What is Hemophilia A?

Hemophilia A: Definition and Clinical Overview

Hemophilia A is an X-linked congenital bleeding disorder resulting from deficiency of functional coagulation factor VIII (FVIII), which is encoded by the F8 gene and primarily produced by liver sinusoidal endothelial cells. 1

Pathophysiology and Genetics

• Hemophilia A is the most common inherited bleeding disorder, accounting for 80-85% of all hemophilia cases with an estimated prevalence of 24.6 cases per 100,000 males at birth 1
• The disorder is caused by mutations in the F8 gene located on the X chromosome, resulting in reduced or absent FVIII activity 1, 2
• Common genetic mutations include:
  • Intron 22 inversions (approximately 50% of severe cases) 2
  • Intron 1 inversions (approximately 5% of severe cases) 2
  • Large gene deletions (approximately 5% of severe cases) 2
  • Point mutations and small insertions/deletions (remaining severe cases and all moderate/mild cases) 2

Disease Classification

• Hemophilia A is classified based on factor VIII levels in plasma 1:
  • Severe: <1 IU/dL (<1% of normal)
  • Moderate: 1-5 IU/dL (1-5% of normal)
  • Mild: >5-40 IU/dL (>5-40% of normal)

Clinical Presentation

• Individuals with severe hemophilia A experience spontaneous bleeding, particularly in joints and muscles, eventually leading to painful and disabling hemophilic arthropathy 1
• Life-threatening bleeding in the brain and other internal organs can occur 1
• Bleeding severity correlates with the degree of factor deficiency 3:
  • Severe hemophilia: spontaneous bleeding into joints and muscles
  • Moderate hemophilia: intermediate bleeding phenotype, sometimes similar to severe hemophilia 1
  • Mild hemophilia: bleeding typically occurs only with surgery or trauma 1

Laboratory Diagnosis

• Characteristic laboratory findings include 4:
  • Prolonged activated partial thromboplastin time (aPTT)
  • Normal prothrombin time (PT)
  • Reduced FVIII activity in plasma
• Mixing tests should be performed to distinguish between factor deficiency and inhibitor presence 4
• Specific factor assays (FVIII, IX, XI, XII) should be measured to confirm diagnosis 4

Treatment Approaches

• Prophylaxis with FVIII replacement products is the standard of care for severely affected patients 1
• The International Society on Thrombosis and Haemostasis (ISTH) strongly recommends prophylaxis over episodic treatment for severe hemophilia 1
• Treatment options include 1, 4:
  • Plasma-derived or recombinant FVIII concentrates
  • Extended half-life FVIII products
  • Emicizumab (a subcutaneous FVIII-mimetic bispecific monoclonal antibody)
  • Gene therapy (emerging option)

Complications

• Development of neutralizing antibodies (inhibitors) against FVIII occurs in 20-35% of patients with severe hemophilia A 1
• When inhibitors develop, bypassing agents are required for bleeding control 4:
  • Recombinant activated factor VII (rFVIIa)
  • Activated prothrombin complex concentrates (aPCCs)
• Hemophilic arthropathy from recurrent joint bleeding is a major cause of morbidity 1

Acquired Hemophilia A vs. Congenital Hemophilia A

• Acquired hemophilia A (AHA) is distinct from congenital hemophilia A 1:
  • AHA is caused by autoantibodies against FVIII rather than genetic mutations
  • AHA typically affects elderly patients with no prior history of bleeding disorders
  • AHA presents with spontaneous bleeding and isolated prolonged aPTT
  • Treatment of AHA focuses on controlling acute bleeding and eradicating autoantibodies

Recent Advances

• Gene therapy using recombinant adeno-associated virus (AAV) vectors to transfer functional F8 genetic information into hepatocytes is an emerging treatment option 1, 5
• Emicizumab provides less frequent dosing regimens (every 1-2 weeks) compared to traditional factor replacement 1

Hemophilia A remains a challenging condition requiring specialized care, but advances in treatment options continue to improve outcomes and quality of life for affected individuals.