Neutralizing blood-borne polyphosphate in vivo provides safe thromboprotection.

Area of Science:

• Biochemistry
• Hematology
• Molecular Biology

Background:

• Polyphosphate is an inorganic polymer with procoagulant properties.
• Factor XII plays a role in the intrinsic pathway of coagulation.

Purpose of the Study:

• To investigate the role of polyphosphate in thrombosis.
• To develop and evaluate polyphosphate inhibitors for thromboprotection.

Main Methods:

• Development of recombinant Escherichia coli exopolyphosphatase (PPX) and a variant (PPX_Δ12) to target polyphosphate.
• Assessment of PPX and PPX_Δ12 effects on thrombin generation, platelet activity, and thrombus formation in vitro and in vivo.
• Evaluation of thromboprotection and bleeding risk in wild-type and factor XII-deficient mice.

Main Results:

• PPX and PPX_Δ12 specifically interfere with polyphosphate-driven thrombin formation.
• Targeting polyphosphate reduces platelet procoagulant activity, fibrin accumulation, and thrombus formation in a factor XII-dependent manner.
• Infusions of PPX and PPX_Δ12 protected mice from arterial thrombosis and venous thromboembolism without increasing bleeding.

Conclusions:

• Polyphosphate is a key driver of thrombosis through a factor XII-dependent mechanism.
• Targeting polyphosphate represents a novel strategy for combating thrombotic diseases with a reduced risk of bleeding.