An autoantibody directed against human thrombin anion-binding exosite in a patient with arterial thrombosis: effects on platelets, endothelial cells, and protein C activation.
An autoantibody, developed by a patient with severe and recurrent arterial thrombosis, was characterized to be directed against the anion-binding exosite of thrombin, and inhibited all thrombin interactions requiring this secondary binding site without interfering with the catalytic site. The effect of the antibody was studied on thrombin interactions with platelets and endothelial cells from human umbilical veins (HUVEC). The autoantibody specifically and concentration-dependently inhibited alpha-thrombin-induced platelet activation and prostacyclin (PGI2) synthesis from HUVEC. It had no effect when gamma-thrombin or the thrombin receptor activation peptide SFLLR were the inducers. The effect of the antibody on protein C activation has been studied. The antibody blocked the thrombin-thrombomodulin activation of protein C. The inhibition of the activation was maximal with a low concentration of thrombomodulin. The fact that the autoantibody inhibited concentration-dependent alpha-thrombin-induced platelet and endothelial cell functions emphasizes the crucial role of the anion-binding exosite of thrombin to activate its receptor. In regard to the pathology, the antibody inhibited two vascular processes implicated in thrombin-antithrombotic functions, PGI2 secretion, and protein C activation, which could be implicated in this arterial thrombotic disease.
Arnaud
E
E
CJF 91-01 INSERM, Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris V, France.
Lafay
M
M
Gaussem
P
P
Picard
V
V
Jandrot-Perrus
M
M
Aiach
M
M
Rendu
F
F
D000838:Anions; D000918:Antibody Specificity; D001323:Autoantibodies / Q000276:immunology / Q000494:pharmacology*; D001665:Binding Sites; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D011464:Epoprostenol / Q000096:biosynthesis; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D011486:Protein C / Q000378:metabolism*; D012701:Serotonin / Q000097:blood; D013917:Thrombin / Q000276:immunology* / Q000494:pharmacology; D018180:Thrombomodulin / Q000502:physiology; D013927:Thrombosis / Q000276:immunology*; D014471:Umbilical Veins
D000838:Anions; D001323:Autoantibodies; D007074:Immunoglobulin G; D011486:Protein C; D018180:Thrombomodulin; D012701:Serotonin; D011464:Epoprostenol; D013917:Thrombin