Failure of Kupffer cell blockade to prevent disseminated intravascular coagulation in endotoxemic rats despite improved survival

Abstract

Objective: Studies were conducted to evaluate the impact of gadolinium chloride (GdCl₃), an agent which blocks the phagocytosis of liver macrophages (Kupffer cells, KC), on the coagulation system and on mortality in a model of rats subjected to a lethal dose of Escherichia coli lipopolysaccharide (LPS) (10 mg/kg body weight, intravenously). Methods: Rats were either pretreated with GdCl₃ (10 mg/kg, i.v., 48 h and 24 h prior to LPS exposure) or saline vehicle. A variety of coagulation parameters such as activated partial prothrombin time (aPTT), fibrinogen, systemic platelet count, antithrombin III (AT III), and activities of factors V, VII, and XII were monitored in the early (1 h) and late time course (16 h) following administration of E.coli LPS. Results: The administration of LPS resulted in the development of disseminated intravascular coagulation (DIC) and was associated with a mortality rate of 47% within 16 h. Blockade of KC by GdCl₃ completely abolished LPS-related mortality (0%). However, despite improved survival, GdCl₃ failed to prevent laboratory and clinical signs of DIC. GdCl₃ per se even contributed to coagulatory and fibrinolytic disorders. Conclusion: These results confirm reports on the protective potential of GdCl₃ pretreatment in experimental endotoxemia. However, the present study does not support the concept of DIC as a strong prognostic criterion for the outcome of sepsis and septic shock. Furthermore, the results presented suggest a minor role for KC in LPS-mediated activation of coagulation and indicate an involvement of KC in LPS-associated lethality independent of the coagulation system.