title: Differential effect of the GPIIb/IIIa antagonist orbofiban on human platelet aggregate formation in vitro.
abstract: Platelet microaggregates have been demonstrated in the systemic circulation of patients with atherosclerotic cardiovascular diseases. Glycoprotein IIb/IIIa antagonists have been reported to play roles in platelet activation, which may be associated with pro-thrombotic events. We report the effect of the orally active GPIIb/IIIa antagonist, orbofiban, on human platelet microaggregate formation in vitro. Laser light scatter (LSS) technology was used to monitor small, medium and large platelet aggregates formed in platelet-rich plasma in response to ADP or thrombin receptor activating peptide (TRAP)-6. ADP at 0.5 microM induced only small platelet aggregates that were prevented by orbofiban in a concentration-dependent manner. Likewise, orbofiban dissolved small aggregates after their formation. In marked contrast, in the presence of strong agonist stimulation (20 microM ADP or 3 microM TRAP-6) which generated primarily large platelet aggregates, orbofiban blocked the large aggregates while significantly augmenting small aggregates by three- to sixfold. The data suggest that GPIIb/IIIa antagonists do not induce platelet microaggregation directly but may augment small platelet microaggregate formation indirectly at conditions of strong stimuli. The percentage of the microaggregate population expressing P-selectin remained the same in the presence of orbofiban, indicating that these small microaggregates remain activated, although the mean intensity of expression was diminished, possibly reflecting the reduced size of the particles or density of P-selectin molecules. In summary, an increase in small platelet microaggregates might have contributed to pro-thrombotic events in orbofiban-treated patients.
authors.affiliation: Cardiovascular Sciences, Bristol-Myers Squibb, Lawrenceville, NJ 19880, USA.
authors.forename: Adrienne L
authors.initials: AL
authors.lastname: Racanelli
authors.forename: Sandra K
authors.initials: SK
authors.lastname: Gibbs
authors.forename: Susan Carr
authors.initials: SC
authors.lastname: Zondlo
authors.forename: Dietmar A
authors.initials: DA
authors.lastname: Seiffert
authors.forename: Steven M
authors.initials: SM
authors.lastname: Friedman
authors.forename: Giora Z
authors.initials: GZ
authors.lastname: Feuerstein
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D000409:Alanine / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D019007:P-Selectin / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D011759:Pyrrolidines / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D019007:P-Selectin; D010446:Peptide Fragments; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011759:Pyrrolidines; C086309:thrombin receptor peptide SFLLRNP; D000244:Adenosine Diphosphate; C120234:orbofiban; D000409:Alanine