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American Journal of Respiratory and Critical Care Medicine Vol 167. pp. 1200-1209, (2003)
© 2003 American Thoracic Society

Blockade of Tissue Factor

Treatment for Organ Injury in Established Sepsis

Martha Sue Carraway, Karen E. Welty-Wolf, Debra L. Miller, Thomas L. Ortel, Steven Idell, Andrew J. Ghio, Lars C. Petersen and Claude A. Piantadosi

Department of Medicine, Duke University Medical Center, Durham, North Carolina; Department of Medicine, University of Texas, Tyler, Texas; and Novo-Nordisk, Copenhagen, Denmark

Correspondence and requests for reprints should be addressed to Martha Sue Carraway, M.D., Division of Pulmonary and Critical Care Medicine, Box 3315, Duke University Medical Center, Durham, NC 27710. E-mail: carra001{at}me.duke.edu

Blockade of tissue factor before lethal sepsis prevents acute lung injury and renal failure in baboons, indicating that activation of coagulation by tissue factor is an early event in the pathogenesis of acute lung injury and organ dysfunction. We hypothesized that blockade of tissue factor would also attenuate these injuries in established sepsis by prevention of further fibrin deposition and inflammation. Twelve male baboons received heat-killed Escherichia coli intravenously followed 12 hours later by live E. coli infusion. Six animals were treated 2 hours after the live bacteria with site-inactivated Factor VIIa, a competitive tissue factor inhibitor, and six animals were vehicle-treated sepsis control subjects. Animals were ventilated and monitored for 48 hours. Physiologic and hematologic parameters were measured every 6 hours, and pathologic evaluation was performed after 48 hours. Animals treated with site inactivated Factor VIIa had less severe lung injury, with preserved gas exchange, better lung compliance and histology scores, and decreased lung wet/dry weight. In treated animals, urine output was higher, metabolic acidosis was attenuated, and renal tubular architecture was protected. Coagulopathy was attenuated, and plasma interleukin-6, interleukin-8, and soluble tumor necrosis factor receptor-1 levels were significantly lower in the treated animals. These results show that blockade of coagulation attenuates acute lung and renal injury in established Gram-negative sepsis accompanied by antiinflammatory effects of therapy.

Key Words: systemic inflammatory response • acute respiratory distress syndrome • multiple organ dysfunction syndrome • coagulation




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