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Originally published online as doi:10.2353/ajpath.2007.070104 on July 19, 2007

Published online before print July 19, 2007
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(American Journal of Pathology. 2007;171:1066-1077.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.070104

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

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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