TY - JOUR
T1 - Thrombocytopenia is associated with a dysregulated host response in critically ill sepsis patients
AU - Claushuis, Theodora A M
AU - van Vught, Lonneke A
AU - Scicluna, Brendon P
AU - Wiewel, Maryse A
AU - Klein Klouwenberg, Peter M C
AU - Hoogendijk, Arie J
AU - Ong, David S Y
AU - Cremer, Olaf L
AU - Horn, Janneke
AU - Franitza, Marek
AU - Toliat, Mohammad R
AU - Nürnberg, Peter
AU - Zwinderman, Aeilko H
AU - Bonten, Marc J M
AU - Schultz, Marcus J
AU - van der Poll, Tom
PY - 2016/6/16
Y1 - 2016/6/16
N2 - 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 9/L, intermediate-low 50 × 109 to 99 × 109/L, low 100 × 109 to 149 × 109/L, or normal 150 × 109 to 399 × 109/L) on admission to the intensive care unit. Sepsis patients with platelet counts 9/L and 50 × 109 to 99 × 109/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 bymeasuring 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 × 109/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 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.
AB - 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 9/L, intermediate-low 50 × 109 to 99 × 109/L, low 100 × 109 to 149 × 109/L, or normal 150 × 109 to 399 × 109/L) on admission to the intensive care unit. Sepsis patients with platelet counts 9/L and 50 × 109 to 99 × 109/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 bymeasuring 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 × 109/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 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.
U2 - 10.1182/blood-2015-11-680744
DO - 10.1182/blood-2015-11-680744
M3 - Article
C2 - 26956172
SN - 0006-4971
VL - 127
SP - 3062
EP - 3072
JO - Blood
JF - Blood
IS - 24
ER -