Tissue factor (TF) is a
glycoprotein which acts as a trigger of the coagulation cascade. TF expression may be induced at the surface of monocytes and endothelial cells by several stimuli including bacterial
endotoxin (LPS) and
cytokines (IL 1 beta,
TNF alpha) and there is a large body of evidence for the involvement of
hypoxia as a primaring factor in the process leading to
thrombosis. To define the molecular basis underlying this phenomenon, we evaluated the relative role of
platelet activating factor (PAF). PAF primed human monocytes and human umbilical vein endothelial cells (HUVEC) for TF expression following exposure to E coli LPS but was unable to enhance the induction of TF expression by IL 1 beta. The priming effect of PAF with regard to LPS occurred in a time- and dose-dependent manner and was inhibited by the PAF receptor antagonist
SR 27417. When HUVEC or monocytes were exposed to an hypoxic environment, a significant rise in LPS-induced TF expression was observed.
Hypoxia had no effect on IL 1-induced TF expression. The enhanced LPS-induced TF expression in both cell types was mediated by PAF as indicated by the inhibition obtained with
SR 27417, added during
hypoxia. Although the importance of
hypoxia in the etiology of
venous thrombosis has been acknowledged for a long time, evaluation of the relative importance of PAF in the process leading to
thrombus formation is still lacking. Stasis-induced
thrombosis performed in the rabbit jugular vein was enhanced in a dose-dependent manner by the prior i.v. administration of LPS (0.05 to 100 micrograms/ kg, i.v.).
SR 27417 administered simultaneously with LPS prevented
thrombus formation with an ED50 value of 0.1 +/- 0.04 mg/kg. These results therefore show that
hypoxia promotes LPS-induced TF expression in HUVEC and human monocytes through a PAF-dependent mechanism in vitro and in vivo.