FVIII 'Aurora' Mutation: The Good Guy in Disguise.

As we are preparing for our TBL #1, we studied 'Hemostasis' with the key players that contribute to the platelet plug and coagulation. Factor-VIII is the anti-hemophilic factor A. Mutations on the F8 gene can affect the levels of Factor VIII. Deficiency in this factor results to Hemophilia A, while excess can source to thrombosis (Factor-VIII is a key player in the intrinsic pathway of coagulation). Hemophilia A is the most common bleeding disorder, among the hemophilias, that you may encounter. 

 

I've enjoyed working as a medical scribe at a hemophilia/thrombosis clinic and one of the providers shared an interesting study that is currently happening. What if I told you that there is a F8 gene mutation that is naturally activated but, it doesn't contradict with other players? At the University of Colorado Anschutz Medical Campus, Aurora, a research team has found a natural "gain-of function" mutation on the F8 gene. By studying a 18-year-old who had FVIII activity of 300-900%, they found that this protein variant would antagonize but not activate APC at its binding site and prevents the cleavage for protein C (Wischmeyer et al., 2024). This does not alter the cascade since blood levels/factors were at normal ranges.

There are other contributors and roles that play into coagulation, but can this genetic "gain-of-function" mutation be beneficial to those who have hemophilia? Gene therapy and products exist to assist hemophilic patients in their daily activities. If this gain-of-function may help those with factor deficiency to reset, what "can go wrong" with gain-of-function? What are your opinions on the GOFR (Gain of Function Research)?

    Joshua Wischmeyer, Christine Baird, Julian Grandvallet Contreras, Alexander Tran, Tsu Phang, Marilyn Manco-Johnson; A Novel Factor VIII Mutation with Increased Activity, Severe Thrombosis and Resistance to Activated Protein C. Blood 2024; 144 (Supplement 1): 135. doi: https://doi.org/10.1182/blood-2024-202202