title: Differential in vitro effects of the platelet glycoprotein IIb/IIIa inhibitors abixicimab or SR121566A on platelet aggregation, fibrinogen binding and platelet secretory parameters.
abstract: The aim of this study was to compare fibrinogen binding, inhibition of platelet aggregation and secretory potential of the MAb abciximab (0.5-5 microg/mL) and the peptidomimetic compound SR121566A (15-250 ng/mL) in vitro in whole blood. Fibrinogen binding was followed by flow cytometry; platelet function was evaluated by light transmittance and by impedance aggregometry. Secretory functions of platelets were evaluated using ATP as marker for early secretion by dense granulae and P-selectin (CD62) for alpha-granular secretion as well as CD63 for lysosomal degranulation. Results showed that fibrinogen binding induced by 5 microM TRAP was maximally inhibited greater than 80% at 3 microg/mL abciximab or at 250 ng/mL SR121566A. At these concentrations of antagonists, platelet aggregation induced by 5 microM ADP or 2 microg/mL collagen was inhibited completely. Expression of CD62 was reduced 34% with abciximab or 15% with SR121566A; CD63 expression was reduced 22% with both agents. With both agents, the EC50 for inhibition of CD62 and CD63 expressions was in similar magnitudes than the EC50 for fibrinogen binding inhibition. With 3 microg/mL abciximab, ATP secretion was maximally reduced to 50% of the control, whereas SR121566A at 250 ng/mL had no inhibitory effect on this parameter. A slight increase in ATP secretion was seen with 0.5 microg/mL abciximab and with SR121566A in concentrations of less than 45 ng/mL. The data suggest a discoupling between the anti-aggregatory and the antisecretory effects of IIb/IIIa antagonists. Because it is not established to what extend CD62 or CD63 expression can be reduced by any means, the reduction by 20-30% obtained by 3 microg/mL abciximab or 250 ng/mL SR121566A might already be the maximum possible inhibition by these agents.
authors.affiliation: Institute of Clinical Pharmacology of the J.W. Goethe University, Frankfurt, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Klinkhardt
authors.forename: C M
authors.initials: CM
authors.lastname: Kirchmaier
authors.forename: D
authors.initials: D
authors.lastname: Westrup
authors.forename: H K
authors.initials: HK
authors.lastname: Breddin
authors.forename: R
authors.initials: R
authors.lastname: Mahnel
authors.forename: J
authors.initials: J
authors.lastname: Graff
authors.forename: M
authors.initials: M
authors.lastname: Hild
authors.forename: S
authors.initials: S
authors.lastname: Harder
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000328:Adult; D000911:Antibodies, Monoclonal / Q000276:immunology*; D015703:Antigens, CD / Q000378:metabolism; D001596:Benzylamines; D001665:Binding Sites; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005340:Fibrinogen / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology; D019007:P-Selectin / Q000378:metabolism; D010880:Piperidines; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000097:blood / Q000494:pharmacology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism; D060149:Tetraspanin 30; D013844:Thiazoles
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D001596:Benzylamines; C554586:CD63 protein, human; D009842:Oligopeptides; D019007:P-Selectin; D010880:Piperidines; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D010980:Platelet Membrane Glycoproteins; C106774:SR 121566; D060149:Tetraspanin 30; D013844:Thiazoles; C047981:arginyl-glycyl-aspartic acid; D000255:Adenosine Triphosphate; D005340:Fibrinogen