Plasma soluble thrombomodulin levels are associated with mortality in the acute respiratory distress syndrome
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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.
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.
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.
KeywordsARDS Thrombomodulin Biomarkers Endothelium Mortality
The study was supported by the following research grants: NIH/NHLBI contracts N01-HR-46046-64 and N01-HR-16146-54 (ARDS Network). NHLBI K23 HL085526 (AS). NHLBI HL51856 (MAM). NHLBI HL110969 (CSC) HL103836 (LBW) and an American Heart Association Established Investigator Award (LBW). National Institutes of Health, National Heart, Lung, and Blood Institute Ards Network. The following persons and institutions participated in the FACTT trial: Steering Committee Chair—G. R. Bernard; Clinical Coordinating Center—D. A. Schoenfeld, B. T. Thompson, N. Ringwood, C. Oldmixon, F. Molay, A. Korpak, R. Morse, D. Hayden, M. Ancukiewicz, A. Minihan; Protocol-Review Committee—J. G. N. Garcia, R. Balk, S. Emerson, M. Shasby, W.Sibbald; Data Safety and Monitoring Board—R. Spragg, G. Corbie-Smith, J. Kelley, K. Leeper, A. S. Slutsky, B. Turnbull, C. Vreim; National Heart, Lung, and Blood Institute—A. L. Harabin, D. Gail, P. Lew, M. Waclawiw; ARDS Clinical Trials Network Consultant—P. Parsons; Clinical Centers—University of Washington, Harborview—L. Hudson, K. Steinberg, M. Neff, R. Maier, K. Sims, C. Cooper, T. Berry-Bell, G. Carter, L. Andersson; University of Michigan—G. B. Toews, R. H. Bartlett, C. Watts, R. Hyzy, D. Arnoldi, R. Dechert, M. Purple; University of Maryland—H. Silverman, C. Shanholtz, A. Moore, L. Heinrich, W. Corral; Johns Hopkins University—R. Brower, D. Thompson, H. Fessler, S. Murray, A. Sculley; Cleveland Clinic Foundation—H. P. Wiedemann, A. C. Arroliga, J. Komara, T. Isabella, M. Ferrari; University Hospitals of Cleveland—J. Kern, R. Hejal, D. Haney; MetroHealth Medical Center—A. F. Connors; University of Colorado Health Sciences Center—E. Abraham, R. McIntyre, F. Piedalue; Denver Veterans Affairs Medical Center—C. Welsh; Denver Health Medical Center—I. Douglas, R. Wolkin; St. Anthony Hospital—T. Bost, B. Sagel, A. Hawkes; Duke University—N. MacIntyre, J. Govert, W. Fulkerson, L. Mallatrat, L. Brown, S. Everett, E. VanDyne, N. Knudsen, M. Gentile; University of North Carolina—P. Rock, S. Carson, C. Schuler, L. Baker, V. Salo; Vanderbilt University—A. P. Wheeler, G. Bernard, T. Rice, B. Christman, S. Bozeman, T. Welch; University of Pennsylvania—P. Lanken, J. Christie, B. Fuchs, B. Finkel, S. Kaplan, V. Gracias, C. W. Hanson, P. Reilly, M. B. Shapiro, R. Burke, E. O’Connor, D. Wolfe; Jefferson Medical College—J. Gottlieb, P. Park, D. M. Dillon, A. Girod, J. Furlong; LDS Hospital—A. Morris, C. Grissom, L. Weaver, J. Orme, T. Clemmer, R. Davis, J. Gleed, S. Pies, T. Graydon, S. Anderson, K. Bennion, P. Skinner; McKay-Dee Hospital—C. Lawton, J. d’Hulst, D. Hanselman; Utah Valley Regional Medical Center—K. Sundar, T. Hill, K. Ludwig, D. Nielson; University of California, San Francisco—M. A. Matthay, M. Eisner, B. Daniel, O. Garcia; San Francisco General—J. Luce, R. Kallet; University of California, San Francisco, Fresno—M. Peterson, J. Lanford; Baylor College of Medicine—K. Guntupalli, V. Bandi, C. Pope; Baystate Medical Center—J. Steingrub, M. Tidswell, L. Kozikowski; Louisiana State University Health Sciences Center—B. deBoisblanc, J. Hunt, C. Glynn, P. Lauto, G. Meyaski, C. Romaine; Louisiana State University Earl K. Long Center—S. Brierre, C. LeBlanc, K. Reed; Alton-Ochsner Clinic Foundation—D. Taylor, C. Thompson; Tulane University Medical Center—F. Simeone, M. Johnston, M. Wright; University of Chicago—G. Schmidt, J. Hall, S. Hemmann, B. Gehlbach, Vinayak, W. Schweickert; Northwestern University—J. Dematte D’Amico, H. Donnelly; University of Texas Health Sciences Center—A. Anzueto, J. McCarthy, S. Kucera, J. Peters, T. Houlihan, R. Steward, D. Vines; University of Virginia—J. Truwit, A. F. Connors, M. Marshall, W. Matsumura, R. Brett; University of Pittsburgh—M. Donahoe, P. Linden, J. Puyana, L. Lucht, A. Verno; Wake Forest University—R. D. Hite, P. Morris, A. Howard, A. Nesser, S. Perez; Moses Cone Memorial Hospital—P. Wright, C. Carter-Cole, J. McLean; St. Paul’s Hospital, Vancouver—J. Russell, L. Lazowski, K. Foley; Vancouver General Hospital—D. Chittock, L. Grandolfo; Mayo Foundation—M. Murray.
Conflicts of interest
All authors declare that they have no conflict of interest.
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