title: Inhibition of polyphosphate as a novel strategy for preventing thrombosis and inflammation.
abstract: Inorganic polyphosphates are linear polymers of orthophosphate that modulate blood clotting and inflammation. Polyphosphate accumulates in infectious microorganisms and is secreted by activated platelets; long-chain polyphosphate in particular is an extremely potent initiator of the contact pathway, a limb of the clotting cascade important for thrombosis but dispensable for hemostasis. Polyphosphate inhibitors therefore might act as novel antithrombotic/anti-inflammatory agents with reduced bleeding side effects. Antipolyphosphate antibodies are unlikely because of polyphosphate's ubiquity and simple structure; and although phosphatases such as alkaline phosphatase can digest polyphosphate, they take time and may degrade other biologically active molecules. We now identify a panel of polyphosphate inhibitors, including cationic proteins, polymers, and small molecules, and report their effectiveness in vitro and in vivo. We also compare their effectiveness against the procoagulant activity of RNA. Polyphosphate inhibitors were antithrombotic in mouse models of venous and arterial thrombosis and blocked the inflammatory effect of polyphosphate injected intradermally in mice. This study provides proof of principle for polyphosphate inhibitors as antithrombotic/anti-inflammatory agents in vitro and in vivo, with a novel mode of action compared with conventional anticoagulants.
authors.affiliation: Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Smith
authors.forename: Sharon H
authors.initials: SH
authors.lastname: Choi
authors.forename: Julie N R
authors.initials: JN
authors.lastname: Collins
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Travers
authors.forename: Brian C
authors.initials: BC
authors.lastname: Cooley
authors.forename: James H
authors.initials: JH
authors.lastname: Morrissey
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000302:isolation & purification / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects; D016503:Drug Delivery Systems / Q000379:methods; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D005343:Fibrinolytic Agents / Q000302:isolation & purification / Q000494:pharmacology*; D006487:Hemostasis / Q000187:drug effects; D057166:High-Throughput Screening Assays; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D011122:Polyphosphates / Q000037:antagonists & inhibitors* / Q000097:blood; D013927:Thrombosis / Q000097:blood / Q000188:drug therapy*
chemical_list: D000893:Anti-Inflammatory Agents; D005343:Fibrinolytic Agents; D011122:Polyphosphates