A POLYMORPHISM OF A PLATELET GLYCOPROTEIN RECEPTOR AS AN INHERITED RISK FACTOR FOR CORONARY THROMBOSIS

Ethan J. Weiss, et al. and Pascal J. Goldschmidt-Clermont MD

New England Journal of Medicine 1996; 334: 1090-94

(From research conducted at Johns Hopkins University School of Medicine)

Background:

Myocardial Infarction (MI) and unstable angina result from the formation of platelet aggregates at the level of plaque. The formation of such ruptures requires the binding of fibrinogen and von Willibrand factor. Platelet glycoprotein IIb/IIIa is a membrane receptor for fibrinogen and von Willebrand factor to platelets, and it is essential for platelet aggregation. It is known to be involved in the pathogenesis of acute coronary syndromes.

Reason for the study:

A high frequency of a particular polymorphism, PlA2of the gene encoding glycoprotein IIIa in kindreds with a high prevalence of premature myocardial infarction was noted.

Methods:

Case controlled, 71 patients with MI or unstable angina referred to a tertiary hospital. 68 inpatient controls without known heart disease. The groups were matched for age, race and sex. Genotype determined two ways; by reverse dot blot hybridization and allele-specific restriction digestion.

Results:

The prevalence of the PlA2 polymorphism was 2.1 times higher among the group suffering from MI (3.6 times in those <60 yrs. old) vs. the group without heart disease (39.4% vs. 19.1%).

Conclusions:

There is a strong association between the PlA2 polymorphism of the glycoprotein IIIa gene and acute coronary thrombosis especially among patients with a coronary event before 60 years of age.

Of Note:

The odds ratio for coronary heart disease associated with the following risk factors:

1. 2.8 - Carriage of the PlA2 allele.
2. 2.2 - Smoking.
3. 1.9 - Hypertension (systolic "e 140 mm Hg).
4. 1.3 - Hypercholesterolemia (total serum cholesterol "e 200 mg/dl.

Where disease was manifest before 60 years of age the following odds ratios were calculated:

1. 6.2 - Carriage of the PlA2 allele.
2. 3.8 - Smoking.
3. 3.7 - Hypercholesterolemia.
4. 2.1 - Hypertension.

*Note a multiple logistic-regression analysis adjusting for the presence of smoking, hypertension, hypercholesterolemia and an age greater than 60 showed an independent association between the PlA2 allele and acute coronary events

Patients in this study positive for the PlA2 allele were likely to have their initial coronary event 7 years before a patient without the polymorphism (51.8 years old vs. 59.2 years old).

Prevalence of the PlA2 phenotype (at least one PlA2 allele) among northern Europeans is 26.5%. Among 100 Caucasians (from the Baltimore, MD area) is 20%. The control group from this study had a prevalence rate of 19.1%

One Final Point:

The results of this study suggest that patients that are PlA2 positive would receive extra benefit from direct anti-glycoprotein IIb/IIIa therapy, thus directing the selection of the most effective antiplatelet therapy for patients with unstable coronary syndromes. (ie. I.V. GP IIb/IIIa blockers, clopidigrel or ticlopidine vs. aspirin).

PlA1/A2 POLYMORPHISM OF PLATELET GLYCOPROTEIN IIIA AND RISKS OF MYOCARDIAL INFARCTION, STROKE, AND VENOUS THROMBOSIS

Paul M. Ridker, et. al.

The Lancet 1997; 349: 385-388

(Research conducted at Brigham and Women's Hospital, Harvard Medical School)

Background:

Others (Weiss et al) have reported a strong association between the presence of the PlA2 polymorphism and elevated risk of myocardial infarction.

Reason for the Study:

To determine whether the results reported by Weiss et al. in the New England Journal of Medicine hold up when looked at in a large cohort of men.

Objective:

To look for a relationship between the presence of the PlA2 allele and the risk of myocardial infarction, stroke and venous thrombosis in a large cohort of men.

Methods:

The Physician's Health Study involved 14,916 men followed for 8.6 years to study the effects of aspirin and ß-carotene on alternate days, both drugs or neither. During the follow up period 374 had their first MI, 209 had a stroke and 121 had a venous thrombosis (704 events in total). The distribution of the PlA2 polymorphism in this group was investigated and compared with another 704 men from the study who remained free of thrombosis.

Results:

The relative risk of any vascular event among men homozygous or heterozygous for PlA2 compared with men homozygous for PlA1 was 0.96. There was no association between risk for MI, stroke or thrombosis and PlA2 allele in men over or under 60 years of age. No association was found between the presence of the PlA2 allele and myocardial infarction, stroke or venous thrombosis.

Conclusions:

The findings of Weiss et al may have been due strictly to chance (statistically possible due to the relatively small sample size in the Weiss study [71 in the primary group and 42 in the analysis of those < 60 compared with 704 and 350 respectively in this study]. A second answer maybe that Weiss's findings were biased due to the controls being taken from hospital in-patients but free of heart disease. A third answer may be that perhaps the effects of the PlA2 allele are applicable only to smokers or some other associated variable (there was a higher proportion of smokers in the Weiss study). A fourth explanation might be related to the fact that patients in Weiss's study were all patients with complicated coronary syndromes and therefore were referred to a tertiary hospital. Finally, the discrepancy in the two studies may be due to the aspirin therapy involved in the Physicians' Health Study. In any case, such an effect would also be a factor in the validity of the results of the Weiss study as well.

Final point:

The finding of this study do not support the hypothesis that the PlA1/A2 polymorphism represents an inherited platelet risk factor for vascular disease. However, evidence of familial aggregation of cardiovascular disease would suggest that such a factor exits. However, unlike with monogeneic syndromes where one pedigree may point to a gene at fault, investigations of complex, polygenic and multifactorial disorders require the study of large, well-characterized populations.

PlA2 POLYMORPHISM AND EFFICACY OF ASPIRIN

Glenn E. Cooke, Paul F. Bray, Jeanette D. Hamlington, Dung M Pharm, Pascal J. Goldschmidt-Clermont

The Lancet 1998; 351: 1253

(Research conducted at Ohio State University, Heart and Lung Institute and Johns Hopkins University School of Medicine)

Background:

It has been previously shown that the PlA2 polymorphism of the glycoprotein IIIa subunit of the fibrinogen receptor (GPIIb/IIIa) is a risk factor for coronary heart disease. Feng et al showed that the PlA2 polymorphism increases platelet aggregation in an allele dependent fashion.

Aspirin is widely used as an antiplatelet drug to prevent arterial thromboembolic events. Aspirin acetylates the enzyme cyclooxygenase (COX-1), and thereby inhibits the production of thromboxane A2 in platelets. However, the mechanism by which thromboboxane A2 induces the expression of high-affinity receptor molecules for fibringen on the surface of the platelets (the final common pathway of platelet activation) remains unknown.

Reason for the Study:

Although other studies have shown the presence of the PlA2 allele to be a risk factor for coronary heart disease some have not. Notably; the Physicians Health Study did not show a relationship. The reason for the discrepancy was sought.

It was hypothesized that the discrepancy between the outcomes in the studies could be related to the exposure of the patients to aspirin at the time of the onset of myocardial infarction.

Objective:

The researchers set out to establish the relative difference in aspirin's aggregation inhibitory effectiveness between those positive for PlA2 polymorphism and those negative.

Method:

A comparison of the aggregation of platelets from fifteen PlA1/A1 homozygotes and eleven PlA1/A2 heterozygotes matched for age, race and gender. The aspirin dosages studied were representative of the concentrations found in patients on aspirin therapy.

Results:

Aggregation in the absence of aspirin was the same in PlA1/A1 and PlA1/A2 platelets was the same. The response of PlA2 platelets to aspirin was much stronger than PlA1/A1 platelets. At therapeutic ranges of aspirin, platelet aggregation inhibition was ten times greater with PLA2 platelets.

Conclusion:

Differences in the exposure of patients to aspirin therapy at the onset of myocardial infarction might account for the discrepancies between studies concerning the relative coronary event risk level associated with the PlA2 allele.

PLATELET GLYCOPROTEIN IIIa POLYMORPHISM, ASPIRIN, AND THROMBIN GENERATION

Anetta Undas, Matek Sanak, Jacek Musial, Andrzej Szczeklik

The Lancet 1999; 353; 982-983

(Research conducted at Jagiellinian University School of Medicine, Krakow, Poland)

Background:

25% of white people exhibit a polymorphism in the gene encoding for glycoprotein IIIa. The presence of the PlA2 allele has been associated with a higher risk of coronary heart disease.

Reason for Study:

To build upon earlier research that has suggested that the apparent risk of thrombosis associated with the PlA2 polymorphism may be related to the ineffectiveness of aspirin in such patients due to altered platelet sensitivity rather than being a direct risk factor for coronary heart disease.

Objective:

To determine if a PlA2 polymorphism could alter the platelet sensitivity to aspirin. To go a step further than Cooke et al who looked the accentuation of platelet aggregation in vitro and instead, measure the generation of thrombin at the site of microvascular injury, the final pathway of hemostasis to which platelets contribute importantly.

Methods:

A comparison was made between two groups of symptomless men with normal serum lipids, 15 positive for the PlA2 allele and 25 negative. Each group was given a 7 day regimen of aspirin 75mg. after which blood was collected and analysed for thrombin generation.

Results:

The average thrombin generation decrease with aspirin therapy 63% in the PlA1 group and 28% in the PlA2 group. The relative risk for the lack of aspirin effect due to the presence of the PlA2 allele was 6.43

Conclusions:

Walter et al (University of Frankfurt) reported that the risk of coronary stent thrombosis was increased fivefold in carriers of the PlA2 polymorphism, despite no differences with non-carriers in clinical characteristics and angiographic variables. Because all patients were treated with aspirin and ticlopidine, Nurden et al wondered whether an altered platelet sensitivity to commonly used therapeutic agents due to the PlA2 polymorphism could be the cause. This study further supports that hypothesis. It is important to note that GPIIb/IIIa can bind either fibrinogen or prothrombin. Reduced binding of PlA2 platelets to fibrinogen in the presence of aspirin may allow for greater binding to prothrombin, with consequent increased production of thrombin. The studies form Cooke, et al. and Undas, et al. are therefore consistent.