DOI: 10.1097/01.CCM.0000220051.19432.05

,  

,  

PMID: 16714997

Issn Print: 0090-3493

Publication Date: 2006/06/01


Print

Do coagulation abnormalities contribute to sepsis associated organ failure?*

Edward Abraham

    loading  Checking for direct PDF access through Ovid

Excerpt

Activation of coagulation cascades has been postulated to play a major role in contributing to morbidity and mortality associated with severe local infection and systemic sepsis. In these settings, endothelial damage leading to microvascular dysfunction was hypothesized to produce altered tissue perfusion and local inflammatory responses that together resulted in clinically significant organ dysfunction, such as acute lung injury. Several agents with potent anticoagulant properties, including recombinant human activated protein C, tissue factor pathway inhibitor, and antithrombin, have been examined in large clinical trials, with only recombinant human activated protein C showing benefit, and then only in patients with high risk of death. The largely negative results associated with interruption of coagulation cascades in patient studies has brought into question the importance of such pathophysiologic mechanisms in producing organ dysfunction in critically ill patients.
The article by Dr. Rijneveld and colleagues (1) in this issue of Critical Care Medicine provides further insights into the possible association or lack thereof between infection-induced coagulation alterations and inflammation. In this study, elevated levels of activated factor VII (FVIIa), tissue factor, and thrombin-antithrombin complexes (TATc) were found in bronchoalveolar lavage fluid from the infected segments of the lungs in patients with pneumonia. Mice with pneumococcal pneumonia also showed increased tissue factor expression as well as TATc in bronchoalveolar lavage fluid. However, whereas inhibition of the tissue factor pathway in Streptococcus pneumonia-infected mice corrected coagulation abnormalities in the lung, there was no effect on mortality from pneumococcal pneumonia or pulmonary inflammatory responses, as determined by neutrophil accumulation in the lungs or levels of macrophage inflammatory protein-2 or keratinocyte-derived chemokine, two murine CXC chemokines that are related to interleukin-8, an important mediator of pulmonary inflammation in human acute lung injury. Interestingly, recent studies with recombinant human activated protein C (rhAPC) showed similar results, with rhAPC being able to affect coagulation alterations found in the lungs of human volunteers exposed to pulmonary lipopolysaccharide, but without modulating cytokine release (2, 3). However, in those studies, rhAPC did decrease neutrophil accumulation into the airspaces, apparently by inhibiting the movement of neutrophils to proinflammatory mediators, such as interleukin-8.
Previous studies using animal models of sepsis had shown that interruption of tissue factor related events resulted in improved survival and less organ system dysfunction. For example, in baboons infused with bacteria, administration of tissue factor pathway inhibitor (TFPI), a recombinant protein that binds to activated factors VII and X to block tissue factor associated signaling, improved survival, decreased circulating proinflammatory cytokine levels, and diminished the severity of organ injury compared with placebo-treated animals (4, 5). Similar beneficial effects were found in baboons treated with anti-tissue factor antibodies in the setting of bacteremia (6). However, TFPI showed no effect on circulating cytokine levels when given to humans exposed to intravenous lipopolysaccharide, even though it completely prevented the endotoxemia-induced coagulopathy (7). At least one possible explanation for these apparently disparate findings is that the animal models in which TFPI or anti-tissue factor antibodies showed efficacy are characterized by the rapid development of profound disseminated intravascular coagulation. Evidence of disseminated intravascular coagulation is found in almost all patients with sepsis and organ dysfunction, as shown by increased circulating levels of D-dimers and TATc, as well as diminished concentrations of protein C and antithrombin (8). However, the degree of activation of coagulation cascades in septic patients is generally less than that present when animals are treated with large infusions of bacteria or high doses of lipopolysaccharide.

Related Topics

    loading  Loading Related Articles