What is Factor VIII deficiency (Hemophilia A)?

Factor VIII Deficiency (Hemophilia A)

Factor VIII deficiency, also known as Hemophilia A, is an X-linked genetic bleeding disorder characterized by a deficiency of functional coagulation factor VIII, resulting in spontaneous and trauma-induced bleeding episodes that can lead to significant morbidity and mortality if not properly managed. 1

Pathophysiology and Classification

Hemophilia A is caused by mutations in the F8 gene located on the X chromosome, which encodes for factor VIII protein primarily produced by liver sinusoidal endothelial cells. This results in:

• Defective coagulation cascade function
• Impaired thrombin generation
• Inadequate fibrin clot formation

Severity classification is based on factor VIII levels:

Severity	Factor VIII Level (IU/dL)
Severe	<1%
Moderate	1-5%
Mild	>5-40%

Clinical Presentation

The clinical manifestations vary based on disease severity:

• Severe hemophilia: Spontaneous bleeding into joints (hemarthroses) and muscles, potential life-threatening bleeding in brain and internal organs
• Moderate hemophilia: Occasional spontaneous bleeding, prolonged bleeding after minor trauma
• Mild hemophilia: Bleeding typically only after surgery or significant trauma

Common bleeding manifestations include:

• Joint bleeding (hemarthroses) - most common in ankles, knees, and elbows
• Muscle hematomas
• Mucosal bleeding (epistaxis, gingival bleeding)
• Hematuria
• Intracranial hemorrhage (life-threatening)

Diagnosis

Diagnosis of hemophilia A involves:

1. Laboratory testing:

   • Prolonged activated partial thromboplastin time (aPTT)
   • Normal prothrombin time (PT)
   • Reduced factor VIII activity levels
   • Mixing studies to distinguish factor deficiency from inhibitors

2. Genetic testing:

   • F8 gene mutation analysis
   • Family history assessment

Treatment Approaches

Replacement Therapy

For patients without inhibitors:

• Factor VIII concentrates (plasma-derived or recombinant)
• Dosing based on severity of bleeding and patient weight
• Formula: Weight (kg) × desired FVIII increase (%) × 0.5 = units required

For Patients with Mild Hemophilia A (FVIII >5%)

• Desmopressin (DDAVP) - stimulates release of von Willebrand factor and FVIII from endothelial cells
  • Dosing: 0.3 μg/kg intravenously 2
  • Administered 30 minutes prior to procedures
  • Not effective for severe hemophilia A (FVIII ≤5%) 2

For Patients with Inhibitors

Approximately 20-35% of severe hemophilia A patients develop neutralizing antibodies (inhibitors) against infused FVIII 1. Treatment options include:

• Bypassing agents:

  • Recombinant activated factor VII (rFVIIa): 90 μg/kg every 2-3 hours until hemostasis 3
  • Activated prothrombin complex concentrates (aPCCs): 50-100 IU/kg every 8-12 hours (maximum 200 IU/kg/day) 3

• Immune tolerance induction (ITI) - for inhibitor eradication:

  • Regular infusions of FVIII to induce immune tolerance
  • Often combined with immunosuppressive therapy

Prophylactic Therapy

Prophylactic therapy is strongly recommended over episodic treatment for severe hemophilia A to prevent joint damage and improve quality of life. 1

• Standard prophylaxis: Regular FVIII infusions (at least once per week)
• Emicizumab: Subcutaneous FVIII-mimetic bispecific monoclonal antibody approved for prophylaxis in patients with or without inhibitors 1

Management of Specific Bleeding Episodes

Joint Bleeding (Hemarthroses)

• Immediate factor replacement
• RICE (Rest, Ice, Compression, Elevation)
• Physical therapy after acute phase

Muscle Bleeding

• Factor replacement therapy
• Immobilization and rest
• Monitor for compartment syndrome

Life-threatening Bleeding

• Immediate factor replacement to 100% activity level
• Hospitalization and close monitoring
• Consideration of adjunctive hemostatic agents

Complications

1. Inhibitor development (20-35% of severe hemophilia A patients) 1

   • Most serious complication of factor replacement therapy
   • Regular monitoring for inhibitors essential

2. Hemophilic arthropathy

   • Chronic joint damage from recurrent hemarthroses
   • Leading cause of morbidity

3. Viral transmission

   • Historical concern with plasma-derived products
   • Modern purification methods have virtually eliminated this risk

Monitoring

• Regular assessment of factor VIII levels
• Inhibitor screening (Bethesda assay)
• Joint health evaluation
• Quality of life assessment

Comprehensive Care Approach

Optimal management requires a multidisciplinary team including:

• Hematologists
• Physical therapists
• Orthopedic specialists
• Genetic counselors
• Psychosocial support

Prevention Strategies

• Genetic counseling for families
• Carrier testing for at-risk females
• Prenatal diagnosis options
• Regular prophylactic therapy to prevent bleeding episodes

Factor VIII deficiency represents a significant clinical challenge requiring specialized care to minimize bleeding complications and optimize quality of life for affected individuals.