title: Thrombocytopenia impairs host defense in gram-negative pneumonia-derived sepsis in mice.
abstract: Thrombocytopenia is a common finding in sepsis and associated with a worse outcome. We used a mouse model of pneumonia-derived sepsis caused by the human pathogen Klebsiella pneumoniae to study the role of platelets in host response to sepsis. Platelet counts (PCs) were reduced to less than a median of 5 × 10(9)/L or to 5 to 13 × 10(9)/L by administration of a depleting antibody in mice infected with Klebsiella via the airways. Thrombocytopenia was associated with strongly impaired survival during pneumonia-derived sepsis proportional to the extent of platelet depletion. Thrombocytopenic mice demonstrated PC-dependent enhanced bacterial growth in lungs, blood, and distant organs. Severe thrombocytopenia resulted in hemorrhage at the primary site of infection, but not in distant organs. PCs of 5 to 13 × 10(9)/L were sufficient to largely maintain hemostasis in infected lungs. Thrombocytopenia did not influence lung inflammation or neutrophil recruitment and did not attenuate local or systemic activation of coagulation or the vascular endothelium. PCs <5 × 10(9)/L even resulted in enhanced coagulation and endothelial cell activation, which coincided with increased proinflammatory cytokine levels. In accordance, low PCs in whole blood enhanced Klebsiella-induced cytokine release in vitro. These data suggest that platelets play an important role in host defense to Klebsiella pneumosepsis.
authors.affiliation: Center for Infection and Immunity Amsterdam, Center for Experimental and Molecular Medicine.
authors.forename: Sacha F
authors.initials: SF
authors.lastname: de Stoppelaar
authors.affiliation: Center for Infection and Immunity Amsterdam, Center for Experimental and Molecular Medicine.
authors.forename: Cornelis
authors.initials: C
authors.lastname: van 't Veer
authors.affiliation: Center for Infection and Immunity Amsterdam, Center for Experimental and Molecular Medicine.
authors.forename: Theodora A M
authors.initials: TA
authors.lastname: Claushuis
authors.affiliation: Center for Infection and Immunity Amsterdam, Center for Experimental and Molecular Medicine.
authors.forename: Bregje J A
authors.initials: BJ
authors.lastname: Albersen
authors.affiliation: Department of Pathology, and.
authors.forename: Joris J T H
authors.initials: JJ
authors.lastname: Roelofs
authors.affiliation: Center for Infection and Immunity Amsterdam, Center for Experimental and Molecular Medicine, Division of Infectious Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Tom
authors.initials: T
authors.lastname: van der Poll
mesh_terms: D000818:Animals; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D005260:Female; D006470:Hemorrhage / Q000097:blood / Q000276:immunology*; D054884:Host-Pathogen Interactions / Q000276:immunology; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D007710:Klebsiella Infections / Q000097:blood / Q000276:immunology* / Q000382:microbiology; D007711:Klebsiella pneumoniae / Q000276:immunology* / Q000502:physiology; D008168:Lung / Q000276:immunology / Q000382:microbiology; D008171:Lung Diseases / Q000097:blood / Q000276:immunology; D008810:Mice, Inbred C57BL; D010976:Platelet Count; D018410:Pneumonia, Bacterial / Q000150:complications / Q000276:immunology* / Q000382:microbiology; D018805:Sepsis / Q000209:etiology / Q000276:immunology* / Q000378:metabolism; D016019:Survival Analysis; D013921:Thrombocytopenia / Q000097:blood / Q000276:immunology*
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators