AN AUTOANTIBODY DIRECTED AGAINST HUMAN THROMBIN ANION-BINDING EXOSITEIN A PATIENT WITH ARTERIAL THROMBOSIS - EFFECTS ON PLATELETS, ENDOTHELIAL-CELLS, AND PROTEIN-C ACTIVATION

An autoantibody, developed by a patient with severe and recurrent arte rial thrombosis, was characterized to be directed against the anion-bi nding exosite of thrombin, and inhibited all thrombin interactions req uiring this secondary binding site without interfering with the cataly tic site. The effect of the antibody was studied on thrombin interacti ons with platelets and endothelial cells from human umbilical veins (H UVEC). The autoantibody specifically and concentration-dependently inh ibited alpha-thrombin-induced platelet activation and prostacyclin (PG I(2)) synthesis from HUVEC. It had no effect when gamma-thrombin or th e thrombin receptor activation peptide SFLLR were the inducers. The ef fect of the antibody on protein C activation has been studied. The ant ibody 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 functi ons emphasizes the crucial role of the anion-binding exosite of thromb in to activate its receptor. In regard to the pathology, the antibody inhibited two vascular processes implicated in thrombin-antithrombotic functions, PGI(2) secretion, and protein C activation, which could be implicated in this arterial thrombotic disease. (C) 1994 by The Ameri can Society of Hematology.