title: Plasma soluble thrombomodulin levels are associated with mortality in the acute respiratory distress syndrome.
abstract: OBJECTIVE
  Thombomodulin (TM) is an activator of protein C and a biomarker for endothelial injury. We hypothesized that (1) elevated plasma levels would be associated with clinical outcomes and (2) polymorphisms in the TM gene would be associated with plasma levels.
  
  
  METHODS
  We studied 449 patients enrolled in the Fluid and Catheter Treatment Trial (FACTT) for whom both plasma and DNA were available. We used logistic regression and receiver operator curves (ROC) to test for associations between soluble TM (sTM) and mortality at 60 days.
  
  
  RESULTS
  Plasma sTM levels were higher in non-survivors than survivors at baseline [median 147 (IQR, 95-218) vs. 89 (56-129) ng/mL, p < 0.0001] and on day 3 after study enrollment [205 (146-302) vs. 127 (85-189), p < 0.0001]. The odds of death increased by 2.4 (95 % CI 1.5-3.8, p < 0.001), and by 2.8 (1.7-4.7, P < 0.001) for every log increase in baseline and day 3 sTM levels, respectively, after adjustment for age, race, gender, severity of illness, fluid management strategy, baseline creatinine, and non-pulmonary sepsis as the primary cause of ARDS. By ROC analysis, plasma sTM levels discriminated between non-survivors and survivors [AUC = 72 % (66-78 %) vs. AUC = 54 % for severity based on Berlin criteria). Addition of sTM improved discrimination based on APACHE III from 77 to 80 % (P < 0.03). sTM levels at baseline were not statistically different among subjects stratified by genotypes of tag SNPs in the TM gene.
  
  
  CONCLUSIONS
  Higher plasma sTM levels are associated with increased mortality in ARDS. The lack of association between the sTM levels and genetic variants suggests that the increased levels of sTM may reflect severity of endothelial damage rather than genetic heterogeneity. These findings underscore the importance of endothelial injury in ARDS pathogenesis and suggest that, in combination with clinical markers, sTM could contribute to risk stratification.
authors: Department of Pediatrics, University of California, San Francisco, CA, USA, saprua@peds.ucsf.edu.
authors: Anil
authors: A
authors: Sapru
authors: Carolyn S
authors: CS
authors: Calfee
authors: Kathleen D
authors: KD
authors: Liu
authors: Kirsten
authors: K
authors: Kangelaris
authors: Helen
authors: H
authors: Hansen
authors: Ludmila
authors: L
authors: Pawlikowska
authors: Lorraine B
authors: LB
authors: Ware
authors: Mustafa F
authors: MF
authors: Alkhouli
authors: Jason
authors: J
authors: Abbott
authors: Jason
authors: J
authors: Abbot
authors: Michael A
authors: MA
authors: Matthay
mesh_terms: D015415:Biomarkers / Q000097:blood; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005838:Genotype; D017052:Hospital Mortality; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012128:Respiratory Distress Syndrome / Q000097:blood* / Q000235:genetics* / Q000401:mortality*; D016019:Survival Analysis; D018180:Thrombomodulin / Q000097:blood* / Q000235:genetics*
chemical_list: D015415:Biomarkers; C546931:THBD protein, human; D018180:Thrombomodulin
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