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

Research output: Contribution to journalArticle

470 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

Fingerprint

Polyphosphates
Platelets
Blood Platelets
Factor XII
Polyps
Plasmas
Thrombosis
Peptide Hydrolases
Hermanski-Pudlak Syndrome
Bradykinin Receptors
Factor XI
Plasma Kallikrein
Kininogens
Capillary Permeability
Bradykinin
Ablation
Microvessels
Coagulation
Hemostasis
Pulmonary Embolism

Keywords

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

Cite this

Müller, F., Mutch, N. J., Schenk, W. A., Smith, S. A., Esterl, L., Spronk, H. M., ... 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

Platelet polyphosphates are proinflammatory and procoagulant mediators in vivo. / Müller, Felicitas; Mutch, Nicola J.; Schenk, Wolfdieter A.; Smith, Stephanie A.; Esterl, Lucie; Spronk, Henri M.; Schmidbauer, Stefan; Gahl, William A.; Morrissey, James H.; Renné, Thomas.

In: Cell, Vol. 139, No. 6, 11.12.2009, p. 1143-1156.

Research output: Contribution to journalArticle

Müller, F, Mutch, NJ, Schenk, WA, Smith, SA, Esterl, L, Spronk, HM, Schmidbauer, S, Gahl, WA, Morrissey, JH & Renné, T 2009, 'Platelet polyphosphates are proinflammatory and procoagulant mediators in vivo', Cell, vol. 139, no. 6, pp. 1143-1156. https://doi.org/10.1016/j.cell.2009.11.001
Müller F, Mutch NJ, Schenk WA, Smith SA, Esterl L, Spronk HM et al. Platelet polyphosphates are proinflammatory and procoagulant mediators in vivo. Cell. 2009 Dec 11;139(6):1143-1156. https://doi.org/10.1016/j.cell.2009.11.001
Müller, Felicitas ; Mutch, Nicola J. ; Schenk, Wolfdieter A. ; Smith, Stephanie A. ; Esterl, Lucie ; Spronk, Henri M. ; Schmidbauer, Stefan ; Gahl, William A. ; Morrissey, James H. ; Renné, Thomas. / Platelet polyphosphates are proinflammatory and procoagulant mediators in vivo. In: Cell. 2009 ; Vol. 139, No. 6. pp. 1143-1156.
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