IV. Anticoagulant activity of compound 48/80: Inhibition of factor VII activation in leukemia THP-1 monocytes

Our previous study described a novel biologic function of compound 48/80 (4 8/80) in the downregulation of monocytic tissue factor (TF)-initiated hyper coagulation in response to bacterial endotoxin (lipopolysaccharide; LPS). T he inhibition was not due to the blockade of LPS cell signaling, as evidenc ed by the unaffected LPS-induced TF synthesis. We herein determined the mec hanism by which 48/80 inhibits the extrinsic coagulation in agonist-challen ged THP-I monocytes. LPS as well as A23187 substantially induced TF activit y. TF synthesis was enhanced by LPS but not by A23187. However, the elevate d FVII binding to monocytes accompanying the up-regulation of factor VII (F VII) activation was uniformly observed in both cases. A 5-min preincubation of the cells with a sheep anti-humanTF antibody (anti-hTF Ab) showed the d ownregulation of FVII activation, indicating a regulatory role of FVII bind ing in the modulation of the extrinsic coagulation. The 48/80 blocked FVII binding to monocytes, leading to the preferential inhibition of FVII activa tion. As the result of the diminished FVIIa formation, monocytic TF-initiat ed extrinsic coagulation was downregulated in agonist-challenged THP-1 mono cytes.