Hemophilia A

Aka: Hemophilia A, Hemophilia, Factor VIII Deficiency, Congenital Factor VIII Deficiency, Classic Hemophilia

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II. Epidemiology

  1. Most common hereditary Coagulation Disorder (1:10,000)
  2. Accounts for 80-90% of Hemophilia cases (remainder are primarily Hemophilia B which is a Factor IX Deficiency)

III. Types

  1. Hemophilia A (Classic Hemophilia)
    1. Factor VIII Deficiency
  2. Hemophilia B (Christmas Disease)
    1. Factor IX Deficiency
  3. Hemophilia C
    1. Rare form of Hemophilia primarily affecting Ashkenazi jewish patients

IV. Grading: Hemophilia severity is based on amount of residual active Clotting Factor

  1. Mild disease: 5-40% of normal Clotting Factor activity maintained
    1. Bleeding occurs only with significant Trauma or major surgery
    2. Bleeding events are uncommon and similar to a frequency of those without Hemophilia
  2. Moderate disease: 1-5% of normal Clotting Factor activity maintained
    1. Bleeding occurs with minor Trauma and may occur spontaneously
    2. Bleeding events may occur monthly
  3. Severe disease: <1% of normal Clotting Factor activity maintained
    1. Accounts for two-thirds of Hemophilia patients
    2. Risk of spontaneous bleeding, and events may occur weekly
    3. Major, life-threatening bleeding includes Intracranial Bleeding, Gastrointestinal Bleeding
    4. Most common bleeding is within joints (hemarthrosis), esp. ankles, knees, elbows

V. Pathophysiology

  1. X-linked recessive deficiency of Factor VIII
    1. Limited to males in most cases (although uncommon cases in females)
    2. Most cases occur in patients with a Family History of Hemophilia A (but spontaneous mutation may occur)
  2. Acquired Hemophilia A
    1. Onset postpartum or in age >60 years old
    2. Associated with markedly increased mortality
    3. Results from Factor 8 autoantibodies that neutralize Factor 8 rendering it inactive
      1. Antibodies are formed in pregnancy, autoimmune disorders, infections or with malignancy
    4. Hemorrhage Management starts with factor replacment as below
      1. Also suppress autoantibodies with Prednisone 1 mg/kg (and Rituximab or Cyclophosphamide)

VI. Symptoms

  1. Excessive bleeding from slight Trauma
    1. Dental extraction
    2. Surgery
  2. Visceral and mucosal bleeding
    1. Gastrointestinal beeding
    2. Epistaxis
  3. Hemarthrosis (intraarticular bleeding)
    1. Most commonly affects ankles, knees, and elbows, but may occur within any joint
    2. Contractures
    3. Degenerative Arthritis

VII. Labs

  1. Partial Thromboplastin Time (PTT) elevated
  2. ProTime (INR/PT) normal
  3. Factor VIII assay decreased

VIII. Management: Recombinant Factor VIII replacement

  1. Indications
    1. Acute Bleeding
    2. Preoperative prophylaxis
  2. Dosing basic regimen
    1. Background
      1. Hemophilia severity is based on amount of residual active Clotting Factor
      2. Half-Life of Factor VIII is 12 hours
      3. Active Factor VIII rises 2% for every Factor VIII unit/kg given
      4. Immune response to factor replacement may occur in some Hemophilia A patients
        1. Patient generates inhibitors that deactivate replacement rendering it less effective
    2. Typical dosing
      1. Factor VIII 50 units/kg every 8-12 hours OR
      2. Factor VIII (desired concentration - current concentration) * wtKg every 8-12 hours
    3. Factor VIII Infusion
      1. Load: 50 units/kg
      2. Infusion: 4-5 units/hour (directed by Factor VIII levels)
    4. Acquired Hemophilia A also requires suppression of Factor VIII autoantibodies (see above)
  3. Dosing in major bleeding (directed by involved region and target Factor VIII levels)
    1. Major injury with active bleeding or preoperative and perioperative prophylaxis and management
      1. Target: 100% initially, then 80-100% until wound healed (14 days)
        1. Follow with 30% of normal Factor VIII Level until Suture removal
      2. Recombinant Factor VIII 50 units/kg every 12 hours (adjusted for healing)
    2. Joint bleeding (hemarthrosis)
      1. Target: 80% in acute period, then 40% every other day of normal Factor VIII Level
      2. Recombinant Factor VIII 40 units/kg initially, then 20 units/kg every other day until healed (1-3 days)
      3. Splint joint and consult orthopedics
    3. Gastrointestinal Bleeding
      1. Target: 100% initially, then 50% of normal Factor VIII Level until healed (7-10 days)
      2. Recombinant Factor VIII 50 units/kg initially, then 30-40 units/kg daily
    4. Genitourinary bleeding
      1. Target: 100% initially, then 30% of normal Factor VIII Level until healed (1-3 days)
      2. Recombinant Factor VIII 50 units/kg initially, then 30-40 units/kg daily
    5. CNS Bleeding
      1. Target: 80-100% initially, then 50-100% of normal Factor VIII Level for 14 days
      2. Recombinant Factor VIII 50 units/kg initially, then 25 units/kg every 12 hours
    6. Oral Bleeding
      1. Target: 100% initially, then 50% of normal Factor VIII Level (1-2 days)
      2. Recombinant Factor VIII 50 units/kg initially, then 25 units/kg daily
      3. Consider topical Fibrinolytic agents
    7. Epistaxis
      1. Target: 80-100% initially, then 30% of normal Factor VIII Level until healed (1-3 days)
      2. Recombinant Factor VIII 40-50 units/kg then 30-40 units/kg daily
    8. Muscle bleeding
      1. Target: 50% of normal Factor VIII Level
      2. Recombinant Factor VIII 20-40 units/kg daily until healed (1-3 days)
  4. Alternative agents when Factor VIII is not available
    1. Cryoprecipitate 10 units
      1. Increases Factor VIII to over 100%
    2. Activated Prothrombin Complex Concentrate (FEIBA)
    3. Non-activated Prothrombin Complex Concentrate (e.g. Kcentra)
  5. References
    1. Deloughery and Orman in Majoewsky (2013) EM:Rap 13(9): 1-4
    2. DiMichele (1996) Pediatr Clin North Am 43(3): 709-36 [PubMed]

IX. Prevention

  1. Medical alert bracelet
  2. Treatment plan from Hemophilia treatment center
  3. Patients may carry their own factor replacment (preferred)

X. References

  1. Swaminathan and Patel in Herbert (2019) EM:Rap 19(10): 1-3
  2. Jones (2024) Am Fam Physician 110(1): 58-64 [PubMed]

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