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Experimental endotoxemia in humans: analysis of cytokine release and
coagulation, fibrinolytic, and complement pathways
SJ van Deventer, HR Buller, JW ten Cate, LA Aarden, CE Hack and A Sturk
Department of Hematology, Academic Medical Center, Amsterdam, The
Netherlands.
Endotoxemia was evoked by bolus injection of Escherichia coli endotoxin (2
ng/kg body weight) in six healthy subjects to investigate the early
kinetics of cytokine release in relation to the development of clinical and
hematologic abnormalities frequently seen in gram-negative septicemia. The
plasma concentration of tumor necrosis factor (TNF) increased markedly
after 30 to 45 minutes, and reached a maximal level after 60 to 90 minutes.
In each volunteer, the initial increase of plasma interleukin 6 (IL-6)
concentrations occurred 15 minutes after the initial TNF increase, and
maximal IL-6 concentrations were reached at 120 to 150 minutes. A transient
increase in body temperature and pulse rate occurred simultaneously with
the initial TNF and IL-6 increases, whereas a significant decrease in blood
pressure occurred after 120 minutes. These changes were proportional to the
changes in TNF and IL-6 concentrations. Coagulation activation, as assessed
by a rise of prothrombin fragments and thrombin-antithrombin III complexes,
was noted after 120 minutes, in the absence of activation of the contact
system. A two- to sixfold increase in the concentrations of tissue
plasminogen activator (t-PA) and von Willebrand factor antigen indicated
endothelial cell activation. This increase started at 120 and 90 minutes,
respectively. The release of t-PA coincided with activation of the
fibrinolytic pathway, as measured by plasmin-alpha 2-antiplasmin complexes.
The fibrinolytic activity of t-PA was subsequently offset by release of
plasminogen activator inhibitor, observed 150 minutes after the endotoxin
injection, and reaching a peak at 240 minutes. No complement activation was
detected. These results show that in humans endotoxin induces an early,
rapidly counteracted fibrinolytic response, and a more long-lasting
activation of thrombin by a mechanism other than contact system activation.
In addition, our data suggest that endotoxin-induced leukopenia and
endothelial cell activation are mediated by TNF.
Volume 76,
Issue 12,
pp. 2520-2526,
12/15/1990
Copyright © 1990 by The American Society of Hematology
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