Platelet polyphosphates are proinflammatory and procoagulant mediators in vivo

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 triggere...

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Published in:Cell Vol. 139; no. 6; p. 1143
Main Authors: 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
Format: Journal Article
Language:English
Published: United States 11.12.2009
Subjects:
Animals
Blood Platelets - metabolism
Bradykinin - metabolism
Factor XII - genetics
Factor XII - metabolism
Fibrin - metabolism
Hermanski-Pudlak Syndrome - metabolism
Humans
Inflammation Mediators - metabolism
Mice
Peptide Hydrolases - metabolism
Plasma
Polyphosphates - metabolism
Receptors, Bradykinin - metabolism
Thrombosis - metabolism
ISSN:1097-4172, 1097-4172
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Summary: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.
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ISSN:1097-4172
1097-4172
DOI:10.1016/j.cell.2009.11.001