title: Effect of glycoprotein IIb/IIIa antagonists on the HIT serum induced activation of platelets.
abstract: Heparin-induced thrombocytopenia is an increasingly common side effect associated with heparin usage. In the more severe manifestation of the syndrome, patients can develop thrombosis; a 10% mortality is associated with heparin induced thrombocytopenia. To date, the therapeutic options for patients with heparin-induced thrombocytopenia are limited. Glycoprotein IIb/IIIa inhibitors have been shown to block platelet aggregation induced by a wide variety of agonists. The ability of antibody 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 aggregometry. Abciximab, YM 337, and SR 121566A were each found to inhibit platelet microparticle formation and P-selectin expression in whole blood, in response to heparin-induced thrombocytopenia positive serum/heparin. In a platelet rich plasma system, the platelet aggregation response was inhibited by all three agents. The IC50 for inhibition of heparin-induced thrombocytopenia positive serum/heparin induced platelet aggregation by SR 121566A was 18 nM, a concentration which was 4 to 8 fold lower than that observed for collagen and arachidonic acid induced aggregation. Adenosine triphosphate release from activated platelets, as measured by luminescence aggregometry, was concentration-dependently inhibited by SR 121566A. These results suggest that glycoprotein Ilb/IIIa inhibitors may be beneficial in the management of heparin-induced thrombocytopenia and warrant further investigation.
authors.affiliation: Cardiovascular Institute and Department of Thoracic and Cardiovascular Surgery, Loyola University Medical Center, Maywood, IL 60153, USA. wjeske@luc.edu
authors.forename: W P
authors.initials: WP
authors.lastname: Jeske
authors.forename: J M
authors.initials: JM
authors.lastname: Walenga
authors.forename: E
authors.initials: E
authors.lastname: Szatkowski
authors.forename: M
authors.initials: M
authors.lastname: Ero
authors.forename: J M
authors.initials: JM
authors.lastname: Herbert
authors.forename: S
authors.initials: S
authors.lastname: Haas
authors.forename: M
authors.initials: M
authors.lastname: Bakhos
mesh_terms: D001596:Benzylamines; D001792:Blood Platelets / Q000502:physiology*; D001798:Blood Proteins / Q000494:pharmacology*; D004347:Drug Interactions; D006493:Heparin / Q000009:adverse effects*; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000276:immunology / Q000494:pharmacology; D010880:Piperidines; D015539:Platelet Activation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors* / Q000276:immunology; D013844:Thiazoles; D013921:Thrombocytopenia / Q000097:blood* / Q000139:chemically induced
chemical_list: D001596:Benzylamines; D001798:Blood Proteins; D007140:Immunoglobulin Fab Fragments; D010880:Piperidines; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; C106774:SR 121566; D013844:Thiazoles; D006493:Heparin