The
hemostatic system is severely disturbed during
endotoxemia, leading to a hypercoagulable state. However, it remains uncertain to what extent
hypercoagulability is the critical factor in determining the
clinical course rather than just the consequence of a severe systemic inflammatory response. To answer this question, we evaluated the evolution of
hemostatic and inflammatory markers, as well as histological features, in mice sensitive and resistant to two models of
endotoxemia:
lipopolysaccharide-injection and cecal
ligation puncture. Genetic (knockout mice) and pharmacological (
PJ34) blockade of the nuclear
enzyme PARP-1 was used to achieve resistance to the
endotoxemia. In both models,
endotoxemia resulted in
antithrombin deficiency, decreased platelets, and
fibrin deposition in organs, which were similar in all groups of mice. By contrast, proinflammatory mediators, inflammatory cell infiltration (especially that mediated by mononuclear cells), and organ degeneration were more intense in sensitive animals. Further studies supported a negative role for the triggering of the coagulation cascade in the mortality associated with the endotoxic
shock.
Hirudin had a minor effect on cell infiltration and organ damage, despite causing a potent inhibition of
fibrin deposition. On the other hand, a sublethal dose of
lipopolysaccharide yielded significant
fibrin deposition but weak activation of the inflammatory response. Our results suggest that activation of coagulation by
endotoxemia is severe and independent of the inflammatory response. However, such activation may act with
fibrin deposition to have a minor influence on survival in
sepsis.