Platelet polyphosphates are proinflammatory and procoagulant mediators in vivo
Standard
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. 1143-56.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - Platelet polyphosphates are proinflammatory and procoagulant mediators in vivo
AU - Müller, Felicitas
AU - Mutch, Nicola J
AU - Schenk, Wolfdieter A
AU - Smith, Stephanie A
AU - Esterl, Lucie
AU - Spronk, Henri M
AU - Schmidbauer, Stefan
AU - Gahl, William A
AU - Morrissey, James H
AU - Renné, Thomas
PY - 2009/12/11
Y1 - 2009/12/11
N2 - 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.
AB - 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.
KW - Animals
KW - Blood Platelets
KW - Bradykinin
KW - Factor XII
KW - Fibrin
KW - Hermanski-Pudlak Syndrome
KW - Humans
KW - Inflammation Mediators
KW - Mice
KW - Peptide Hydrolases
KW - Plasma
KW - Polyphosphates
KW - Receptors, Bradykinin
KW - Thrombosis
U2 - 10.1016/j.cell.2009.11.001
DO - 10.1016/j.cell.2009.11.001
M3 - SCORING: Journal article
C2 - 20005807
VL - 139
SP - 1143
EP - 1156
JO - CELL
JF - CELL
SN - 0092-8674
IS - 6
ER -