Consumptive coagulopathy is associated with a disturbed host response in patients with sepsis

Abstract

Background: A prolonged prothrombin time (PT) is a common feature in sepsis indicating consumptive coagulopathy.

Objectives: To determine the association between a prolonged PT and aberrations in other host response mechanisms in sepsis.

Methods: Patients admitted to the intensive care unit with sepsis were divided in quartiles according to the highest PT value measured within 24 h after admission. The host response was evaluated by measuring 19 plasma biomarkers reflecting pathways implicated in sepsis pathogenesis and by blood leukocyte gene expression profiling.

Measurements and main results: Of 1524 admissions for sepsis, 386 (25.3%) involved patients with a normal PT (≤12.7 s); the remaining quartiles entailed 379 (24.9%) patients with a slightly prolonged PT (12.8 ≤ PT ≤ 15.0 s), 383 (25.1%) with an intermediately prolonged PT (15.1 ≤ PT ≤ 17.2 s), and 376 (24.7%) with an extremely prolonged PT (≥17.3 s). While patients with an extremely prolonged PT showed an increased crude mortality up to 1 year after admission, none of the prolonged PT groups was independently associated with 30-day adjusted mortality. Comparison of the host response between patients with a normal PT or an extremely prolonged PT matched for baseline characteristics including severity of disease showed that an extremely prolonged PT was associated with impaired anticoagulant mechanisms, a more disturbed endothelial barrier integrity and increased systemic inflammation, and blood leukocyte transcriptomes indicating more prominent metabolic reprogramming and protein catabolism.

Conclusion: A prolonged PT is associated with stronger anomalies in pathways implicated in the pathogenesis of sepsis, suggesting that activation of coagulation impacts other host response mechanisms.

Keywords: endothelium inflammation; host response; intensive care unit; prothrombin time; sepsis.

FIGURE 1

Flowchart of patient inclusion. ICU, intensive care unit; IV, intravenous; PT, prothrombin time

FIGURE 2

Prothrombin time and platelet counts over time in patients with sepsis stratified according to prothrombin time on admission to the intensive care unit (ICU). Data are mean and standard error of the mean. Numbers below x‐axis indicate number of patients still present in the intensive care unit for each group

FIGURE 3

Biomarkers reflecting coagulation activation in patients with sepsis stratified according to prothrombin time on admission and matched for discordant baseline parameters. Data are expressed as box and whisker diagrams depicting the median and lower quartile, upper quartile, and their respective 1.5 interquartile range as whiskers (as specified by Tukey). Dotted lines indicate median values obtained in 27 healthy age‐matched subjects. Biomarker distribution on ICU admission was compared using a nonparametric Mann‐Whitney U test. **p < .01, ***p < .001, ****p < .0001. APTT, activated partial thromboplastin time; PT, prothrombin time

FIGURE 4

Biomarkers reflecting endothelial cell activation and barrier function in patients with sepsis stratified according to prothrombin time on admission and matched for discordant baseline parameters. Data are expressed as box and whisker diagrams depicting the median and lower quartile, upper quartile, and their respective 1.5 interquartile range as whiskers (as specified by Tukey). Dotted lines indicate median values obtained in 27 healthy age‐matched subjects. Biomarker distribution on intensive care unit admission was compared using a nonparametric Mann‐Whitney U test. **p < .01. ***p < .001. ANG, angiopoietin; sE‐Selectin, soluble E‐selectin; sICAM, soluble intercellular adhesion molecule

FIGURE 5

Biomarkers reflecting systemic inflammation in patients with sepsis stratified according to prothrombin time on admission and matched for discordant baseline parameters. Data are expressed as box and whisker diagrams depicting the median and lower quartile, upper quartile, and their respective 1.5 interquartile range as whiskers (as specified by Tukey). Dotted lines indicate median values obtained in 27 healthy age‐matched subjects. Biomarker distribution on intensive care unit admission was compared using a nonparametric Mann‐Whitney U test. **p < .01, ***p < .001. IL, interleukin; MMP, matrix metalloproteinase

FIGURE 6

Leukocyte genomic responses and associated biological pathways in patients with sepsis stratified according to prothrombin time on admission and matched for discordant baseline parameters. A, Volcano plot illustrating the differences in leukocyte genomic responses (integrating log2 foldchanges and multiple‐test adjusted probabilities) between sepsis patients with normal PT (PT ≤ 12.7 s) and healthy subjects (left) and patients with extremely prolonged PT (PT ≥ 17.3 s) and healthy subjects (right). Considering adjusted p < .05, 8239 and 8972 genes were identified as differentially expressed in patients with normal PT versus healthy subjects, and patients with extremely prolonged PT versus healthy subjects, respectively. Blue dots represent significantly underexpressed genes (adjusted p < .05, fold expression <−1.2) whereas red dots represent significantly overexpressed genes (adjusted p < .05, fold expression >1.2) in patients relative to healthy controls. Horizontal dotted line indicates multiple‐test adjusted Benjamini‐Hochberg (BH) p < .05 threshold. B, Venn‐Euler representation of differentially expressed genes in sepsis patients with extremely prolonged PT and normal PT versus healthy subjects (adjusted p < .05). Red arrows denote overexpressed genes; blue arrows denote underexpressed genes. C, Dot plot depicting the common response (log2 foldchanges) of patients with extremely prolonged PT and normal PT compared to healthy subjects. r, Spearman's correlation coefficient. D, Volcano plot illustrating the differences in leukocyte genomic responses between sepsis patients with extremely prolonged PT and patients with normal PT upon admission. Considering adjusted p < .05, 277 genes were identified as differentially expressed in patients with extremely prolonged PT versus patients with normal PT. E, Ingenuity pathway analysis of commonly underexpressed genes in patients with extremely prolonged PT versus patients with normal PT. –log (Benjamini‐Hochberg (BH)) p value, negative log10‐transformed p value corrected for multiple comparisons; PPAR, peroxisome proliferator‐activated receptor; PT, prothrombin time; RAR, retinoid acid receptor