EFFECT OF GLYCOPROTEIN IIB IIIA ANTAGONISTS ON THE HIT SERUM-INDUCED ACTIVATION OF PLATELETS/

Heparin-induced thrombocytopenia is an increasingly common side effect associated with heparin usage. In the more severe manifestation of th e syndrome, patients can develop thrombosis; a 10% mortality is associ ated with heparin induced thrombocytopenia. To date, the therapeutic o ptions for patients with heparin-induced thrombocytopenia are limited. Glycoprotein IIb/IIIa inhibitors have been shown to block platelet ag gregation induced by a wide variety of agonists. The ability of antibo dy and synthetic small molecule inhibitors of glycoprotein IIb/IIIa to block in vitro activation and aggregation of platelets in response to heparin-induced thrombocytopenia positive serum/heparin was examined using flow cytometry, platelet aggregometry, and luminescence aggregom etry, Abciximab, YM 337, and SR 121566A were each found to inhibit pla telet microparticle formation and P-selectin expression in whole blood , in response to heparin-induced thrombocytopenia positive serum/hepar in. In a platelet rich plasma system, the platelet aggregation respons e was inhibited by all three agents. The IC50 for inhibition of hepari n-induced thrombocytopenia positive serum/heparin induced platelet agg regation by SR 121566A was 18 nM, a concentration which was 4 to 8 fol d lower than that observed for collagen and arachidonic acid induced a ggregation, Adenosine triphosphate release from activated platelets, a s measured by luminescence aggregometry, was concentration-dependently inhibited by SR 121566A. These results suggest that glycoprotein IIb/ IIIa inhibitors may be beneficial in the management of heparin-induced thrombocytopenia and warrant further investigation. (C) 1998 Elsevier Science Ltd.