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. Findings

  1. Excessive bleeding from slight Trauma
    1. Dental extraction
    2. Surgery
  2. Visceral and mucosal bleeding
    1. Gastrointestinal beeding
    2. Hematuria
    3. Epistaxis
  3. Hemarthrosis (intraarticular bleeding)
    1. Most commonly affects ankles, knees, and elbows, but may occur within any joint
    2. Joint Swelling may be preceded by Paresthesias, pain or joint warmth prior
    3. Contractures
    4. Degenerative Arthritis
  4. Intramuscular Hematomas
    1. May affect deep space with occult Hematomas
    2. Iliopsoas Muscle related retroperitoneal Hematomas (may occur spontaneously without Trauma)
      1. Retroperitoneal Hemorrhage is among the Leading Causes of Death in Hemophilia
  5. Intracranial Hemorrhage
    1. Leading cause of death in Hemophilia

VII. Labs

  1. Partial Thromboplastin Time (PTT) elevated
  2. ProTime (INR/PT) normal
  3. Bleeding Time is normal
  4. Factor VIII assay decreased
    1. Factor VIII is considered 100% when measured at 1 unit factor/ml plasma
    2. Normal Hemostasis occurs when activity 50-150% (0.5 to 1.5 units/ml)

VIII. Imaging

  1. Have a low threshold for CT imaging with new symptom presentations in Hemophilia
    1. Acute Headache (esp. with Altered Level of Consciousness)
    2. Acute spontaneous flank or Abdominal Pain

IX. 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
        1. Contrast with Factor IX replacement which increases 1% for every unit given
        2. Therefore calculated Factor VIII replacement is multiplied by 0.5 (see below)
      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 * 0.5 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. 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
      3. Avoid antifibrinolytic medications (TXA, EACA) in Hematuria (risk of thrombotic ureteral obstruction)
    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 (e.g. Tranexamic Acid)
      4. Other systemic agents
        1. See Tranexamic Acid (TXA) and E-aminocaproic acid (EACA, Amicar) below
    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. Moderate Bleeding
    1. Dosing
      1. Factor VIII 25 units/kg
    2. Indications
      1. Hematomas with dissection or involving soft tissue or Muscle
      2. Traumatic Epistaxis
      3. Oral Mucosal or Tongue Lacerations
      4. Dental extractions
      5. Hemarthrosis with late presentations (or unresponsive to treatment)
      6. Severe Hematuria
  5. Mild Persistent Bleeding
    1. Dosing
      1. Factor VIII 12.5 units/kg
      2. Desmopressin 0.3 mcg/kg IV over 30 minutes (or via nasal spray)
        1. See below
    2. Indications
      1. Deep Lacerations
      2. Major spontaneous Epistaxis
      3. Major Oral Mucosa or Tongue bites
      4. Mild Hematuria
      5. Early hemarthrosis
      6. Muscle Hematoma
  6. Mild Intermittent Bleeding
    1. No factor replacement needed
    2. Indications
      1. Abrasions and mild Lacerations
      2. Minor, controlled spontaneous Epistaxis
      3. Superficial Oral Mucosal or Tongue bites
      4. Minor Hematoma
  7. Alternative agents when Factor VIII is not available
    1. Cryoprecipitate 10 units
      1. Increases Factor VIII to over 100%
    2. Prothrombin Complex Concentrate (PCC, Kcentra)
    3. Factor VIII inhibitor-bypassing activity (FEIBA)
  8. Adjunctive Medications
    1. Consult Intervention Radiology and surgery for localized Hemorrhage source control
    2. Avoid antifibrinolytic medications (TXA, EACA) in Hematuria (risk of thrombotic ureteral obstruction)
    3. Tranexamic Acid (TXA, preferred)
      1. See Tranexamic Acid for IV dosing
      2. Oral: Take 1 g four times daily for 3-8 days
    4. E-aminocaproic acid (EACA, Amicar, adult dosing)
      1. Less potent than TXA, with greater toxicity and a shorter Half-Life
      2. IV: 4-5 g load IV, then 1 g/h infusion
      3. Oral: 4 g every 4-6 hours orally for 2-8 days
    5. Desmopressin 0.3 mcg/kg IV over 30 minutes (or via nasal spray)
      1. Only effective in mild Hemophilia (will not work in moderate to severe)
      2. Triggers release of VWF into plasma from cellular stores
        1. Immediately increases Factor VIII by 2-3x
      3. Strong Diuretic effect
        1. Risk of hypnatremia (avoid in age <2 years due to cerebral edema risk)
        2. Decrease total fluid fluid intake if >1 dose taken in a day
  9. Precautions
    1. Some Hemophilia patients develop antibodies to Factor VIII or Factor IX
      1. Results in lower efficacy of factor replacement
  10. 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]

X. Prevention

  1. Medical alert bracelet
  2. Treatment plan from Hemophilia treatment center
  3. Patients may carry their own factor replacement (preferred)
  4. Emicizumab
    1. Monoclonal Antibody that mimics activated Factor VIII
    2. Effective even when Factor VIII antibodies are present

XI. References

  1. Hoag, Jundoria, Dave and Lopez (2026) Crit Dec Emerg Med 40(7): 4-13
  2. Swaminathan and Patel in Herbert (2019) EM:Rap 19(10): 1-3
  3. Jones (2024) Am Fam Physician 110(1): 58-64 [PubMed]

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