Inhibitors of Polyphosphate and Neutrophil Extracellular Traps.

The contact pathway of blood clotting has received intense interest in recent years as studies have linked it to thrombosis, inflammation, and innate immunity. Because the contact pathway plays little to no role in normal hemostasis, it has emerged as a potential target for safer thromboprotection, relative to currently approved antithrombotic drugs which all target the final common pathway of blood clotting. Research since the mid-2000s has identified polyphosphate, DNA, and RNA as important triggers of the contact pathway with roles in thrombosis, although these molecules also modulate blood clotting and inflammation via mechanisms other than the contact pathway of the clotting cascade. The most significant source of extracellular DNA in many disease settings is in the form of neutrophil extracellular traps (NETs), which have been shown to contribute to incidence and severity of thrombosis. This review summarizes known roles of extracellular polyphosphate and nucleic acids in thrombosis, with an emphasis on novel agents under current development that target the prothrombotic activities of polyphosphate and NETs.

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Déclaration de conflit d'intérêts

S.V., S.A.S., J.H.M., and J.N.K. are inventors on issued patents and pending patent applications covering novel inhibitors of polyphosphate and NETs, some of which are optioned to TSRL, Inc., for licensing from the University of Michigan and the University of British Columbia. J.H.M. reports grants from the National Institutes of Health, and J.N.K. reports grants from the Canadian Institutes of Health Research and the Natural Sciences and Engineering Council of Canada. The laboratory of J.H.M. receives some research funding from Kerafast, Inc., through the sales of polyphosphates and polyphosphate derivatives.