Genetic Variants of Platelet Glycoprotein Receptors and
Risk of Stroke in Young Women
Alexander P. Reiner, MD; Prasanna N. Kumar, MD; Stephen M. Schwartz, PhD;
W.T. Longstreth, Jr, MD, MPH; Rachel M. Pearce, MS; Frits R. Rosendaal, MD;
Bruce M. Psaty, MD, PhD; David S. Siscovick, MD, MPH
Background and Purpose—A number of studies have examined the relationship between genetic platelet glycoprotein variants and early-onset atherothrombotic disease, particularly acute myocardial infarction. Data on the association of these genetic susceptibility markers with ischemic stroke are more limited, and their role in hemorrhagic stroke has not been previously examined.
Methods—We performed genotype analysis for 5 cornmon diallelic platelet glycoprotein polymorphisms in a population-based study of 78 white women aged <45 years with arterial stroke (36 ischemic cases and 42 hemorrhagic cases) and 346 demographically similar control subjects.
Results—The 807T variant of glycoprotein la was associated with a 2-fold increased risk of ischemic stroke (age-adjusted odds ratio [OR]=2.24; 95% CI=0.99 to 5.06). The Met145 allele of glycoprotein Iba was associated with a trend toward an increased risk of ischemic stroke that was more pronounced in the homozygous state (OR= 10.36), but the CI is extremely wide because of the small numbers of subjects (95% CI= 1.43 to 79.34). Homozygosity for the Ser843 allele of the glycoprotein Ilb was associated with an ^5-fold increased risk of ischemic stroke among subgroups of women who carried a diagnosis of hypertension or diabetes (OR=4.51; 95% CI=1.01 to 20.13) or had elevated plasma homocysteine levels (OR=5.94; 95% CI=1.53 to 23.05). The genotype distributions for all 5 platelet glycoprotein polymorphisms were similar among hemorrhagic stroke cases and controls.
Conclusions—Several inherited platelet glycoprotein variants may be associated with an increased risk of ischemic stroke in young women. These associations seemed to be confined to women with other cardiovascular risk factors. Additional studies involving larger numbers of subjects are needed to confirm these preliminary findings. (Stroke. 2000;31:1628-1633.)
Key Words: platelets · polymorphism · stroke, hemorrhagic · stroke, ischemic
P
latelet thrombosis is mediated by several platelet mem-brane receptor complexes, including glycoprotein Ib/IX, glycoprotein la/IIa, and glycoprotein Ilb/IIIa (Table 1). Sev-eral genetic platelet glycoprotein variants have been associ-ated with an increased risk of early-onset atherothrombotic disease, particularly acute myocardial infarction.1 The poten-tial contributions of these genetic platelet glycoprotein vari-ants to the occurrence of ischemic stroke have been examined in a smaller number of studies. The Pro33 variant of platelet glycoprotein lila and the Met'45/VNTR-B allele of glycopro-tein Iba have been associated with ischemic stroke in some studies, but not in others.2~8 Two other common platelet glycoprotein dimorphisms, glycoprotein Ilb Ile/Ser843 and glycoprotein la Glu/Lys505, were not associated with ischemic stroke in a single study,7 but the Ile843 variant of glycoprotein Ilb was recently associated with increased mortalityfollow-ing ischemic stroke in an elderly patient population.9 A nucleotide 807T variant of glycoprotein la that correlates with increased platelet surface levels of glycoprotein la/IIa (the platelet collagen receptor)10 was recently associated with an increased risk of ischemic stroke with onset at a young age.11
The inconsistent results of studies examining the risk of stroke associated with genetic platelet glycoprotein variants may be partly due to differences in demographic character-istics between study populations. For example, genetic pro-thrombotic factors may be more important in younger indi-viduals or premenopausal women'2·13 who are less likely to have advanced atherosclerotic disease. Furthermore, the ef-fect of single genetic factors on the risk of stroke may be weak when analyzed individually but may be more pro-nounced in the presence of other common genetic or
envi-Received February 21, 2000; final revision received April 18, 2000; accepted April 18, 2000.
From the Departments of Medicine (A.P.R, B.M.P., D.S.S.), Epidemiology (S.M.S, W.T.L., B.M.P., D.S.S.), Neurology (W.T.L.), and Cardiovascular Health Research Unit (A.P.R., S.M.S, R.M.P., B.M.P., D.S.S.), University of Washington, Seattle; Department of Pathology, PSG Institute of Medical Sciences and Research, Tamilnadu, India (P.N.K.); Fred Hutchinson Cancer Research Center, Seattle, Wash (S.M.S); and the Hemostasis and Thrombosis Research Center and Department of Clinical Epidemiology, University Hospital Leiden (Netherlands) (F.R.R.).
Correspondence to Alexander P. Reiner, MD, University of Washington, Box 359756, Seattle, WA 98195-9756. E-mail apreiner@u.washington.edu © 2000 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org
TABLE 1. Platelet Glycoprotein Receptor Polymorphisms Implicated in Atherothrombotic Disease Platelet Receptor Glycoprotein Ib/IX Glycoprotein la/lla Glycoprotein llb/llla Major Ligand(s) vWF Collagen Fibrinogen, vWF Function Initial platelet adhesion
Stahle platelet adhesion Stahle platelet adhesion; platelet cohesion
Polymorphisms Glycoprotein Iba Thr/Met145
Glycoprotein Iba VNTR Glycoprotein la C807T Glycoprotein llb Ile/Ser843
Glycoprotein lila Leu/Pro33
vWF indicates von Willebrand factor; VNTR, variable number of tandem repeats.
ronmental cardiovascular risk factors (eg, hypertension, smoking, obesity). We therefore assessed the association of 5 common platelet glycoprotein polymorphisms with stroke in young women (aged <45 years) and examined potential interactions between these genetic variants and other tradi-tional cardiovascular risk factors.
Subjects and Methode
This analysis is based on data and genetic material collected in a population-based case-control study of incident nonfatal stroke in young women.14·13 The study population consisted of women aged
18 to 44 years residing in 3 contiguous counties in western Washington State between July l, 1991, and February 28, 1995. All subjects gave informed consent according to a protocol approved by the University of Washington and participating local hospitals. Stroke was defined äs evidence of new focal neurological deficit(s) with no other apparent cause (ie, brain tumor, infection, subdural hematoma, seizure, or other neurological condition) lasting >24 hours. On the basis of review of hospital records, brain imaging studies, and lumbar puncture results, strokes were further classifled by the study neurologist (W.T.L.) äs ischemic, hemorrhagic, venous, or "other" (including arterial dissections). Random-digit telephone dialing was used to identify female control subjects, who were frequency matched to the age distribution of the cases.
One hundred forty-nine of 198 eligible patients with nonfatal stroke and 525 of 684 eligible control subjects were willing to participate ih an in-person interview. The interview involved ascer-tainment of demographic characteristics and histories of traditional cardiovascular risk factors, including hypertension, diabetes, ciga-rette smoking, hypercholesterolemia, height, weight, contraceptive practices, menstrual Status, and frequency of vigorous exercise. All interview questions elicited Information about the time period before each subject's reference date, which was the date of stroke for cases and a date assigned at random from among the potential stroke occurrence dates for controls. A woman was classified äs hyperten-sive, diabetic, or hypercholesterolemic if she reported ever receiving the diagnosis by a physician. Smokers were defined äs subjects who reported smoking both currently (within a month of the reference date) and regularly (a5 cigarettes per week for 2:6 consecutive months). Obesity was defined äs a body mass index £:27.3 kg/m . Physical inactivity was defined äs exercising vigorously <1 time per week. Hyperhomocysteinemia was defined äs a serum homocysteine level >12.6 μηιοΙ/L.
At the time of interview, venous blood samples were collected into EDTA-treated evacuated tubes from 106 participating stroke cases (54 hemorrhagic, 41 ischemic, 2 venous, and 9 "other") and from 391 participating control subjects. Plasma and genomic DNA samples were prepared äs described previously.14·15 Genotyping for 5 platelet
glyco-protein polymorphisms (glycoglyco-protein lila Leu/Pro33, glycoprotein llb
Ile/Ser843, glycoprotein Iba Thr/Met145, glycoprotein la Glu/Lys505, and
glycoprotein la C807T) was performed by polymerase chain reaction amplification of genomic DNA followed by restriction enzyme digestion (polymerase chain reaction-restriction fragment length polymorphism), according to previously published methods.16-18
In a previous analysis of the overall study sample, we determined that there was a significantly greater proportion of black women among the hemorrhagic stroke cases (11.8%) and ischemic stroke cases (11.7%) man among the control subjects (2.5%).14 Since the distnbution of
platelet glycoprotein alleles differs according to race, white and black subjects must be analyzed separately. However, because of the inade-quate number of black women in the control group, we restricted the companson of platelet glycoprotein genotypes to the subset of study subjects with DNA samples who were white (36 ischemic stroke cases, 42 hemorrhagic stroke cases, and 346 controls).
Platelet glycoprotein allele frequencies were calculated by gene counting. The association of platelet glycoprotein genotypes with stroke was examined by unconditional logistic regression adjusted for age and was expressed äs odds ratios (ORs) and 95% CIs. Unless otherwise noted, ORs for the 5 biallelic platelet glycoprotein polymorphisms were calculated comparing individuals who were either heterozygous or homozygous for the less common allele with individuals who were homozygous for the more common allele. We also assessed the extent to which associations with platelet glycoprotein polymorphisms were mod-ified by other cardiovascular risk factors, including smoking, obesity, hypertension, diabetes, and hyperhomocysteinemia, through analyses stratified on these cardiovascular risk factors.
Results
A comparison of the characteristics of stroke cases and control subjects among the subset of white women with DNA samples is presented in Table 2. The frequencies of various cardiovascular risk factors among ischemic stroke cases, hemorrhagic stroke cases, and control subjects were similar to those previously reported in an analysis based on a larger sample size from this study population.14 Current cigarette
smoking, hypertension, and physical inactivity were more common in both ischemic stroke cases and hemorrhagic stroke cases than control subjects. Higher plasma levels of total homocysteine were also noted in both the ischemic and hemorrhagic stroke patients compared with control subjects. In contrast, higher frequencies of obesity and diabetes were confined to the ischemic stroke cases.
The genotype distributions of the 5 platelet glycoprotein polymorphisms among the ischemic stroke cases and control subjects are compared in Table 3. A trend toward an associ-ation with risk of ischemic stroke was observed for the glycoprotein la C807T, glycoprotein Iba Thr/Met145, and
glycoprotein llb Ile/Ser843 polymorphisms, but none of these
1630 Stroke July 2000
TABLE 2. Characteristics of Stroke Patients and Control Subjects
Age, y Mean Mediän Range Premenopausal, %
Current oral contraceptive use, % Current smokers, % Obesity, % Hypertension, % Diabetes, % Hypercholesterolemia, % Hyperhomocystememia, % Physical inactivity, % Ischemic Stroke Gases (n =36) 37.6 39.0 21-44 91.7 11.4 33.3 47.1 33.3 22.2 8.3 37.1 77.8 Hemorrhagic Stroke Cases (n=42) 36.0 37.0 18-44 88.1 11.9 47.6 23.8 23.8 4.8 16.7 39.0 59.5 Control Subjects (n =346) 37.8 39.0 19-44 96.0 11.0 20.8 26.5 9.0 3.2 16.3 25.2 49.4
associated with the 807T allele was highest in the subgroup of women (16 cases and 91 controls) who were obese (OR=3.24; 95% CI=0.86 to 12.18) and in the subgroup of women (13 cases and 86 controls) who had elevated plasma homocysteine levels (OR=4.03; 95% CI=0.83 to 19.67).
The presence of > l copy of the Met145 allele of
glycopro-tein Iba was associated with a more modestly increased risk of ischemic stroke (OR=1.48; 95% CI=0.64 to 3.41). The risk associated with the Met145 allele of glycoprotein Iba was
highest in the subgroup of women (15 cases and 40 controls) who carried a diagnosis of either hypertension or diabetes (OR=3.86; 95% CI=0.98 to 15.17). In the overall study population, the increased risk associated with the Met145
variant was primarily due to an overrepresentation of the
Met/Met145 genotype among the ischemic stroke cases (5.6%)
compared with the controls (0.6%). This results in a large point estimate for the risk of ischemic stroke associated with Met145 homozygosity (age-adjusted OR= 10.63), but the CI is
extremely wide (95% CI=1.43 to 79.34) because of the relatively low frequency of this genotype.
Homozygosity for the Ser843 allele of glycoprotein Ilb was
also more prevalent in ischemic stroke cases (22.2%) than controls (14.4%) (OR=1.69; 95% CI=0.73 to 3.92). The risk of ischemic stroke associated with carrying 2 copies of the Ser843 allele was particularly high in the subgroup of women
with hypertension or diabetes (OR=4.51; 95% CI=1.01 to 20.13) and in the subgroup of women with elevated plasma homocysteine levels (OR=5.94; 95% CI=1.53 to 23.05). By TABLE 3. Platelet Glycoprotein Allele Frequencies and Genotypes in Ischemic Stroke Cases and Controls
Allele Frequency Polymorphism Glycoprotein Ilb Ile/Ser843 Glycoprotein lila Leu/Pro33 Glycoprotein la Glu/Lys505 Glycoprotein la C807T Glycoprotein Ib« Thr/Met145 Allele He843 Ser343 Leu33 Pro33 Glu505 Lys505 807C 807T Ihr145 Met145 Cases 0.569 0.431 0.833 0.167 0.917 0.083 0.514 0.486 0.861 0.139 Controls 0.630 0.370 0.838 0.162 0.909 0.091 0.627 0.373 0.916 0.084 Genotype Ile843/lle843 Ile^/Ser843 Ser^/Ser843 Leu33/Leu33 Leu33/Pro33 Pro33/Pro33 Glu505/Glu505 Glu505/Lys505 Lys505/Lys505 807(C/C) 807(OT) 807(T/T) Thr"VThr'45 Thr'45/Met145 Met'45/Met145 Genotype Frequency No. of Cases (%) 13(36.1) 15(41.7) 8 (22.2) 25 (69.4) 10(27.8) 1 (2.8) 30 (83.3) 6(16.7) 0 (0.0) 8 (22.2) 21 (58.3) 7(19.4) 28 (77.8) 6(16.7) 2 (5.6) No. of Controls (%) 140(40.5) 156(45.1) 50(14.4) 241 (69.7) 98 (28.3) 7 (2.0) 286 (82.7) 57(16.4) 3 (0.9) 135(39.0) 164(47.4) 47(13.6) 290 (83.8) 54(15.6) 2 (0.6) OR* (95% CI) 1.20(0.59-245) 1 01 (0.48-2.13) 0.96(0.38-2.41) 2.24 (0.99-5.06) 1.48(0.64-3.41)
TABLE 4. Platelet Glycoprotein Allele Frequencies and Genotypes in Hemorrhagic Stroke Gases and Controls
Allele Frequency Polymorphism Glycoprotein llb Ile/Ser843 Glycoprotein lila Leu/Pro33 Glycoprotein la Glu/Lys505 Glycoprotein la C807T Glycoprotein Iba Thr/Met145 Allele He843 Ser843 Leu33 Pro33 Glu505 Lys505 807C 807T Thr145 Met145 Cases 0631 0.369 0833 0.167 0.905 0.095 0619 0.381 0.905 0.095 Controls 0.630 0.370 0.838 0.162 0909 0091 0.627 0.373 0.916 0.084 Genotype Ile843/lle843 ||g843/Ser843 Ser^/Ser843 Leu33/Leu33 Leu33/Pro33 Pro33/Pro33 Glu505/Glu505 Glu505/Lys505 Lys505/Lys505 807(C/C) 807(CAT) 807(T/T) Thrl45AThr145 Thr"5/Met145 Met145/Met145 Genotype No. of Cases (%) 16(38.1) 21 (50.0) 5(11.9) 28 (66.7) 14(33.3) 0 (0.0) 34 (81 .0) 8(19.0) 0 (0.0) 15(35.7) 22 (52.4) 5(11.9) 34 (81 0) 8(19.1) 0 (0.0) Frequency No. of Controls (%) 140(40.5) 156(45.1) 50(14.4) 241 (69.7) 98 (28.3) 7 (2.0) 286 (82.7) 57(16.4) 3 (0.9) 135(39.0) 164(47.4) 47(13.6) 290 (83.8) 54(15.6) 2 (0.6) OR* (95% Cl) 1 13(0.58-2.20) 1.01 (0.55-2.19) 1.08(0.47-2.47) 1.23(0.63-2.43) 1.24(0.54-2.85)
*ORs are adjusted for age and calculated comparing carners of 1 or 2 copies of the less common allele (eg, carners of glycoprotein llb Ser843) to mdividuals who are homozygous for the more common allele (eg, carners of glycoprotein llb Ile843/lle843 genotype).
contrast, the risk associated with homozygosity for the glycoprotein llb Ser843 allele was not increased in women
without hypertension or diabetes (OR=0.94; 95% CI=0.27 to 3.33) or in women with normal plasma homocysteine levels (OR=0.83; 95% CI=0.23 to 2.94).
The genotype distributions of the 5 platelet glycoprotein polymorphisms in hemorrhagic stroke cases and control subjects are compared in Table 4. The genotype distributions were similar between hemorrhagic stroke cases and controls, either overall or in the presence or absence of other cardio-vascular risk factors (data not shown).
Discussion
Our results suggest possible associations between 3 platelet glycoprotein polymorphisms, glycoprotein la C807T, glyco-protein llb Ile/Ser843, and glycoprotein Iba Thr/Met145, and
risk of ischemic stroke in young women. Although the observed associations were modest, and the study was limited by small numbers of stroke cases, 2 features of the study suggest that these preliminary results may represent authentic associations. First, there was evidence that the risk of ische-mic stroke associated with these genetic platelet glycoprotein variants was highest in subgroups of women with other known cardiovascular risk factors. These results are consis-tent with previous studies that indicate the importance of genetic prothrombotic factors in combination with other cardiovascular risk factors in the occurrence of atherothrom-botic diseases such äs myocardial infarction in young adults.19-21 Second, we did not observe an association
be-tween any of the platelet glycoprotein polymorphisms and risk of hemorrhagic stroke, a disorder that does not involve platelet-dependent thromboembolism.
Glycoprotein la/IIa is the major platelet collagen receptor and is responsible for platelet adherence to exposed vascular subendothelium. The 807T allele of glycoprotein la was recently associated with a statistically significant 3-fold increased risk of stroke in men and women aged <50 years but was not associated with stroke in patients aged >50 years." Our results in young women indicate an «=2-fold increased risk of ischemic stroke associated with the 807T variant that was highest in women who were either obese or had elevated plasma homocysteine levels. An increased risk of myocardial infarction associated with the glycoprotein la 807T allele similarly has been reported in young obese men.22
The platelet glycoprotein Ib/IX complex is the major platelet receptor for von Willebrand factor and is responsible for initial platelet adhesion and activation following exposure to vascular subendothelium under high shear rates. Gonzalez-Conejero et al4 and Sonoda et al5 each reported a 2- to 3-fold
increased risk of ischemic stroke or transient ischemic attack in men and women who possessed >1 copy of the Met145
allele. Our results indicate a trend toward an increased risk of ischemic stroke associated with the presence of >1 copy of the Met145 allele in young women, particularly in the
sub-group of women who were hypertensive or diabetic. More-over, women who possessed 2 copies of the glycoprotein Iba Met145 allele had an «=10-fold increased risk of ischemic
stroke, although this estimate of effect was statistically unstable because of the small sample size and relatively low frequency of the Met145 variant.
The bridging of adjacent platelets through the glycoprotein Ilb/IIIa receptor is important for thrombus formation, and glycoprotein Ilb/IIIa inhibitors are used increasingly in the treatment of atherothrombotic disease. Carter et al2 reported
glycopro-1632 Stroke July 2000
tein lila and risk of atherothrombotic stroke only in the subgroup of patients aged <50 years. Wagner et al3 reported a trend toward an association between the Pro33 variant of platelet glycoprotein lila and cerebral infarction in women aged <45 years when the analysis was restricted to whites. In contrast, we found no association between the glycoprotein lila Pro33 variant and risk of ischemic stroke in our population of young white women. Our negative findings are consistent with the results of 2 other case-control studies,6·7 äs well äs a prospective study of male physicians.8
The platelet glycoprotein Ilb/IIIa receptor contains another prevalent polymorphism, glycoprotein üb Ile/Ser843. Two studies have not observed an association between the Ile/ Ser843 polymorphism of glycoprotein Ilb and risk of cerebro-vascular disease in older patient populations.7·9 Our results suggest a trend toward an association with increased risk of ischemic stroke in young women who are homozygous for the Ser843 variant. The risk associated with the glycoprotein Ilb Ser/Ser843 genotype was most pronounced in women with hypertension or diabetes (OR=4.51; 95% CI=1.01 to 20.13) and in women with elevated plasma homocysteine levels (OR=5.94; 95% CI=1.53 to 23.05). Although the CIs were wide around these point estimates, they did not overlap 1.0. A recent preliminary report indicated that platelets containing the glycoprotein Ilb Ser843 allele demonstrate increased in vitro platelet aggregation and clot retraction compared with those lacking the Ser843 allele23 and thus provides a possible explanation for the association between the Ser843 variant and risk of atherothrombotic disease.
Our findings are in contrast with another recent study that noted an association between the more common Ile843 variant of glycoprotein Ilb and increased risk of poststroke mortality in an older patient population.9 Since our study analyzed only women who survived their acute event, it is possible that the women who died acutely had an overrepresentation of the Ile841 variant. Given the possible increased in vitro thrombo-genicity of the Ser843 variant,23 one may speculate that the less adhesive Ile843 allele is associated with a increased tendency toward embolization of a preexisting platelet thrombus; this might account for increased mortality following the acute atherothrombotic event.9
Several limitations of our study should be noted. First, the relatively small number of cases and the performance of multiple subgroup analyses may increase the likelihood of a spurious association (type I statistical error). In this regard, some polymorphisms that have been associated with stroke or myocardial infarction in smaller studies have not been verified in larger, prospective studies.1·8 Second, the small number of cases decreases the likelihood of detecting weak associations (type II error). Third, blood samples for DNA analysis were collected at the time of subject interview; thus, äs noted above, our study includes only women who survived an acute stroke. Therefore, if a particular platelet glycoprotein allele was associated with increased morbidity or early mortality, the effect could be underestimated because of exclusion of women who died acutely or were severely disabled. Fourth, our results apply to white, premenopausal women with acute stroke and may not be generalized to other demographic and ethnic groups.
Thus, confirmation of the role of genetic platelet glyco-protein variants äs risk factors for early-onset ischemic stroke requires further study involving larger numbers of subjects and other populations.
Acknowledgments
This study was supported by a contract from the National Institute for Child Health and Human Development (NO1-HD-3107) and a grant from the Boeing Company. The authors thank Fran Chard, Karen Graham, Carol Handley-Dahl, Judy Kaiser, Marlene Bengeult, Carol Ostergard, Denise Koriander, Barb Twaddell, Sandy Tronsdal, and Jill Ashman for assistance with the study, and Kaelen Aramaki and Benjamin Siscovick for providing excellent technical assistance.
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