THE THROMBOMODULIN PROTEIN-C PROTEIN-S ANTICOAGULANT PATHWAY MODULATES THE THROMBOGENIC PROPERTIES OF THE NORMAL RESTING AND STIMULATED ENDOTHELIUM

We investigated the role of the thrombomodulin (TM)/protein C/protein S anticoagulant pathway in modulating the thrombogenic properties of t he endothelium. Endothelial cells (ECs) were placed in parallel-plate flow chambers and exposed to nonanticoagulated human blood at a venous wall shear rate (50 s(-1)). Fibrin deposition on resting ECs treated with a control IgG1 was negligible. In contrast, a significant amount of fibrin deposited when TM expression was specifically suppressed by >95% by preincubating ECs with an anti-TM IgG1. Similarly, fibrin depo sited on interleukin 1-stimulated ECs, but the fibrin deposition was f urther increased threefold with anti-TM IgG1. Comparable results were found when ECs were perfused at 650 s(-1). When TM surface activity wa s enhanced by 150% by treating ECs with active phorbol ester (4-phorbo l 12-myristate 13-acetate; PMA), the deposition of fibrin was 30% lowe r than on ECs not pretreated with PMA. Finally, fibrin deposition on s timulated ECs was significantly higher in 11 untreated patients with w ell-characterized deficiencies of protein C or S or heterozygous facto r V Leiden mutation than in 11 healthy individuals, and it was signifi cantly correlated to basal plasma levels of thrombin-antithrombin comp lexes. Thus, this study underlines the central role of the TM/protein C/protein S pathway in modulating the thrombogenic status of resting a nd stimulated ECs and indicates that basal coagulation system markers may be helpful in monitoring patients presenting a disorder of this an ticoagulant pathway.