title: Low incidence of paradoxical platelet activation by glycoprotein IIb/IIIa inhibitors.
abstract: The human platelet antigen-1 (HPA-1, Pl(A)) polymorphism has been proposed to influence the inhibitory actions of abciximab. Thus, we hypothesized that this polymorphism might also be the cause for paradoxical activation of platelets by GPIIb/IIIa inhibitors. The effects of abciximab (1-10 microg/ml), tirofiban (3-30 nM), or eptifibatide (0.3-3 microg/ml) on basal and ADP (3 microM)-induced CD62P externalization were measured in n=62 healthy blood donors and n=177 patients with stable coronary artery disease. All subjects were genotyped for the human platelet antigen-1 (HPA-1, Pl(A)) polymorphism by GALIOS(R) and fluorescence correlation spectroscopy. Although a significant platelet hyperreactivity was observed in the patients, the HPA-1 genotype did not influence basal or ADP-induced CD62P expression. A moderate (twofold) stimulation of CD62P expression by abciximab but not by tirofiban or eptifibatide was observed in one patient. Interestingly, this patient carried the HPA-1 b/b genotype. In no other subject any activation of platelets by GP IIb/IIIa inhibitors was observed and there were no statistically significant differences between HPA-1 genotypes with respect to the effects of GP IIb/IIIa inhibitors on basal or ADP-stimulated CD62P expression. It is concluded that paradoxical platelet activation by abciximab is a rare (<2%) phenomenon. HPA-1 b/b genotype might be a contributing factor but clearly does not predict platelet activation by GP IIb/IIIa inhibitors.
authors.affiliation: Institut für Pharmakologie und Klinische Pharmakologie, Heinrich-Heine-Universität, Universitätsklinikum Düsseldorf, Moorenstr. 5, D-40225, Düsseldorf, Germany. weberar@uni-duessel.dorf.de
authors.forename: Artur-Aron
authors.initials: AA
authors.lastname: Weber
authors.forename: Dan
authors.initials: D
authors.lastname: Meila
authors.forename: Collin
authors.initials: C
authors.lastname: Jacobs
authors.forename: Stephanie
authors.initials: S
authors.lastname: Weber
authors.forename: Malte
authors.initials: M
authors.lastname: Kelm
authors.forename: Bodo E
authors.initials: BE
authors.lastname: Strauer
authors.forename: Rainer B
authors.initials: RB
authors.lastname: Zotz
authors.forename: Rüdiger E
authors.initials: RE
authors.lastname: Scharf
authors.forename: Karsten
authors.initials: K
authors.lastname: Schrör
mesh_terms: D000077284:Abciximab; D000244:Adenosine Diphosphate / Q000494:pharmacology; D000328:Adult; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D016824:Antigens, Human Platelet / Q000235:genetics; D016022:Case-Control Studies; D003324:Coronary Artery Disease / Q000097:blood / Q000235:genetics; D000077542:Eptifibatide; D005260:Female; D005838:Genotype; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology; D015994:Incidence; D039661:Integrin beta3; D008297:Male; D008875:Middle Aged; D019007:P-Selectin / Q000032:analysis; D010455:Peptides / Q000494:pharmacology; D015539:Platelet Activation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D011110:Polymorphism, Genetic; D000077466:Tirofiban; D014443:Tyrosine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000911:Antibodies, Monoclonal; D016824:Antigens, Human Platelet; C061248:ITGB3 protein, human; D007140:Immunoglobulin Fab Fragments; D039661:Integrin beta3; D019007:P-Selectin; D010455:Peptides; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; C083451:human platelet antigen 1b; D014443:Tyrosine; D000244:Adenosine Diphosphate; D000077466:Tirofiban; D000077542:Eptifibatide; D000077284:Abciximab