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.