What is factor 8 (FVIII) deficiency?

Factor 8 Deficiency (Hemophilia A)

Factor 8 deficiency, also known as hemophilia A, is a congenital X-linked bleeding disorder caused by deficiency of functional coagulation factor VIII (FVIII), which results in an increased risk of excessive bleeding that varies according to baseline factor plasma levels. 1

Definition and Classification

• Hemophilia A results from deficiency of functional coagulation factor VIII due to pathogenic variants in the F8 gene 1
• Hemophilia A is classified based on factor VIII plasma levels:
  • Severe: <1 IU/dL (international unit per deciliter)
  • Moderate: 1-5 IU/dL
  • Mild: >5-40 IU/dL 1

Epidemiology

• Hemophilia A is more common than hemophilia B, accounting for about 80-85% of all hemophilia cases 1
• The estimated prevalence of hemophilia A at birth is 24.6 cases per 100,000 males 1
• It affects approximately 1,125,000 individuals worldwide 1

Genetics

• Hemophilia A is an X-linked recessive disorder, primarily affecting males 1
• Most individuals with hemophilia A have pathogenic variants in the F8 gene located on the X chromosome 1
• Common genetic mutations include:
  • Intron 22 inversion (prevalent in high-responder patients)
  • Large deletions
  • Small deletions
  • Nonsense mutations 2

Clinical Manifestations

• Individuals with severe forms of hemophilia not treated with prophylaxis may experience spontaneous bleeding 1
• The most frequent bleeding sites are joints (hemarthroses) and muscles 1
• Individuals with mild deficiency may bleed only upon surgical procedures or trauma 1
• Individuals with moderate hemophilia generally have an intermediate bleeding phenotype but may sometimes present with clinical features similar to severe hemophilia 1
• Intracranial bleeds and bleeds into internal organs may be life-threatening 3

Diagnosis

• Prolonged activated partial thromboplastin time (aPTT) is a common laboratory finding 1
• Specific factor assays should be performed to measure FVIII levels 1
• Mixing tests can help distinguish between factor deficiency and the presence of an inhibitor 1
• Genetic testing can identify specific mutations in the F8 gene 2

Treatment

Replacement Therapy

• Bleeding can be mitigated by episodic or prophylactic replacement of FVIII with clotting factor concentrates 1
• Factor concentrates may be:
  • Plasma-derived (manufactured from human plasma)
  • Recombinant (manufactured using mammalian cell culture systems)
    • Standard half-life
    • Extended half-life 1
• Recombinant FVIII provides an increase in plasma levels of Factor VIII and can temporarily correct the coagulation defect 4

Prophylaxis vs. Episodic Treatment

• For severe hemophilia A, prophylactic treatment is strongly recommended over episodic treatment of bleeding events 1
• Prophylaxis has shown large benefits in reducing the risk of bleeding with minimal adverse events 1
• Regular prophylaxis has led to a paradigm shift in outcomes, with patients now able to achieve near-normal life expectancy 3

Complications

Inhibitor Development

• Treatment with FVIII concentrates may lead to the development of antibodies (inhibitors) against the infused clotting factor 1
• The cumulative incidence of inhibitors is higher for patients with severe hemophilia A (20-35%) 1
• Main risk factors for inhibitor development include:
  • Hemophilia severity
  • F8 genotype
  • Cumulative exposure to FVIII concentrates 1
• Baseline inhibitor status has a substantial heritability (~55%) involving F8-mutation-specific components and genetic contributions from immune-mediated disease genes 5

Management of Patients with Inhibitors

• Bypassing agents such as recombinant activated FVII (FVIIa) and activated prothrombin complex concentrate can be used to treat patients with inhibitors 1
• Emicizumab, a non-replacement therapy, is an alternative for prophylactic treatment of patients with severe hemophilia A with and without inhibitors 1
• Immune tolerance induction has been used as standard treatment to eradicate FVIII inhibitors but is not successful in about 30% of individuals 1

Recent Advances

• Non-replacement therapies have emerged as new treatment options 1
• Gene therapy for hemophilia A has progressed remarkably and could soon become a reality 3
• Extended half-life products have reduced treatment burden by requiring less frequent infusions 1

Long-term Outcomes

• With modern treatment, individuals with hemophilia can now achieve virtually normal life expectancy and quality of life 3
• Without adequate treatment, hemophilia A can lead to chronic joint damage (arthropathy) from repeated bleeding episodes 3
• Emerging evidence suggests FVIII may play roles beyond hemostasis, including in cardiovascular health, angiogenesis, and bone health 6