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Oxidized PDI promotes thrombus formation in oxidative stress
Moua Yang1,2,3, Osamede Clinton Owegie1, Anika Patel3
1Bloodworks Northwest Research Institute, Seattle, WA.
Blood
|March 5, 2026
Summary
Protein disulfide isomerase (PDI) oxidation, not reduction, drives blood clot formation. Targeting PDI
Area of Science:
- Biochemistry
- Hematology
- Molecular Biology
Background:
- Protein disulfide isomerase (PDI) is crucial for thrombus formation and a potential antithrombotic target.
- PDI acts as a redox sensor, but its role as a reductase or oxidase in thrombosis is unclear.
Purpose of the Study:
- To investigate the role of PDI's redox state in thrombus formation.
- To determine if PDI's reductase or oxidase activity is primarily responsible for promoting thrombosis.
Main Methods:
- Utilized pharmacological agents (LOC14) and PDI mutants to modulate PDI's redox state.
- Assessed thrombus formation in vivo using FeCl3-induced arterial thrombosis and cremaster arteriole injury models.
- Employed PDI mutants (C53A, C56A, R120D, T101A) to evaluate sulfenylation-mediated oxidation and peroxide-induced oxidation.
Main Results:
- LOC14, an inhibitor of PDI reductase activity, promoted thrombus formation and platelet accumulation.
- A modified LOC14 analog reversed these prothrombotic effects, as did blocking antibodies against PDI.
- PDI mutants unable to undergo peroxide-mediated oxidation showed impaired thrombus formation in oxidative stress conditions (GPx3-/- mice).
- Wild-type PDI and a specific mutant (R120D) restored thrombus formation after PDI knockdown, but the R120D mutant failed under oxidative stress.
Conclusions:
- PDI-catalyzed oxidation, particularly peroxide-mediated oxidation, is a key driver of in vivo thrombus formation.
- PDI's prothrombotic function is linked to its oxidative capacity, especially under conditions of oxidative stress.
- These findings highlight PDI oxidation as a critical mechanism in thrombosis and a potential therapeutic target.
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