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 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.
Müller
Felicitas
F
Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institutet, Stockholm S-171 76, Sweden.
Mutch
Nicola J
NJ
Schenk
Wolfdieter A
WA
Smith
Stephanie A
SA
Esterl
Lucie
L
Spronk
Henri M
HM
Schmidbauer
Stefan
S
Gahl
William A
WA
Morrissey
James H
JH
Renné
Thomas
T
D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D001920:Bradykinin / Q000378:metabolism; D005174:Factor XII / Q000235:genetics / Q000378:metabolism; D005337:Fibrin / Q000378:metabolism; D022861:Hermanski-Pudlak Syndrome / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D051379:Mice; D010447:Peptide Hydrolases / Q000378:metabolism; D010949:Plasma; D011122:Polyphosphates / Q000378:metabolism*; D018002:Receptors, Bradykinin / Q000378:metabolism; D013927:Thrombosis / Q000378:metabolism
D018836:Inflammation Mediators; D011122:Polyphosphates; D018002:Receptors, Bradykinin; D005174:Factor XII; D005337:Fibrin; D010447:Peptide Hydrolases; D001920:Bradykinin