What are the causes of Factor VIII (8) deficiency, also known as Hemophilia A?

From the Guidelines

Factor 8 deficiency (hemophilia A) is primarily caused by genetic mutations in the F8 gene located on the X chromosome, which is why it predominantly affects males through X-linked recessive inheritance. Women can be carriers of the mutation and may experience mild symptoms. About 30% of cases occur without a family history due to spontaneous mutations 1. Acquired factor 8 deficiency can develop later in life through autoimmune conditions where the body produces antibodies against its own factor 8, often associated with pregnancy, autoimmune disorders like rheumatoid arthritis or lupus, certain cancers, or as a reaction to medications. Severe liver disease can also cause factor 8 deficiency since the liver produces many clotting factors. Von Willebrand disease, while technically a different condition, can present with reduced factor 8 activity because von Willebrand factor protects factor 8 from degradation in the bloodstream.

Key Points

• Hemophilia A results from deficiency of functional coagulation factor (F)VIII and is more common than hemophilia B, accounting for about 80% to 85% of all hemophilia cases 1.
• The estimated prevalence of hemophilia A and B (all severities) at birth is 24.6 and 5.0 cases per 100,000 males, respectively 1.
• Individuals with hemophilia live with an increased risk of excessive bleeding, which varies according to the baseline factor plasma levels 1.
• Treatment approaches differ based on whether the deficiency is inherited or acquired, with replacement therapy being common for inherited forms and immunosuppression often needed for acquired forms. Recently, nonreplacement therapies have emerged as new treatment options for hemophilia, such as emicizumab, an alternative to FVIII concentrates and bypassing agents for the prophylactic treatment of patients with severe hemophilia A with and without inhibitors 1.

Considerations

• The cumulative incidence of inhibitors is higher for patients with severe hemophilia A (20%-35%) than with severe hemophilia B (4%-9%) 1.
• The main risk factors for inhibitor development are hemophilia severity, F8/F9 genotype, and cumulative exposure to FVIII and FIX concentrates 1.
• Bypassing agents such as recombinant activated FVII (FVIIa) and activated prothrombin complex concentrate can be used to treat patients with inhibitors whose bleeding does not respond to replacement of the deficient factor 1.

From the Research

Causes of Factor VIII Deficiency

The causes of Factor VIII deficiency, also known as Hemophilia A, are attributed to genetic mutations in the F8 gene.

• The F8 gene mutations can result in quantitative deficiency of coagulation factor VIII (FVIII) 2.
• These mutations can be in the form of premature truncation variants, missense mutations, or splice-site variants 2.
• Large deletions and small insertions and deletions in the F8 gene can also predict unfavorable immune tolerance induction outcome in people with severe hemophilia A and high-responding inhibitors 3.
• A novel deletion mutation of the F8 gene, such as the c.6343delC variant, can also cause hemophilia A by affecting the production of factor VIII 4.
• The genetic variants in the F8 gene can lead to the development of neutralizing anti-FVIII antibodies (inhibitors) in some individuals with hemophilia A 5.

Genetic Mutations

The genetic mutations in the F8 gene can be classified into different types, including:

• Premature truncation variants (nonsense, frameshift) 2
• Missense mutations 2
• Splice-site variants 2
• Large deletions 3
• Small insertions and deletions 3
• Novel deletion mutations, such as the c.6343delC variant 4

Relationship between Genetic Variants and Disease Severity

There is a relationship between the genetic variants in the F8 gene and the disease severity of hemophilia A.

• Certain genetic variants, such as high-impact genetic variants (nonsense and frameshift), can increase the risk of inhibitor development 2.
• The location of the genetic variant in the F8 gene, such as the heavy or light chain, can also influence the risk of inhibitor development 2.
• The type of genetic variant, such as large deletions or small insertions and deletions, can predict unfavorable immune tolerance induction outcome in people with severe hemophilia A and high-responding inhibitors 3.