Researchers at the Children’s Hospital of Philadelphia (CHOP) have made strides in understanding Hemophilia A, a rare bleeding disorder caused by a deficiency in the clotting protein factor VIII (FVIII). Their study, published in the journal Blood, explores how activated FVIII interacts with other clotting factors and its regulation within the body. This research aims to inform both pathology and therapeutic drug design.
The team utilized preclinical models to examine two biological processes that deactivate activated FVIII. One process involves an enzyme called activated protein C (APC), which regulates blood coagulation by cleaving FVIII. The other process involves a spontaneous event known as A2 dissociation, where part of the activated FVIII molecule breaks away.
Findings from this study reveal that interactions with activated FIX and FX significantly affect pathways for deactivating activated FVIII. These insights have led to developing an engineered FVIII variant resistant to inactivation. Ongoing studies are comparing this gain-of-function variant against current treatment options for Hemophilia A.
“Our findings provide new insight into how the FVIII protein is regulated, which could be leveraged to improve FVIII function for therapeutic benefit,” said Lindsey A. George, Director of Clinical In Vivo Gene Therapy and an attending physician in the Division of Hematology at CHOP. “In the long run, we hope these findings will inform novel therapeutic development for individuals living with Hemophilia A.”
This research received support from NIH/NHLBI T32 8247140823-12 and K08 HL14699 grants and awards from the Hemostasis and Thrombosis Research Society (HTRS), Spark Therapeutics, and HTRS Medical Student Development.
The study titled “Factor IXa and Factor X Influence Factor VIIIa Stability and Inactivation Mechanisms In Vitro and In Vivo” by Morris et al., was published online on July 15, 2025.
