Differential in vitro effects of the platelet glycoprotein IIb/IIIa inhibitors abixicimab or SR121566A on platelet aggregation, fibrinogen binding and platelet secretory parameters.
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.
Klinkhardt
U
U
Institute of Clinical Pharmacology of the J.W. Goethe University, Frankfurt, Germany.
Kirchmaier
C M
CM
Westrup
D
D
Breddin
H K
HK
Mahnel
R
R
Graff
J
J
Hild
M
M
Harder
S
S
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
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