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 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.
Cadroy
Y
Y
Laboratoire de Recherche sur I'Hémostase et la Thrombose, Hôpital Purpan, Toulouse, France.
Diquélou
A
A
Dupouy
D
D
Bossavy
J P
JP
Sakariassen
K S
KS
Sié
P
P
Boneu
B
B
D001792:Blood Platelets / Q000502:physiology*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000503:physiopathology*; D006801:Humans; D010973:Platelet Adhesiveness; D011486:Protein C / Q000502:physiology*; D017293:Protein S / Q000502:physiology*; D015398:Signal Transduction; D013314:Stress, Mechanical; D018180:Thrombomodulin / Q000502:physiology*; D013927:Thrombosis / Q000209:etiology / Q000503:physiopathology*
D011486:Protein C; D017293:Protein S; D018180:Thrombomodulin