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Children’s Hospital of Philadelphia Researchers Show Clotting Proteins Affect Stability in Preclinical Models of Hemophilia A

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Children’s Hospital of Philadelphia Researchers Show Clotting Proteins Affect Stability in Preclinical Models of Hemophilia A
Study offers important foundation in the development of therapeutic drug design
July 16, 2025

Hemophilia A (HA) is a rare bleeding disorder characterized by a deficiency of the clotting protein factor VIII (FVIII). Likewise, excess FVIII can raise the risk of dangerous blood clots in the veins. Researchers at Children’s Hospital of Philadelphia (CHOP) sought to better understand how the body regulates activated FVIII function, especially in interactions with other clotting factors, to inform associated pathology and therapeutic drug design. The findings were reported in the journal Blood. 

Using preclinical models, researchers investigated two biological processes that inactivate activated FVIII. One involved cleavage of the protein by an enzyme called activated protein C (APC), which plays a role in regulating blood coagulation, and the other pertains to part of the activated FVIII molecule spontaneously breaking away, known as A2 dissociation. 

The researchers found that interactions with activated FIX and FX can profoundly impact activated FVIII inactivation pathways and demonstrated that both mechanisms of activated FVIII regulation are important in vivo. Researchers note that the insights gained from the study are important because they have led to an engineered FVIII variant that is resistant to inactivation and ongoing studies are exploring how well the gain-of-function variant works compared to current treatment options for HA. 

Lindsey A. George, MD
Lindsey A. George

“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 work was supported by NIH/NHLBI T32 8247140823-12 and K08 HL14699. The Hemostasis and Thrombosis Research Society (HTRS) Mentored Research Award for Gene Therapy in Hemophilia A sponsored by Spark Therapeutics and HTRS Medical Student Development award.

Morris et al. “Factor IXa and Factor X Influence Factor VIIIa Stability and Inactivation Mechanisms In Vitro and In Vivo.” Blood. Online July 15, 2025. DOI: 10.1182/blood.2024027705.

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