The process of hemostasis mediated by blood platelets is complex and involves several receptor-ligand interactions. Most platelet receptors are protein complexes with two or more polypeptide subunits in the platelet membrane. Interindividual differences in platelet responsiveness are usually found, and thus it is reasonable to suggest that in certain circumstances inherited variations in platelet glycoproteins (GP) may contribute to their functional heterogeneity. In fact, three major platelet membrane adhesion receptors – the GPIb-IX-V complex, integrin α2β1 (GPIa-IIa) and integrin α2bβ3 (GPIIb-IIIa) – present genetic polymorphisms that can affect platelet responsiveness.1–6 Identification of such polymorphisms may thus be useful to assess disease predisposition and response to therapy.

The GPIb-IX-V complex mediates the initial adhesion of platelets to the subendothelial matrix under high shear stress conditions, via von Willebrand factor (vWF) binding.7 The GPIb subunit is composed of two disulfide-linked polypeptides, GPIbα and GPIbβ. GPIbα, the largest protein of the complex, contains the binding sites for vWF and α-thrombin, both platelet activator ligands.8 At least three previously described polymorphisms may influence the function and expression of the GPIbα subunit: a molecular weight polymorphism due to a variable number of tandem repeats (VNTR) within the mucin-like macroglycopeptide region of GPIbα,1 a threonine-to-methionine substitution at amino acid 145 that forms the basis of the HPA-2 platelet alloantigen system,2 and a polymorphic variation at position -5 from the ATG start codon, where either T or C is present, called the Kozak polymorphism.3

Integrin α2β1, also called the GPIa-IIa complex, is a major collagen receptor in platelets and other cell types. GPIa-IIa mediates platelet adhesion to collagen after an initial subendothelial interaction mediated by GPIb-IX-V and vWF.9 The T allele of the C807T polymorphism within the coding region of the GPIa gene (ITGA2) has been associated with high expression of the receptor and with possible platelet hyperreactivity, even though this polymorphism does not alter amino acids.4,5

The β3 integrin subunit (GPIIIa) plays a pivotal role in platelet aggregation. The β3 subunit forms a heterodimeric complex with the α2b integrin subunit (GPIIb). The major ligands for this glycoprotein are fibrinogen and vWF, when they are immobilized or in circulation after platelet activation.10 There are at least nine GPIIIa polymorphisms,11 incompatibility for the HPA-1 (PlA) alloantigens being the most common cause of fetal and neonatal alloimmune thrombocytopenia in Caucasians.6 Studies on the functional consequences of this polymorphism in thrombotic diseases have yielded conflicting results,12,13 but an increase in platelet reactivity has been reported in Pl (A2) carriers compared with Pl (A1/A1) individuals.14

In view of the importance of genetic variants in platelet function and the controversy surrounding the clinical correlation between them and prothrombotic conditions, further studies appear to be required in specific populations, that will lead to a better understanding of molecular markers with important roles in platelet function. Since there are no data regarding platelet polymorphism frequencies in the Portuguese population, the aim of this study is to assess allelic and genotypic frequencies of polymorphisms that can affect platelet function, namely the Kozak, VNTR and HPA-2 polymorphisms of the GP1BA gene (GPIbα), the PlA polymorphism of the ITGB3 gene (GPIIIa), and the C807T polymorphism of the ITGA2 gene (GPIa) in a normal Portuguese population.

Table 2 shows the allelic and genotypic frequencies obtained in the Portuguese population for the five polymorphisms. No major differences were observed compared with results from other Caucasian populations.15 Concerning GPIbα, no bb genotype for the HPA-2 polymorphism or A allele for VNTR were found. The A allele has been described mainly in Japanese and Native American populations.16 Our population is in Hardy-Weinberg equilibrium for the five polymorphisms.

There were no available data regarding the allelic frequencies of platelet glycoprotein polymorphisms in the Portuguese population. All these polymorphisms can affect platelet function. GPIIb-IIIa is the most frequent glycoprotein in the platelet surface membrane and the Leu33Pro substitution (PlA polymorphism) is located in the PSI (plexin-semaphorin-integrin) domain, which is known to bind proteins and participate in integrin activation.17 The HPA-2 polymorphism of GPIbα is near the binding site for vWF,2 VNTR affects GPIbα molecular size1 and Kozak is near the start codon, which could influence the expression rate of the gene.3 The T allele of the C807T polymorphism of GPIa has also been associated with a higher expression of this glycoprotein on the platelet surface.4

Platelet membrane glycoproteins, as key elements for normal primary hemostasis, have also been associated with platelet hyperreactivity and thrombotic mechanisms. A number of clinical studies have reported conflicting data on the association of platelet polymorphisms and increased tendency for thrombosis, and differences between populations may contribute to the contradictory results.18–20 The Portuguese population has now been characterized in terms of major platelet glycoprotein polymorphisms. Our results are of interest in future studies that aim to assess the role of platelet glycoproteins as genetic markers involved in individual predisposition to prothrombotic conditions and in patient response to therapy.

The authors have no conflicts of interest to declare.