Discovery of New Genetic Variant Could Transform Hemophilia A Treatment

Research study background

A recent discovery by researchers from the Hemophilia and Thrombosis Center at the University of Colorado Anschutz Medical Campus and the Hematology Program at Children’s Hospital Colorado has the potential to transform future treatment strategies for hemophilia A. Hemophilia A is a serious inherited bleeding disorder caused by changes in the Factor 8 gene that lead to a deficiency in factor FVIII (FVIII), an essential blood-clotting protein. The standard therapy for hemophilia involves burdensome FVIII infusions, typically given to patients every few days to help prevent bleeding in the joints and other areas.

Investigators identified a rare, naturally occurring gain-of-function mutation in FVIII when studying a banked plasma sample collected during a CU Anschutz-led prospective study of individuals with thrombosis, stroke and related clotting disorders. The findings, published in the New England Journal of Medicine, highlight the translational power of affiliation between the two programs, which unites cross-campus expertise to advance treatment and research of bleeding and clotting disorders in children and adults.

The sample came from a male patient treated at Children’s Colorado, 18 years old at the time, who had experienced severe, recurrent thromboses that began in infancy and continued throughout his life, ultimately leading to his death at age 33. Standard laboratory testing showed unusually high FVIII clotting activity, three to nine times higher than in control plasma, while all other clotting factors and assays appeared normal. Investigators used calibrated automated thrombogram assays to measure the rate and amount of thrombin generation, a key enzyme in blood clot formation. When thrombomodulin was added to trigger the body’s natural anticoagulant, activated protein C (APC), the sample showed rapid thrombin generation with little reduction, indicating strong APC resistance. This effect was not seen in more than 400 comparison samples with high FVIII levels, suggesting that the FVIII protein itself was abnormally overactive.

Whole-genome sequencing identified a previously unknown heterozygous missense mutation (p.Arg590Ser) in the F8 gene’s A2 domain on the X chromosome. Researchers named this discovery FVIII Aurora. Structural modeling indicated the mutation is located near binding regions for two key regulators of clotting, APC and activated factor IX. It was not near any thrombin-binding sites. Further testing confirmed Aurora FVIII is only minimally responsive to APC, and computer modeling found a protrusion at the surface that may interfere with normal APC binding.

Clinical implications

Study authors noted that FVIII Aurora could represent a promising new therapeutic target for hemophilia A, potentially restoring normal clotting. Unlike excessive bleeding caused by low FVIII activity, this variant produced the opposite effect. It appears to amplify thrombin generation by stabilizing the A2 domain and extending its activation, similar to factor IX Padua, a hyperactive variant used in gene therapy for hemophilia B to enhance clotting efficiency.

The team is now producing recombinant FVIII to study how FVIII Aurora influences clotting, seeking insights that could guide development of safer, longer-lasting therapies for people with hemophilia A.