Role of tumor necrosis factor in the pathogenesis of intravascular coagulopathy of sepsis: potential new therapeutic implications.
Tumor necrosis factor (TNF) induced by bacterial lipopolysaccharide (LPS) was shown to have an important role in precipitation of septic shock and disseminated intravascular clotting (DIC). At the endothelial level TNF down-regulates thrombomodulin (thus preventing protein C formation) and inhibits the production of tissue plasminogen activator (t-PA), thus impairing anticoagulant mechanisms. On the other hand, TNF up-regulates the production of procoagulant factors such as t-PA inhibitor (PAI), tissue factor and platelet activating factor (PAF). These effects create an imbalance between procoagulant and anticoagulant mechanisms, in favor of the former. TNF also activates polymorphonuclears (PMNs), and increases their chemotaxis and adherence to endothelial surfaces by up-regulation of specific endothelial (ELAM-1) and PMN (CDw18) adherence proteins. The damage inflicted by activated PMN to the endothelial cell promotes tissue factor exposure and PAI release, with initiation of the characteristic explosive coagulation process of DIC, facilitated by the dissociation between pro- and anticoagulant mechanisms induced by TNF. These newly discovered mechanisms precipitating septic shock and DIC enable consideration of new treatments for this condition as anti-TNF antibodies or TNF inhibitors, anti-ELAM-1 antibodies anti-tissue factor antibodies, administration of activated factor C, etc. These therapeutic approaches may revolutionize the treatment of septic shock and DIC in the next decade.
Aderka
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Department of Medicine T, Sourasky Medical Center (Ichilov Hospital), Tel Aviv, Israel.
D000818:Animals; D004211:Disseminated Intravascular Coagulation / Q000209:etiology* / Q000503:physiopathology / Q000628:therapy; D004285:Dogs; D006801:Humans; D018805:Sepsis / Q000150:complications*; D012772:Shock, Septic / Q000209:etiology* / Q000503:physiopathology / Q000628:therapy; D014409:Tumor Necrosis Factor-alpha
D014409:Tumor Necrosis Factor-alpha