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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:520-527.)
© 1997 American Heart Association, Inc.

Articles

The Thrombomodulin/Protein C/Protein S Anticoagulant Pathway Modulates the Thrombogenic Properties of the Normal Resting and Stimulated Endothelium

Y. Cadroy; A. Diquélou; D. Dupouy; J.P. Bossavy; K.S. Sakariassen; P. Sié; ; B. Boneu

From the Laboratoire de Recherche sur l'Hémostase et la Thrombose, Pavillon Ch Lefèbvre, Hôpital Purpan (Y.C., A.D., D.D., J.P.B., B.B.), and the Faculté de Sciences Pharmaceutiques (P.S.), Toulouse, France; and Nycomed Pharma AS, Oslo, Norway (K.S.S.).

Abstract We investigated the role of the thrombomodulin (TM)/protein C/protein S anticoagulant pathway in modulating the thrombogenic properties of the 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 deposited on interleukin 1–stimulated ECs, but the fibrin deposition was further increased threefold with anti-TM IgG1. Comparable results were found when ECs were perfused at 650 s^-1. When TM surface activity was enhanced by 150% by treating ECs with active phorbol ester (4'-phorbol 12-myristate 13-acetate; PMA), the deposition of fibrin was 30% lower than on ECs not pretreated with PMA. Finally, fibrin deposition on stimulated ECs was significantly higher in 11 untreated patients with well-characterized deficiencies of protein C or S or heterozygous factor V Leiden mutation than in 11 healthy individuals, and it was significantly correlated to basal plasma levels of thrombin-antithrombin complexes. Thus, this study underlines the central role of the TM/protein C/protein S pathway in modulating the thrombogenic status of resting and stimulated ECs and indicates that basal coagulation system markers may be helpful in monitoring patients presenting a disorder of this anticoagulant pathway.

Key Words: endothelium • thrombomodulin • protein C • protein S • thrombosis

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