Antagonists of platelet fibrinogen receptor are less effective in carriers of Pl(A2) polymorphism of beta(3) integrin.
The polymorphism Leu(33)-->Pro (platelet-specific antigen; Pl(A1/A2)) of platelet GPIIIa is a potential risk factor for arterial thrombosis. However, its influence on platelet function remains controversial and little is known about its impact on platelet sensitivity to GPIIb-IIIa antagonists. Our objective was to compare the effectiveness of various GPIIb-IIIa antagonists in Pl(A2)(+) and Pl(A2)(-) carriers. Platelet aggregation was monitored in healthy donors including Pl(A2)(-) (N=31) and Pl(A2)(+) subjects (N=27; 23 Pl(A1/A2), 4 Pl(A2)/(A2)) using the impedance and turbidimetric aggregation techniques. We evaluated the inhibition of ADP- and collagen-induced aggregation by disintegrins, kistrin and echistatin, and the low-molecular-weight blockers, GR144053F ((4-[4-[4-(aminoiminomethyl]-1-piperazinyl]-1-piperidineacetic acid, hydrochloride trihydrate) and eptifibatide (N(6)-(aminoiminomethyl)-N(2)-(3-mercapto-1-oxopropyl-L-lysylglycyl-L-alpha-aspartyl-L-tryptophyl-L-propyl-L-cysteinamide, cyclic (1-->6)-disulfide). Kistrin (10-30 nmol/l) inhibited ADP- and collagen-induced aggregation stronger in Pl(A2)(-) donors than in Pl(A2)(+) donors; there was a significant difference between 50% inhibitory concentrations (IC(50)). The same tendency occurred with moderate concentrations of eptifibatide (40-100 nmol/l) and also at low concentrations of GR144053F (5-10 nmol/l) and high concentrations of echistatin (80-150 nmol/l), although in the case of the two latter inhibitors, the estimated IC(50) values were not significantly different. In conclusion, GPIIb-IIIa blockers representing various classes are less effective inhibitors of platelet aggregation in Pl(A2)(+) carriers; however, the effect of the genotype is both agonist- and antagonist-dependent.
Rozalski
Marcin
M
Laboratory of Haemostasis and Haemostatic Disorders, Medical University of Łódź, ul. Narutowicza 96, 90-141 Łódź, Poland.
Watala
Cezary
C
D000328:Adult; D000077542:Eptifibatide; D005260:Female; D005838:Genotype; D006801:Humans; D039661:Integrin beta3 / Q000235:genetics*; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D009391:Nephelometry and Turbidimetry; D010455:Peptides / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D011110:Polymorphism, Genetic; D039341:Receptors, Fibrinogen / Q000037:antagonists & inhibitors*
C090662:GR 144053; D039661:Integrin beta3; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D010879:Piperazines; D010880:Piperidines; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D039341:Receptors, Fibrinogen; C057986:echistatin; C067623:kistrin; D000077542:Eptifibatide