What are the diagnostic steps and treatments for factor 8 deficiency?

Diagnostic Steps and Treatment for Factor VIII Deficiency

The diagnosis of Factor VIII deficiency requires specific coagulation tests including prolonged activated partial thromboplastin time (aPTT) with normal prothrombin time (PT), followed by Factor VIII activity assay, while treatment depends on severity and involves factor replacement therapy with recombinant or plasma-derived Factor VIII concentrates. 1

Diagnostic Algorithm for Factor VIII Deficiency

Initial Laboratory Screening

• Coagulation Profile:
  • Prolonged aPTT with normal PT and normal thrombin time suggests a defect in the intrinsic pathway 2
  • Normal platelet count should be present 3

Confirmatory Testing

1. Mixing Studies:

   • Mix patient plasma with normal plasma in 1:1 ratio
   • Immediate and 2-hour incubation tests should be performed 2
   • Complete correction suggests factor deficiency
   • Incomplete correction after incubation suggests inhibitor presence 2

2. Factor Assays:

   • Measure Factor VIII, IX, XI, and XII levels 2
   • Isolated low Factor VIII level is diagnostic of Factor VIII deficiency 4
   • One-stage clotting assay: Most commonly used method that measures FVIII activity through correction of aPTT in FVIII-deficient plasma 5
   • Chromogenic assay: More sensitive for detecting severe hemophilia 4

3. Inhibitor Testing:

   • Bethesda assay to quantify inhibitor titer if suspected 2
   • For acquired inhibitors, report the titer corresponding to dilution closest to 50% inhibition 2

4. Additional Testing When Indicated:

   • Lupus anticoagulant testing to rule out false positives 2
   • Genetic testing:
     • DNA analysis for mutations in F8 gene
     • MLPA (Multiplex Ligation-dependent Probe Amplification) technique to detect large deletions 6

Classification of Severity

• Severe: Factor VIII activity <1% of normal
• Moderate: Factor VIII activity 1-5% of normal
• Mild: Factor VIII activity >5% to <40% of normal

Treatment of Factor VIII Deficiency

Acute Bleeding Management

Based on the FDA-approved Factor VIII concentrate dosing 1:

1. Minor Bleeding (early hemarthrosis, mild muscle bleeding):

   • Target Factor VIII level: 20-40% of normal
   • Dose: 10-20 IU/kg
   • Frequency: Every 12-24 hours (every 8-24 hours for patients under age 6)
   • Duration: Until bleeding resolves (approximately 1-3 days)

2. Moderate Bleeding (muscle bleeding, oral cavity bleeding, definite hemarthroses):

   • Target Factor VIII level: 30-60% of normal
   • Dose: 15-30 IU/kg
   • Frequency: Every 12-24 hours (every 8-24 hours for patients under age 6)
   • Duration: Until bleeding resolves (approximately 3 days or more)

3. Major Bleeding (intracranial, gastrointestinal, retroperitoneal):

   • Target Factor VIII level: 60-100% of normal
   • Dose: 30-50 IU/kg
   • Frequency: Every 8-24 hours (every 6-12 hours for patients under age 6)
   • Duration: Until bleeding is resolved

Calculation of Factor VIII Dose

• Required dose (IU) = body weight (kg) × desired Factor VIII rise (IU/dL or % of normal) × 0.5 (IU/kg per IU/dL) 1
• Expected Factor VIII increase (IU/dL) = [total dose (IU)/body weight (kg)] × 2 1

Perioperative Management

• Maintain Factor VIII levels according to the type of surgery
• For major surgery, maintain levels at 60-100% of normal

Special Considerations

Acquired Factor VIII Deficiency (Acquired Hemophilia A)

• Characterized by autoantibodies against Factor VIII
• Requires different management approach:
  • Bypassing agents (recombinant Factor VIIa or activated prothrombin complex concentrates)
  • Immunosuppressive therapy for inhibitor eradication 2

Monitoring Therapy

• Regular Factor VIII activity assays to ensure adequate levels
• Monitor for development of inhibitors, especially in previously treated patients 1

Common Pitfalls in Diagnosis

1. False Normal Results:

   • Immediate correction in mixing studies doesn't exclude inhibitors; time-dependent incubation is essential 2
   • Different aPTT reagents have variable sensitivities; using multiple reagents may be necessary 7

2. Artifactual Results:

   • All intrinsic factors may appear decreased due to in vitro depletion by inhibitor 2
   • Lupus anticoagulant can cause false low factor levels 2

3. Missed Diagnosis in Females:

   • Female carriers with skewed X-inactivation may have low Factor VIII levels
   • Large deletions in F8 gene may be missed by conventional sequencing but detected by MLPA 6

By following this systematic diagnostic and treatment approach, clinicians can effectively manage patients with Factor VIII deficiency to reduce morbidity and mortality associated with bleeding complications.