Journal
BLOOD
Volume 141, Issue 16, Pages 2022-2032Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2022018083
Keywords
-
Categories
Funding
- National Institutes of Health, National Heart, Lung, and Blood Institute [P01 HL139420]
- Bayer
Ask authors/readers for more resources
In this study, we generated FIXa variants with altered reactivity to plasma inhibitors and found that delayed FIXa inhibition has a major impact on reducing bleeding and promoting thrombus formation.
Factor IXa (FIXa) plays a pivotal role in coagulation by contributing to FX activation via the intrinsic pathway. Although antithrombin (AT) and other plasma inhibitors are thought to regulate FIXa procoagulant function, the impact of FIXa inhibition on thrombin generation and clot formation in vivo remains unclear. Here, we generated FIXa variants with altered reactivity to plasma inhibitors that target the FIXa active site but maintain procoagulant function when bound to its cofactor, FVIIIa. We found that selected FIXa variants (eg, FIXa-V16L) have a prolonged activity half-life in the plasma due, in part, to AT resistance. Studies using hemophilia B mice have shown that delayed FIXa inhibition has a major impact on reducing the bleeding phenotype and promoting thrombus formation following administration of FIX protein. Overall, these results demonstrate that the regulation of FIXa inhibition contributes in a major way to the spatial and temporal control of coagulation at the site of vascular injury. Our findings provide novel insights into the physiological regulation of FIXa, enhance our understanding of thrombus formation in vivo via the intrinsic pathway, and suggest that altering FIXa inhibition could have therapeutic benefits.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available