Defective platelet response to arachidonic acid and thromboxane A₂ in subjects with Pl^A2 polymorphism of β₃ subunit (glycoprotein IIIa)

Abstract

Summary. The membrane complex a IIb b 3 is the major receptor for fibrinogen and is involved in platelet adhesion and aggregation. Evidence has been presented that the Pl A2 allele of the b 3 Pl A1/A2 gene polymorphism might be an independent risk factor for coronary thrombosis, but the matter is still controversial. We investigated the relationship between this polymorphism and possible alterations of platelet functions in vitro. The platelet adhesion to fibrinogen-coated microplate wells and the aggregation induced by several different agonists were tested in 63 healthy volunteers, among them, 49 subjects with Pl A1/A1 polymorphism, 12 subjects with Pl A1/A2 polymorphism and two subjects with Pl A2/A2 polymorphism. Subjects with Pl A1/A2polymorphism or with Pl A2/A2 polymorphism showed significantly lower platelet responses as compared with Pl A1/A1 subjects when either arachidonic acid or the thromboxane A 2 analogue, U46619, were used as agonists.In resting condition and after thrombin or ADP stimulation, platelet function was normal in all the subjects. An increased sensitivity to the anti-aggregatory effect of acetylsalicylic acid was observed in platelets from subjects with the Pl A2 allele. Finally, using a flow-cytometric evaluation and determining the b-thromboglobulin plasma levels, we did not find any evidence of a Pl A2 platelet hyperreactivity ex vivo. Our findings are not consistent with the hypothesis that the purported increase of cardiovascular risk in these subjects may be as a result of platelet hyperactivation. On the contrary, the Pl A2 allele is associated with a platelet functional deficiency, specifically linked to the activation of the fibrinogen receptor by thromboxane A 2 .

Effect of the PlA2 alloantigen on the function of β3-integrins in platelets

“…57 Similarly, Cooke and coworkers reported that the platelets of Pl A1 /Pl A2 heterozygotes were more sensitive to the inhibitory effects of aspirin, 58 whereas Andrioli and colleagues reported that Pl A2 platelets were hyporesponsive to thromboxane A 2 . 39 In addition, Goodall and coworkers found increased fibrinogen binding to Pl A2 platelets stimulated by ADP, but not when the platelets were stimulated by thrombin. 59 On the other hand, Meiklejohn and colleagues reported that there was no difference in fibrinogen binding to ADP-stimulated Pl A1 and Pl A2 platelets.…”

Role of β3 Integrin in Acute Renal Allograft Rejection in Humans

“…The association noted in the Salido study was thought to result from patients with the Pl A2 genotype as having greater platelet/coagulative system activity and a higher incidence of thrombotic events. It is interesting that the difference noted between these two studies has similarly been described in other reports that examined the importance of the Pl A polymorphism in patients with ischemic heart disease with different demographics and treatment protocols (12,(15)(16)(17).…”

Genetic variation in glycoprotein IIb/IIIa (GPIIb/IIIa) as a determinant of the responses to an oral GPIIb/IIIa antagonist in patients with unstable coronary syndromes

“…25 However, other studies have failed to show any functional effect of the Pl A2 polymorphism. [20][21][22] In this substudy of the OPUS trial of orbofiban, the frequency of the Pl A2 allele was no higher in patients presenting with an unstable coronary syndrome compared with that reported by several investigators in stable coronary syndromes or noncardiac patients. 14,16 Moreover, there was no association between the Pl A polymorphism and the subsequent occurrence of the primary end point of the study, a composite of death, MI, recurrent ischemia at rest leading to rehospitalization or urgent revascularization, or stroke.…”

“…19 However, other studies have failed to show any enhanced effect. [20][21][22] Patients, materials, and methods …”