RETINOIC ACID REDUCES INDUCTION OF MONOCYTE TISSUE FACTOR AND TISSUE FACTOR FACTOR VIIA-DEPENDENT ARTERIAL THROMBUS FORMATION

Agents that downregulate the induction of monocyte/macrophage tissue f actor (TF) activity may attenuate the thrombotic risk associated with mechanical restoration of vessel patency or artificial arterial grafti ng. In such events, procoagulant macrophages in the atherosclerotic pl aque and procoagulant monocytes adherent to artificial materials may b e exposed to the blood stream. Ishii et al (Blood 80:2556, 1992) repor ted that induction of endothelial TF is downregulated by all-trans ret inoic acid (ATRA), and Conese et al (Thromb Haemost 66:662, 1991) repo rted that retinoids downregulate monocyte procoagulant activity (PCA). These findings led us to investigate the effect of ATRA on monocyte T F expression, and to study the effect of ATRA on monocyte-induced thro mbus formation in a model system of human arterial thrombogenesis. Ind uction of PCA in human peripheral blood monocytes by 0.5 mu g/mL lipop olysaccharide (LPS) was dose dependently reduced by ATRA, reaching a r eduction 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 c oncentration of 10(-6) mol/L. Adherence of monocytes to plastic cover slips (Thermanox, Miles Laboratories, Naperville, IL) also triggered i nduction of cellular PCA, which was inhibited by more than 80% by an a nti-TF monoclonal antibody (MoAb) (P < .002). Inclusion of ATRA (10(-6 ) mol/L) reduced this PCA by 40% (P < .03), and the TF antigen express ion by 30% (P < .0001). Exposure of Thermanox adherent monocytes to Ro wing nonanticoagulated human blood in a parallel-plate perfusion chamb er device at an arterial wall shear rate of 650 s(-1) elicited signifi cant fibrin deposition and platelet thrombus formation. Partial interr uption of this thrombus formation was achieved by 10(-6) mol/L ATRA, w hich reduced the fibrin deposition by 80% (P < .02) and platelet throm bus 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 T F-PCA, and may reduce thrombotic complications at sites of plaque rupt ure, at plaque disruption after percutaneous transluminal angioplasty procedures, or on surfaces introduced by artificial arterial grafting. (C) 1995 by The American Society of Hematology.