Platelet polyphosphates are proinflammatory and procoagulant mediators in vivo.

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.

• Authors: 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
• Journal: Cell (Cell) Vol. 139 Issue 6 Pg. 1143-56 (Dec 11 2009) ISSN: 1097-4172 [Electronic] United States
• PMID: 20005807 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Inflammation Mediators
• Polyphosphates
• Receptors, Bradykinin
• Factor XII
• Fibrin
• Peptide Hydrolases
• Bradykinin

Topics

• Animals
• Blood Platelets (metabolism)
• Bradykinin (metabolism)
• Factor XII (genetics, metabolism)
• Fibrin (metabolism)
• Hermanski-Pudlak Syndrome (metabolism)
• Humans
• Inflammation Mediators (metabolism)
• Mice
• Peptide Hydrolases (metabolism)
• Plasma
• Polyphosphates (metabolism)
• Receptors, Bradykinin (metabolism)
• Thrombosis (metabolism)