Platelet Glycoproteins

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Platelets work in concert with coagulation factors to maintain hemostasis. In ACS, platelet activation plays a major role in the arterial thrombosis of coronary arteries. Whereas a fibrin clot dominates in patients with totally occluded ST-segment AMI, platelet clots are more responsible for the partial occlusions observed in non-ST-segment AMI and unstable angina (16). There are several glycoprotein (GP) receptor complexes found on the platelet surface that facilitate the binding functions of

Fig. 1. (A) The initial phase of primary heomstasis. Platelets bind to the GP Ib-IX-V receptor complex to von Willebrand factor (vWf) under high stress on the subendothelial matrix. Weibel-Palade (WPB) bodies from the endothelial cells bind to the GPIb-IX-V receptor. (B) The secondary phase of hemostasis. In the presence of collagen, platelets are activated causing expression of the GP IIb/IIIa receptor, which stimulates platelets to aggregate. (Used with permission from Kandzari, D. E., and Goldschmidt-Clermont, P. J. Platelet polymorphisms and ischemic heart disease: moving beyond traditional risk factors. J. Am. Coll. Cardiol. 38:1028-1031, 2001.)

Fig. 1. (A) The initial phase of primary heomstasis. Platelets bind to the GP Ib-IX-V receptor complex to von Willebrand factor (vWf) under high stress on the subendothelial matrix. Weibel-Palade (WPB) bodies from the endothelial cells bind to the GPIb-IX-V receptor. (B) The secondary phase of hemostasis. In the presence of collagen, platelets are activated causing expression of the GP IIb/IIIa receptor, which stimulates platelets to aggregate. (Used with permission from Kandzari, D. E., and Goldschmidt-Clermont, P. J. Platelet polymorphisms and ischemic heart disease: moving beyond traditional risk factors. J. Am. Coll. Cardiol. 38:1028-1031, 2001.)

platelets (17). The role of these glycoproteins is shown in Fig. 1. GP Ib-V-IX receptor binds to the von Willebrand factor receptor and is involved with the adhesion of platelets to the suben-dothelium, particularly under the conditions of high sheer stress. GP Ia-IIa receptor binds to collagen and also stimulates platelet adhesion to endothelial surfaces. GP IIb/IIIa is the most abundant receptor and functions to bind fibrinogen. Sheer forces from systole and many different agonists can activate the GP IIb/IIIa receptor. Once activated, aggregation occurs by the binding of multiple platelets to the fibrinogen molecule. The GP IIb/IIIa receptor is of particular interest for cardiologists, as inhibitors to the receptor are used to treat patients with ACS and as a prophylactic measure for patients undergoing percutaneous coronary intervention (PCI).

Specific mutations to either GP IIb or IIIa might result in a reduced or possibly enhanced binding to of platelets to fibrino-gen. A widely studied polymorphism is in the GPIIIa receptor, a change from cytosine to thymidine at nucleotide 1565, resulting in the substitution from a leucine to a proline. The A2 allele frequency is 16% with a 2% incidence of homozygotes among Caucasians. The allele frequency at 7% is lower among Asians. This particular mutation has been implicated in immune-mediate platelet destruction, an allogen referred to as PIA2. As with other polymorphisms studied for arterial thrombosis, the literature contains contradictory findings (18,19). However, for the GP IIIa polymorphism, a meta-analysis of 9 studies on 7920 CAD cases and controls produced an odds ratio of 1.12, which barely reached statistical significance (95% CI: 1.01-1.24) (3).

A recent study has suggested that the presence of the PIA2 polymorphism might correlate to a higher degree of myocar-dial injury after elective cardiopulmonary bypass surgery (20). Using cardiac troponin I as a marker of myocardial damage, patients with one or two PIA2 alleles had more cardiac injury than the wild type. The authors suggested that the patients with the polymorphism had enhanced platelet adhesion and aggre-gability, creating a more robust platelet plug. This data might have an impact on patients who underwent emergency bypass surgery after a failed coronary angioplasty procedure. Although treatment with glycoprotein IIb/IIIa inhibitors is not warranted during cardiac bypass because of the potential for bleeding (21), it is widely used prior to angioplasty. Patients with the PIA2 genotype might benefit from prophylactic platelet transfusions (22).

Given the importance of GP Ilb/IIIa receptor inhibitors as therapeutic agents in patients with ACS, it might be important to determine if GP IIb/IIIa polymorphisms affect the success of these drugs. One study clearly showed that the PIA2 genotype following abciximab use was associated by reduced platelet inhibition and suggested that it might contribute to an unfavorable outcome (23). Studies that attempted to correlate GP IIIa polymorphisms with clinical outcomes have been published. Laule et al. (24) found no association of the A2 allele for the 30-d composite end points (target-vessel revascularization, AMI, and death) when 653 cases were examined. In contrast, Kastrati et al.reported higher restenosis rates at 6 mo for the A2 allele (OR: 1.35; 95% CI: 1.07-1.70) among 1150 coronary angioplasty patients (25). Unfortunately, the effect of GP IIIa polymorphisms on the success of GP IIb/IIIa inhibitor therapy were not examined, as these inhibitors were not given to patients in either of these studies. Given the low rate of adverse events for patients given GP IIb/IIIa inhibitors, a fairly large clinical trial will be necessary to document the effect. Such a study is unlikely to be funded by a pharmaceutical company, as it might view such testing as a hinderance for widespread use of these drugs.

There has been published data on the polymorphisms of other platelet glycoproteins. GP IIb is designated as the human platelet alloantigen(HPA)-3. A polymorphism exists at position 943, where there is a change from T^G, resulting in the substitution of an isoleucine for a serine. The allele frequency for the mutation is about 40% with 12-15% homozygotes. Preliminary studies suggest that the HPA-3 polymorphism is not associated with the presence of CAD (26).

Glycoprotein Ia (also known as integrin a2P:) is part of the GP Ia/IIa heterodimer and functions to adhere platelets to injured vessel walls, and it is designated as the human platelet allogen-5. There are two silent polymorphisms present in the GP Ia gene. At position 807, there is a C^T substitution, and at 873, there is a G^A substitution. These polymorphisms are linked. In both cases, there is no change in the amino acid sequence. Although silent mutations do not result in the alteration of the actual glycoprotein product, they might be associated with mutations in regulatory regions, such as the gene promoter. Alternately, changes in the DNA sequence might influence the survival of mRNA such that the amount of protein produced is altered. The detection of these polymorphisms is achieved by use of allele-specific fluorescence probes. Other polymorphisms have been identified at nucleotide 1648, where there is a G^A change that results in the substitution of gluta-mine for lysine. This polymorphism is linked to the C807T gene, with the AA1648 found exclusively with CC807 and GG1648 with TT807. There is a rare polymorphism (frequency <0.01) at nucleotide 2531 involving a C^T substitution.

Furihata et al. identified three major alleles (and one rare allele) combining polymorphisms a nucleotides 807, 1648, and 2531 (27). Using flow cytometry and specific monoclonal antibodies, these investigators showed that these alleles expressed different densities of receptors (summarized in Table 4). The frequencies of these alleles are 39%, 53%, and 7.6%. Heterozygote mixtures of these alleles produce receptor densities that are intermediate to the homozygote genotypes (28). The

Table 4

Alleles of the GPIa Gene and Correlation to Receptor Levels

Table 4

Alleles of the GPIa Gene and Correlation to Receptor Levels

Allele No.

Genotype

Receptor density

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