(Circulation. 1997;96:3281-3286.)
© 1997 American Heart Association, Inc.
Articles |
Coronary Artery Disease and Polymorphisms in a Receptor Mediating Shear Stress–Dependent Platelet Activation
From the Department of Medicine, School of Medicine, Keio University (M.M., Y.M., T.Z., Y.I.), Tokyo; Second Department of Internal Medicine, Kyorin University (K.K., N.A., H.Y., K.I.), Tokyo; and Medical Center, Sakura Bank (G.W.), Tokyo, Japan.
Correspondence to Mitsuru Murata, MD, Department of Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160, Japan.
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Abstract |
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Background Platelets play pivotal roles in coronary thrombosis, and antiplatelet therapies are widely used for coronary artery disease (CAD). However, the effects of genetic variation in platelets on CAD are poorly understood. We have assessed the association between CAD and polymorphisms in a platelet receptor for von Willebrand factor, the glycoprotein (GP) Ib/IX complex, which mediates shear stress–dependent platelet activation.
Methods and Results Genotypes of the 
-chain of the
receptor (GP Ib, 145Thr/Met) were determined in 91
patients with myocardial infarction (MI) or angina pectoris whose
lesions were confirmed by coronary angiography as well as in
105 individuals from the general population with no history of angina
or other heart diseases and normal resting ECGs. There was no
homozygote for Met/Met in either the control or patient groups. The
prevalence of the Thr/Met genotype (T/M) in all patients was
not significantly different from that in the control group. However,
the frequency of T/M was significantly higher in patients aged 
60
years (31.8%) than in control subjects aged 60 years (16.0%;
P<.05, odds ratio=2.5). An association was also
demonstrated between CAD and the other polymorphism of GP Ib, a
variable number of tandem repeats of a 13–amino acid sequence,
which is known to be linked to the 145Thr/Met
polymorphism. There was an association between the frequency of the
T/M genotype and the angiographic severity of CAD: 11.1% for
Gensini score <40 versus 50.0% for Gensini score 
40
(P=.0015). There was no difference in the distribution
of GP Ib genotypes between patients with MI and those with
angina pectoris.
Conclusions This study suggests that the presence of the Met
allele in GP Ib is a risk factor for the prevalence and severity
of CAD in individuals aged 60 years. The results need to be confirmed
in a large-scale study of incident case subjects and matching control
subjects.
Key Words: coronary disease • risk factors • platelets • glycoproteins • genetics
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Introduction |
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Angiographic and angioscopic investigations have demonstrated the role of thrombus formation in the pathogenesis of acute coronary syndromes.1,2 For coronary thrombosis, platelet function is believed to be a key factor.3–6 Platelets may be also involved in the development of atherosclerosis.7,8 Adhesion of platelets to damaged blood vessels initiates platelet thrombus formation and, by releasing growth factors, leads to proliferation of vascular cells. Recent studies have revealed that platelets under blood flow can be activated by high shear stress generated in stenosed arteries or arterioles, without chemical agonists. This shear-induced platelet activation is dependent on an adhesive ligand, vWF, and its platelet receptor, GP Ib/IX complex.9–14 It is now believed that binding of vWF to GP Ib/IX initiates intracellular signals resulting in activation of another platelet receptor, GP IIb/IIIa complex, to form platelet clumps.15–17
The roles of the vWF–GP Ib/IX interaction in the development of coronary stenosis and acute coronary syndromes have been implicated in recent reports. Animals that were congenitally devoid of vWF were less prone to develop atherosclerosis,18,19 and agents that block either vWF or GP Ib/IX inhibited and delayed coronary occlusion in animal models.20,21 Moreover, an elevated plasma level of vWF is a poor prognostic factor for coronary heart disease22 as well as an independent risk factor for subsequent acute coronary events in patients with angina pectoris.23
Two genetic polymorphisms have been reported in the coding sequence
of the gene encoding the -chain of GP Ib (GP
Ib).14,24–26 The first polymorphism, a C/T
transition at nucleotide 1018 (numbers according to Wenger
et al27), results in an amino acid dimorphism (Thr/Met) at
residue 145 of GP Ib, which is located within the vWF-binding domain
of the receptor. This polymorphism is a known molecular basis of a
platelet alloantigen system, HPA 2a/2b, and is involved in the
development of platelet transfusion
refractoriness.24,25 The second polymorphism is the
variable number (one to four) of 13–amino acid sequence
repeats.14 This "size polymorphism" is known to be
strongly associated with the first polymorphism, alleles with
one or two repeats being linked to 145Thr whereas
alleles with three or four repeats are linked to
145Met.28 However, the functional consequences
of these polymorphisms in the receptor are still unknown.
Therefore, we sought to assess the relationships between these polymorphisms and the prevalence and severity of CAD. We have evaluated the frequencies of the genotypes in patients with angiographically proven CAD and control subjects.
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Methods |
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Patients and Control Subjects
Blood samples were collected consecutively from 91 genetically unrelated Japanese patients with either MI (n=66) or angina pectoris (n=25) at an outpatient clinic of Kyorin University Hospital (Tokyo, Japan) if the patient was judged to be eligible for this study. All patients had been diagnosed as having CAD, and all were alive at the time of genotyping. The criteria for entry were as follows: for MI, diagnosis was based on clinical symptoms, appropriate new onset of ECG changes, and elevated serum creatine phosphokinase levels. Only patients whose diagnosis of MI had been made at this hospital were entered into the study. All but 8 patients with MI were evaluated by coronary angiography. For angina pectoris, diagnosis was made according to clinical symptoms and ECG findings, and only patients whose coronary lesions had been confirmed by coronary angiography were eligible for entry into the study. Patients having an affected vessel with >50% reduction of lumen size (
75%
stenosis by American Heart Association classification) were
entered into the study. Patients enrolled in the study were considered
prevalence cases. For patients with MI, their age at first event was
recorded, whereas for patients with angina pectoris, the age at
which coronary angiography was performed was recorded. One hundred five control subjects recruited at Hibiya Medical Center (Tokyo, Japan) for their regular checkup were consecutively enrolled into the study. They were a genetically unrelated Japanese population without any symptoms who had no history of angina or other heart diseases and who had normal resting ECGs. Clinical data including smoking history, blood pressure, serum total cholesterol level, triglyceride level, HDL cholesterol level, and diabetes status were collected from medical records of patients. These data of control subjects were collected from regular checkup sheets.
Documentation of CAD Severity
To determine the severity of CAD, we used two systems:
Gensini's coronary artery scoring method29 and
affected vessel number. In the former scoring system, the geometrically
increasing severity of lesions, the cumulative effects of multiple
obstructions, the significance of their locations, the modifying
influence of the collaterals, and the size and quality of the distal
vessels were taken into consideration.29 In the latter
system, the severity of CAD was expressed simply by affected vessel
numbers (one-vessel, two-vessel, or three-vessel disease). A lesion at
the left main coronary artery was regarded as two-vessel
disease.
Preparation of Genomic DNA and Determination of GP Ib
Genotypes
Blood was obtained from peripheral veins after
informed consent was obtained from patients and control subjects.
Genomic DNA was isolated from leukocytes as described.30 To
genotype the first polymorphism, a 591-bp DNA fragment of
GP Ib that contains the dimorphism at nucleotide 1018
(amino acid residue 145) was amplified by PCR with the use of a DNA
thermal cycler (Perkin Elmer, Takara Biomedicals) as described
previously.25 Briefly, the reaction was performed in a
final volume of 100 µL containing 1 µg of genomic DNA, 10
mmol/L Tris (pH 8.3), 50 mmol/L KCl, 1.5
mmol/L MgCl2, 0.01% gelatin, 0.2 mmol/L
of each deoxynucleotide triphosphate, and 2.5 U of Taq
polymerase. The two oligonucleotide primers used were
5'-GGACGTCTCCTTCAACCGGC (nucleotide number 899 to 918) and
5'-GCTTTGGTGGGGAACTTGAC (1470 to 1489). After a 30-cycle PCR, each
cycle consisting of 94°C for 1 minute, 63°C for 1 minute, and
72°C for 1 minute, with a final extension at 72°C for 7 minutes,
the PCR product was digested with restriction enzyme Bbi
II (Takara Shuzo) at 37°C for 3 hours followed by a 2% agarose gel
electrophoresis. Bbi II digestion of the amplified material
from the allele containing ATG (M) at codon 145 would result in
visible DNA fragments of 387 and 201 bp, whereas PCR products from
ACG (T)–containing alleles would be cut into visible fragments of
271, 201, and 116 bp. For the second polymorphism, two
oligonucleotide primers, 5'-ACACTTCACATGGAACTCCAT
(nucleotide number 1626 to 1645) and
5'-GGGTCATTTCTGGAGCTCTC (1995 to 2014) were synthesized. PCR was
performed as described above except that 0.1 mmol/L
7-deaza-2'-deoxyguanosine-5'-triphosphate was added for 30 cycles, each
consisting of 96°C for 1 minute for denaturation, 51°C for 1 minute
for annealing, and 72°C for 1 minute for extension. The amplified DNA
fragments would be 389, 428, 467, and 506 bp if the genomic DNAs
contained alleles with one, two, three, and four tandem repeats,
respectively.
Statistics
Statistical analyses of frequency counts were performed
with the use of the 
2 test or Fisher's exact test for
small samples. Differences in the frequency of a GP Ib
genotype (T/M) between patients and control subjects were
considered to be statistically significant when the probability values
were <.05. The OR was used as a measure of the risk of CAD in patients
having the T/M genotype versus those having the T/T
genotype. Variability in sampling associated with the estimated
OR was assessed by two-sided 95% CI. An OR (95% CI) >1 was
considered significant. A logistic regression analysis was
performed to evaluate the interaction between the GP Ib
genotypes and other variables in relation to the prevalence
of CAD. Independent variables included in the analysis were
age (quantitative), sex (male or female), smoking (yes or no),
hypertension (yes or no), diabetes mellitus (yes or no),
hypercholesterolemia (yes or no), and
hypertriglyceridemia (yes or no). The
analysis was executed by the SPSS statistical program version
7.5 for Windows.
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Results |
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The 91 patients ranged in age from 41 to 74 years (60.7±8.7 years, mean±SD); there were 64 men (70.3%) and 27 women (29.7%, Table 1
). When only patients aged 60
years were analyzed (n=44, of whom there were 36 men
[81.8%]), the mean age was 53.9±6.6 years. The patient group had a
higher prevalence of selected coronary risk factors (smoking,
hypertension, diabetes mellitus, and
hypertriglyceridemia) than control
subjects. The patient group consisted of 66 MI patients and 25 angina
patients.
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Genotype frequencies of the patients and control subjects are
shown in Table 2. There was no homozygote
for M/M either in patients or the control group. The frequency of
heterozygotes (T/M) was 16.2% in the control group, which was very
comparable to the frequency reported previously.31 The
frequency of the T/M genotype was higher in the patient group
(22.0%), but the difference was not statistically significant
(P=.30; OR=1.5; 95% CI, 0.7 to 3.2). However, when only
patients aged 60 years were analyzed, the frequency of the
T/M genotype was 31.8%, which was significantly higher than
that of the control group (16.0%; P<.05; OR=2.5; 95% CI,
1.1 to 5.8).
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Association of the GP Ib genotype with CAD (standardized for
age, sex, and other coronary risk factors including smoking,
hypertension, diabetes mellitus,
hypercholesterolemia and
hypertriglyceridemia) was analyzed
among subjects aged 60 years by the use of a logistic regression
model. This model provided an OR of 5.8 (95% CI, 1.6 to 21.0;
P=.0073) for the relation between CAD and the GP Ib T/M
genotype adjusted for all other variables, suggesting that
the GP Ib genotype is an independent risk factor for
CAD.
We next analyzed the relationship between CAD and the second
polymorphism, the variable number of repeats of a 13–amino
acid sequence, which is known to be linked to the
145Thr/Met polymorphism. The frequency of each
allele in our control group was similar to that reported
previously26 (Table 3).
However, the allele frequencies for three and four repeats were
higher in our patient group than in our control group (4.8% for
patients versus 0.6% for control subjects for three repeats; 17.7%
for patients versus 5.7% for control subjects for four repeats). When
the allele distribution was compared between patients and control
subjects, the difference was statistically significant
(P=.003; Table 3). Linkage between the two GP Ib
polymorphisms was also analyzed. There was one control
subject with the T/M genotype who had alleles with one
repeat and two repeats, but all other subjects with the T/M
genotype had either a three- or four-repeat allele, a
finding compatible with previous studies.28 In addition,
there was one patient with the T/T genotype who had alleles
with one and three repeats, but all other subjects with the T/T
genotype were without three or four repeats (data not shown in
tables).
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The relationship between the GP Ib genotype and disease
status among patients aged 60 years is shown in Table 4. The frequency of the T/M
genotype was 31.2% for patients with MI and 33.3% for angina
patients (P=NS). On the other hand, we found a relationship
between the genotype and the severity of CAD. The
genotype frequency of T/M was 50.0% in patients with a G-score
40 and 11.0% for patients with a G-score <40 (P=.0015
when compared by use of a 2x3 contingency table). When CAD severity
was classified by affected vessel number, 27.8% of patients had
single-vessel disease, 30.8% had two-vessel disease, and 42.9% had
three-vessel disease (OR=2.0, 2.3, and 3.9, respectively, compared with
the control group), although the difference did not reach statistical
significance (P=.18 by use of a 2x4 contingency table).
This trend still existed even if individuals with diabetes mellitus
were excluded; 25.0% had single-vessel disease, 33.3% had two-vessel
disease, and 66.7% had three-vessel disease (OR=1.7, 2.6, and 10.3,
respectively, compared with nondiabetic subjects in the control
group).
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Discussion |
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The present study provides clear evidence that polymorphisms in the platelet GP Ib/IX receptor are associated with increased risk for the prevalence and severity of CAD. We have found an age dependency in the frequency of the T/M genotype in the patient group: 12.8% for individuals aged >60 years and 31.8% for those aged
60 years, compared with 22.0% for all ages. If only
individuals aged 50 years were analyzed, 42% of patients had
the T/M genotype compared with 17% in the control group aged
50 years (data not shown in tables). Conversely, the frequency of the
T/M genotype in our control group did not differ significantly
when compared between different age groups. Thus, although the age
distribution in our total control group was different from that in the
total patient group, it is unlikely that this affected the results.
Moreover, a logistic regression analysis revealed that T/M
genotype was an independent risk factor for CAD for those aged
60 years, even after adjustment for age, sex, and other
coronary risk factors.
The association between CAD and GP Ib was also evident when
analyzed by another polymorphism, the variable number
of tandem repeats of a 13–amino acid sequence within the
macroglycopeptide domain of GP Ib, which is closely linked to the
145Thr/Met dimorphism.28 The frequencies of the
four alleles (one to four repeats) in our control group were very
comparable to that reported previously for the general Japanese
population,26 but the distribution was significantly
different from that observed in our patient group, three or four
repeats being more frequent in patients than in control subjects
(P=.003; Table 3
)
The frequency of the T/M genotype did not differ significantly
between angina and MI patient groups. We have found, however, a strong
relationship between T/M heterozygotes and severity of CAD in patients
aged 60 years. As shown in Table 4, the frequency of the T/M
genotype in individuals aged 60 years was 50.0% for patients
with a G-score 40 and 11.0% for those with a G-score <40
(P=.0015), or 27.8% for single-vessel disease, 30.8% for
two-vessel disease, and 42.9% for three-vessel disease, although in
the latter classification, the difference did not reach statistical
significance.
Because platelets are believed to play crucial roles in
coronary thrombosis, we initially assumed that the association
of the T/M genotype was stronger with MI than with angina.
However, our results indicated that the genotype distributions
were not significantly different between the two groups (frequency of
the T/M genotype was 31.2% for MI compared with 33.3% for
angina; Table 4). Rather, the polymorphism was associated with the
angiographic severity of CAD. Although the role of platelets in the
development of CAD is still not clearly understood, one can speculate
that platelets, by adhering through the GP Ib/IX receptor to
damaged endothelium or subendothelial
tissues with subsequent release of growth factors, may participate in
coronary atherosclerosis. The molecular basis
that underlies the association of the GP Ib polymorphism and CAD
is not known. The Thr/Met dimorphism at residue 145 of GP Ib was
originally described as a molecular basis of a platelet alloantigen
system. Kuijpers et al24 and Murata et al25
showed a relationship between the presence of the
145Met-containing allele and the HPA 2b alloantigen on
platelets, and the causative role of 145Met for HPA 2b
was confirmed by the expression of a 145Met-containing GP
Ib protein in heterologous mammalian cells.25 Although
residue 145 is located in the vWF-binding domain of the GP Ib/IX
receptor, no functional difference has been reported between
platelets with and without GP Ib
145Met.14,32 However, in vitro experiments
reported thus far have been performed using
nonphysiological agonists to induce vWF–GP Ib/IX
interaction. Thus, a functional difference between the two forms of the
GP Ib/IX receptor in vivo could still be possible. It could be
speculated that the vWF binding function might differ between the
145Thr- and 145Met-containing receptors or that
GP Ib with 145Met (three or four repeats) is longer in
size and thus places the vWF-binding global domain farther away from
the platelet plasma membrane. In that case, vWF, which is a large,
multimeric molecule, would be more easily accessible to the
binding site on the receptor.
Recently, a polymorphism in GP IIb/IIIa, another platelet receptor relevant for platelet aggregation, has been shown to be associated with CAD,33 although conflicting results have also been reported.34,35 GP IIb/IIIa is the final common pathway of activation signals generated by various stimuli and is a key molecule for platelet aggregation and thus has been a recent target of antiplatelet therapy. However, because the PlA2 allele (the less frequent allele) is very rare in Japan,31 it is unlikely that this polymorphism contributed to the prevalence of CAD in the present study. On the contrary, we have provided new evidence that the other major platelet receptor, GP Ib/IX, is associated with CAD. This receptor is unique in that it mediates platelet activation specifically under high shear stress conditions that are generated in stenosed arteries or capillaries.9,10
In conclusion, we have described a new genetic risk factor for CAD. However, the results need to be confirmed in a large study of incident cases and matching control subjects. Additional basic and clinical studies will elucidate the roles of GP Ib/IX in the development of CAD and acute coronary syndromes, as well as whether antiplatelet interventions targeting the platelet receptor could be of some benefit.
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Selected Abbreviations and Acronyms |
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Received April 8, 1997; revision received July 17, 1997; accepted August 1, 1997.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Mandelkorn JB, Wolf NM, Singh S, Shechter JA, Kersh RI, Rodgers DM, Workman MB, Bentivoglio LB, Laporte SM, Meister SG. Intracoronary thrombus in nontransmural myocardial infarction and in unstable angina pectoris. Am J Cardiol. 1983;52:1–6.[Medline] [Order article via Infotrieve]
2. Sherman CT, Litvack F, Grundfest W, Lee M, Hickey A, Chaux A, Kass R, Blanche C, Matloff J, Morgenstern L, Ganz W, Swan HJC, Forrester J. Coronary angioscopy in patients with unstable angina pectoris. N Engl J Med. 1986;315:913–919.[Abstract]
3. Fitzgerald DJ, Roy L, Catella F, Fitzgerald GA. Platelet activation in unstable coronary artery disease. N Engl J Med. 1986;315:983–989.[Abstract]
4. Trip MD, Manger Cats V, van Capelle FJL, Vreeken J. Platelet hyperreactivity and prognosis in survivors of myocardial infarction. N Engl J Med. 1990;322:1549–1554.[Abstract]
5.
Thaulow E, Erikssen J, Sandvik L, Stormorken H, Cohen
PF. Blood platelet count and function are related to total and
cardiovascular death in apparently healthy men.
Circulation. 1991;84:613–617.
6. Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes. N Engl J Med. 1992;356:242–250.
7.
Goldberg ID, Stemerman MB. Vascular permeation of
platelet factor-4 after endothelial injury.
Science. 1980;209:611–612.
8. Ip JH, Fuster V, Israel D, Badimon L, Badimon J, Chesebro JH. The role of platelets, thrombin and hyperplasia in restenosis after coronary angioplasty. J Am Coll Cardiol. 1991;17:77B–88B.
9.
Peterson DM, Stathopoulos NA, Giorgio TD, Hellumus JD,
Moake JL. Shear-induced platelet aggregation requires von
Willebrand factor and platelet glycoproteins Ib
and IIb-IIIa. Blood. 1987;69:625–628.
10. Ikeda Y, Handa M, Kawano K, Kamata T, Murata M, Araki Y, Anbo H, Kawai Y, Watanabe K, Itagaki I, Sakai K, Ruggeri ZM. The role of von Willebrand factor and fibrinogen in platelet aggregation under varying shear stress. J Clin Invest. 1991;87:1234–1240.
11. Weiss HJ. Flow-related platelet deposition on subendothelium. Thromb Haemost. 1995;74:117–122.[Medline] [Order article via Infotrieve]
12.
Kroll MH, Hellums JD, McIntire LV, Schafer AI, Moak JL.
Platelets and shear stress. Blood. 1996;88:1525–1541.
13.
Roth GJ. Developing relationships: arterial
platelet adhesion, glycoprotein Ib, and leucine-rich
glycoproteins. Blood. 1991;77:5–19.
14. Lopez JA. The platelet glycoprotein Ib-IX complex. Blood Coagul Fibrinolysis. 1994;5:97–119.[Medline] [Order article via Infotrieve]
15. Ikeda Y, Handa M, Kamata T, Kawano K, Kawai Y, Watanabe K, Kawakami K, Sakai K, Fukuyama M, Itagaki I, Yoshioka A, Ruggeri ZM. Transmembrane calcium influx associated with von Willebrand factor binding to GP Ib in the initiation of shear-induced platelet aggregation. Thromb Haemost. 1993;69:496–502.[Medline] [Order article via Infotrieve]
16.
Chow TW, Hellums JD, Moake KL, Kroll MH. Shear
stress-induced von Willebrand factor binding to platelet
glycoprotein Ib initiates calcium influx associated with
aggregation. Blood. 1992;80:113–120.
17.
Kroll MH, Hellums JD, Guo Z, Durante W, Razdan K,
Hrbolich JK, Schafer AI. Protein kinase C is activated in
platelets subjected to pathological shear stress. J Biol
Chem. 1993;268:3520–3524.
18.
Nichols TC, Bellinger DA, Johnson TA, Lamb MA, Griggs
TR. von Willebrand's disease prevents occlusive thrombosis in
stenosed and injured porcine coronary arteries. Circ
Res. 1986;59:15–26.
19. Nichols TC, Bellinger DA, Reddick RL, Read MS, Koch GG, Brinkhous KM Griggs TR. Role of von Willebrand factor in arterial thrombosis. Circulation. 1991;83(suppl IV):IV-56-IV-64.
20.
Strony J, Phillips M, Brands D, Moake J, Adelman B.
Aurintricarboxylic acid in a canine model of coronary artery
thrombosis. Circulation. 1990;81:1106–1114.
21.
Yao SK, Ober JC, Garfinkel LI, Hagay Y, Ezov N,
Ferguson JJ, Anderson HV, Panet A, Gorecki M, Buja LM, Willerson JT.
Blockade of platelet membrane glycoprotein Ib receptors
delays intracoronary thrombogenesis, enhances
thrombolysis, and delays coronary artery
reocclusion in dogs. Circulation. 1994;89:2822–2828.
22.
Jansson JH, Nilsson TK, Johnson O. von
Willebrand factor in plasma: a novel risk factor for recurrent
myocardial infarction and death. Br Heart J. 1991;66:351–355.
23.
Thompson SG, Kienast J, Pyke SDM, Haverkate F, van de
Loo JCW. Hemostatic factors and the risk of myocardial infarction or
sudden death in patients with angina pectoris. N Engl J
Med. 1995;332:635–641.
24.
Kuijpers RWAM, Faber NM, Cuypers HThM, Ouwehand WH, von
dem Borne AEGKr. NH2-terminal globular domain of human
platelet glycoprotein Ib has a
methionine145/threonine145 amino acid
polymorphism, which is associated with the HPA-2 (Ko) alloantigens.
J Clin Invest. 1992;89:381–384.
25.
Murata M, Furihata K, Ishida F, Russell SR, Ware J,
Ruggeri ZM. Genetic and structural characterization of an amino acid
dimorphism in glycoprotein Ib involved in platelet
transfusion refractoriness. Blood. 1992;79:3086–3090.
26.
Moroi M, Jung SM, Yoshida N. Genetic polymorphism
of platelet glycoprotein Ib. Blood. 1984;64:622–629.
27.
Wenger RH, Kieffer AN, Wicki N, Clemetson KJ. Structure
of the human platelet membrane glycoprotein Ib gene.
Biochem Biophys Res Commun. 1988;156:389–395.[Medline]
[Order article via Infotrieve]
28.
Ishida F, Furihata K, Ishida K, Yan J, Kitano K,
Kiyosawa K, Furuta S. The largest variant of platelet
glycoprotein Ib has four tandem repeats of 13 amino
acids in the macroglycopeptide region and a genetic linkage with
methionine145. Blood. 1995;86:1356–1360.
29. Gensini GG. A more meaningful scoring system for determining the severity of coronary heart disease. Am J Cardiol. 1983;51:606.[Medline] [Order article via Infotrieve]
30. Blin N, Stafford DW. A general method for isolation of high molecular weight DNA from eukaryocytes. Nucleic Acids Res. 1976;3:2303–2308.
31. Legler TJ, Kohler M, Mayr WR, Panzer S, Ohto H, Fischer GF. Genotyping of the human platelet antigen systems 1 through 5 by multiplex polymerase chain reaction and ligation-based typing. Transfusion. 1996;36:426–431.[Medline] [Order article via Infotrieve]
32. Nurden AT. Polymorphisms of human platelet membrane glycoproteins: structure and clinical significance. Thromb Haemost. 1995;74:345–351.[Medline] [Order article via Infotrieve]
33.
Weiss EJ, Bray PF, Tayback M, Schulman SP, Kickler TS,
Becker LC, Weiss JL, Gerstenblith G, Goldschmidt-Clermont PJ. A
polymorphism of platelet glycoprotein receptor as
an inherited risk factor for coronary thrombosis.
N Engl J Med. 1996;334:1090–1094.
34.
Marian AJ, Brugada R, Kleinman NS. Platelet
glycoprotein IIIa PlA polymorphism and myocardial
infarction. N Engl J Med. 1996;335:1071–1072.
35. 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]
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 R. D. McBane II Genetically Determined Procoagulant States and Heparin Use Seminars in Cardiothoracic and Vascular Anesthesia, December 1, 2003; 7(4): 427 - 442. [Abstract] [PDF]
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H. Ulrichts, K. Vanhoorelbeke, S. Cauwenberghs, S. Vauterin, H. Kroll, S. Santoso, and H. Deckmyn Von Willebrand Factor But Not {alpha}-Thrombin Binding to Platelet Glycoprotein Ib{alpha} Is Influenced by the HPA-2 Polymorphism Arterioscler Thromb Vasc Biol, July 1, 2003; 23(7): 1302 - 1307. [Abstract] [Full Text] [PDF]
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T. J. Kunicki The Influence of Platelet Collagen Receptor Polymorphisms in Hemostasis and Thrombotic Disease Arterioscler Thromb Vasc Biol, January 1, 2002; 22(1): 14 - 20. [Abstract] [Full Text] [PDF]
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 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]
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 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]
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 J. Mikkelsson, M. Perola, A. Penttila, and P. J. Karhunen Platelet Glycoprotein Ib{alpha} HPA-2 Met/VNTR B Haplotype as a Genetic Predictor of Myocardial Infarction and Sudden Cardiac Death Circulation, August 21, 2001; 104(8): 876 - 880. [Abstract] [Full Text] [PDF]
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 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]
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M. B. Frank, A. P. Reiner, S. M. Schwartz, P. N. Kumar, R. M. Pearce, P. G. Arbogast, W. T. Longstreth Jr, F. R. Rosendaal, B. M. Psaty, and D. S. Siscovick The Kozak sequence polymorphism of platelet glycoprotein Ib{alpha} and risk of nonfatal myocardial infarction and nonfatal stroke in young women Blood, February 15, 2001; 97(4): 875 - 879. [Abstract] [Full Text] [PDF]
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 A. Sonoda, M. Murata, D. Ito, N. Tanahashi, A. Ohta, Y. Tada, E. Takeshita, T. Yoshida, I. Saito, M. Yamamoto, et al. Association Between Platelet Glycoprotein Ib{alpha} Genotype and Ischemic Cerebrovascular Disease Stroke, February 1, 2000; 31(2): 493 - 497. [Abstract] [Full Text] [PDF]
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J. S. Mruk, M. W. I. Webster, M. Heras, J. M. Reid, D. E. Grill, and J. H. Chesebro Flavone-8-Acetic Acid (Flavonoid) Profoundly Reduces Platelet-Dependent Thrombosis and Vasoconstriction After Deep Arterial Injury In Vivo Circulation, January 25, 2000; 101(3): 324 - 328. [Abstract] [Full Text] [PDF]
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C. Q. Li, S. F. Garner, J. Davies, P. A. Smethurst, M. R. Wardell, and W. H. Ouwehand Threonine-145/Methionine-145 variants of baculovirus produced recombinant ligand binding domain of GPIbalpha express HPA-2 epitopes and show equal binding of von Willebrand factor Blood, January 1, 2000; 95(1): 205 - 211. [Abstract] [Full Text] [PDF]
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 A. M. Malek, S. L. Alper, and S. Izumo Hemodynamic Shear Stress and Its Role in Atherosclerosis JAMA, December 1, 1999; 282(21): 2035 - 2042. [Abstract] [Full Text] [PDF]
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R. Gonzalez-Conejero, M. L. Lozano, J. Rivera, J. Corral, J. A. Iniesta, J. M. Moraleda, and V. Vicente Polymorphisms of Platelet Membrane Glycoprotein Ibalpha Associated With Arterial Thrombotic Disease Blood, October 15, 1998; 92(8): 2771 - 2776. [Abstract] [Full Text] [PDF]
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