title: The effect of glycoprotein IIIa PIA 1/A2 polymorphism on the PFA-100 response to GP IIb IIa receptor inhibitors-the importance of anticoagulants used.
abstract: Antithrombotic drugs including glycoprotein (GP) IIb IIIa receptor inhibitors have significantly reduced ischaemic events in coronary disease. Variability in the response to GP receptor inhibitors has been observed both with healthy individuals and in clinical studies. One single nucleotide polymorphism on GP IIIa (PI(A1/A2)) correlates with increased risk for cardiovascular events in many studies. In this study we investigated whether this polymorphism associates with individual differences in the response to GP IIb IIIa receptor inhibitors in healthy individuals. Fresh blood samples were collected randomly from individuals without a history of coronary disease. Blood samples were anticoagulated with either sodium citrate or with PPACK. The ability of different GP IIb IIIa receptor inhibitors (tirofiban, eptifibatide and abciximab) to inhibit platelet aggregation was investigated using a commercial PFA-100 analyser. At baseline, the function of platelets with different PI(A) genotypes did not differ from each other. With sodium citrate anticoagulated samples, tirofiban prolonged the closure time slightly more rapidly when platelets with PI(A 2 A 2) genotype were used than with other genotypes (p<0.05) both on epinephrine-collagen and ADP-collagen coated membranes. With eptifibatide or abciximab no differences were observed. If an anticoagulant not affecting Ca(2+) concentration (PPACK) was used, no differences were observed between different GP IIIa genotypes and the ability of any of the GP IIb IIIa receptor inhibitors to prolong the closure time. The effect of tirofiban and eptifibatide was significantly affected by the anticoagulant used (p<0.001), whereas abciximab functioned equally regardless of the anticoagulant. Glycoprotein IIIa PI(A2) allele has been found in many studies to associate with risk of thrombosis. In healthy controls the function of GP IIb IIIa receptor inhibitors on platelets with different PI(A) genotypes was modified by anticoagulants used. PI(A) polymorphism does not explain the interindividual variance in the response to GP IIb IIIa receptor inhibitors in healthy individuals. The study, however, demonstrates the importance of the anticoagulant used in in vitro studies and the important role of Ca(2+) concentration with tirofiban and eptifibatide, but not with abciximab.
authors.affiliation: Tampere University Hospital, Heart Center, P.O. Box 2000, Tampere Fin-33521, Finland. katriina.aalto-setala@uta.fi
authors.forename: Katriina
authors.initials: K
authors.lastname: Aalto-Setälä
authors.forename: Pekka J
authors.initials: PJ
authors.lastname: Karhunen
authors.forename: Jussi
authors.initials: J
authors.lastname: Mikkelsson
authors.forename: Kari
authors.initials: K
authors.lastname: Niemelä
mesh_terms: D000328:Adult; D000925:Anticoagulants / Q000494:pharmacology*; D002318:Cardiovascular Diseases / Q000453:epidemiology / Q000235:genetics; D005091:Exons; D005260:Female; D005838:Genotype; D006801:Humans; D039661:Integrin beta3 / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010979:Platelet Function Tests; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D020641:Polymorphism, Single Nucleotide; D015912:Thrombolytic Therapy
chemical_list: D000925:Anticoagulants; D039661:Integrin beta3; D019039:Platelet Glycoprotein GPIIb-IIIa Complex