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Progress of fibrinolysis during tumor necrosis factor infusions in humans.
Concomitant increase in tissue-type plasminogen activator, plasminogen
activator inhibitor type-1, and fibrin(ogen) degradation products
VW van Hinsbergh, KA Bauer, T Kooistra, C Kluft, G Dooijewaard, ML Sherman and W Nieuwenhuizen
Gaubius Institute TNO, Leiden, The Netherlands.
Several investigators have reported that tumor necrosis factor (TNF) can
alter the production of plasminogen activator type-1 (PAI-1) and
plasminogen activators (PAs) by endothelial cells in vitro. We have
examined the in vivo effects of recombinant human TNF administration on
fibrinolysis as assessed by parameters in plasma during a 24-hour period of
continuous TNF infusion to 17 cancer patients with active disease. The
plasma levels of PAI activity increased sevenfold after 3 and 24 hours of
TNF infusion. This was the result of an increase of PAI- 1 antigen; PAI-2
antigen was not detectable. Plasma concentrations of tissue-type PA (t-PA)
antigen increased twofold to fivefold after 3 and 24 hours of TNF infusion,
whereas urokinase-type PA antigen levels in plasma remained unaltered.
After 3 hours of TNF infusion the plasma levels of alpha 2-antiplasmin were
slightly decreased, 5% on average, suggesting that fibrinolysis continued.
After 24 hours of TNF infusion a highly significant increase in fibrin-
plus fibrinogen-degradation products, and separately of fibrin degradation
products and fibrinogen degradation products, was found. This indicates
that fibrinolysis persisted, at least partly, in the presence of high
levels of PAI activity. Whereas PAI-1 production increased, t-PA production
by human endothelial cells in vitro remains unaltered or even decreases on
TNF addition. It has been shown previously that TNF infusion in our
patients results in thrombin and fibrin generation. Therefore, it is
possible that thrombin, not TNF, is the actual stimulus for t-PA production
in our patients. We speculate that fibrin is formed during TNF infusions
and that plasmin is generated by t-PA action immediately on the initial
formation of (soluble) fibrin molecules. Such a process may explain the
generation of degradation products of both fibrin and fibrinogen during
infusion of TNF in patients.
Volume 76,
Issue 11,
pp. 2284-2289,
12/01/1990
Copyright © 1990 by The American Society of Hematology
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