Abstract
Although it has long been known that patients with sepsis often have thrombocytopenia and that septic patients with severe thrombocytopenia have a poor prognosis and higher mortality, the role of platelets in the pathogenesis of sepsis is poorly understood. Here we report a protective role of platelets in septic shock. We show that experimental thrombocytopenia induced by intraperitoneal injection of an anti-glycoprotein Ibα monoclonal antibody increases mortality and aggravates organ failure, whereas transfusion of platelets reduces mortality in lipopolysaccharide-induced endotoxemia and a bacterial infusion mouse sepsis model. Plasma concentrations of proinflammatory cytokines TNF-α and IL-6 are elevated by thrombocytopenia and decreased by platelet transfusion in septic mice. Furthermore, we identify that platelets protect from septic shock by inhibiting macrophage-dependent inflammation via the COX1/PGE₂/EP4-dependent pathway. Thus, these findings demonstrate a previously unappreciated role for platelets in septic shock and suggest that platelet transfusion may be effective in treating severely septic patients.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Antibodies, Anti-Idiotypic / pharmacology
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Blood Platelets / cytology
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Blood Platelets / immunology*
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Cyclooxygenase 1 / genetics
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Cyclooxygenase 1 / immunology
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Dinoprostone / genetics
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Dinoprostone / immunology
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Disease Models, Animal
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Gene Expression Regulation
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Humans
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Inflammation / chemically induced
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Inflammation / genetics
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Inflammation / pathology
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Inflammation / prevention & control
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Interleukin-6 / biosynthesis
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Interleukin-6 / immunology
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Lipopolysaccharides / pharmacology
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Macrophages, Peritoneal / drug effects
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Macrophages, Peritoneal / immunology*
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Macrophages, Peritoneal / pathology
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Male
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Membrane Proteins / genetics
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Membrane Proteins / immunology
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Mice
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Mice, Inbred C57BL
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Platelet Glycoprotein GPIb-IX Complex / immunology
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Platelet Transfusion*
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Receptors, Prostaglandin E, EP4 Subtype / genetics
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Receptors, Prostaglandin E, EP4 Subtype / immunology
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Shock, Septic / chemically induced
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Shock, Septic / genetics
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Shock, Septic / pathology
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Shock, Septic / therapy*
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Signal Transduction
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Thrombocytopenia / chemically induced
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Thrombocytopenia / genetics
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Thrombocytopenia / pathology
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Thrombocytopenia / prevention & control*
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Tumor Necrosis Factor-alpha / biosynthesis
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Tumor Necrosis Factor-alpha / immunology
Substances
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Antibodies, Anti-Idiotypic
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Interleukin-6
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Lipopolysaccharides
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Membrane Proteins
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Platelet Glycoprotein GPIb-IX Complex
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Ptger4 protein, mouse
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Receptors, Prostaglandin E, EP4 Subtype
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Tumor Necrosis Factor-alpha
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Cyclooxygenase 1
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Ptgs1 protein, mouse
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Dinoprostone