CLINICAL STUDIES: INTERVENTIONAL CARDIOLOGY
PlA2, a variant of GPIIIa implicated in coronary thromboembolic complications
Pascal J. Goldschmidt-Clermont, MD, FACCa,
Glen E. Cooke, MDa,
Gregory M. Eaton, MDa and
Philip F. Binkley, MD, FACCa
a Heart and Lung Institute and Division of Cardiology, Department of Internal Medicine, College of Medicine and Public Health, The Ohio State University, Columbus, Ohio, USA
Reprint requests and correspondence: Dr. Pascal J. GoldschmidtClermont, Heart and Lung Institute, 514 Medical Research Facility, 420 W. 12th Street, Columbus, Ohio 43210
goldschmidt-1{at}medctr.osu.edu
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The PlA2 polymorphism of GPIIb-IIIa
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Ischemic heart disease (IHD) and adverse events after coronary stent placement represent polygenic disorders. They correspond to complex traits induced not only by multiple genes but also by the interaction of these genes with the environment. Multiple loci likely to be implicated in IHD are polymorphic, such that there are two or more variant forms of the gene in the population. These variants have been created by mutations that can change the coding sequence of the gene in question. A missense mutation, for example, would produce a different form of the encoded protein, whose function might be slightly altered compared
with the ancestor protein. Alternatively, the mutation, might fall within the regulatory domains of a gene, thereby changing the level of expression of the gene product and/or when and where the gene is being activated. The specific impact of such mutations is further dependent on a variety of factors, both genetic and environmental.
The platelet antigen 2 (PlA2) polymorphism represents one such variant that has been implicated in arterial thrombosis (1–3). Due to the substitution of a cytosine for a thymidine at position 1565 in exon 2 of the glycoprotein IIIa (GPIIIa or integrin Beta3) gene, the PlA2 variant displays a proline instead of a leucine at amino acid 33 (4). Hence, the ancestor gene is called PlA1 and the variant gene PlA2, such that individuals can be PlA1/A1 homozygous, PlA1/A2 heterozygous or PlA2/A2 homozygous. Glycoprotein IIIa, together with GPIIb, constitutes the fibrinogen receptor (GPIIb-IIIa), whose engagement represents the final common pathway for platelet activation (5). Therefore, GPIIIa with its PlA2 polymorphism is positioned as a candidate gene that contributes to arterial thromboembolic complications. The PlA2 polymorphism affects the structure of GPIIb-IIIa, an assumption that was supported by the discovery of the PlA2 variant as the cause for a severe form of neonatal alloimmune thrombocytopenia.
We initially observed a high prevalence of PlA2 positivity in a population of siblings of patients with a history of premature IHD (IHD manifestations before age 60) (6) and in patients with severe unstable coronary syndromes (7). In complex traits, it is unlikely that individual genes have an effect that would account for more than a few percent of the variance. Consistent with this concept, in a meta-analysis, we have found that the relative risk of myocardial infarction (MI) associated with PlA2 is small (1.2) but significant (p = 0.034) (8). Several studies have not confirmed the association between PlA2 and MI, in particular, the Physicians’ Health Study (9). Hence, as a consequence of such discrepancy among well conducted epidemiological studies, the link between PlA2 and spontaneous MI is perceived as controversial (2). In contrast with epidemiological data, most studies on the molecular effect of the PlA2 polymorphism on GPIIb-IIIa function have been consistent. These studies have shown that the L33P mutation results in increased platelet responsiveness (10,11).
Genetic factors can influence illnesses in very specific ways. Considering that a clinical diagnosis of MI encompasses a complex phenotype, the relative impact of the PlA2 polymorphism on MI may vary according to multiple factors, including the presence or absence of ST elevation, associated diseases like diabetes, gender, age, environment and medications. Studies of patients who have died suddenly and at a young age can be highly instructive, as the culprit lesion can be identified and characterized, and the number of contributing modifiers is often limited. Indeed, sudden death is a prominent first manifestation of coronary artery disease in younger individuals, such that sudden death victims do not have the opportunity to benefit from drugs that could interfere with the effect of a gene variant. Mikkelsson et al. (12) have reported that the prevalence of PlA2 is elevated in sudden death victims whose coronary vessels contain a thrombus. They also reported that PlA1/A1 homozygous individuals have a heightened atherosclerotic plaque burden compared with their PlA2 counterparts. These results suggest that PlA2, in conjunction with other genetic and environmental risk factors, might contribute to driving the course of atherosclerosis toward a path of coronary plaque rupture and thrombus formation.
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Endovascular coronary procedures and PlA2
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Catheter-based intervention with stent placement has become a preferred management for patients with symptomatic coronary disease (both acute coronary ischemic syndromes and acute MI). Although associated with a risk that is not negligible, the procedure has become safer because of technological advances and the availability of powerful antithrombotic drugs (13). The use of intracoronary stents has improved the immediate and short-term efficacy of endovascular procedures by maximizing acute procedural luminal gain and reducing the unfavorable geometric vascular remodeling of stenotic coronary vessels. We have hypothesized that, to be efficient, an antithrombotic strategy must target the impact of specific susceptibility genes implicated in coronary thrombosis under various clinical circumstances (14). This principle is pertinent to strategies directed towards minimizing thromboembolic complications after stent revascularization. Platelet antigen 2 was the first platelet polymorphism implicated in thromboembolic complications associated with stent placement (15).
Several classes of drugs are clinically utilized to reduce platelet activity during coronary stenting: 1) acetylsalicylate (ASA), 2) thrombin antagonists (unfractionated heparin, mainly), 3) thienopyridine derivatives (clopidogrel and ticlopidine), and 4) GPIIb-IIIa antagonists (ReoPro or abciximab, Tirofiban or aggrastat, and Integrilin or eptafibitide). The role of dipyridamole for stent patients has not yet been established but could be of interest for drug combination strategies. Two combinations of drugs have been highly successful in reducing adverse events associated with coronary stent placement: a) ASA plus an antithrombin plus a thienopyridine derivative or b) aspirin plus an antithrombin plus a GPII-IIIa blocker. It is likely that the multidrug approach has the potential of covering a larger number of "thrombotic susceptibility genes" compared with single agent therapy. Experiments performed in vitro have consistently shown an increased responsiveness to agonists of platelets displaying the PlA2 polymorphism (10,11). In this context, the study of Kastrati et al. (17) published in this issue can be viewed as investigating whether standard antithrombotic strategies have reached a sufficient level of control for the thrombotic diathesis conferred by the PlA2 polymorphism.
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PlA2 and adverse events after stent placement
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There have been three studies published on the topic of PlA2 and adverse events after stent revascularization. Walter et al. (15) studied 318 consecutive patients who received a coronary stent for indications of dissection, acute occlusion or suboptimal angioplasty. The primary end points of death, MI, stent thrombosis and coronary bypass surgery were followed over a period of 30 days after stent placement. All patients received aspirin and heparin during the procedure. Ticlopidine, 250 mg per day, was started and given for the next four weeks, in combination with aspirin (100 mg per day), which was continued indefinitely. Occlusion of the stent vessel was more frequent in PlA2 positive individuals (9.5% in PlA2 positive patients vs. 1.9% in PlA1/A1 homozygous, odds ratio: 5.26, p = 0.01). There was also an excess of MI in the PlA2 positive patient group.
Laule et al. (16) studied 1,000 consecutive patients with angiographically confirmed coronary artery disease, 653 of whom received intervention (280 with stent placements and 102 with directional coronary atherectomy). A composite end point of death, MI and target vessel revascularization (TVR) was followed for 30 days after intervention. All patients received aspirin and heparin during the procedure and after the procedure aspirin (100 mg indefinitely). Stented patients also received ticlopidine 500 mg daily for four weeks. A total of 41 patients reached the 30-day composite end point (6.3%). For the 653 who received intervention, the odds ratio for the composite end point (PlA2 positive vs. PlA1/A1) was 1.36, 1.46 for TVR and 1.31 for MI (nonsignificant). For the stented patients, the odds ratio for the composite end point (PlA2 positive vs. PlA1/A1) was 1.42, 1.78 for TVR and 1.24 for MI (nonsignificant). Due to the small number of homozygous PlA2/A2, the analysis pooled PlA2/A2 with PlA1/A2 patients.
The study by Kastrati et al. (17) included 1,759 consecutive patients with stable or unstable angina and successful stent placement. The composite end point of death, MI and urgent revascularization was followed for 30 days after stent placement. All patients received aspirin (100 mg twice a day) indefinitely and ticlopidine (250 mg twice a day) for four weeks. Patients with residual thrombi or flow limiting dissection received abciximab (bolus plus 12 h infusion). Angiographic stent thrombosis occurred in 2.1% of PlA2 positive, versus 1.7% of the PlA1/A1 homozygous patients (nonsignificant). Death and Q-wave MI were significantly more frequent in PlA2 carriers. Moreover, PlA2/A2 homozygous patients (n = 46) had either a clear trend or a significantly higher event rate compared with heterozygous and PlA1/A1 homozygous patients. The primary end point was reached in 5.4% for PlA1/A1 patients, PlA1/A2 4.8% and PlA2/A2 13.0% (p = 0.06); the incidence of death or MI was 4.3% for PlA1/A1 patients, PlA1/A2 4.2% and PlA2/A2 13.0% (p = 0.02), and the incidence of angiographic stent thrombosis was 1.7% for PlA1/A1 patients, PlA1/A2 1.5% and PlA2/A2 8.7% (p = 0.002). PlA2 positive patients with stent thrombosis tended to be younger than PlA1/A1 homozygous patients with stent thrombosis. In a multivariate model, the PlA2/A2 genotype was associated with an adverse outcome after stenting (odds ratio: 2.6), compared with the PlA1/A1 genotype. Only 12.1% of the patients received abciximab.
From the analysis of these three studies that surveyed 2,357 patients for a period of 30 days, one may conclude that the PlA2 polymorphism of GPIIIa represents a risk factor for adverse events in patients undergoing coronary stenting. Although all three studies were conducted by expert investigators, they differ in their complication rates and in their conclusion relative to the strength of the impact of PlA2 on adverse events. Although some unrecognized factor(s) may have contributed to such a discrepancy, it is notable that the studies were not uniform in terms of the antithrombotic regimen provided to the patients (Table 1). For example, in the study by Walter et al. (15), whose findings support that PlA2 has a powerful effect on adverse events (OR:5.3), the patients received only 100 mg of ASA and 250 mg of ticlopidine daily for four weeks. In the report of Laule et al. (16), patients received 100 mg of ASA and 500 mg of ticlopidine (but no GPIIb-IIIa blocker), and the effects of PlA2 was less pronounced (OR:1.5). Finally, Kastrati and colleagues in this issue (17) have reported an even smaller effect of PlA2 (OR:1.2), and their patients received 200 mg of ASA, 500 mg of ticlopidine, and a small minority of patients received abciximab.
It is tempting to speculate that differences in the PlA2 effect among studies was due to the strength of the antithrombotic regimen. As indicated earlier, we have hypothesized that, to be efficient, an antithrombotic strategy must target a specific susceptibility gene implicated in coronary thrombosis, including thrombotic events that follow stent placement. According to this theory, most PlA1/A1 patients may find enough protection against adverse events after stent placement from an antithrombotic strategy that includes heparin, ASA ( 325 mg daily) and a thienopyridine derivative (full dose) for four to six weeks. The PlA1/A2 heterozygous patients would need the same triple therapy, but a dose of ASA of 160 mg daily might suffice (14), while the duration of the administration of thienopyridine derivative (clopidogrel, 75 mg daily) might need to be extended for a period of six to 12 months. Whereas the "toughest nuts to crack", the PlA2/A2 homozygous platelets, may need a GPIIb-IIIa blocker to lower their risk to the level of PlA1/A1 or PlA1/A2 patients, in addition to receiving ASA (325 mg daily), clopidogrel (75 mg daily for 6 to 12 months) and heparin. Additional large scale studies will be needed to test the usefulness of stratifying procedural risk with knowledge of PlA status in patients undergoing catheter based interventions. Considering important issues of safety and increasing cost, it might be of interest not only to stratify risk with genomic information but then target the use of increasingly powerful and costly antithrombotic strategies to those patients who will derive the greatest benefits.
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PlA2 and restenosis
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In a previous study of 1,150 consecutive patients with successful coronary stent placements and followed for an average of 163 days, Kastrati et al. (18) showed that PlA2 positive patients have a significantly higher rate of restenosis (defined angiographically as 50% diameter stenosis at six months after procedure): 53.1% in PlA2/A2, 46.1% in PlA1/A2 and 38.4% in PlA1/A1 patients. The effect of PlA2 on restenosis rate was particularly pronounced for women: 52% restenosis for PlA2 positive versus 33% for PlA1/A1 homozygous women compared with 45% restenosis for PlA2 positive versus 40% for PlA1/A1 homozygous men.
The use of stents for coronary interventions has expanded our understanding of the pathophysiology of restenosis, as it has nearly eliminated the component of "recoil" of the vessel wall from the restenotic process. In the presence of a stent, the contribution of neointimal hyperplasia (smooth muscle cell proliferation) to restenosis is more important than after conventional balloon angioplasty. Platelet adhesion and aggregation does contribute substantially to restenosis by promoting the migration and growth of smooth muscle cells (19). Even when acute stent thrombosis is efficiently prevented in PlA2 carriers using combination antiplatelet therapy with ASA, heparin and ticlopidine, the residual platelet accumulation might be sufficient to promote restenosis. It may, therefore, be reasonable to extend the duration of the administration of a thienopyridine such as clopidogrel, which causes fewer chronic hematological side effects than ticlopidine, to a full six-month course for patients with the PlA2 polymorphism. Such genomic-based therapeutic decisions are currently being tested and could have a substantial effect on the efficacy and the cost of antiplatelet therapy in the context of stent placement and restenosis.
Other polymorphisms have been studied in the context of restenosis. The blood level of angiotensin-converting enzyme (ACE) has been linked to an insertion/deletion (I/D) polymorphism of the ACE gene, such that DD genotype carriers have a higher level of ACE than either ID or II. Although, the I/D polymorphism is not associated with restenosis after balloon angioplasty, the D allele is a risk factor for restenosis after coronary stent implantation (20). In contrast, the HPA-3 polymorphism of platelet GPIIb (Bak) is not associated with an increase in the risk of thrombosis and restenosis over one year after coronary stent placement (21).
In summary, over the past few years, we have seen an exponential rise of genetic information that may turn out to be of great relevance not only for assessment of risk for individual patients but also for the design of tailored therapeutic strategies, the pharmacogenetic approach to therapy. By utilizing a pharmacogenetic approach to therapy in patients undergoing percutaneous coronary intervention with stent placement, we should be able to tailor the combination of antiplatelet drugs that most accurately suppress risk for acute thrombosis and prevent restenosis, thereby enhancing the clinical benefit, without exposing the patient to the unnecessary risk of bleeding and society, in general, to excess health care costs.
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Footnotes
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Editorials published in Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
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References
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The PlA2 polymorphism of...
Endovascular coronary procedures...