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Evidence that postoperative fibrinolytic shutdown is mediated by plasma
factors that stimulate endothelial cell type I plasminogen activator
inhibitor biosynthesis
J Kassis, J Hirsh and TJ Podor
Department of Pathology, McMaster University, Hamilton, Ontario, Canada.
Postoperative fibrinolytic shutdown has been attributed to an increase in
plasma levels of type I plasminogen activator inhibitor (PAI-1) activity
and may contribute to postoperative venous thrombosis. The purpose of this
study was to determine whether the postoperative increase in PAI-1 is
contributed to by a plasma mediator(s) that stimulates PAI-1 synthesis and
secretion by vascular endothelium. Plasma samples collected from patients
(N = 11) before and after surgery for total hip replacement were (1)
assayed for endogenous plasma PAI-1 antigen and activity, and (2) incubated
with cultured human umbilical vein endothelial cells (HUVECs) and PAI-1
antigen and activity measured in the conditioned medium (CM). Eighteen
hours after surgery, endogenous plasma levels of PAI-1 antigen and activity
were increased by 225% (P = .003) and 190% (P = .04), respectively over the
preoperative values. In addition, compared with preoperative plasma,
postoperative plasma increased HUVEC secretion of PAI-1 antigen and
activity by 99% (P = .001) and 66% (P = .002), respectively. This increase
in HUVEC PAI-1 secretion reflects an increase in PAI-1 mRNA expression and
protein biosynthesis as confirmed by metabolic radiolabeling,
immunoprecipitation, and Northern blot analysis. Ultra- filtration
experiments indicate that the postoperative plasma mediator(s) that
stimulates HUVEC PAI-1 biosynthesis is in a molecular weight (MW) range of
approximately 30 to 100 Kd. Heat treatment (56 degrees C; 30 minutes) of
postoperative plasma abolished the induction of HUVEC PAI-1 production.
Enzyme-linked immunosorbent assay and immunoneutralization experiments
indicate that tumor necrosis factor- alpha (TNF alpha) and interleukin-1
alpha (IL-1 alpha) do not contribute to the postoperative plasma effect on
HUVEC PAI-1 synthesis. These observations demonstrate that postoperative
patient plasma contains a factor(s) that may stimulate endothelial cell
PAI-1 biosynthesis in vivo and thus mediate postoperative fibrinolytic
shut- down.
Volume 80,
Issue 7,
pp. 1758-1764,
10/01/1992
Copyright © 1992 by The American Society of Hematology
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