Nontoxic polyphosphate inhibitors reduce thrombosis while sparing hemostasis.

Area of Science:

• Biochemistry
• Pharmacology
• Hematology

Background:

• Polyphosphate (polyP), secreted by activated platelets, is implicated in thrombosis and represents a potential antithrombotic target.
• Existing polyP inhibitors, often polycationic, exhibit significant in vivo toxicity due to multiple primary amines.
• There is a need for safer antithrombotic agents targeting polyP.

Purpose of the Study:

• To evaluate a novel class of nontoxic polycationic compounds, universal heparin reversal agents (UHRAs), as inhibitors of polyP procoagulant activity.
• To assess the antithrombotic potential and safety profile of selected UHRA compounds in preclinical models.

Main Methods:

• In vitro assessment of UHRA compounds' ability to inhibit polyP-mediated procoagulant activity.
• In vivo evaluation of UHRA compounds (UHRA-9 and UHRA-10) in mouse models of arterial thrombosis.
• Assessment of bleeding risk using mouse tail bleeding tests, comparing UHRA compounds to heparin.

Main Results:

• Several UHRA compounds demonstrated potent inhibition of polyP procoagulant activity in vitro.
• UHRA-9 and UHRA-10 significantly reduced arterial thrombosis in mouse models.
• UHRA-9 and UHRA-10 exhibited significantly less bleeding compared to equivalent doses of heparin in bleeding tests.

Conclusions:

• Nontoxic polycationic UHRA compounds effectively inhibit polyP and demonstrate antithrombotic efficacy in vivo.
• UHRA-9 and UHRA-10 represent a promising new platform for developing antithrombotic agents with reduced toxicity and bleeding side effects.
• These findings support targeting procoagulant anionic polymers like polyP for safer antithrombotic therapies.