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Absence of Thrombin-Activatable Fibrinolysis Inhibitor Protects against Sepsis-Induced Liver Injury in Mice¹

Rosemarijn Renckens^2,*, Joris J. T. H. Roelofs, Simone A. J. ter Horst^¶, Cornelis van 't Veer^*, Stefan R. Havik, Sandrine Florquin, Gerry T. M. Wagenaar^¶, Joost C. M. Meijers and Tom van der Poll^*,

^* Laboratory of Experimental Internal Medicine, Department of Pathology, Department of Vascular Medicine, and Department of Infectious Diseases, Tropical Medicine and AIDS, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and ^¶ Department of Pediatrics, Leiden University Medical Center Leiden, The Netherlands

Thrombin-activatable fibrinolysis inhibitor (TAFI), also known as carboxypeptidase R, has been implicated as an important negative regulator of the fibrinolytic system. In addition, TAFI is able to inactivate inflammatory peptides such as complement factors C3a and C5a. To determine the role of TAFI in the hemostatic and innate immune response to abdominal sepsis, TAFI gene-deficient (TAFI^–/–) and normal wild-type mice received an i.p. injection with Escherichia coli. Liver TAFI mRNA and TAFI protein concentrations increased during sepsis. In contrast to the presumptive role of TAFI as a natural inhibitor of fibrinolysis, TAFI^–/– mice did not show any difference in E. coli-induced activation of coagulation or fibrinolysis, as measured by plasma levels of thrombin-anti-thrombin complexes and D-dimer and the extent of fibrin depositions in lung and liver tissues. However, TAFI^–/– mice were protected from liver necrosis as indicated by histopathology and clinical chemistry. Furthermore, TAFI^–/– mice displayed an altered immune response to sepsis, as indicated by an increased neutrophil recruitment to the peritoneal cavity and a transiently increased bacterial outgrowth together with higher plasma TNF- and IL-6 levels. These data argue against an important part for TAFI in the regulation of the procoagulant-fibrinolytic balance in sepsis and reveals a thus far unknown role of TAFI in the occurrence of hepatic necrosis.

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