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 coagulation studies with activated partial thromboplastin time (aPTT), specific factor assays, and mixing studies to confirm diagnosis and determine severity.

Laboratory Evaluation

First-Line Tests

• Coagulation profile:
  • Activated Partial Thromboplastin Time (aPTT) - typically prolonged in hemophilia
  • Prothrombin Time (PT) - usually normal in hemophilia
  • Thrombin Time (TT) - usually normal in hemophilia
  • Complete Blood Count (CBC) with platelet count - usually normal in hemophilia 1

Mixing Studies

• Mix patient plasma with normal pooled plasma in a 1:1 ratio
• Perform immediately and after 2-hour incubation at 37°C
• Correction pattern interpretation:
  • Complete correction suggests factor deficiency (hemophilia)
  • Incomplete correction suggests presence of an inhibitor
  • Time-dependent inhibition (prolongation after incubation) is typical of factor VIII autoantibodies 2, 1

Specific Factor Assays

• Measure intrinsic pathway factors:
  • Factor VIII (hemophilia A)
  • Factor IX (hemophilia B)
  • Factor XI (hemophilia C)
  • Factor XII (not associated with bleeding but can affect aPTT) 1

Classification of Severity Based on Factor Levels

• Severe: <1% of normal factor activity (<0.01 IU/mL)
• Moderate: 1-5% of normal factor activity (0.01-0.05 IU/mL)
• Mild: 5-40% of normal factor activity (0.05-0.4 IU/mL) 2

Additional Testing

For Suspected Acquired Hemophilia

• Bethesda assay to quantify inhibitor titer
• Determination of inhibitor kinetics (type 1 vs. type 2)
• Consider testing for underlying conditions:
  • Autoimmune disorders
  • Malignancy
  • Medication review 2

For Suspected von Willebrand Disease (differential diagnosis)

• von Willebrand factor antigen (VWF:Ag)
• Ristocetin cofactor activity (VWF:RCo)
• Factor VIII activity 3

Special Considerations

Technical Factors Affecting Results

• Different aPTT reagents have varying sensitivities to factor deficiencies:
  • Ellagic acid-based reagents (SynthAFax, Dade Actin, Cephascreen) are preferred for monitoring certain factor replacement therapies
  • Silica-based reagents may show different results 4
• Proper sample processing is essential:
  • Avoid hemolysis
  • Process samples promptly
  • Consider double centrifugation for lupus anticoagulant testing 1

Common Pitfalls

• Immediate correction of aPTT with normal plasma does not exclude acquired hemophilia A
• Lupus anticoagulant can cause artifactual lowering of factor levels
• Factor inhibitors may not be initially apparent and may require re-screening after several days 2
• Age-specific reference ranges should be used, especially in pediatric patients 1

Diagnostic Algorithm

1. Initial screening: aPTT, PT, TT, CBC with platelets
2. If aPTT is prolonged with normal PT:
   • Perform mixing studies
   • If mixing studies show correction: Measure specific factor levels (VIII, IX, XI)
   • If mixing studies show no correction: Perform Bethesda assay for inhibitors and lupus anticoagulant testing
3. If factor VIII or IX deficiency is confirmed:
   • Determine severity based on factor level
   • Consider genetic testing for family counseling
   • Evaluate for inhibitors if previously diagnosed with hemophilia 2, 1

By following this systematic approach, clinicians can accurately diagnose hemophilia, determine its type and severity, and guide appropriate treatment decisions to reduce morbidity and mortality associated with bleeding complications.