Differential inhibition of adenosine diphosphate- versus thrombin receptor-activating peptide-stimulated platelet fibrinogen binding by abciximab due to different glycoprotein IIb/IIIa activation kinetics.
The exposure of internal glycoprotein (GP) IIb/IIIa receptors has been proposed to explain the incomplete inhibition of aggregation of thrombin receptor-activating peptide (TRAP)-stimulated platelets by abciximab. However, a marked and rapid externalization of GPIIb/IIIa was also observed upon stimulation with 30 microM adenosine diphosphate (ADP). ADP-induced fibrinogen binding was completely inhibited by 10 microg/mL abciximab, 30 nM tirofiban, or 3 microg/mL eptifibatide, while fibrinogen binding induced by 100 microM TRAP was inhibited only by 50%. Interestingly, striking differences in fibrinogen binding kinetics in ADP- versus TRAP-stimulated platelets were observed. ADP-induced fibrinogen binding was much slower than that of abciximab. These differences in the fibrinogen binding rate were due to differential GPIIb/IIIa activation kinetics because the actual fibrinogen binding rate (measured by adding fibrinogen after platelet activation) was similar in ADP- and TRAP-stimulated platelets. Thus, the TRAP-induced GPIIb/IIIa activation rate would allow significant amounts of fibrinogen to occupy externalized GPIIb/IIIa receptors even in the presence of the inhibitor.
Weber
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AA
Department of Pharmacology and Clinical Pharmacology, Heinrich-Heine University, Düsseldorf, Germany.
Schrör
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D000077284:Abciximab; D000244:Adenosine Diphosphate / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D019921:Biotinylation; D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D000077542:Eptifibatide; D005340:Fibrinogen / Q000378:metabolism*; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology*; D007700:Kinetics; D010455:Peptides / Q000494:pharmacology; D010973:Platelet Adhesiveness / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D011506:Proteins / Q000494:pharmacology*; D018179:Receptors, Thrombin; D000077466:Tirofiban; D014443:Tyrosine / Q000031:analogs & derivatives / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D007140:Immunoglobulin Fab Fragments; D010455:Peptides; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011506:Proteins; D018179:Receptors, Thrombin; D014443:Tyrosine; D000244:Adenosine Diphosphate; D005340:Fibrinogen; D000077466:Tirofiban; D000077542:Eptifibatide; D000077284:Abciximab