© 1999 American Heart Association, Inc.
Thrombosis |
Glycoprotein IIIa PlA Polymorphism Associates With Progression of Coronary Artery Disease and With Myocardial Infarction in an Autopsy Series of Middle-Aged Men Who Died Suddenly
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Abstract—Glycoprotein IIIa (GPIIIa) has a key role in the aggregation of thrombocytes, and it also mediates intimal hyperplasia after endothelial injuries; the possible association of the PlA1/A2 polymorphism of the gene for GPIIIa with coronary thrombosis and with the progression of coronary artery disease (CAD) is still to be confirmed. Therefore, the association of the PlA polymorphism with the development of coronary atherosclerosis, coronary narrowing, and myocardial infarction (MI) was studied in a prospective, consecutive autopsy series of 300 middle-aged, white Finnish men (33 to 69 years) suffering sudden out-of-hospital or violent death. Coronary atherosclerosis was measured morphometrically and the coronary stenosis percentage determined from a cast rubber model of the coronary tree. We found a significant inverse relation (P=0.01) between the PlA2-positive genotype and coronary artery stenosis. The frequency of possessing the PlA2 allele was significantly (odds ratio [OR] 0.45, 95% confidence interval [CI] 0.22 to 0.98) lower among men with >50% coronary stenosis (18.3%) than among those with <25% stenosis (32.9%). Although the PlA polymorphism was not directly associated with MI, the PlA2 allele was present in 11 of the 22 men (50%) with MI and coronary thrombosis (OR 6.6, 95% CI 2.1 to 22.8) but in only 6 of the 47 (12.8%) with MI associated with severe stenosis in the absence of thrombosis. In line with this result, men possessing the PlA2 allele also had a larger area of fissured and ulcerated complicated lesions in their coronary arteries (P<0.05). The present results suggest that the PlA polymorphism is involved in the development of CAD and MI. Men with the PlA2 allele may harbor more thin-walled, vulnerable coronary plaques, plaques prone to rupture, leading to massive, fatal thrombosis. In contrast, men homozygous for the PlA1 allele may more often show stable plaques and present with infarction caused by progressive coronary stenosis.
Key Words: platelet glycoprotein GPIIb/IIIa complex • coronary thrombosis • myocardial infarction • polymorphisms • genetics
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
In addition to environmental and acquired risks, genetic factors most probably play a significant role in the development of coronary artery disease (CAD), thrombosis, and myocardial infarction (MI) and may modify the effect of other known risk factors. Platelet aggregation with subsequent thrombus formation is a key event in the development of acute coronary syndromes and the sudden death of patients with coronary heart disease. Fissuring or rupture of an atheromatous plaque is followed by the activation of platelet GPIIb/IIIa (
IIbß3 integrin)
fibrinogen receptors, resulting in fibrinogen binding, platelet
aggregation, and thrombus formation.1 2 3 Slow progression
of atherosclerosis is dependent on shear-induced
platelet adhesion to the exposed subendothelial
matrix and to an enlarging mural thrombus at sites of vessel
stenosis, whereas acute occluding thrombosis is usually caused
by rupture of a thin-walled, atheromatous plaque
distant from the site of the culprit stenosis.4 5
GPIIIa (ß3-integrin) is also expressed in the
endothelium and in vascular smooth muscle cells
(VSMCs).6 7 Its function is related to VSMC responses to
endothelial injuries caused by, eg,
hemodynamic shear stress, smoking, diabetes, and
hypertension.8 9 10 11 12 13
vß3 integrin is a
receptor that mediates different kinds of stimuli to VSMCs, causing
their proliferation and subsequent fibrous tissue generation and
intimal hyperplasia after injuries.6 10 14 15 Platelet PlA polymorphism of the GPIIIa gene is produced by a single point mutation in exon 2 of the GPIIIa gene, leading to substitution of leucine (PlA1) for proline (PlA2) and consequent changes in the protein conformation and spatial orientation of the fibrinogen-binding region.16 The functional importance of the PlA polymorphism as an important inherited risk factor for MI was first suggested by Weiss and colleagues.17 Subsequent studies on associations between the PlA2 allele and acute coronary events have, however, been controversial.18 19 20 21 22 23 24 25 More controversy was added by the recent findings that platelets from individuals possessing the PlA2 allele bind either less26 or more27 fibrinogen than do platelets from PlA1 homozygotes and also by the finding that the response to thrombin differs between the genotypes.28
In this study, we evaluated the association of platelet PlA1/A2 polymorphism with the development of CAD, coronary narrowing, and MI in a prospective autopsy series of middle-aged, white Finnish men who had died suddenly or violently. This population is particularly suitable for genetic association studies of coronary heart disease because Finns have 1 of the world's highest death rates due to CAD,29 and the population is genetically young and relatively isolated.30
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Prospective Autopsy Series of Middle-Aged Men
The original study population comprised a prospective series of 300 white men, aged 33 to 69 years, who were subjected to a medicolegal autopsy at the Department of Forensic Medicine, University of Helsinki, from 1991 to 1992. This autopsy series included 42% of all deaths of those <65 years of age during those years in the area of Helsinki and its surroundings. The reason for the medicolegal autopsy was unexpected sudden or violent death occurring outside a hospital, often unwitnessed. The cause of death was recent MI in 12.0% (n=36), old MI in 11.0% (n=33), sudden coronary death with no histological MI in 10.3% (n=31), other cardiac causes 5.3% (n=16), other diseases 21.3% (n=64), and violent deaths (suicides and accidents) 40.0% (n=120). The study was approved by the Ethics Committee of the Department of Forensic Medicine, University of Helsinki.
Measuring the Percent Stenosis in Silicone Rubber Casts of
the Coronary Arteries
At autopsy, coronary angiography was performed by use of
vulcanizing liquid-silicone rubber mixed with lead oxide as the
contrast medium. This procedure does not dislodge attached thrombus
from its site and has been successfully used in the routine
postmortem diagnosis of thrombotic and other complications after
coronary artery bypass surgery.31 The proximal,
middle, and distal stenoses of the main trunks of the left
anterior descending coronary artery, left circumflex artery,
and right coronary artery were measured from the cast rubber
model with a mauser.
The percent stenosis was obtained by dividing the diameter (millimeters) of the artery with the greatest stenosis by the diameter of the nearest proximal undamaged part of the cast model of the artery. These measurements were available for 272 cases that composed the final study population.
Measuring the Area of Atherosclerosis by
Computer-Assisted Morphometry of Coronary Arteries
Coronary arteries were fixed in 10% buffered formalin
and stained for fat by the Sudan IV staining method. The areas of the
fatty streaks, raised fibrous lesions, and complicated lesions (with
fissures, hematoma, or thrombosis)32 were measured by
computer-assisted morphometry.
Confirmation of MI
At autopsy, the presence of MI in the series was confirmed by
macroscopic and histological examination of the
myocardium. Coronary thrombosis was recorded
during opening of the coronary arteries after angiography.
Diagnostic studies of MI were done independent of any
measurements of the cast or the arteries. Of the series of 272 cases,
34 men had died of recent MI and an additional 2 had suffered an acute,
fatal, occluding coronary thrombosis without
histological features of acute MI, owing to their short
survival time. These 36 cases were grouped together as "recent MI
cases" for statistical analysis.
Of these recent MI cases, 16 (44.4%) were associated with acute coronary thrombosis. Old, nonfatal MI was diagnosed in an additional 33 cases, of which a macroscopic organizing thrombus was observed in 6 cases (18.2%). Thus, among these 69 men with MI, 22 (31.9%) were associated with coronary thrombosis, whereas in the remaining 47 (68.1%) men with MI, a thrombus could not be found.
Determination of PlA Genotypes
The polymorphism of cytosine/thymine in exon 2
of the GPIIIa gene was detected by polymerase chain reaction and
restriction digestion. Genomic DNA (10 to 30 
g) extracted from
frozen cardiac muscle samples taken at autopsy was used in each
amplification. DNA was amplified with a PTC 100 (Perkin-Elmer)
for 37 cycles of denaturation at 94°C for 45 seconds, annealing at
53°C for 45 seconds, and extension at 72°C for 60 seconds. The
final extension step was at 72°C for 4 minutes. The 266
bp-product was then incubated at 37°C for 1 hour with 10 U of
MspI. The resulting fragments were then separated by size in
a 2% agarose gel and visualized by ethidium bromide staining.
Risk Factors for CAD
A spouse, relative, or close friend of the deceased could
be interviewed in 147 cases. Among questions pertaining to risk factors
for sudden death, questions were included that delineated past and
recent smoking habits as well as previous illnesses. On the basis of
these interviews, men were classified as smokers (n=99) and nonsmokers
(n=32). Ex-smokers (n=16) were excluded from statistical
analysis. Hypertension had been diagnosed before death in 50
men and diabetes in 22. The final subpopulation with interview data
thus consisted of 131 men.
Statistical Analysis
The data analysis for stenosis and areas of
atherosclerotic changes was based on ANCOVA, in which the possible
confounding effects of age, body mass index, diabetes, hypertension,
and smoking (if data were available) were taken into account by
including them into the model as covariates. The results for
stenosis are based on logarithmically transformed data but are
also presented as crude statistics. Analysis on the
presence or absence of thrombosis in men with MI is based on logistic
regression. The computation was carried out on a Sun/UNIX mainframe
with BMDP Statistical Software (1993 version). The odds
ratios and their 95% confidence intervals were calculated with
Confidence Interval Analysis (CIA) software on a personal
computer.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Prevalence of PlA1/A2 Alleles
In the population of 272 men, the frequency of PlA1 was 87% and that of PlA2 13%. Respective frequencies for genotypes were 75.0% for PlA1/A1, 22.4% for PlA1/A2, and 2.6% for PlA2/A2. Frequencies of PlA1 and PlA2 were identical (87% and 13%) in the subpopulation of 131 men for whom interview data were available. The genotypes for the 272 men were in Hardy-Weinberg equilibrium. The frequencies of alleles in this series were similar to those reported on a population basis in Finland (A2 14%, A1 86%)33 . The main characteristics of men with the PlA1/A1 genotype and men with the PlA2 allele in the population of 272 men and in the subpopulation of 131 are presented in Table 1
. No
significant differences existed in these parameters between
the 2 populations or between genotypes.
|
Coronary Narrowing and the PlA1/A2
Polymorphism
For multivariate analysis, we chose the
highest percent stenosis measured from silicone casts to
represent the severity of coronary stenosis.
Possession of the PlA2 allele was
significantly (P=0.01) associated with less-severe
coronary stenosis. This association remained
significant (P<0.05) when interview data were brought into
the model (Table 2), and the association
was also significant in the group of men with no interview data. No
further association was found for the PlA
polymorphism in comparison of 1-vessel disease to multiple-vessel
stenosis.
|
To discover the effect of the PlA
genotype on the progression of stenosis, we divided the
men into 3 groups on the basis of measurements of the coronary
silicone rubber casts: men with smooth, healthy coronary
arteries or narrowings <25%, men with moderate coronary
narrowing between 25% and 50%, and men with severe stenosis
of >50% in any of the main coronary artery trunks. There was
a significant, gradual decrease in the
PlA2-positive genotype (Figure 1) across the range from the first group
of men with stenosis <25% to the third group with >50%
stenosis (OR 0.47, 95% CI 0.23 to 0.99), and also when
comparing the second group with stenosis between 25% and 50%
to the third group (OR 0.68, 95% CI 0.35 to 1.4). This association
remained significant and similarly gradual after we adjusted the
interview data and also in men with no interview data.
|
Coronary Atherosclerosis and
PlA1/A2 Polymorphism
The highest percentage for each morphological change in total
vessel area in the 3 vessels was chosen to represent the
severity of that individual variable for
atherosclerosis. The mean percent areas of fatty
streaks (P=0.6), raised fibrous lesions (P=0.2),
and complicated lesions (P=0.2) showed no association with
PlA polymorphism (Table 2
).
However, when the results were adjusted for interview data in the
subgroup of 131 men, those possessing the PlA2
allele had significantly (P<0.05) larger areas of
complicated lesions in their coronary arteries compared with
the PlA1 homozygotes (Table 2). To further
analyze this association, we divided the crude area of
complicated lesions by the crude summed areas of fatty and fibrous
lesions (ie, the plaque area) to obtain the proportion of complicated
lesions in the coronary plaques. In men with the
PlA2 allele, the complicated area in the
coronary plaques was also significantly (P<0.05)
larger.
MI and PlA1/A2 Polymorphism
We could find no direct association between MI and the
PlA polymorphism before (P=0.9) or
after (P=0.5) adjusting for the interview data. However, the
prevalence of the PlA2 allele was
significantly higher (P<0.001) in men with an MI caused by
coronary thrombosis than in men with an MI without thrombosis.
Of the 22 men with an MI and coronary thrombosis, 11 had the
PlA2 allele, whereas in the 47 men with MI
without thrombosis, it was present in only 6 (OR 6.6, 95% CI 2.1
to 22.8; Figure 2). When interview data
was included in the analysis (data available for 40 of the
cases with MI), the association of the PlA2
allele still showed a significant association (P<0.005)
with MI and thrombosis (Table 3). The
association was also significant in the group of men with no interview
data.
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Here we present the results of the first autopsy study on the association of PlA polymorphisms with coronary atherosclerosis, coronary narrowing, and MI. We found that possession of the PlA2 allele was associated with less-narrowed coronary arteries and a larger area of complicated lesions, both in coronary arteries and coronary plaques, as well as MI due to coronary thrombosis. This suggests an association for the PlA polymorphism with the development of CAD. Because our measurements were made directly from the coronary arteries, the stage of CAD and the percent stenosis, as well as the presence of MI and coronary thrombosis, could be determined reliably. Our approach thus circumvents many of the problems encountered in phenotyping clinical patients with CAD or MI. The postmortem measurements of stenosis in our study may correlate well angiographically measured stenosis because we measured stenosis by using a vulcanized rubber model of the arteries, not by histological examination.34
Weiss et al17 were the first to report an association between the PlA polymorphism and MI. They found that the PlA2 allele was positively associated with MI and that this association was even stronger in their group of patients <60 years old. This finding has been supported by other studies,19 20 22 but conflicting results have also been reported18 21 in similar series comprising patients with MI as well as in a large, prospective series of >14 000 men.23
Previous studies proposing an association between MI and the PlA2 allele have been criticized for a too small patient series for allelic association studies,17 for too few cases with thrombosis among patients with the PlA2 allele,25 or for an abnormally low percentage of the PlA2 allele among controls.17 Controversies involving these studies have also been ascribed to differences in the populations studied, to selection of controls, to ethnicity, and to definition of phenotype,17 19 as well as to the lack of any genetic effect in patients >60,17 24 and recently to the effect of use of aspirin.35 Another confounding factor between study populations has been the inclusion or exclusion of women. Possible sex differences in GPIIb/IIIa activation have been reported.36
Discrepancies in previous studies on the association of the PlA2allele with MI may stem from the fact that MI does not always have a similar pathogenesis. In acute coronary thrombosis, the rupture of a vulnerable plaque with an extensive lipid core and a thin, fibrous cap accounts for two thirds of the cases, whereas the remaining one third are caused by erosion of fibrous plaques.4 37 In addition, in one quarter to three quarter of cases involving sudden cardiac death, no thrombosis can be found, and the recent MI is often due to progressive arterial narrowing, or death is caused by arrhythmias arising from old, myocardial infarct scars in the absence of a recent MI.4 5 38 39 40 41 42 The frequency of thrombosis in our MI cases was similar to a recent large autopsy study on out-of-hospital ischemic heart disease.42
In their results, Ridker et al23 could confirm no connection between PlA polymorphism and cardiovascular events. Nor in our study was MI directly associated with the PlA polymorphism. However, 50% of our patients with MI associated with coronary thrombosis carried the PlA2 allele, whereas only 12.8% of the men with MI in the absence of thrombosis were PlA2-positive. We now believe that 1 explanation may be that patients with ruptured vulnerable plaques, subsequent acute thrombosis, and MI requiring thrombolysis become more or less preferentially selected for clinical hospital series. In contrast, men with MI caused by stable, stenosed plaques may die suddenly of arrhythmias and never reach the hospital. Thus, the results of Weiss and colleagues17 of a higher occurrence of PlA2 in patients with MI may have, at least in part, resulted from association of the PlA2 allele with more vulnerable coronary plaques. This might also be the possible explanation for the lack of any association in the study of Ridker et al,23 who obviously included among their MI cases both hospital infarcts and sudden out-of-hospital MI cases. On a population basis, our results are consistent with another recent study on Finnish MI survivors, which found the PlA2 allele to be associated with a higher risk for MI in a population-based sample.43 In further support of our results for coronary arteries, we also found the PlA2 allele to be associated with larger areas of complicated lesions in the abdominal aorta.44
The association between the PlA1 homozygotes and more stenotic, stable plaques may be the result of genotypic differences in the VSMC proliferation and fibrous tissue generation in the intima after endothelial injury, due to differences in the function of the endothelial/VSMC ß3 integrins, which mediate these responses.6 10 14 15 This hyperplastic response may be weaker in men with the PlA2 allele, and thus, the coronary plaques of men with the PlA2 allele may have thinner fibrous caps, and their plaques may be less stenotic and more prone to rupture. Genotypic differences in thrombosis may also be due to differences in platelet aggregability.17
Owing to the sudden and unexpected death, cholesterol levels of the deceased were not available because they had not been measured at any point during the lives of our cases. This is why we could not control for the possible confounding effect of serum cholesterol in the statistical analyses.
In conclusion, we found a significant relation between possession of the PlA2 allele and slower progression of coronary artery stenosis. Our results thus support the concept of the functional importance of the PlA polymorphism. The higher prevalence of the PlA2 allele among men with MI associated with coronary thrombosis is likely due to the thinner fibrous caps of their atheromatous plaques and/or more reactive platelets. These thin-walled, vulnerable plaques are more prone to rupture and cause acute coronary thrombosis. On the other hand, in PlA1 homozygotes, intimal hyperplasia may be more extensive, resulting in progressive coronary stenosis with stable plaques and "silent" occlusion of the vessel lumen.
|
Acknowledgments |
|---|
This study has received financial support from the Yrjö Jahnsson Foundation (to J.M., V.S., J.P., P.K.), the Finnish Foundation of Alcohol Research (to J.M., V.S., J.P., P.K.), the Pirkanmaa Regional Fund of the Finnish Cultural Foundation (J.M., P.K.), and the Medical Research Fund of Tampere University Hospital (J.M., P.L., P.K.). The authors are grateful to Seppo Tyynelä for measurements of the coronary cast narrowings as well as for morphometric analysis of the coronary arteries, together with Juhani Vartiainen; to Hilkka-Liisa Vuorikivi for histological sections and fat staining of the arteries; and to Tarja Ruotsalainen for creating the computerized file of the autopsy data.
Received November 6, 1998; accepted February 15, 1999.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Chesebro JH, Fuster V. Thrombosis in unstable angina. N Engl J Med. 1992;327:192–194.[Medline] [Order article via Infotrieve]
2. Badimon L, Chesebro JH, Badimon JJ. Thrombus formation on ruptured atherosclerotic plaques and rethrombosis on evolving thrombi. Circulation. 1992;86(suppl III):III-74–III-85.
3.
Lefkovits J, Plow EF, Topol EJ. Platelet
glycoprotein IIb/IIIa receptors in
cardiovascular medicine. N Engl J
Med. 1994;332:1553–1558.
4. Fuster V, Badimon JJ, Badimon L, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes. N Engl J Med. 1992;326:242–250.[Medline] [Order article via Infotrieve]
5.
Mehta D, Curwin J, Gomes A, Fuster V. Sudden death in
coronary artery disease: acute ischemia versus
myocardial substrate. Circulation. 1997;96:3215–3223.
6. Davies MG, Hagen PO. Pathobiology of intimal hyperplasia. Br J Surg.. 1994;81:1254–1269.[Medline] [Order article via Infotrieve]
7. Ruoslahti E, Engvall E. Integrins and vascular extracellular matrix assembly. J Clin Invest. 1997;100:53S–56S.
8. Pittilo RM. Cigarette smoking and endothelial injury: a review. Adv Exp Med Biol. 1990;273:61–78.[Medline] [Order article via Infotrieve]
9. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993;362:801–809.[Medline] [Order article via Infotrieve]
10. Shattil SJ. Function and regulation of the ß3 integrins in hemostasis and vascular biology. Thromb Haemost. 1995;74:149–155.[Medline] [Order article via Infotrieve]
11. Taddei S, Salvetti A. Endothelial dysfunction in hypertension. Adv Exp Med Biol. 1997;423:235–246.
12. Gimbrone MAJ, Cybulsky MI, Kume N, Collins T, Resnick N. Vascular endothelium: an integrator of pathophysiological stimuli in atherogenesis. Ann N Y Acad Sci. 1995;748:122–132.[Medline] [Order article via Infotrieve]
13.
Ross R. Mechanisms of disease:
atherosclerosis: an inflammatory disease. N
Engl J Med. 1999;340:115–126.
14.
Schini-Kerth VB, Bassus S, Fisslthaler B, Kirchmaier
CM, Busse R. Aggregating human platelets stimulate the expression
of thrombin receptors in cultured vascular smooth muscle cells via the
release of transforming growth factor-ß1 and
platelet-derived growth factor AB. Circulation. 1997;96:3888–3896.
15.
Stouffer GA, Hu Z, Sajid M, Li H, Jin G, Nakada MT,
Hanson SR, Runge MS. ß3 Integrins are upregulated after vascular
injury and modulate thrombospondin- and thrombin-induced proliferation
of cultured smooth muscle cells. Circulation. 1998;97:907–915.
16.
Honda S, Honda Y, Bauer B, Ruan C, Kunicki TJ. The
impact of three-dimensional structure on the expression of PlA
alloantigens on human integrin ß3. Blood. 1995;86:234–242.
17.
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;334:1090–1094.
18.
Marian AJ, Brugada R, Kleiman NS. Platelet
glycoprotein IIIa PlA
polymorphism and myocardial infarction. N Engl J
Med. 1996;335:1071–1072.
19. Goldschmidt-Clermont PJ, Bray PF. Platelet glycoprotein IIIa PlA polymorphism and myocardial infarction. N Engl J Med. 1996;335:1073–1074.
20. Carter AM, Ossei-Gerning N, Grant PJ. Platelet glycoprotein IIIa PlA polymorphism in young men with myocardial infarction. Lancet. 1996;348:485–486.[Medline] [Order article via Infotrieve]
21. Osborn SV, Hampton KK, Smillie D, Channer KS, Daly ME. Platelet glycoprotein IIIa gene polymorphism and myocardial infarction. Lancet. 1996;348:1309–1310.[Medline] [Order article via Infotrieve]
22. Carter AM, Ossei-Gerning N, Grant PJ. Platelet glycoprotein IIIa PlA polymorphism and myocardial infarction. N Engl J Med. 1996;335:1072–1073.
23. Ridker PM, Hennekens CH, Schmitz C, Stampfer MJ, Lindpaintner K. PlA1/A2 polymorphism of platelet glycoprotein IIIa and risks of myocardial infarction, stroke, and venous thrombosis. Lancet. 1997;349:385–388.[Medline] [Order article via Infotrieve]
24.
Carter AM, Ossei-Gerning N, Wilson IJ, Grant PJ.
Association of the platelet PlA
polymorphism of glycoprotein IIb/IIIa and the
fibrinogen Bß 448 polymorphism with myocardial infarction and
extent of coronary artery disease. Circulation. 1997;96:1424–1431.
25. Walter DH, Schächinger V, Elsner M, Dimmeler S, Zeiher AM. Platelet glycoprotein IIIa polymorphisms and risk of coronary stent thrombosis. Lancet. 1997;350:1217–1219.[Medline] [Order article via Infotrieve]
26. Goldschmidt-Clermont PJ, Weiss EJ, Shear WS. Platelets from PlA2(-) individuals bind more exogenous fibrinogen than platelets from PlA2(+) individuals. Blood. 1996;88:26a. Abstract.
27. Zotz RB, Deitenbeck R, Rehfeld ISB, et al. Increased platelet sensitivity related to the GPIIIa polymorphism (HPA-1b/PlA2). Circulation. 1997;96(suppl I):I-660. Abstract.
28. Lasne D, Krenn M, Pingault V, Arnaud E, Fiessinger JN, Aiach M, Rendu F. Interdonor variability of platelet response to thrombin receptor activation: influence of PlA2 polymorphism. Br J Haematol.. 1997;99:801–807.[Medline] [Order article via Infotrieve]
29. Pekkanen J, Nissinen A, Puska P, Punsar S, Karvonen MJ. Risk factors and 25 year risk of coronary heart disease in a male population with a high incidence of the disease: the Finnish cohorts of the Seven Countries Study. BMJ. 1989;299:81–85.
30. De la Chapelle A. Disease gene mapping in isolated human populations: the example of Finland. Am J Hum Genet. 1993;30:857–865.
31. Karhunen PJ, Männikkö A, Penttilä A, Liesto K. Diagnostic angiography in postoperative autopsies. Am J Forensic Med Pathol. 1989;303–309.
32.
Stary HC, Chandler AB, Dinsmore RE, Fuster V, Glagov S
Insull W Jr, Rosenfeld ME, Schwartz CJ, Wagner WD, Wissler RW. A
definition of advanced types of atherosclerotic lesions and a
histological classification of
atherosclerosis: a report from the Committee on
Vascular Lesions of the Council on
Arteriosclerosis, American Heart Association.
Circulation. 1995;92:1355–1374.
33. Kekomaki S, Partanen J, Kekomaki R. Platelet alloantigens HPA-1, -2, -3, -5 and -6 in Finns. Transfus Med. 1995;5:193–198.[Medline] [Order article via Infotrieve]
34.
Mann JM, Davies MJ. Assessment of the severity of
coronary artery disease at postmortem examination: are the
measurements clinically valid? Br Heart J. 1995;74:528–530.
35. Cooke GE, Bray PF, Hamlington JD, Pham DM, Goldschmidt-Clermont PJ. PlA2 polymorphism and efficacy of aspirin. Lancet. 1998;351:1253.[Medline] [Order article via Infotrieve]
36. Faraday N, Goldschmidt-Clermont PJ, Bray PF. Gender differences in platelet GPIIb-IIIa activation. Thromb Haemost. 1997;77:748–754.[Medline] [Order article via Infotrieve]
37.
Farb A, Burke AP, Tang AL, Liang TY, Mannan P, Smialek
J, Virmani R. Coronary plaque erosion without rupture into a
lipid core: a frequent cause of coronary thrombosis in sudden
coronary death. Circulation. 1996;93:1354–1363.
38. Davies MJ, Thomas A. Thrombosis and acute coronary-artery lesions in sudden cardiac ischemic death. N Engl J Med. 1984;310:1137–1140.[Abstract]
39.
Davies MJ, Bland JM, Hangartner JR, Angelini A,
Thomas AC. Factors influencing the presence or absence of acute
coronary artery thrombi in sudden ischemic death.
Eur Heart J. 1989;10:203–208.
40.
Farb A, Tang AL, Burke AP, Sessums L, Liang Y,
Virmani R. Sudden coronary death: frequency of active
coronary lesions, inactive coronary lesions, and
myocardial infarction. Circulation. 1995;92:1701–1709.
41. Warnes CA, Roberts WC. Sudden coronary death: comparison of patients with to those without coronary thrombus at necropsy. Am J Cardiol. 1984;54:1206–1211.[Medline] [Order article via Infotrieve]
42.
Leach IH, Blundell JW, Rowley JM, Turner DR. Acute
ischaemic lesions in death due to ischaemic heart disease: an autopsy
study of 333 cases of out-of-hospital death. Eur Heart
J. 1995;16:1181–1185.
43.
Pastinen T, Perola M, Niini P, Terwilliger J, Salomaa
V, Vartiainen E, Peltonen L, Syvanen A. Array-based multiplex
analysis of candidate genes reveals two independent and
additive genetic risk factors for myocardial infarction in the Finnish
population. Hum Mol Genet. 1998;7:1453–1462.
44. Mikkelsson J, Perola M, Kauppila LI, Laippala P, Savolainen V, Pajarinen J, Penttilã A, Karhunen PJ. The GPIIIa PlA polymorphism in the progression of abdominal aortic atherosclerosis. Atherosclerosis. 1999. In press.
This article has been cited by other articles:
 |
|
 |
|
  J. A. Hernesniemi, P. J. Karhunen, N. Oksala, M. Kahonen, M. Levula, R. Rontu, E. Ilveskoski, O. Kajander, S. Goebeler, L. E. Viiri, et al. Interleukin 18 gene promoter polymorphism: a link between hypertension and pre-hospital sudden cardiac death: the Helsinki Sudden Death Study Eur. Heart J., August 17, 2009; (2009) ehp316v1. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Sucker, M. Schmitz, G. R. Hetzel, B. Grabensee, B. Maruhn-Debowski, L. Ostojic, R. E. Scharf, and R. B. Zotz Are Prothrombotic Variants of Platelet Glycoprotein Receptor Polymorphisms Involved in the Pathogenesis of Thrombotic Microangiopathies? Clinical and Applied Thrombosis/Hemostasis, August 1, 2009; 15(4): 402 - 407. [Abstract] [PDF]
|
|
|
|
 |
|
 N. K.J. Oksala, M. Heikkinen, J. Mikkelsson, T. Pohjasvaara, M. Kaste, T. Erkinjuntti, and P. J. Karhunen Smoking and the Platelet Fibrinogen Receptor Glycoprotein IIb/IIIA PlA1/A2 Polymorphism Interact in the Risk of Lacunar Stroke and Midterm Survival Stroke, January 1, 2007; 38(1): 50 - 55. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. E. Bojesen, K. Juul, P. Schnohr, A. Tybjaerg-Hansen, and B.o. G. Nordestgaard Platelet glycoprotein IIb/IIIa PlA2/PlA2 homozygosity associated with risk of ischemic cardiovascular disease and myocardial infarction in young men: The Copenhagen City Heart Study J. Am. Coll. Cardiol., August 20, 2003; 42(4): 661 - 667. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Pontiggia, R. Lassila, S. Pederiva, H.-R. Schmid, M. Burger, and J. H. Beer Increased Platelet-Collagen Interaction Associated With Double Homozygosity for Receptor Polymorphisms of Platelet GPIa and GPIIIa Arterioscler Thromb Vasc Biol, December 1, 2002; 22(12): 2093 - 2098. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. A. Kajander, P. J. Karhunen, and H. T. Jacobs The relationship between somatic mtDNA rearrangements, human heart disease and aging Hum. Mol. Genet., February 1, 2002; 11(3): 317 - 324. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H Douglas, K Michaelides, D A Gorog, E Durante-Mangoni, N Ahmed, G J Davies, and E G D Tuddenham Platelet membrane glycoprotein Ib{alpha} gene -5T/C Kozak sequence polymorphism as an independent risk factor for the occurrence of coronary thrombosis Heart, January 1, 2002; 87(1): 70 - 74. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.Y. Streifler, N. Rosenberg, A. Chetrit, R. Eskaraev, B.A. Sela, R. Dardik, A. Zivelin, B. Ravid, J. Davidson, U. Seligsohn, et al. Cerebrovascular Events in Patients With Significant Stenosis of the Carotid Artery Are Associated With Hyperhomocysteinemia and Platelet Antigen-1 (Leu33Pro) Polymorphism Stroke, December 1, 2001; 32(12): 2753 - 2758. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Barakat, S. Kennon, G. A. Hitman, E. Aganna, C. P. Price, P. G. Mills, K. Ranjadayalan, B. North, H. Clarke, and A. D. Timmis Interaction between smoking and the glycoprotein IIIa P1A2 polymorphism in Non-ST-elevation acute coronary syndromes J. Am. Coll. Cardiol., November 15, 2001; 38(6): 1639 - 1643. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. E. Kandzari and P. J. Goldschmidt-Clermont Platelet polymorphisms and ischemic heart disease: moving beyond traditional risk factors J. Am. Coll. Cardiol., October 1, 2001; 38(4): 1028 - 1032. [Full Text] [PDF]
|
|
|
|
 |
|
 J. S. Bennett, F. Catella-Lawson, A. R. Rut, G. Vilaire, W. Qi, S. C. Kapoor, S. Murphy, and G. A. FitzGerald Effect of the PlA2 alloantigen on the function of {beta}3-integrins in platelets Blood, May 15, 2001; 97(10): 3093 - 3099. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. S. Williams and P. F. Bray Genetics of Arterial Prothrombotic Risk States Experimental Biology and Medicine, May 1, 2001; 226(5): 409 - 419. [Abstract] [Full Text]
|
|
|
|
|
|
J. Mikkelsson, M. Perola, P. Laippala, A. Penttila, and P. J. Karhunen Glycoprotein IIIa PlA1/A2 polymorphism and sudden cardiac death J. Am. Coll. Cardiol., October 1, 2000; 36(4): 1317 - 1323. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. A Kunnas, P. Laippala, A. Penttilä, T. Lehtimäki, and P. J Karhunen Association of polymorphism of human alpha oestrogen receptor gene with coronary artery disease in men: a necropsy study BMJ, July 29, 2000; 321(7256): 273 - 274. [Full Text]
|
|
|
|
|
|
P. J. Goldschmidt-Clermont, G. E. Cooke, G. M. Eaton, and P. F. Binkley PlA2, a variant of GPIIIa implicated in coronary thromboembolic complications J. Am. Coll. Cardiol., July 1, 2000; 36(1): 90 - 93. [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||