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Helical Organization of Blood Coagulation Factor VIII on Lipid Nanotubes
Published on: June 3, 2014
Factor VIII Aurora: A Naturally Occurring Gain of Function FVIII Variant with Enhanced FIXa Affinity
Johnathan J Morris1, Robert J Davidson2, Connor T Watson1
1Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States.
Blood
|July 14, 2026
Summary
Factor VIII Aurora (FVIII-R571S), a naturally occurring variant, shows enhanced potency due to increased FIXa affinity, leading to thrombosis. This variant explains gain-of-function phenotypes and reduced APC resistance in hemophilia A.
Area of Science:
- Hematology
- Molecular Biology
- Biochemistry
Background:
- Factor VIII Aurora (FVIII-R571S) is a novel, naturally occurring enhanced-potency Factor VIII variant.
- This variant was identified in a patient experiencing recurrent thrombosis and early mortality.
- The patient's plasma displayed heightened procoagulant activity and diminished responsiveness to activated protein C (APC).
Purpose of the Study:
- To elucidate the underlying mechanism of the enhanced potency and prothrombotic phenotype of FVIII-R571S.
- To investigate the biochemical and functional properties of the FVIII-R571S variant in vitro and in vivo.
Main Methods:
- Generation of recombinant FVIII-R571S for in vitro and in vivo studies.
- Assays included one-stage and chromogenic substrate assays to measure procoagulant activity.
- Biochemical analyses determined FVIIIa-R571S affinity for FIXa, A2-domain dissociation, and APC inactivation.
- In vivo studies utilized hemophilia A mice for tail clip and thrombosis models.
Main Results:
- FVIII-R571S exhibited a 6-fold increase in one-stage assay activity, with comparable chromogenic activity to wild-type FVIII (FVIII-WT).
- Activated FVIII-R571S (FVIIIa-R571S) demonstrated a 10-20-fold higher affinity for FIXa, explaining the discrepancy in assay activities.
- In vivo, FVIII-R571S showed a 4-5-fold increase in potency in hemophilia A mice and promoted greater platelet and fibrin accumulation in a thrombosis model.
Conclusions:
- The prothrombotic phenotype of FVIII-R571S is attributed to increased FIXa affinity, enhancing FVIIIa-FIXa complex assembly and function.
- This increased affinity confers reduced A2-domain dissociation and functional APC resistance, unifying the gain-of-function phenotype.
- Understanding FVIII-R571S provides insights into Factor VIII function, thrombotic disorders, and potential therapeutic targets.
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