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Hemoglobin enhances the production of tissue factor by endothelial cells in
response to bacterial endotoxin
RI Roth
Department of Laboratory Medicine, University of California School of
Medicine, San Francisco.
Human endothelial cells respond to bacterial endotoxin (lipopolysaccharide
[LPS]) with changes that transform the endothelium into a surface with
prominent procoagulant properties. Production of tissue factor (TF) in
response to LPS is a major alteration that favors coagulation. Biologic
activities of LPS have previously been shown to be enhanced by the presence
of hemoglobin. Therefore, the ability of human hemoglobin (Hb) to modulate
TF production by cultured human umbilical vein endothelial cells (HUVEC)
was investigated. Cell-free Hb (10 mg/mL), either purified native (HbAo) or
chemically cross-linked (alpha alpha Hb), was incubated with LPS (0.1
microgram/mL), and the mixtures then were added to HUVEC in culture. TF
activity was quantified with a clotting assay and TF protein was measured
with an enzyme-linked immunosorbent assay. Hb preparations greatly enhanced
the production of TF activity (11- to 25-fold greater than TF produced by
HUVEC alone) compared with minimal TF activity generated by LPS alone (only
twofold greater than HUVEC alone). The enhancement of LPS-induced TF
activity was Hb concentration-dependent over a range of 1 to 100 mg/mL.
Cross-linked alpha alpha Hb also greatly enhanced the production of TF
protein compared with TF protein generated by LPS alone (12-fold greater v
3.5-fold greater than HUVEC alone, respectively). The enhancement of
LPS-induced TF protein was Hb concentration-dependent over a range of 0.1
to 2 mg/mL. Enhancement of TF activity by Hb required new protein
synthesis. These results show that human Hb can augment the ability of LPS
to induce endothelial cell TF and suggest that hemolysis associated with
disseminated intravascular coagulation during sepsis may further stimulate
coagulation. In addition, these results suggest a potential mechanism for
generalized thrombosis in animals that has been associated with the
infusion of cell-free Hb for resuscitation.
Volume 83,
Issue 10,
pp. 2860-2865,
05/15/1994
Copyright © 1994 by The American Society of Hematology
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