EFFECT OF SR121566A, A POTENT GP IIB-IIIA ANTAGONIST, ON THE HIT SERUM HEPARIN-INDUCED PLATELET-MEDIATED ACTIVATION OF HUMAN ENDOTHELIAL-CELLS

Heparin-induced thrombocytopenia (HIT) is a common adverse effect of h eparin therapy that carries a risk of serious thrombotic events. This condition is caused by platelet aggregation, which is mediated by anti -heparin/platelet factor 4 antibodies. Sera from patients with HIT in the presence of platelets, induced the expression of E-selectin, VCAM, ICAM-1 and tissue factor and the release of IL1 beta, IL6, TNF alpha and PAI-1 by human umbilical vein endothelial cells (HUVECs) in vitro and initiated platelet adhesion to activated HUVECs, These effects whi ch occurred in a time-dependent manner were significant in the first 1 -2 h of incubation and reached a maximum after 6 to 9 h. The GP Ilb-II Ia receptor antagonist SR121566A which has been shown to block platele t aggregation induced by a wide variety of agonists including HIT seru m/heparin, reduced in a dose-dependent manner the HIT serum/heparin-in duced, platelet mediated expression and release of the above mentioned proteins. The IC50 for inhibition of HIT serum/heparin-induced platel et dependent HUVEC activation by SR121566A was approximately 10-20 nM. ADP, but not serotonin release, also appeared to be involved as apyra se and ATP gamma S blocked platelet-dependent, HIT serum/heparin-induc ed cell surface protein expression and cytokine release by HUVECs. Inc reased platelet adherence to HIT serum/heparin-activated HUVECs was in hibited by SR121566A and, to a lesser extent, by apyrase and ATP gamma S, showing that platelet activation and release was at the origin of the HIT serum/heparin-induced expression of these proteins by HUVECs. Thus, sera from patients with HIT induced the expression of adhesive a nd coagulation proteins and the release of cytokines by HUVECs through the activation of platelets which occurred in a GP IIb-IIIa-dependent manner, a process that could be selectively blocked by SR121566A.