sample handling (refrigeration, delayed processing) causes falsely low results 3
• Relying solely on aPTT (normal in 50% of Type 1 VWD) or bleeding time (poor sensitivity and specificity) misses many cases 1
• Assuming normal FVIII excludes VWD—FVIII may be normal in Type 2 variants 3