Semin Thromb Hemost
DOI: 10.1055/s-0043-1768936
Review Article

Inhibitors of Polyphosphate and Neutrophil Extracellular Traps

Sreeparna Vappala
1   Department of Pathology and Laboratory Medicine, Centre for Blood Research, Life Science Institute, University of British Columbia, Vancouver, British Columbia, Canada
Stephanie A. Smith
2   Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan
Jayachandran N. Kizhakkedathu
1   Department of Pathology and Laboratory Medicine, Centre for Blood Research, Life Science Institute, University of British Columbia, Vancouver, British Columbia, Canada
3   Department of Chemistry, School of Biomedical Engineering, University of British Columbia, Vancouver, British Columbia, Canada
James H. Morrissey
2   Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan
› Author Affiliations
Funding This work was supported by National Institutes of Health grant R35 HL135823 (J.H.M.), Canadian Institutes of Health Research grant 201610PJT (J.N.K.), and Natural Sciences and Engineering Council of Canada grant RGPIN-2018-03828 (J.N.K.). J.N.K. is a Tier 1 Canada Research Chair in Immunomodulating Materials and Immunotherapy.


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.

Publication History

Article published online:
16 May 2023

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