Possible involvement of cytokines in diffuse intravascular coagulation and thrombosis.

Recently, basic and clinical advances have provided insights into the molecular events that link inflammation with blood coagulation and thrombosis. At least in cell culture, the inflammatory cytokines, especially tumour necrosis factor alpha (TNF) and interleukin 1-beta (IL-1), are major mediators that can elicit changes in cell phenotype. With respect to coagulation, one of the clot-promoting and one of the inhibitory pathways seem especially prone to modulation by these cytokines. Whenever Tissue Factor contacts the blood, coagulation is initiated rapidly. These cytokines can elicit Tissue Factor production on endothelium and monocytes. Thus, the cytokines elaborate Tissue Factor formation intravascularly. This contrasts with the normal situation in which Tissue Factor is located exclusively in the extravascular space, largely on fibroblasts, where it is expressed constitutively. Furthermore, cytokines, especially interleukin 6 (IL-6), can stimulate new platelet formation, and the new platelets responding to IL-6 have increased sensitivity to thrombin activation and increased procoagulant activity. Regulating the clotting process are a large number of anticoagulant and fibrinolytic mechanisms. The three major anticoagulant mechanisms appear to involve antithrombin-heparin, Tissue Factor pathway inhibitor (TFPI) and the Protein C pathway. Of these, the Protein C pathway appears to be the primary target for cytokine action. The Protein C pathway is initiated when thrombin binds to thrombomodulin (TM). TM is expressed constitutively on endothelium. In tissue culture, TNF, IL-1 or endotoxin lead to a slow loss of TM and endothelial cell Protein C receptor (EPCR) from the cell surface. In addition, Protein S levels decrease in patients with disseminated intravascular coagulation (DIC). Taken together, these results suggest that cytokines should elicit massive thrombotic responses when administered systemically. At near toxic levels, TNF fails to elicit an overt DIC or thrombotic response in patients, although sensitive markers of coagulation do detect changes in coagulation in response to TNF. In baboons, very high levels of TNF also fail to elicit fibrinogen or platelet consumption. However, if the Protein C pathway is blocked, these cytokines can elicit either DIC or deep-vein thrombosis, depending on the conditions. Thrombus formation is potently potentiated by impeding flow and/or by catheterization. DIC is facilitated by providing membrane surfaces, possibly mimicking complement mediated platelet activation/damage that occurs in shock. Thus, available evidence suggests important roles for inflammatory cytokines in DIC and thrombosis, but they seem insufficient by themselves to elicit overt thrombotic responses without secondary stimuli. Current data suggest that anti-inflammatory drugs are a viable candidate to blocking DIC or thrombosis without impairing the haemostatic balance.