Poly-P as Modulator of Hemostasis, Thrombosis, and Inflammation

Abstract

Polyphosphate (polyP), consisting of linear polymers of inorganic phosphates, is ubiquitous in biology. PolyP metabolism has been most extensively explored in microbes, but until very recently, roles for polyP in mammalian cells have been poorly understood. In 2004, polyP was shown to be a major component of dense granules in human platelets, and to be secreted upon platelet activation.1 In 2006, we demonstrated that polyP is a potent modulator of the blood clotting system.2 Subsequent work from our lab and others has shown that polyP accelerates blood clotting and slows fibrinolysis, in a manner that is highly dependent on polymer length.3 Long-chain polyP (present in infectious microorganisms) potently triggers the contact pathway and may participate in innate immunity/host responses to pathogens. PolyP of the size secreted by platelets (60 to 100 phosphates long) accelerates factor V activation, abrogates the anticoagulant activity of tissue factor pathway inhibitor, enhances fibrin clot structure, and greatly accelerates factor XI activation by thrombin. PolyP also enhances the proinflammatory activity of histones and inhibits complement. PolyP is a potential antithrombotic drug target, with a novel mechanism of action and possibly fewer bleeding side-effects compared to conventional anticoagulant drugs.4 1. Ruiz FA, Lea CR, Oldfield E, Docampo R. Human platelet dense granules contain polyphosphate and are similar to acidocalcisomes of bacteria and unicellular eukaryotes. J Biol Chem . 2004;279(43):44250-44257. 2. Smith SA, Mutch NJ, Baskar D, Rohloff P, Docampo R, Morrissey JH. Polyphosphate modulates blood coagulation and fibrinolysis. Proc Natl Acad Sci U S A . 2006;103(4):903-908. 3. Morrissey JH, Smith SA. Polyphosphate as modulator of hemostasis, thrombosis, and inflammation. J Thromb Haemost . 2015;13 Suppl 1:S92-97. 4. Travers RJ, Shenoi RA, Kalathottukaren MT, Kizhakkedathu JN, Morrissey JH. Nontoxic polyphosphate inhibitors reduce thrombosis while sparing hemostasis. Blood . 2014;124(22):3183-3190. Disclosures Morrissey: Novo Nordisk: Consultancy, Honoraria, Research Funding; rEVO Biologics: Consultancy, Honoraria; Paul, Weiss, Rifkind, Wharton & Garrison LLP: Consultancy; Cayuga Pharmaceuticals: Consultancy; PrevThro Pharmaceuticals: Equity Ownership; Kerafast, Inc.: Research Funding.