Researchers Uncover A Previously Underappreciated Mechanism that Turns Off Clotting Factor in Hemophilia A

Researchers at Children’s Hospital of Philadelphia (CHOP) have outlined a mechanism responsible for turning off coagulation factor VIII (FVIII), the protein that is lacking in hemophilia A, leading to uncontrolled bleeding events. The findings, which were recently published in Blood, uncover a relevant mechanism that was previously thought to have a marginal role in controlling FVIII function that could potentially be exploited for targeted therapies.

FVIII circulates in blood tightly bound to its carrier protein, von Willebrand factor, and becomes an active cofactor known as FVIIIa when it separates from its carrier. FVIIIa consists of three subunits: an A2-domain and two metal ion-stabilized subunits. Given that previous in vitro studies showed spontaneous A2-domain dissociation was much faster at inactivating FVIIIa than cleavage by activated protein C (APC), spontaneous dissociation of the A2-domain was seen as the primary cause of FVIIIa inactivation.

However, despite decades of FVIII research in vitro, the role of APC in FVIIIa regulation in vivo had not been examined, so the researchers decided to characterize the role of APC cleavage in inactivating FVIIIa. To do so, they created a FVIII variant that was resistant to APC cleavage and found the variant resisted cleavage by APC without altering its clotting abilities or stability, which conferred an approximate 4- to 5-fold increased ability to stop bleeding events.

“These data show that APC has an in vivo regulatory role in FVIIIa function, which was previously thought to be relatively insignificant,” said senior author Lindsey A. George, MD, an attending physician in the Division of Hematology at CHOP. “Future considerations may be given to exploiting factor VIIIa resistance to APC to develop novel hemophilia A therapeutics, particularly gene-based therapies.”

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