Thrombosis Caused by Factor XI Gly397Ser Mutation with Enhanced Procoagulant Activity
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View abstract on PubMed
Summary
This summary is machine-generated.A novel Factor XI (FXI) mutation, Gly397Ser (G397S), was identified in a patient with deep venous thrombosis (DVT). This mutation enhances FXI activity, leading to increased clotting risk and resistance to clot breakdown.
Area Of Science
- Hematology
- Molecular Biology
- Genetics
Background
- Elevated Factor XI (FXI) levels are linked to increased venous thromboembolism (VTE) risk.
- Genetic mutations causing elevated FXI levels have not been previously identified.
Purpose Of The Study
- To investigate a novel pathogenic FXI mutation, Gly397Ser (G397S), identified in a patient with deep venous thrombosis (DVT).
- To elucidate the molecular mechanisms by which the FXI G397S mutation contributes to thrombotic events.
Main Methods
- Patient genetic sequencing to identify FXI mutations.
- In vitro expression and functional characterization of the FXI G397S mutant protein.
- Enzyme kinetic assays (Km, kcat) and activation studies using polyanions, thrombin, and FXIIa.
- Assays for FXI's activity against Factor IX (FIX) and inhibition by Protease Nexin 2 (PN2).
- Clot lysis assays to assess fibrinolytic resistance.
Main Results
- The FXI G397S mutant showed a 2-fold increase in FXI activity (FXI:C) relative to antigen (FXI:Ag).
- Mutant FXIa exhibited significantly increased catalytic efficiency (kcat) and enhanced activation by thrombin in the presence of heparin.
- The G397S mutation conferred resistance to clot lysis, dependent on thrombin-activatable fibrinolysis inhibitor (TAFI).
Conclusions
- The FXI G397S mutation enhances FXIa activity primarily through increased activation, leading to sustained thrombin generation.
- This hypercoagulable state, coupled with fibrinolytic resistance, underlies the patient's predisposition to DVT.
- Identifies a novel genetic cause for FXI-related thrombophilia.
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