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Retinoic acid reduces induction of monocyte tissue factor and tissue
factor/factor VIIa-dependent arterial thrombus formation
RM Barstad, MJ Hamers, RW Stephens and KS Sakariassen
Nycomed Bioreg AS, Oslo, Norway.
Agents that downregulate the induction of monocyte/macrophage tissue factor
(TF) activity may attenuate the thrombotic risk associated with mechanical
restoration of vessel patency or artificial arterial grafting. In such
events, procoagulant macrophages in the atherosclerotic plaque and
procoagulant monocytes adherent to artificial materials may be exposed to
the blood stream. Ishii et al (Blood 80:2556, 1992) reported that induction
of endothelial TF is downregulated by all-trans retinoic acid (ATRA), and
Conese et al (Thromb Haemost 66:662, 1991) reported that retinoids
downregulate monocyte procoagulant activity (PCA). These findings led us to
investigate the effect of ATRA on monocyte TF expression, and to study the
effect of ATRA on monocyte-induced thrombus formation in a model system of
human arterial thrombogenesis. Induction of PCA in human peripheral blood
monocytes by 0.5 microgram/mL lipopolysaccharide (LPS) was dose dependently
reduced by ATRA, reaching a reduction of 56% at 10(-5) mol/L ATRA (P <
.0001). A 38% reduction (P < .0007) in LPS- induced TF antigen
expression was observed at an ATRA concentration of 10(-6) mol/L. Adherence
of monocytes to plastic cover slips (Thermanox, Miles Laboratories,
Naperville, IL) also triggered induction of cellular PCA, which was
inhibited by more than 80% by an anti-TF monoclonal antibody (MoAb) (P <
.002). Inclusion of ATRA (10(-6) mol/L) reduced this PCA by 40% (P <
.03), and the TF antigen expression by 30% (P < .0001). Exposure of
Thermanox adherent monocytes to flowing nonanticoagulated human blood in a
parallel-plate perfusion chamber device at an arterial wall shear rate of
650 s-1 elicited significant fibrin deposition and platelet thrombus
formation. Partial interruption of this thrombus formation was achieved by
10(-6) mol/L ATRA, which reduced the fibrin deposition by 80% (P < .02)
and platelet thrombus formation by 50% (P < .05). In comparison,
incubation of adherent monocytes with the anti-TF MoAb before the blood
exposure, reduced the fibrin deposition by 83% (P < .02) and platelet
thrombus volume by 75% (P < .0008). Thus, ATRA is an effective
down-regulator of monocyte TF- PCA, and may reduce thrombotic complications
at sites of plaque rupture, at plaque disruption after percutaneous
transluminal angioplasty procedures, or on surfaces introduced by
artificial arterial grafting.
Volume 86,
Issue 1,
pp. 212-218,
07/01/1995
Copyright © 1995 by The American Society of Hematology

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