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Published online before print July 19, 2007
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Copyright © 2007 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2007.070104

Accepted for publication May 31, 2007.

Article

Sepsis-Induced Coagulation in the Baboon Lung Is Associated with Decreased Tissue Factor Pathway Inhibitor

Haiwang Tang*, Lacramioara Ivanciu*, Narcis Popescu*, Glenn Peer*, Erik Hack{dagger}, Cristina Lupu*, Fletcher B. Taylor Jr*{ddagger}, and Florea Lupu*{ddagger}@

From the Cardiovascular Biology Research Program,* Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma; the Department of Immunopathology,{dagger} Sanquin Research at CLB and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and the Department of Pathology,{ddagger} Oklahoma University Health Sciences Center, Oklahoma City, Oklahoma

@ To whom correspondence should be addressed. E-mail: florea-lupu{at}omrf.ouhsc.edu.


  Abstract

Increased tissue factor (TF)-dependent procoagulant activity in sepsis may be partly due to decreased expression or function of tissue factor pathway inhibitor (TFPI). To test this hypothesis, baboons were infused with live Escherichia coli and sacrificed after 2, 8, or 24 hours. Confocal and electron microscopy revealed increased leukocyte infiltration and fibrin deposition in the intravascular and interstitial compartments. Large amounts of TF were detected by immunostaining in leukocytes and platelet-rich microthrombi. TF induction was documented by quantitative reverse transcriptase-polymerase chain reaction, enzyme-linked immunosorbent assay, and coagulation assays. Lung-associated TFPI antigen and mRNA decreased during sepsis, and TFPI activity diminished abruptly at 2 hours. Blocking antibodies against TFPI increased fibrin deposition in septic baboon lungs, suggesting that TF-dependent coagulation might be aggravated by reduced endothelial TFPI. Decreased TFPI activity coincided with the release of tissue plasminogen activator and the peak of plasmin generation, suggesting that TFPI could undergo proteolytic inactivation by plasmin. Enhanced plasmin produced in septic baboons by infusion of blocking antibodies against plasminogen activator inhibitor-1 led to decreased lung-associated TFPI and unforeseen massive fibrin deposition. We conclude that activation of TF-driven coagulation not adequately countered by TFPI may underlie the widespread thrombotic complications of sepsis.




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J. T.B. Crawley and D. A. Lane
The Haemostatic Role of Tissue Factor Pathway Inhibitor
Arterioscler. Thromb. Vasc. Biol., February 1, 2008; 28(2): 233 - 242.
[Abstract] [Full Text] [PDF]


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Copyright © 2007 by the American Society for Investigative Pathology.