Discovery of FVIII “Aurora” Mutation Opens New Perspectives for Hemophilia A Therapy.

Researchers from the University of Colorado have identified a naturally occurring gain-of-function mutation in factor VIII (FVIII), designated Arg590Ser and named “FVIII Aurora,” in an 18-year-old male with a history of recurrent, life-threatening thromboses since birth. Laboratory evaluation revealed markedly elevated clotting FVIII activity (300–900% of normal) with normal FVIII antigen and chromogenic activity, alongside increased thrombin generation velocity and reduced responsiveness to activated protein C.

Calibrated automated thrombogram (CAT) assays demonstrated accelerated thrombin production, while CAT with thrombomodulin (CAT-TM) confirmed minimal thrombin reduction in the presence of activated protein C. Genetic sequencing identified the heterozygous missense mutation c.1768C>A in the F8 gene (p.Arg590Ser), located in the A2 domain — a region critical for interactions with activated factor IX and activated protein C. Structural modeling predicted that the variant’s altered conformation could stabilize the A2 domain and prolong factor X activation, contributing to excessive thrombin generation.

Functionally, FVIII Aurora shares conceptual similarities with factor IX Padua, used in hemophilia B therapy, and may represent a future candidate for recombinant protein development in hemophilia A, potentially reducing infusion frequency. However, the prothrombotic potential warrants careful evaluation before clinical application.

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