|
|
 Previous Article | Table of Contents | Next Article 
Blood, 1 July 2001, Vol. 98, No. 1, pp. 36-40
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Platelet glycoprotein Ib Kozak polymorphism is
associated with an increased risk of ischemic
stroke
Ross I. Baker,
John Eikelboom,
Elizabeth Lofthouse,
Nicole Staples,
Vahid Afshar-Kharghan,
José A. López,
Yang Shen,
Michael C. Berndt, and
Graeme Hankey
From the Thrombosis and Haemophilia Service and Stroke
Unit, Royal Perth Hospital, Department of Medicine, University of
Western Australia, Perth, Australia; the Preventative Cardiology and
Therapeutics Program, McMaster University, Hamilton, Canada; the Baker
Medical Research Institute, Melbourne, Australia; and the Thrombosis
Research Section, Department of Medicine, Baylor College of Medicine,
Houston, TX.
 |
Abstract |
Platelets are pivotal to the process of arterial thrombosis
resulting in ischemic stroke. Occlusive thrombosis is initiated by the
interaction of von Willebrand factor (vWf) and platelet glycoprotein
(GP) Ib . Three polymorphisms have been described in GP Ib (Kozak
T/C polymorphism, variable number of tandem repeats [VNTR], and the
human platelet antigen 2a [HPA-2a] [Thr] or HPA-2b [Met] at
position 145), each of which may enhance the vWf and GP Ib
interaction. This study investigated whether these polymorphisms are
candidate genes for first-ever ischemic stroke. A hospital-based case-control study was conducted of 219 cases of first-ever ischemic stroke and 205 community controls randomly selected from the electoral roll and stratified by age, sex, and postal code. The subtypes of
stroke were classified, the prevalence of conventional risk factors was
recorded, and blood was collected to perform genotyping analysis for
Kozak C or T alleles, VNTR, and HPA-2a/b. It was found that the Kozak
T/C genotype was over-represented in the stroke group (32.2%) compared
with controls (22.8%) (odds ratio [OR], 1.6; 95% confidence
interval [CI], 1.03-2.54; P < .03), and the
association was still present even after adjusting for conventional
risk factors. There was a trend in the increased prevalence of HPA-2a/b
in stroke patients (15%) compared with controls (9.9%) (adjusted OR,
1.8; 95% CI, 0.94-3.4; P = .07). No associations were
seen with the VNTR polymorphism or with any of the polymorphisms with
stroke subtype. It was concluded that the Kozak T/C polymorphism, which
is associated with an increase in platelet GP Ib surface expression,
is an independent risk factor for first-ever ischemic stroke.
(Blood. 2001;98:36-40)
© 2001 by The American Society of Hematology.
| |
Introduction |
Ischemic stroke is a frequent cause of death
worldwide and remains a common cause of persistent
disability.1,2 A large number of risk factors have been
identified and prevention strategies, such as smoking cessation,
reducing elevated blood pressure, lowering cholesterol, and maintaining
good diabetic control, have been successful in reducing the disease
burden.3 However, only two thirds of all strokes can be
attributed to these modifiable risk factors.4 A family
history of stroke is also known to be a predisposing
factor,4 and other genetic variations such as platelet and
coagulation factor polymorphisms may contribute to a further proportion
of strokes.
Platelets are pivotal to the process of arterial thrombosis that leads
to ischemic stroke.5 Occlusive thrombus is almost exclusively initiated by plaque rupture and adhesion of platelets to
subendothelial von Willebrand factor (vWf) by its specific platelet
receptor, the chain of the glycoprotein (GP) Ib-IX-V complex.6,7 This interaction generates powerful signals
leading to platelet activation and further platelet recruitment that
ultimately leads to thrombus formation.8,9 Alternatively,
thrombus can also develop in partially obstructed atherosclerotic
arteries through high-shear-induced binding of fluid phase vWf to
platelet GP Ib, which again activates platelets independent of other
agonists.8,9 Platelet activation has been consistently
shown to be present in patients with acute ischemic stroke, both at the
time of stroke and subsequently in the chronic phase.10 It
is clear that ongoing platelet activation is still occurring in these
patients despite best medical management with the current antiplatelet
agents or oral anticoagulants. One possible reason is that these drugs
do not prevent shear-induced platelet activation mediated by GP Ib and vWf.7,8
The vWf and GP Ib interaction is therefore a target for
investigation in patients with ischemic stroke. Recently, 3 relatively frequent polymorphisms in GP Ib have been described in the general population,11 each of which could increase the potential
for shear-induced platelet activation by enhancing the efficiency of
the binding of vWf to GP Ib. The Kozak dimorphism detected by the
presence of either thymine (T) or cytosine (C) at position  5 from the
initiator ATG start codon, influences messenger RNA translation and the
amount of GP Ib on the platelet surface.12 The C allele
proportionally increases the amount of GP Ib expressed on the
platelet surface.12 It is plausible that increasing the density of receptor would predispose to enhanced attachment of vWf,
causing platelet activation. Two other polymorphisms affect the
structure of GP Ib. One causes a change in the length of the
polypeptide by a variation in the number of 13 amino acid tandem
repeats (VNTR) in the mucinlike macroglycopeptide
region.13-15 The length varies by multiples of either 1 (D
allele), 2 (C allele), 3 (B allele), or 4 (A allele).15,16
This polymorphism may have important implications for the function of
GP Ib, as each added repeat would position the ligand-binding region
further away from the platelet membrane surface, making it more
accessible to ligand binding and more susceptible to shear forces. The
other GP Ib polymorphism within the vWf- and thrombin-binding
leucine-rich repeat region is based on the presence of threonine or
methionine at position 145.16-18 This polymorphism is the
basis for the human platelet antigen 2 (HPA-2) (Ko) platelet
allo-antigen system.16-18 It has been shown that
methionine 145 (HPA-2b) is in linkage disequilibrium with the VNTR
alleles A and B.16,18
The Kozak polymorphism has not been examined in a large number of
patients with ischemic stroke and conflicting results have been
obtained in 4 reports regarding the importance of the VNTR and HPA-2
polymorphisms in ischemic stroke.19-22 To help clarify this issue, the present study examined the prevalence of the VNTR, HPA-2, and Kozak polymorphisms in a large number of patients with confirmed ischemic stroke classified by etiologic subtype and a similar
number of people randomly selected from the electoral roll.
| |
Patients and methods |
Selection of patients
Consecutive patients presenting to a university teaching
hospital in Western Australia between March 1996 and June 1998 with a
first-ever ischemic stroke were approached for consent to participate in our study that was approved by the Ethics Committee of Royal Perth
Hospital. Stroke was defined as a clinical syndrome characterized by
rapidly developing clinical symptoms or signs of focal and, at times,
global loss of brain function with symptoms lasting more than 24 hours
or leading to earlier death and with no apparent cause other than that
of vascular origin.23 Ischemic stroke was defined as a
stroke with either a normal computed tomography (CT) brain scan or
evidence of a recent infarct in the clinically relevant area of the
brain on a CT or magnetic resonance imaging (MRI) brain scan performed
within 3 weeks of the event or at autopsy.24 Patients with
cerebral hemorrhage or cerebral venous thrombosis were not included.
Baseline demographic data (age and sex), history of conventional
vascular risk factors (hypertension, diabetes, hyperlipidemia, and
current smoker), and history of previous vascular events (myocardial
infarction, angina, claudication, and amputation) were obtained. All
patients underwent a CT brain scan. Echocardiography and extracranial
duplex ultrasound were performed at the discretion of the clinician. An
overnight fasting blood sample was obtained for biochemical and genetic
analyses within 7 days of the acute stroke event.
On the basis of clinical evaluation and results of imaging studies, the
study neurologist (G. J. H.) (who remained blinded to the
results of GP Ib genotyping) classified all strokes into 4 major
subtypes according to the following predefined criteria.24 (1) Large-artery disease included ischemic stroke with (a)
evidence of extracranial or intracranial occlusive large artery disease (eg, Doppler or angiographic), (b) no major cardioembolic
source (atrial fibrillation, recent myocardial infarction [in the past 6 weeks], endocarditis, or prosthetic heart valve), and (c)
clinical opinion that the most likely cause of brain infarction was
atherothrombosis involving the aortic arch, carotid arteries, or major
branches (main stem middle cerebral artery), or vertebral, basilar, and posterior cerebral arteries. (2) Small-artery disease included ischemic
stroke with (a) consciousness and higher cerebral function maintained; (b) one of the classical lacunar syndromes (ie,
pure motor hemiparesis, pure hemisensory loss, pure hemisensory-motor loss, or ataxic hemiparesis) or nonlacunar small-artery clinical syndromes (eg, basilar branch artery syndromes); and (c) CT
or MRI brain scan, performed within 3 weeks of symptom onset, that was
either normal or showed a small deep infarct in the basal ganglia,
internal capsule, or brainstem. (3) Cardioembolic disease included
ischemic stroke with (a) a major cardioembolic source, (b) no definite evidence of occlusive large artery disease,
and (c) clinical opinion that the most likely cause of brain
infarction was embolism from the heart. (4) Other included ischemic
stroke that did not meet the criteria for one of the categories
outlined above (eg, periprocedural, hypoperfusion, dissection, or
procoagulant state), or when there was more than one likely explanation
(eg, concurrent large-artery occlusive disease and major cardioembolic source).
Control subjects were randomly selected from the Western
Australian electoral roll, stratified by 5-year age group, sex, and postal code. A letter of invitation to participate, together with a
stamped and self-addressed envelope, was sent to potential controls. Nonresponders were contacted by telephone. Controls who agreed to
participate in the study were given the option of attending the
hospital outpatient clinic or being visited at home by the study nurse.
Baseline demographic data (age and sex), history of conventional
vascular risk factors, and history of previous vascular events were
obtained for each control. A blood sample was obtained for genetic analysis.
DNA amplification
Genomic DNA was prepared from peripheral blood leucocytes by use
of a Triton X-100 (Merck, Melbourne, Australia) salt precipitation method.25 Polymerase chain reaction (PCR) was
performed by using a Perkin Elmer Cetus DNA thermal cycler
(Norwalk, CT). Approximately 100 ng genomic DNA was amplified using 10 µM of each primer, 1-2 U Taq polymerase (Biotech, Perth,
Australia), and 20 µM each deoxynucleotide triphosphate in buffer
containing 67 mM Tris-HCl (pH 8.8), 17 mM ammonium sulfate, 1.5 mM
magnesium chloride, 0.45% Triton X-100, and 0.2 mg/mL gelatin. The DNA
fragments were generated from a 35-cycle PCR consisting of 40 seconds
at 95°C (denaturing), 40 seconds at 60°C (annealing), and 1 minute
at 72°C (extension).
For detection of the Kozak polymorphism, the sequence of the upstream
primer was 5'-GAGAGAAGGACGGAGTCGAG-3' and that of the downstream primer
was 5'-GGTTGTGTCTTTCGGCAGG-3' as previously described.12
Samples were restriction digested using 2 U Ppu MI (New
England Biolabs, Beverly, MA) at 37°C for several hours. Digestion of
the amplified product from T/T produced 3 bands (125 base pair [bp],
157 bp, and 175 bp), from C/C 2 bands (125 and 332 bp), and from
heterozygotes C/T 4 bands (125 bp, 157 bp, 175 bp, and 332 bp).
The VNTR polymorphism was detected by using the upstream primer
5'-TCCACTGCTTCTCTAGACAG-3' and the downstream primer
5'-GGCTGATCAAGTTCAGGGAT-3'.
The HPA-2 polymorphism was detected by allele-specific hybridization,
using the common upstream primer 5'-GATGGGACGCTGCCAGTGCTG-3' with
either the downstream primer for Thr,
5'-CTTCTCCAGCTTGGGTGTGGGAG-3', or the downstream
primer for Met, 5'-CTTCTCCAGCTTGGGTGTGGGAA-3'.
All DNA fragments were subjected to electrophoresis on 2% agarose gels
and visualized under ultraviolet light after staining with
ethidium bromide.
Statistical analysis
The association of the Kozak, VNTR, and HPA-2
polymorphisms with ischemic stroke was assessed by using a logistic
regression model with patient or control as the dependent variable,
adjusting for conventional cardiovascular risk factors (smoking,
hypertension, diabetes, hyperlipidemia, and previous vascular event).
The results were expressed as the odds ratios (ORs) together with their
95% confidence intervals (CIs). Baseline differences between cases and
controls were examined by means of the unpaired Student t test for continuous variables and the chi-square test for categorical data. Differences were considered statistically significant for P values  .05.
| |
Results |
Clinical characteristics and vascular disease factor data
for our patient and control groups are analyzed in Table
1. Age and sex were similar for the 219 cases and 205 controls. As expected, cases were more likely to have had
a history of hypertension (P < .001), diabetes
(P < .001), smoking (P < .001), and
previous vascular event (P < .001).
View this table:
[in this window]
[in a new window]
|
Table 1.
Distribution of baseline demographics and conventional
cardiovascular risk factors in cases and controls
|
|
The genotypic distribution of the patients and controls are shown in
Table 2. The prevalence of the
heterozygous Kozak T/C genotype was 32.2% in patients, compared with
22.8% among the controls (P < .03; OR, 1.62; 95% CI,
1.03-2.54). There was no difference between cases and controls in the
prevalence of the VNTR and the HPA-2 polymorphisms, although there was
a trend in the prevalence of the HPA-2a/b in stroke patients (15.0%)
compared with that of controls at 9.9% (OR, 1.58; 95% CI, 0.85-2.8;
P = .14). Logistic regression was used to adjust for age,
sex, and conventional cardiovascular risk factors. The Kozak T/C
genotype was found to be an independent risk factor for stroke
(adjusted OR, 1.61; 95% CI, 1.00-2.59; P = .05). A
similar trend existed for the HPA-2a/b genotype (adjusted OR, 1.8; 95%
CI, 0.94-3.4), but it was not significant (P = .07). No
significant associations were seen with the VNTR polymorphism.
View this table:
[in this window]
[in a new window]
|
Table 2.
Distributions of Kozak, variable number of tandem repeats,
and human platelet antigen-2 mutations in cases and controls
|
|
The distribution of the glycoprotein Ib genotypes was examined
according to the subtypes of stroke as seen in Table
3. No association was seen between any of
the polymorphisms and the subtype of stroke (large artery, small
artery, cardioembolic, and other type of stroke).
| |
Discussion |
This report identifies that the Kozak GP Ib polymorphism is an
independent risk factor for ischemic stroke. The frequency (22.8%) of the T/C genotype in the predominantly Caucasian
Australian population was similar to a report of the French Caucasian
population (23.1%) and within the frequency of 15% to 30% of 4 other
different ethnic populations.12 We found that the T/C
genotype was elevated in the stroke group (32.2%) with an unadjusted
OR of 1.6 (95% CI, 1.03-2.54; P < .03). This increased
relative risk was still apparent even when conventional cardiovascular
risk factors such as hypertension, diabetes, hyperlipidemia, smoking,
and previous vascular event were adjusted with an OR of 1.6 (95% CI,
1.0-2.59; P = .05). The CC homozygotes were uncommon, and
the study was not powered to examine the role of the CC genotype alone.
There appeared to be no overrepresentation of the Kozak polymorphism with the particular subtype of stroke.
The reason why the Kozak polymorphism may be important in the
pathogenesis of ischemic stroke could be because the presence of the C
allele increases the level of GP Ib on the platelet surface.12 With the use of flow cytometry in washed
platelets, the amount of GP Ib on the surface of the platelet has
been shown to be proportional to the amount of the C allele. Although
this finding was not supported by another report,26 when
the C allele was transfected into Chinese hamster ovary cells, it
resulted in a proportional increase in surface GP Ib
expression.12 Compared with the common T/T genotype
(100%), the C/C homozygotes expressed the most (157% ± 26%) and
the T/C heterozygotes an intermediate amount (128% ± 16%) of GP
Ib.12 Because the GP Ib molecule is important for
platelet adhesion to the vessel wall and binds vWf under conditions of
high shear stress,7 it is likely that increasing the
relative density of GP Ib on the surface of the platelet
would make platelets more adhesive and possibly also to be more readily
activated by shear stress, causing thrombosis and vessel occlusion. It
may be one mechanism to explain why patients with ischemic stroke have
evidence of ongoing platelet activation that is seen even in the
chronic phase10,21,27 and is associated with poststroke
mortality.21
The strengths of our study are that we assembled an inception cohort of
more than 200 patients with ischemic stroke and a similar number of
community-based controls selected at random from the electoral roll.
The diagnosis and etiologic subtype of stroke was made by a single
experienced neurologist (G. J. H.) on predefined and accepted
objective criteria.23,24 He remained blinded to the GP
Ib results. All causes of stroke were included, particularly those
with cardioembolic stroke that can be overlooked and can confound the
results of other case-control stroke studies. Another small study of
104 patients could not find a difference in the Kozak polymorphism and
cerebrovascular disease.26 However, the recruitment was
different because the control group consisted of patients admitted to
the hospital with other undefined illnesses and a substantial number of
patients had transient ischemic attacks (30%). Patients with transient
ischemic attack were excluded from our cohort because they rarely
present to the hospital, and there is a greater degree of imprecision
in the diagnosis, diluting the focus on confirmed cases of ischemic
stroke. Also in our study, a number of other design factors were
considered that are likely to reduce bias and to diminish any
differences between cases and controls. First, the clinical
characteristics and demographics of our cohort are representative of
typical cases admitted to a large metropolitan teaching hospital (Table
1). They are mostly older than 60 years and frequently have other
coexisting and significant cardiovascular risk factors. Second,
socioeconomic status is an important cardiovascular risk factor, so we
stratified the selection of controls by postal code, which is an
established surrogate marker for socioeconomic status. Last, controls
were included in the study irrespective of whether they had a past
history of vascular disease. Even after adjustment for this bias, using
a logistic regression model, the Kozak polymorphism was still a significant independent risk factor for ischemic stroke. In addition there was no significant difference between the frequency of the T/C
polymorphism between those with (23.5%) or without (28.7%) vascular
disease. It makes any positive finding in our series more significant
and generally applicable to all patients with ischemic stroke.
Our study has several potential limitations. First, although cases were
classified prospectively and recruited consecutively and controls were
randomly selected from the community, potential confounding can never
be entirely eliminated in an observational study. Second, the small
number of cases among the etiologic subtypes of ischemic stroke may
have limited the power of our study to detect potentially important
differences in the prevalence of the GP Ib polymorphisms between
these groups.
Other gene polymorphisms of GP Ib have been described. One is the
VNTR that is in linkage disequilibrium with the HPA-2 polymorphism at
position 145.16,18 The A and B VNTR variants are
associated with methionine 145 (HPA-2b).16,18 We found a
trend toward the association between the HPA-2a/b genotype and ischemic
stroke that was more apparent when conventional risk factors were
considered (adjusted OR, 1.8; 95% CI, 0.94-3.4; P = .07).
Previous studies concerning the HPA-2 polymorphism are conflicting, but
all show a trend of increased risk with the HPA2a/b polymorphism. The
significance of the VNTR polymorphism data is also different in several
reported studies. The results are summarized in Table
4. Like the present study, one
study of 609 stroke patients found no association between the genotype
distribution of VNTR in patients and in controls.21 This
is further supported by the finding that, although the levels of plasma
markers of platelet activation (PF4 and  -thromboglobulin) were
generally elevated in the stroke group, no differences could be
demonstrated according to VNTR genotype.21 In a small
study, there was a link between the B allele and the BC genotype (OR, 2.83) for cerebrovascular disease.19 Like another
report21 the BC genotype was uncommon in our stroke
population (2.1% control versus 2.4% patient). These differences in
the apparent significance of the GP Ib polymorphisms in stroke are
therefore probably due to variations in the background genotype
frequencies of these mutations among normal populations of different
ethnic backgrounds, to different patient and control recruitment,
to variation in the inclusion criteria, or to differences in
attributable risks to other cardiovascular factors in the various
cohorts.
View this table:
[in this window]
[in a new window]
|
Table 4.
Published studies of the prevalence of the variable
number of tandem repeats B/C and human platelet antigen-2a/b
polymorphisms in ischemic stroke
|
|
We found little variation in the prevalence of the GP Ib
polymorphisms and the classification of ischemic stroke according to
large-, small-artery, and cardioembolic stroke. One recent study
suggests the HPA-2b allele may be more important in those patients with
transient ischemic attack (OR, 4.3) followed by lacunar infarction (OR,
2.2) then by atherothrombotic stroke (OR, 1.5).22 However,
in that study the distribution of type of stroke was different and the
cohort was younger when compared with our group of patients.
These differences in case demographics may account for the lack of
association in our study. It suggests that larger studies are required
to clarify the effect of the GP Ib polymorphisms in subtypes of
ischemic stroke or transient ischemic attack.
Our findings show that the Kozak GP Ib polymorphism is an
independent risk factor for ischemic stroke regardless of etiology. However, further studies are needed to define the role of the other
platelet polymorphisms and the interaction of known cardiovascular risk
factors with the GP Ib polymorphisms.
| |
Footnotes |
Submitted October 2, 2000; accepted March 1, 2001.
Supported by the National Heart Foundation of Australia and by the
Royal Perth Hospital Medical Research Foundation. J.E. is the
recipient of an Overseas Research Fellowship from the Haematology Society of Australia and New Zealand and the University of Western Australia.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
Reprints: Ross I. Baker, Thrombosis and Haemophilia Service,
Department of Haematology, Royal Perth Hospital, GPO Box X2213, Perth,
6847, Australia; e-mail: rossco{at}cyllene.uwa.edu.au.
| |
References |
1.
Murray CJL, Lopez AD.
Mortality by cause for eight regions of the world: global burden of disease study.
Lancet.
1997;349:1269-1276[CrossRef][Medline]
[Order article via Infotrieve].
2.
Murray CJL, Lopez AD.
Global mortality, disability, and the contribution of risk factors: global burden of disease study.
Lancet.
1997;349:1436-1442[CrossRef][Medline]
[Order article via Infotrieve].
3.
Hankey GJ.
Stroke. How large a public health problem, and how can the neurologist help?
Arch Neurol.
1999;56:748-754[Abstract/Free Full Text].
4.
Whisnant JP.
Modeling of risk factors for ischemic stroke. The Willis Lecture.
Stroke.
1997;28:1839-1843.
5.
Zoppo GJ.
The role of platelets in ischemic stroke.
Neurology.
1998;51:S9-14[Abstract/Free Full Text].
6.
Andrews RK, Lopez JA, Berndt MC.
Molecular mechanisms of platelet adhesion and activation.
Int J Biochem Cell Biol.
1997;29:91-105[CrossRef][Medline]
[Order article via Infotrieve].
7.
Ruggeri ZM.
Von Willebrand factor.
J Clin Invest.
1999;99:559-564[Medline]
[Order article via Infotrieve].
8.
Kroll MH, Hellums JD, McIntyre LV, et al.
Platelets and shear stress.
Blood.
1996;88:1525-1541[Free Full Text].
9.
Ruggeri ZM, Dent JA, Saldivar E.
Contribution of distinct adhesive interactions to platelet aggregation in flowing blood.
Blood.
1999;94:172-178[Abstract/Free Full Text].
10.
Grau AJ, Ruf A, Vogt A, et al.
Increased fraction of circulating activated platelets in acute and previous cerebrovascular ischemia.
Thromb Haemost.
1998;80:298-301[Medline]
[Order article via Infotrieve].
11.
López JA, Andrews RK, Afshar-Kharghan V, et al.
Bernard-Soulier syndrome.
Blood.
1998;91:4397-4418[Free Full Text].
12.
Afshar-Kharghan V, Li CQ, Khoshnevis-Asl M, et al.
Kozak sequence polymorphism of the glycoprotein (GP) 1b gene is a major determinant of the plasma membrane levels of the platelet GP 1b-IX-V complex.
Blood.
1999;94:186-191[Abstract/Free Full Text].
13.
Corral J, Gonzalez-Conejero R, Lazano ML, et al.
New alleles of the platelet glycoprotein Ib gene.
Br J Haematol.
1998;103:997-1003[CrossRef][Medline]
[Order article via Infotrieve].
14.
Moroi M, Jung SM, Yoshida N.
Genetic polymorphism of platelet glycoprotein Ib.
Blood.
1984;64:622-629[Abstract/Free Full Text].
15.
López JA, Ludwig EH, McCarthy BJ.
Polymorphism of human glycoprotein Ib results from a variable number of tandem repeats of a 13-amino acid sequence in the mucin-like macroglycopeptide region. Structure/function implications.
J Biol Chem.
1992;267:10055-10056[Abstract/Free Full Text].
16.
Ishida F, Furihata K, Ishida K, et al.
The largest variant of platelet glycoprotein Ib has four tandem repeats of 13 amino acids in the macroglycopeptide region and a genetic linkage with methionine 145.
Blood.
1995;86:1356-1360.
17.
Kaski S, Kekomaki R, Partanen J.
Systematic screening for genetic polymorphism in human platelet glycoprotein Ib.
Immunogenetics.
1996;44:170-176[CrossRef][Medline]
[Order article via Infotrieve].
18.
Simsek S, Bleeker PMM, van der Schoot CE, et al.
Association of a variable number of tandem repeats (VNTR) in glycoprotein Ib and HPA-2 alloantigens.
Thromb Haemost.
1994;72:757-760[Medline]
[Order article via Infotrieve].
19.
Gonzalez-Conejero R, Lazono ML, Rivera J, et al.
Polymorphisms of platelet membrane glycoprotein Ib associated with arterial thrombotic disease.
Blood.
1998;92:2771-2776[Abstract/Free Full Text].
20.
Carlsson LE, Greinacher A, Spitzer C, et al.
Polymorphisms of the human platelet antigens HPA-1, HPA-2, HPA-3, and HPA-5 on the platelet receptors for fibrinogen (GPIIb/IIIa), von Willebrand factor (GPIb/IX), and collagen (GPIa/IIa) are not correlated with an increased risk of stroke.
Stroke.
1997;28:1392-1395[Abstract/Free Full Text].
21.
Carter AM, Catto AJ, Bamford JM, et al.
Platelet GP IIIa PlA and GP Ib variable number tandem repeat polymorphisms and markers of platelet activation in acute stroke.
Artioscler Thromb Vasc Biol.
1998;7:1124-1131.
22.
Sonada A, Murata M, Ito D, et al.
Association between platelet glycoprotein 1b genotype and ischemic cerebrovascular disease.
Stroke.
2000;31:493-497[Abstract/Free Full Text].
23.
Hatano S.
Experience from a multicentre stroke register: a preliminary report.
Bull World Health Organ.
1976;54:541-553[Medline]
[Order article via Infotrieve].
24.
Warlow CP, Dennis MS, van Gijn J, et al.
Stroke: A Practical Guide To Management. Oxford United Kingdom: Blackwell Scientific Productions; 1996.
25.
Wang L, Hirayasu K, Ishizawa M, et al.
Purification of genomic DNA from human whole blood by isopropanol-fractionation with concentrated Nal and SDS.
Nucleic Acids Res.
1994;22:1774-1775[Free Full Text].
26.
Corral J, Lozano ML, Gonzalez-Conejero R, et al.
A common polymorphism flanking the ATG initiator codon of GP1b does not affect expression and is not a major risk factor for arterial disease.
Thromb Haemost.
2000;83:23-28[Medline]
[Order article via Infotrieve].
27.
Iwamoto T, Kubo H, Takasaki M.
Platelet activation in the cerebral circulation in different subtypes of ischemic stroke and Binswanger disease.
Stroke.
1995;26:52-56[Abstract/Free Full Text].
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
C. Kleinschnitz, S. F. De Meyer, T. Schwarz, M. Austinat, K. Vanhoorelbeke, B. Nieswandt, H. Deckmyn, and G. Stoll
Deficiency of von Willebrand factor protects mice from ischemic stroke
Blood,
April 9, 2009;
113(15):
3600 - 3603.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. M. Maguire, A. Thakkinstian, J. Sturm, C. Levi, L. Lincz, M. Parsons, S. Whyte, and J. Attia
Polymorphisms in Platelet Glycoprotein 1b{alpha} and Factor VII and Risk of Ischemic Stroke: A Meta-Analysis
Stroke,
June 1, 2008;
39(6):
1710 - 1716.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Kleinschnitz, M. Pozgajova, M. Pham, M. Bendszus, B. Nieswandt, and G. Stoll
Targeting Platelets in Acute Experimental Stroke: Impact of Glycoprotein Ib, VI, and IIb/IIIa Blockade on Infarct Size, Functional Outcome, and Intracranial Bleeding
Circulation,
May 1, 2007;
115(17):
2323 - 2330.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. P. Casas, A. D. Hingorani, L. E. Bautista, and P. Sharma
Meta-analysis of Genetic Studies in Ischemic Stroke: Thirty-two Genes Involving Approximately 18 000 Cases and 58 000 Controls
Arch Neurol,
November 1, 2004;
61(11):
1652 - 1661.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
J. F. Meschia
Addressing the Heterogeneity of the Ischemic Stroke Phenotype in Human Genetics Research
Stroke,
December 1, 2002;
33(12):
2770 - 2774.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
Top
Abstract
Introduction