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Blood. 2014 Nov 20;124(22):3183-90. doi: 10.1182/blood-2014-05-577932. Epub 2014 Sep 8.

Nontoxic polyphosphate inhibitors reduce thrombosis while sparing hemostasis.

Author information

1
Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL; and.
2
Centre for Blood Research and Department of Pathology and Laboratory Medicine, and.
3
Centre for Blood Research and Department of Pathology and Laboratory Medicine, and Department of Chemistry, University of British Columbia, Vancouver, BC, Canada.

Abstract

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.

PMID:
25202141
PMCID:
PMC4239329
DOI:
10.1182/blood-2014-05-577932
[Indexed for MEDLINE]
Free PMC Article

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