Plenary Paper THROMBOSIS AND HEMOSTASIS Nontoxic polyphosphate inhibitors reduce thrombosis while sparing hemostasis

Polyphosphate (polyP) is a highly anionic, linear polymer of inorganic phosphate that accumulates inmany infectiousmicroorganisms and is secreted by activated human platelets. Studies from our laboratory and others have shown that platelet polyP acts as a procoagulant stimulus at a number of points in the coagulation cascade. Although we do not currently understand all the mechanisms behind the ability of polyP to accelerate clotting, our present understanding of the role of platelet polyP in hemostasis and thrombosis suggests that it may contribute more heavily to thrombosis. Additionally, its role as an accelerant rather than a required component of the final common pathway of the coagulation cascademakes platelet polyP an attractive therapeutic target for novel antithrombotics with potentially decreased bleeding risk compared with conventional therapies, all of which target essential enzymes within the coagulation cascade. Cationic polymers make attractive candidates for high-affinity polyP inhibitors, and such polymers, including polyethylenimine and polyamidoamine (PAMAM) dendrimers, have proven effective in attenuating thrombosis in proof-of-principle studies that identified polyP as a therapeutic target. These polymers are positively charged because of the presence of multiple primary amines, which allows them to bind to and inhibit polyP, but this property can also promote binding to proteins and cell surfaces and thus lead to cellular toxicity, platelet activation, and coagulopathy mediated by fibrinogen aggregation. This severely limits the realworld usefulness of the previously identified polyP inhibitors. Recently Kizhakkedathu and coworkers developed a family of dendritic polymer-based universal heparin reversal agents (UHRAs) as synthetic antidotes to all heparin-based anticoagulants. These UHRAs were designed by assembling multifunctional cationic groups into the core of a dendritic polymer; they are then shielded from nonspecific interactions with blood components by using a protective layer of short-chain polyethylene glycol (PEG), resulting in increased biocompatibility compared with conventional cationic polymers. Although the development and synthesis of UHRA compounds resulted in the identification of important new heparin reversal agents, we also realized that within the UHRA family of compounds we might find polymer structures that could function as nontoxic polyP inhibitors. Their extremely low toxicity, coupled with the ease with which their chemical composition and pharmacologic properties can be varied, makes UHRA compounds ideal candidates for testing and developing this novel class of antithrombotic agents targeting polyP. This study reports the successful identification of