Platelet polyphosphates are proinflammatory and procoagulant mediators in vivo

Felicitas Müller, Nicola J. Mutch, Wolfdieter A. Schenk, Stephanie A. Smith, Lucie Esterl, Henri M. Spronk, Stefan Schmidbauer, William A. Gahl, James H. Morrissey, Thomas Renné

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487 Citations (Scopus)

Abstract

Platelets play a central role in thrombosis, hemostasis, and inflammation. We show that activated platelets release inorganic polyphosphate (polyP), a polymer of 60-100 phosphate residues that directly bound to and activated the plasma protease factor XII. PolyP-driven factor XII activation triggered release of the inflammatory mediator bradykinin by plasma kallikrein-mediated kininogen processing. PolyP increased vascular permeability and induced fluid extravasation in skin microvessels of mice. Mice deficient in factor XII or bradykinin receptors were resistant to polyP-induced leakage. PolyP initiated clotting of plasma via the contact pathway. Ablation of intrinsic coagulation pathway proteases factor XII and factor XI protected mice from polyP-triggered lethal pulmonary embolism. Targeting polyP with phosphatases interfered with procoagulant activity of activated platelets and blocked platelet-induced thrombosis in mice. Addition of polyP restored defective plasma clotting of Hermansky-Pudlak Syndrome patients, who lack platelet polyP. The data identify polyP as a new class of mediator having fundamental roles in platelet-driven proinflammatory and procoagulant disorders.
Original languageEnglish
Pages (from-to)1143-1156
Number of pages14
JournalCell
Volume139
Issue number6
DOIs
Publication statusPublished - 11 Dec 2009

Keywords

  • animals
  • blood platelets
  • bradykinin
  • factor XII
  • fibrin
  • Hermanski-Pudlak syndrome
  • humans
  • inflammation mediators
  • mice
  • peptide hydrolases
  • plasma
  • polyphosphates
  • receptors, bradykinin
  • thrombosis

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  • Cite this

    Müller, F., Mutch, N. J., Schenk, W. A., Smith, S. A., Esterl, L., Spronk, H. M., Schmidbauer, S., Gahl, W. A., Morrissey, J. H., & Renné, T. (2009). Platelet polyphosphates are proinflammatory and procoagulant mediators in vivo. Cell, 139(6), 1143-1156. https://doi.org/10.1016/j.cell.2009.11.001