Phosphatidylserine-blocking nanoparticles inhibit thrombosis without increased bleeding in mice

Area of Science:

• Biochemistry
• Pharmacology
• Vascular Biology

Background:

• Phosphatidylserine (PS) is a procoagulant phospholipid found on activated vascular cells.
• PS is a potential drug target for modulating thrombosis with a potentially lower bleeding risk than current therapies.

Purpose of the Study:

• To evaluate the antithrombotic capabilities and bleeding effects of a liposomal formulation, DPAL, in mouse models.
• To assess DPAL's selective binding to PS-enriched surfaces.

Main Methods:

• In vitro testing of DPAL binding to human and murine platelets.
• In vivo assessment of thrombosis and bleeding in mice after DPAL administration following arterial injury and tail amputation.
• Investigation of DPAL incorporation into hemostatic clots and toxicity in endothelial cell cultures.

Main Results:

• DPAL demonstrated selective binding to PS-positive platelets, inhibited by Annexin V or Ano6 deletion.
• DPAL prolonged prothrombin time but did not inhibit platelet aggregation or alter blood cell counts.
• DPAL dose-dependently reduced arterial thrombosis induced by FeCl3 without significantly increasing bleeding or causing endothelial cell death.

Conclusions:

• DPAL effectively reduces thrombogenesis by selectively binding to PS, with a favorable safety profile regarding bleeding.
• DPAL represents a potential new therapeutic approach for modulating thrombin generation in various clinical contexts.