What is the initial workup for a patient suspected of having hemophilia?

Initial Workup for Suspected Hemophilia

The initial workup for a patient suspected of having hemophilia should include activated partial thromboplastin time (aPTT), specific factor assays (FVIII, IX, XI, XII), and mixing studies to distinguish between factor deficiency and inhibitor presence. 1

Step-by-Step Diagnostic Algorithm

1. Initial Laboratory Testing

• Order aPTT as the primary screening test - isolated prolongation of aPTT is characteristic of hemophilia 2
• Order prothrombin time (PT) - typically normal in hemophilia 3
• Complete blood count with platelet count to rule out other bleeding disorders 4

2. Mixing Studies

• Perform mixing tests if aPTT is prolonged to distinguish between factor deficiency and inhibitor presence 1
• Mix patient plasma with normal plasma in 1:1 ratio and measure aPTT immediately and after 2 hours of incubation 1
• Interpretation:
  • Complete correction of aPTT indicates factor deficiency 3
  • Incomplete correction or prolongation after incubation suggests inhibitor presence 1
  • Note: Immediate correction does not exclude acquired hemophilia - further testing is still required if clinical presentation is suggestive 1, 4

3. Specific Factor Assays

• Measure FVIII, IX, XI, and XII levels regardless of mixing test results 1
• Classification of hemophilia severity based on factor levels:
  • Severe: <1% activity
  • Moderate: 1-5% activity
  • Mild: >5% and <40% of normal 1

4. Inhibitor Testing

• If inhibitor is suspected, perform Bethesda assay to quantify inhibitor titer 1
• For accurate results, ensure patient has not received factor replacement for at least:
  • 48 hours for FVIII-deficient cases
  • 72 hours for FIX-deficient cases 1
• Report the titer corresponding to the dilution closest to 50% inhibition 1
• Inhibitors are considered relevant if ≥0.6 Bethesda units (BU) per mL on two separate occasions within 1-4 weeks 1

5. Additional Testing for Differential Diagnosis

• Test for lupus anticoagulant if mixing studies suggest inhibitor presence 1, 4
• In complex cases, FVIII antibody ELISA may help distinguish between lupus anticoagulant and acquired FVIII inhibitor 1, 4
• Consider factor assays at higher serial dilutions of test plasma to attenuate inhibitor effect 1

Important Clinical Considerations

• The clinical presentation should guide testing - spontaneous bleeding into joints and muscles is characteristic of severe hemophilia 2
• Family history is crucial - hemophilia A and B are X-linked recessive disorders 2
• Acquired hemophilia should be considered in patients with no family history, especially in:
  • Postpartum women
  • Patients with autoimmune disorders
  • Elderly patients
  • Patients with malignancy 3, 5

Common Pitfalls to Avoid

• Do not rely solely on aPTT for diagnosis - approximately 10% of patients with acquired hemophilia may not have bleeding at diagnosis 5
• Do not assume normal mixing test excludes hemophilia - specific factor assays are essential 1
• Do not wait for bleeding to worsen before completing diagnostic workup 4
• Be aware that lupus anticoagulant can cause artefactual lowering of factor levels 1
• Inhibitor titers may not correlate well with bleeding severity, especially in acquired hemophilia 4, 5

Follow-up Testing

• For patients diagnosed with hemophilia with inhibitors, monitor inhibitor titers regularly 1
• After inhibitor eradication in acquired hemophilia, follow up with aPTT and FVIII:C monitoring:
  • Monthly during first six months
  • Every 2-3 months up to 12 months
  • Every six months during second year and beyond 1