Intensive Care Medicine

, Volume 41, Issue 3, pp 470–478 | Cite as

Plasma soluble thrombomodulin levels are associated with mortality in the acute respiratory distress syndrome

  • Anil SapruEmail author
  • Carolyn S. Calfee
  • Kathleen D. Liu
  • Kirsten Kangelaris
  • Helen Hansen
  • Ludmila Pawlikowska
  • Lorraine B. Ware
  • Mustafa F. Alkhouli
  • Jason Abbot
  • Michael A. Matthay
  • The NHLBI ARDS Network



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.


ARDS 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.

Supplementary material

134_2015_3648_MOESM1_ESM.tiff (3.7 mb)
Supplementary material 1 (TIFF 3836 kb) Supplementary Fig. 1. Box plots of sTM levels collected at baseline among subjects with ARDS stratified by the cause of ALI. Patients with ARDS with sepsis as the primary cause of ARDS had higher sTM levels (p < 0.001). Panel A Day 0, Panel B Day 3
134_2015_3648_MOESM2_ESM.tiff (1.9 mb)
Supplementary material 2 (TIFF 1934 kb) Supplementary Fig. 2. Receiver Operator Characteristic Curves depicting improvement in the discriminatory ability of APACHE III score with addition of sTM levels to the model. The area under curve increased from 77 % to 80 % (p < 0.03)


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Copyright information

© Springer-Verlag Berlin Heidelberg and ESICM 2015

Authors and Affiliations

  • Anil Sapru
    • 1
    • 2
    Email author
  • Carolyn S. Calfee
    • 3
  • Kathleen D. Liu
    • 3
  • Kirsten Kangelaris
    • 3
  • Helen Hansen
    • 4
  • Ludmila Pawlikowska
    • 5
    • 6
  • Lorraine B. Ware
    • 7
    • 8
  • Mustafa F. Alkhouli
    • 1
  • Jason Abbot
    • 9
  • Michael A. Matthay
    • 9
  • The NHLBI ARDS Network
  1. 1.Department of PediatricsUniversity of CaliforniaSan FranciscoUSA
  2. 2.Department of PediatricsSan FranciscoUSA
  3. 3.Medicine and AnesthesiaUniversity of CaliforniaSan FranciscoUSA
  4. 4.Molecular Epidemiology LaboratoryUniversity of CaliforniaSan FranciscoUSA
  5. 5.Anesthesia and Perioperative CareUniversity of CaliforniaSan FranciscoUSA
  6. 6.Institute for Human GeneticsUniversity of CaliforniaSan FranciscoUSA
  7. 7.Department of Medicine and PathologyVanderbilt UniversityNashvilleUSA
  8. 8.Department of Microbiology and ImmunologyVanderbilt UniversityNashvilleUSA
  9. 9.Cardiovascular Research Institute, Departments of Medicine and AnesthesiaUniversity of CaliforniaSan FranciscoUSA

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