Pl^A2:

DEFECT: The Pl^A2 polymorphism is a single point transition at position 1565 in exon 2 of the gene encoding the Glycoprotein (GP) IIIa subunit of the GP IIb/IIIa receptor complex. The polymorphism results in the substitution of proline for leucine at amino acid position 33 (Leu33Pro).

FREQUENCY: The gene variance is seen in between 15%-20% of Caucasian people, 8-16% in Blacks, and is seen less frequently with Asian people.

MODE OF ACTION: Activation of the GP IIb/IIIa receptor complex results in the binding of fibrinogen and von Willebrand factor, platelet aggregation, and thrombus formation.

ASSOCIATED RISK: The polymorphism is associated with a nearly three-fold increased risk for coronary thrombosis and subsequent myocardial infarction (MI). Pl^A2 carriers also have increased rates of restenosis following coronary stent placement.

METHOD OF DETECTION: Allele-specific PCR. Possible Clinical Utility: Patients about to undergo interventional procedures for coronary artery disease, and all patients presenting with CAD, especially younger patients (<60 years of age), should be tested for this polymorphism.

PLa2 White Paper: PLa2 Test: Introduction to Clinical Practice

References:

1. Weiss EJ, Bray PF, Tayback M, Schulman SP, Kickler TS, Becker LC, Weiss JL, Gerstenblith G, Goldschmidt-Clermont PJ.; A polymorphism of a platelet glycoprotein receptor as an inherited risk factor for coronary thrombosis. N Engl J Med 1996 Apr 25;334(17):1090-4

The researchers observed a strong association between the Pl^A2 polymorphism of the glycoprotein IIIa gene and acute coronary thrombosis, and this association was strongest in patients who had had coronary events before the age of 60 years. The prevalence of the Pl^A2 polymorphism was 2.1 higher among the group with MI than the group with heart disease. The prevalence was even higher (3.6) in MI patients under 60 years of age. Among subjects with the Pl^A2 polymorphism, the odds ratio for having a coronary event was 2.8. In the patients less than 60 years of age at the onset of disease, the odds ratio was 6.2.


2. Kastrati A, Schomig A, Seyfarth M, Koch W, Elezi S, Bottiger C, Mehilli J, Schomig K, von Beckerath N; Pl^A polymorphism of platelet glycoprotein IIIa and risk of restenosis after coronary stent placement. Circulation 1999 Mar 2;99(8):1005-10

This study showed a significant association between the Pl^A polymorphism of glycoprotein IIIa and the risk of restenosis after coronary stent placement. The risk was more pronounced in patients homozygous for Pl^A2 allele and in female patients. Among 1150 consecutive patients with successful coronary stent placement, patients with the Pl^A2 allele demonstrated a significantly higher restenosis rate than did those without (47% versus 38%; OR, 1.42). The risk was highest in homozygous carriers of Pl^A2 (53.1% restenosis rate). After adjustment for several clinical and angiographic characteristics, the presence of the Pl^A2 allele remained a significantly independent risk factor for restenosis (adjusted OR, 1.35). The influence of the Pl^A2 allele on restenosis was stronger in women. Women with Pl^A2 had a restenosis rate of 52% compared with the 33% incidence among women homozygous for Pl^A1 (OR, 2.21).


3. Walter DH, Schachinger V, Elsner M, Dimmeler S, Zeiher AM; Platelet glycoprotein IIIa polymorphisms and risk of coronary stent thrombosis. Lancet 1997 Oct 25;350(9086):1217-9

Patients with the Pl^A2 allele have five-fold increased risk of coronary stent thrombosis. On multivariate regression analysis PI^A1/A2 genotype was the only significant independent predictor of stent thrombosis.

4. Zotz RB, Winkelmann BR, Nauck M, Giers G, Maruhn-Debowski B, Marz W, Scharf RE; Polymorphism of platelet membrane glycoprotein IIIa: human platelet antigen 1b (HP^A-1b/Pl^A2) is an inherited risk factor for premature myocardial infarction in coronary artery disease. Thromb Haemost 1998 Apr;79(4):731-5

Among patients with acute or recent onset myocardial infarction (< 1 year), the prevalence of Pl^A2 allele was higher than among patients with coronary artery disease, compared to those with CAD but without myocardial infarction (33 percent vs. 14 percent, p = 0.016). In patients under 60 years of age this difference was even more pronounced (45 percent vs. 15 percent, p = 0.003). Therefore, Pl^A2 is a risk factor for MI in patients with CAD, and not for CAD itself. Unlike conventional risk factors Pl^A2 does not represent a risk factor for coronary artery disease itself but appears to be associated with increased platelet thrombogenicity.

5. Mikkelsson J, Perola M, Kauppila LI, Laippala P, Savolainen V, Pajarinen J, Penttila A, Karhunen PJ; The GPIIIa Pl(A) polymorphism in the progression of abdominal aortic atherosclerosis. Atherosclerosis 1999 Nov 1;147(1):55-60

The area of complicated lesions was significantly greater in men with Pl(A2)-positive genotypes compared to A1 homozygotes. The association with complicated lesions was especially strong in men over 60 (P=0.002). These results suggest that Pl(A) polymorphism is involved in the progression of atherosclerosis in the abdominal aorta.


6. Mikkelsson J, Perola M, Laippala P, Savolainen V, Pajarinen J, Lalu K, Penttila A, Karhunen PJ; Glycoprotein IIIa Pl(A) polymorphism associates with progression of coronary artery disease and with myocardial infarction in an autopsy series of middle-aged men who died suddenly. Arterioscler Thromb Vasc Biol 1999 Oct;19(10):2573-8

The Pl(A2) allele was present in 50% of patients with MI and coronary thrombosis (OR 6.6), compared to only 12.8% of patients with MI associated with severe stenosis in the absence of thrombosis. Men possessing the Pl(A2) allele also had a larger area of fissured and ulcerated complicated lesions in their coronary arteries (P<0.05). Men with the Pl(A2) allele may harbor more thin-walled, vulnerable coronary plaques, plaques prone to rupture, leading to massive, fatal thrombosis. In contrast, men homozygous for the Pl(A1) allele may more often show stable plaques and present with infarction caused by progressive coronary stenosis.

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