Recently, basic and clinical advances have provided insights into the molec
ular events that link inflammation with blood coagulation and thrombosis. A
t least in cell culture, the inflammatory cytokines, especially tumour necr
osis 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 p
rone 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 elabora
te Tissue Factor formation intravascularly. This contrasts with the normal
situation in which Tissue Factor is located exclusively in the extravascula
r space, largely on fibroblasts, where it is expressed constitutively.
Furthermore, cytokines, especially interleukin 6 (1L-6), can stimulate new
platelet formation, and the new platelets responding to IL-6 have increased
sensitivity to thrombin activation and increased procoagulant activity. Re
gulating the clotting process are a large number of anticoagulant and fibri
nolytic mechanisms. The three major anticoagulant mechanisms appear to invo
lve antithrombin-heparin, Tissue Factor pathway inhibitor (TFPI) and the Pr
otein C pathway. Of these, the Protein C pathway appears to be the primary
target for cytokine action. The Protein C pathway is initiated when thrombi
n binds to thrombomodulin (TM). TM is expressed constitutively on endotheli
um. In tissue culture, TNF, IL-l or endotoxin lead to a slow loss of TM and
endothelial cell Protein C receptor (EPCR) from the cell surface. In addit
ion, Protein S levels decrease in patients with disseminated intravascular
coagulation (DIC). Taken together, these results suggest that cytokines sho
uld 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 f
ail to elicit fibrinogen or platelet consumption. However, if the Protein C
pathway is blocked, these cytokines can elicit either DIC or deep-vein thr
ombosis, depending on the conditions. Thrombus formation is potently potent
iated by impeding flow and/or by catheterization. DIC is facilitated by pro
viding membrane surfaces, possibly mimicking complement mediated platelet a
ctivation/damage that occurs in shock. Thus, available evidence suggests im
portant roles for inflammatory cytokines in DIC and thrombosis, but they se
em 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 haemos
tatic balance.