title: Thrombocytopenia is associated with a dysregulated host response in critically ill sepsis patients.
abstract: Preclinical studies have suggested that platelets influence the host response during sepsis. We sought to assess the association of admission thrombocytopenia with the presentation, outcome, and host response in patients with sepsis. Nine hundred thirty-one consecutive sepsis patients were stratified according to platelet counts (very low <50 × 10(9)/L, intermediate-low 50 × 10(9) to 99 × 10(9)/L, low 100 × 10(9) to 149 × 10(9)/L, or normal 150 × 10(9) to 399 × 10(9)/L) on admission to the intensive care unit. Sepsis patients with platelet counts <50 × 10(9)/L and 50 × 10(9) to 99 × 10(9)/L presented with higher Acute Physiology and Chronic Health Evaluation scores and more shock. Both levels of thrombocytopenia were independently associated with increased 30-day mortality (hazard ratios with 95% confidence intervals 2.00 [1.32-3.05] and 1.72 [1.22-2.44], respectively). To account for baseline differences besides platelet counts, propensity matching was performed, after which the association between thrombocytopenia and the host response was tested, as evaluated by measuring 17 plasma biomarkers indicative of activation and/or dysregulation of pathways implicated in sepsis pathogenesis and by whole genome blood leukocyte expression profiling. In the propensity matched cohort, platelet counts < 50 × 10(9)/L were associated with increased cytokine levels and enhanced endothelial cell activation. All thrombocytopenic groups showed evidence of impaired vascular integrity, whereas coagulation activation was similar between groups. Blood microarray analysis revealed a distinct gene expression pattern in sepsis patients with <50 × 10(9)/L platelets, showing reduced signaling in leukocyte adhesion and diapedesis and increased complement signaling. These data show that admission thrombocytopenia is associated with enhanced mortality and a more disturbed host response during sepsis independent of disease severity, thereby providing clinical validity to animal studies on the role of platelets in severe infection.
authors.affiliation: Center for Experimental and Molecular Medicine, The Center for Infection and Immunity, and.
authors.forename: Theodora A M
authors.initials: TA
authors.lastname: Claushuis
authors.affiliation: Center for Experimental and Molecular Medicine, The Center for Infection and Immunity, and.
authors.forename: Lonneke A
authors.initials: LA
authors.lastname: van Vught
authors.affiliation: Center for Experimental and Molecular Medicine, The Center for Infection and Immunity, and Department of Clinical Epidemiology and Biostatistics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;
authors.forename: Brendon P
authors.initials: BP
authors.lastname: Scicluna
authors.affiliation: Center for Experimental and Molecular Medicine, The Center for Infection and Immunity, and.
authors.forename: Maryse A
authors.initials: MA
authors.lastname: Wiewel
authors.affiliation: Department of Intensive Care Medicine, Department of Medical Microbiology, and Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands;
authors.forename: Peter M C
authors.initials: PM
authors.lastname: Klein Klouwenberg
authors.affiliation: Center for Experimental and Molecular Medicine, The Center for Infection and Immunity, and.
authors.forename: Arie J
authors.initials: AJ
authors.lastname: Hoogendijk
authors.affiliation: Department of Intensive Care Medicine, Department of Medical Microbiology, and Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands;
authors.forename: David S Y
authors.initials: DS
authors.lastname: Ong
authors.affiliation: Department of Intensive Care Medicine.
authors.forename: Olaf L
authors.initials: OL
authors.lastname: Cremer
authors.affiliation: Department of Intensive Care, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;
authors.forename: Janneke
authors.initials: J
authors.lastname: Horn
authors.affiliation: Cologne Center for Genomics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, and.
authors.forename: Marek
authors.initials: M
authors.lastname: Franitza
authors.affiliation: Cologne Center for Genomics.
authors.forename: Mohammad R
authors.initials: MR
authors.lastname: Toliat
authors.affiliation: Cologne Center for Genomics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany; and.
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.affiliation: Department of Clinical Epidemiology and Biostatistics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;
authors.forename: Aeilko H
authors.initials: AH
authors.lastname: Zwinderman
authors.affiliation: Department of Medical Microbiology, and.
authors.forename: Marc J
authors.initials: MJ
authors.lastname: Bonten
authors.affiliation: Department of Intensive Care, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;
authors.forename: Marcus J
authors.initials: MJ
authors.lastname: Schultz
authors.affiliation: Center for Experimental and Molecular Medicine, The Center for Infection and Immunity, and 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: D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D016638:Critical Illness / Q000401:mortality; D016207:Cytokines / Q000097:blood*; D005260:Female; D006801:Humans; D007362:Intensive Care Units; D008297:Male; D008875:Middle Aged; D010976:Platelet Count; D011379:Prognosis; D018805:Sepsis / Q000097:blood* / Q000150:complications* / Q000175:diagnosis / Q000401:mortality; D016019:Survival Analysis; D013921:Thrombocytopenia / Q000097:blood / Q000150:complications* / Q000175:diagnosis / Q000401:mortality
chemical_list: D015415:Biomarkers; D016207:Cytokines