Mortality and platelet depletion occur independently of fibrinogen consumption in murine models of tumour necrosis factor-mediated systemic inflammatory responses.
Tumour necrosis factor (TNF) is known to have procoagulant activity, and platelet depletion is a feature of TNF-mediated systemic inflammatory responses. The aim of this study was to investigate the role of fibrinogen consumption in the development of TNF-mediated systemic inflammatory responses and in the associated depletion of platelets. Three murine models of TNF-mediated systemic inflammatory responses were examined: the systemic toxicity reactions (STR) induced by TNF or lipopolysaccharide (LPS) and severe malaria (SM), a prominently neurological complication of Plasmodium berghei ANKA infection in susceptible mice. There was an acceleration in the consumption of fibrinogen during TNF-STR but not during LPS-STR or SM. However, a concomitant reduction in platelet count was found in all conditions. Mice preliminarily depleted in fibrinogen by treatment with ancrod, an enzyme that specifically degrades fibrinogen, showed no protection against mortality during TNF- or LPS-STR or SM, although they were protected against tissue damage during a modification of the classical local Shwartzman reaction. During TNF- and LPS-STR platelets were even lower in ancrod-treated than control mice and during SM they were not significantly different. This study shows that fibrinogen consumption, although accelerated by the direct injection of TNF, is not necessary for the development of TNF-mediated systemic inflammatory responses in mice, at variance with local pathology, and does not contribute to the associated depletion of platelets.
Senaldi
G
G
Amgen Inc., Thousand Oaks, CA 91320-1789, USA.
Piguet
P F
PF
D000721:Ancrod / Q000627:therapeutic use; D000818:Animals; D001792:Blood Platelets / Q000166:cytology*; D003029:Coagulants / Q000378:metabolism* / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D005340:Fibrinogen / Q000378:metabolism* / Q000494:pharmacology; D005343:Fibrinolytic Agents / Q000627:therapeutic use; D007457:Iodine Radioisotopes; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D010962:Plasmodium berghei; D010976:Platelet Count; D011517:Prothrombin Time; D011994:Recombinant Proteins / Q000276:immunology / Q000494:pharmacology; D018746:Systemic Inflammatory Response Syndrome / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology* / Q000494:pharmacology
D003029:Coagulants; D005343:Fibrinolytic Agents; D007457:Iodine Radioisotopes; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D005340:Fibrinogen; D000721:Ancrod