How is tissue factor activation

The most important homeostatic mechanisms that inhibit coagulation are: 1 the antithrombin III-heparin sulfate system, which inhibits thrombin and factor Xa; 2 tissue factor protease inhibitor, which is composed of three Kunitz-type protease inhibitor domains, and directly inhibits factor Xa and mediates a negative feedback on tissue factor expression and factor VIIa 29,30 , and 3 the protein C pathway 31, The protein C pathway is activated when thrombin binds to the endothelial surface protein thrombomodulin or CD and is facilitated by the transmembrane endothelial protein C receptor In sepsis, endothelial damage and the presence of proinflammatory stimuli e.

The molecular links between inflammation and coagulation are unquestionable. Inflammation promotes coagulation by leading to intravascular tissue factor expression and down-regulation of the fibrinolytic and protein C anticoagulant pathways. Protein C and antithrombin III are quickly depleted in sepsis as the body attempts to reestablish equilibrium 6.

In fact, the level of circulating protein C is inversely related to mortality in patients with severe sepsis. Septic shock is a major health problem. It is the leading cause of death in intensive care units. Early studies of septic shock focused on inflammation as the dominant process causing vascular endothelial injury and the so-called sepsis cascade. However, given the universal failure of specific anti-inflammatory therapies in clinical trials of septic patients, a search for a more complex and multifactorial pathogenesis was undertaken The new paradigm that has emerged from those investigations, which has radically changed the view of sepsis, is the current understanding that the disease process is caused by a loss of homeostasis between inflammation, coagulation, and fibrinolysis This new paradigm is supported by the recent finding that recombinant activated protein C significantly reduces mortality in patients with sepsis Bacterial LPS and the inflammatory cytokines, TNF-a and interleukin-1, have been shown to be important mediators of septic shock One mechanism by which the proinflammatory mediators contribute to septic shock is by stimulating tissue factor expression, which in turn activates the coagulation cascade 37, In experimental animal models of gram-negative septic shock, a monoclonal antibody against tissue factor attenuates coagulopathy and protects against death Infectious endocarditis is characterized by the formation of valvular vegetations consisting of bacteria embedded within a platelet-fibrin meshwork.

Tissue factor plays a key role in the development of these vegetations. From in vitro studies, it has been discovered that Staphylococcus aureus infection induces tissue factor synthesis and expression on endothelial cells and monocytes While endothelial cells play an important role in the early events of vegetation formation, monocytes participate by intensifying fibrin deposition 44, There is some controversy about the importance of live or killed bacteria in tissue factor induction 45, Recently, it was demonstrated that the cell wall peptidoglycan of S.

The kinetics of tissue factor induction by LPS and peptidoglycan is similar, with maximal procoagulant activity developing within 4 h. However, LPS is a fold more potent stimulus of tissue factor expression compared to peptidoglycan Although S. With these organisms, it is hypothesized that the formation of the vegetation is induced by tissue factor expressed by monocytes, rather than the endothelial cells.

Aspergillus fumigatus is an angioinvasive fungus, and invasive aspergillosis is characterized by vascular invasion with subsequent thrombosis and tissue infarction We have developed an in vitro model of interaction of A. Our data indicate that A. Candida albicans is another angioinvasive fungus. However, vascular thrombosis is not usually seen at foci of candidal infection. Interestingly, we found that C. Similarly, in a patient with candidemia, it was found that the monocytes did not express tissue factor.

In contrast, monocytes from patients with systemic bacterial infections strongly expressed tissue factor These observations suggest that tissue factor expression is tightly controlled and is induced only in response to specific microbial pathogens. In conclusion, activation of endothelial cell tissue factor-mediated procoagulant activity is a key event in the pathogenesis of several types of infection.

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