title: Nontoxic polyphosphate inhibitors reduce thrombosis while sparing hemostasis.
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.
authors.affiliation: Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL; and.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Travers
authors.affiliation: Centre for Blood Research and Department of Pathology and Laboratory Medicine, and.
authors.forename: Rajesh A
authors.initials: RA
authors.lastname: Shenoi
authors.affiliation: Centre for Blood Research and Department of Pathology and Laboratory Medicine, and.
authors.forename: Manu Thomas
authors.initials: MT
authors.lastname: Kalathottukaren
authors.affiliation: Centre for Blood Research and Department of Pathology and Laboratory Medicine, and Department of Chemistry, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Jayachandran N
authors.initials: JN
authors.lastname: Kizhakkedathu
authors.affiliation: Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL; and.
authors.forename: James H
authors.identifier: http://orcid.org/0000-0002-1570-1569
authors.initials: JH
authors.lastname: Morrissey
mesh_terms: D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D050091:Dendrimers / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D005343:Fibrinolytic Agents / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D006487:Hemostasis / Q000187:drug effects*; D006493:Heparin / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D011122:Polyphosphates / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D013917:Thrombin / Q000378:metabolism; D013927:Thrombosis / Q000097:blood / Q000517:prevention & control*
chemical_list: D050091:Dendrimers; D005343:Fibrinolytic Agents; D011122:Polyphosphates; C000595465:UHRA-10; C000595464:UHRA-9; D006493:Heparin; D013917:Thrombin