Nontoxic polyphosphate inhibitors reduce thrombosis while sparing hemostasis

Abstract

Key Points Polyphosphate inhibitors are antithrombotics with a novel mechanism of action and reduced bleeding side effects compared with heparin. Originally identified polyphosphate inhibitors were all toxic; this study reports the development of safe and effective alternatives.

The end of knight-errantry in GVHD studies

“…1 It compared the addition of mycophenolate mofetil to steroids vs steroids/placebo to treat newly diagnosed acute graft-versus-host disease (GVHD). Unfortunately, it failed to show a significant difference in outcomes.…”

Polyphosphate: a target for thrombosis attenuation

“…Because long-chain polyP is more effective in triggering the contact pathway of blood coagulation and is abundant in microbes, a potential clinical use of these compounds in sepsis and disseminated intravascular coagulation is envisaged. 1 Overall, this study dramatically changes our insights regarding the role of polyP in thrombosis and sets the stage for the pursuit of new clinically useful compounds.…”

“…1 C ollectively, arterial thrombosis and venous thromboembolism are leading causes of death in the developed world, and a better understanding of their pathogenic mechanisms will contribute to the development of safe and effective drugs. A case in point is understanding the role of anionic compounds such as polyP in their pathogenesis.…”

“…1 In contrast, several dendritic polymer-based universal heparin reversal agents (UHRAs) containing multiple cationic groups with a protective layer of polyethylene glycol (PEG) have very low toxicity and still inhibit anionic compounds. 1 By measuring the ability of these novel UHRA compounds to inhibit polyP-thrombin binding and polyP-initiated plasma clotting, Travers et al were able to select 4 inhibitors for further testing. 1 The compounds did Interestingly, the mode of action of these compounds differs from that of conventional antithrombotics.…”

“…1 By measuring the ability of these novel UHRA compounds to inhibit polyP-thrombin binding and polyP-initiated plasma clotting, Travers et al were able to select 4 inhibitors for further testing. 1 The compounds did Interestingly, the mode of action of these compounds differs from that of conventional antithrombotics. Because long-chain polyP is more effective in triggering the contact pathway of blood coagulation and is abundant in microbes, a potential clinical use of these compounds in sepsis and disseminated intravascular coagulation is envisaged.…”