Polyphosphate (
polyP) is secreted by activated platelets and has been shown to contribute to
thrombosis, suggesting that it could be a novel antithrombotic target. Previously reported
polyP inhibitors based on polycationic substances, such as
polyethylenimine,
polyamidoamine dendrimers, and
polymyxin B, although they attenuate
thrombosis, all have significant toxicity in vivo, likely due to the presence of multiple primary
amines responsible for their
polyP binding ability. In this study, we examined a novel class of nontoxic polycationic compounds initially designed as universal
heparin reversal agents (UHRAs) to determine their ability to block
polyP procoagulant activity and also to determine their utility as antithrombotic treatments. Several UHRA compounds strongly inhibited
polyP procoagulant activity in vitro, and 4 were selected for further examination in mouse models of
thrombosis and hemostasis. Compounds
UHRA-9 and
UHRA-10 significantly reduced arterial
thrombosis in mice. In mouse tail
bleeding tests, administration of
UHRA-9 or
UHRA-10 was associated with significantly less
bleeding compared with therapeutically equivalent doses of
heparin. Thus, these compounds offer a new platform for developing novel
antithrombotic agents that target procoagulant anionic
polymers such as
polyP with reduced toxicity and
bleeding side effects.