This Article Full Text Full Text (PDF) Online Supplement All Versions of this Article: 200606-827OCv1 175/1/69    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Christie, J. D. Search for Related Content PubMed PubMed Citation Articles by Christie, J. D.

Association of Protein C and Type 1 Plasminogen Activator Inhibitor with Primary Graft Dysfunction

Division of Pulmonary, Allergy, and Critical Care Medicine, and Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; Division of Pulmonary, Allergy, and Critical Care Medicine, Vanderbilt University, Nashville, Tennessee; Division of Pulmonary and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, Alabama; Division of Pulmonary, Allergy, and Critical Care Medicine, University of Michigan, Ann Arbor, Michigan; Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Johns Hopkins University Hospital, Baltimore, Maryland; Division of Pulmonary and Critical Care Medicine, Stanford University, Stanford, California; and Division of Pulmonary, Allergy, and Critical Care Medicine, Columbia University College of Physicians and Surgeons, and Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York

Correspondence and requests for reprints should be addressed to Jason D. Christie, M.D., M.S., Division of Pulmonary, Allergy, and Critical Care Medicine, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, 423 Guardian Drive, 719 Blockley Hall, Philadelphia, PA 19104. E-mail: jchristi{at}cceb.med.upenn.edu

Background: Acute lung injury is characterized by hypercoagulability and impaired fibrinolysis. We hypothesized that lower protein C and higher type 1 plasminogen activator inhibitor (PAI-1) levels in plasma would be associated with primary graft dysfunction (PGD) after lung transplantation.

Design: Prospective, multicenter cohort study.

Methods: We measured plasma levels of protein C and PAI-1 before lung transplantation and 6, 24, 48, and 72 h after allograft reperfusion in 128 lung transplant recipients at six centers. The primary outcome was grade 3 PGD (Pa_O2/FI_O2 < 200 with alveolar infiltrates) 72 h after transplantation. Biomarker profiles were evaluated using logistic regression and generalized estimating equations.

Results: Patients who developed PGD had lower protein C levels 24 h posttransplantation than did patients without PGD (mean ± SD [relative to control]: 64 ± 27 vs. 92 ± 41%, respectively; p = 0.002). Patients with PGD also had PAI-1 levels that were almost double those of patients without PGD at 24 h (213 ± 144 vs. 117 ± 89 ng/ml, respectively; p < 0.001). Throughout the 72-h postoperative period, protein C levels were significantly lower (p = 0.007) and PAI-1 levels were higher (p = 0.026) in subjects with PGD than in others. These differences persisted despite adjustment for potential confounders in multivariate analyses. Higher recipient pulmonary artery pressures, measured immediately pretransplantation, were associated with higher PAI-1 levels and increased risk of PGD.

Conclusion: Lower postoperative protein C and higher PAI-1 plasma levels are associated with PGD after lung transplantation. Impaired fibrinolysis and enhanced coagulation may be important in PGD pathogenesis.

Key Words: primary graft dysfunction • reperfusion injury • lung transplantation • type 1 plasminogen activator inhibitor • protein C

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject There is growing evidence that impaired fibrinolysis and increased coagulation play a role in acute lung injury pathogenesis. However, little is known about the role of coagulation and fibrinolysis in primary graft dysfunction in humans. What This Study Adds to the Field Elevation in plasma levels of PAI-1 and depression in protein C are associated with primary graft dysfunction.

 

This article has been cited by other articles:

				J. D. Christie, C. V. Shah, S. M. Kawut, N. Mangalmurti, D. J. Lederer, J. R. Sonett, V. N. Ahya, S. M. Palmer, K. Wille, V. Lama, et al. Plasma Levels of Receptor for Advanced Glycation End Products, Blood Transfusion, and Risk of Primary Graft Dysfunction Am. J. Respir. Crit. Care Med., November 15, 2009; 180(10): 1010 - 1015. [Abstract] [Full Text] [PDF]

				S. M. Kawut, J. Okun, D. Shimbo, D. J. Lederer, J. De Andrade, V. Lama, A. Shah, A. Milstone, L. B. Ware, A. Weinacker, et al. Soluble P-Selectin and the Risk of Primary Graft Dysfunction After Lung Transplantation Chest, July 1, 2009; 136(1): 237 - 244. [Abstract] [Full Text] [PDF]

				C. L. Lau, Y. Zhao, J. Kim, I. L. Kron, A. Sharma, Z. Yang, V. E. Laubach, J. Linden, G. Ailawadi, and D. J. Pinsky Enhanced fibrinolysis protects against lung ischemia-reperfusion injury. J. Thorac. Cardiovasc. Surg., May 1, 2009; 137(5): 1241 - 1248. [Abstract] [Full Text] [PDF]

				J. C. Lee and J. D. Christie Primary Graft Dysfunction Proceedings of the ATS, January 15, 2009; 6(1): 39 - 46. [Abstract] [Full Text] [PDF]

				T. Iwata, A. Philipovskiy, A. J. Fisher, R. G. Presson Jr., M. Chiyo, J. Lee, E. Mickler, G. N. Smith, I. Petrache, D. B. Brand, et al. Anti-Type V Collagen Humoral Immunity in Lung Transplant Primary Graft Dysfunction J. Immunol., October 15, 2008; 181(8): 5738 - 5747. [Abstract] [Full Text] [PDF]

				P. A. Corris and J. D. Christie Update in Transplantation 2007 Am. J. Respir. Crit. Care Med., May 15, 2008; 177(10): 1062 - 1067. [Full Text] [PDF]

				H. A. Yegen, D. J. Lederer, R. G. Barr, J. S. Wilt, Y. Fang, E. Bagiella, F. D'Ovidio, J. M. Okun, J. R. Sonett, S. M. Arcasoy, et al. Risk Factors for Venous Thromboembolism After Lung Transplantation Chest, August 1, 2007; 132(2): 547 - 553. [Abstract] [Full Text] [PDF]