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.

Patients: 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.

Measurements and 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.

Fig. 1

sTM levels collected at a baseline and b day 3 among subjects with ARDS stratified by mortality. sTM levels were higher among non-survivors (p < 0.0001)

Fig. 2

Mortality at 60 days (y-axis) among subjects with ARDS stratified by quartiles of plasma sTM levels (x-axis) at baseline (a) and day 3 (b). There is increasing mortality with increasing quartiles of plasma sTM levels (p < 0.001)

Fig. 3

Ventilator-free days and organ failure-free days (y-axis) among subjects with ARDS stratified by quartiles of plasma sTM levels (x-axis) at baseline (a) and Day 3 (b). There are fewer ventilator-free and organ failure-free days with increasing quartiles of plasma sTM levels (P < 0.001)

Fig. 4

Receiver operator characteristic curves depicting improvement in the discriminatory ability of categories of severity based on Berlin criteria (right panel) and PF ratio (left panel) with addition of sTM levels to the model. The area under curve increased from 54 to 72 % (p < 0.001) and 57 to 73 % (p < 0.001), respectively