This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Carter, A. M. Articles by Grant, P. J. Search for Related Content PubMed PubMed Citation Articles by Carter, A. M. Articles by Grant, P. J. Related Collections Acute Stroke Syndromes Genetics of Stroke Risk Factors for Stroke

(Stroke. 1999;30:2606.)
© 1999 American Heart Association, Inc.

Original Contributions

Association of the Platelet Glycoprotein IIb HPA-3 Polymorphism With Survival After Acute Ischemic Stroke

Angela M. Carter, PhD; Andrew J. Catto, MRCP; John M. Bamford, MD Peter J. Grant, MD

From the Unit of Molecular Vascular Medicine, Research School of Medicine, University of Leeds, Leeds General Infirmary, and Department of Neurology, St. James’ University Hospital (J.M.B.), Leeds, UK.

Correspondence to Peter J. Grant, Unit of Molecular Vascular Medicine, Research School of Medicine, G Floor, Martin Wing, Leeds General Infirmary, Leeds, LS1 3EX, UK.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose—The role of polymorphisms of the platelet glycoprotein (GP) IIb/IIIa receptor in the development of cardiovascular disease has been the subject of intensive research. The aim of this study was to determine the association of the HPA-3 polymorphism of platelet GPIIb with ischemic stroke and subsequent survival and to identify possible interactions of HPA-3 with classic risk factors.

Methods—HPA-3 genotype was determined by restriction fragment length polymorphism in 515 patients with ischemic stroke and 423 healthy, age-matched control subjects.

Results—There was no significant difference in the genotype distribution of patients and controls, nor was there any difference when patients were subclassified into small- and large-vessel disease. The genotype distribution of the 231 patients subsequently dying during 2.8 years of follow-up (aa=45.0%, ab=46.8%, bb=8.2%) was significantly different from that of those still alive (aa=37.0%, ab=48.2%, bb=14.8%) (P=0.03). In a Cox regression model, the relative risks for poststroke mortality in patients of aa and ab genotype compared with those of bb genotype were 2.42 (95% CI, 1.24 to 4.71) and 2.13 (95% CI, 1.09 to 4.17), respectively, after we accounted for confounding factors. In addition, significant interactions of HPA-3 with the Pl^A polymorphism of GPIIIa (P=0.002) and with fibrinogen (P=0.01) were identified in relation to mortality.

Conclusions—HPA-3 is related to poststroke mortality, and the significant interaction of HPA-3 with Pl^A and fibrinogen suggests that it may in some way influence the interaction of GPIIb/IIIa with fibrinogen, particularly in the presence of high fibrinogen.

Key Words: mortality • platelet glycoprotein GPIIb/IIIa complex • polymorphism (genetics) • stroke, ischemic

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Enhanced platelet activation has been found in subjects with myocardial infarction (MI)^{1 2} and stroke.^{3 4 5} Platelet activation results in a conformational change in the glycoprotein (GP) IIb/IIIa receptors on the platelet surface, which facilitates binding of soluble fibrinogen and platelet aggregation.⁶ GPIIb/IIIa (_IIbß₃) is a member of the integrin family of cell adhesion molecules,⁷ and its importance in the pathogenesis of cardiovascular disease has been highlighted by the clinical use of anti-GPIIb/IIIa agents.⁸ The genes encoding the platelet IIb and IIIa glycoproteins are located on chromosome 17, lying within a 260-kb fragment in the region 17q21 to 22 with GPIIb 3' to GPIIIa,⁹ and polymorphisms of the genes encoding GPIIb/IIIa have been described.¹⁰

The report of Bray et al¹¹ describing the increased incidence of the A2 allele of the platelet glycoprotein IIIa Pl^A polymorphism in subjects with coronary thrombosis has led to an increased interest in the potential role of polymorphisms of platelet glycoprotein receptors in relation to the development of cardiovascular disease.^{12 13 14} HPA-3 (Bak^a/Bak^b) is a common polymorphism of platelet GPIIb that, like the Pl^A polymorphism, gives rise to posttransfusion purpura and neonatal alloimmune thrombocytopenic purpura.¹⁵ HPA-3 results from a T to G base change coding for an isoleucine to serine amino acid substitution at position 843 of the GPIIb heavy chain.¹⁵ This polymorphism lies adjacent to the binding region of the PMI-1 antibody, which has been shown to inhibit platelet-collagen interactions.¹⁶

The aim of this study was to determine the genotype distribution of HPA-3 in subjects with ischemic stroke and healthy, age-matched control subjects and to determine its association with (1) the GPIIIa Pl^A polymorphism; (2) levels of fibrinogen and ß-thromboglobulin (ß-TG); and (3) stroke, stroke subtype, and poststroke mortality.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The recruitment and characteristics of patients and control subjects have been fully described elsewhere.¹⁷ Briefly, 515 patients with acute ischemic stroke, confirmed by noncontrast cranial CT scan, were recruited within 10 days of the event and subclassified into subjects with probable small- and large-vessel disease, as previously described.¹⁷ Four hundred twenty-three healthy, age-matched control subjects were recruited from local Family Health Services Authority general practice registers. All patients were registered with the Office of National Statistics for notification of death. Mortality data available until the end of March 1998 are presented in this study. All subjects gave informed consent according to a protocol approved by the United Leeds Teaching Hospitals National Health Service Trust Ethics Committee.

HPA-3 genotype was determined by polymerase chain reaction amplification of a 253-bp product with the use of specific oligonucleotide primers, as described by Unkelbach et al,¹⁸ with subsequent digestion with 4 U of FokI for 2 hours at 37°C followed by 2% agarose gel electrophoresis. The presence of Ile at position 843 resulted in cleavage of the 253-bp fragment into fragments of 126 and 127 bp, whereas the presence of Ser was characterized by the uncleaved 253-bp fragment. A number of samples were sequenced to ensure the accuracy of genotyping by this method. Genotypes were classified as aa (Ile, Ile), ab (Ile, Ser), and bb (Ser, Ser). Pl^A genotype and levels of ß-TG and fibrinogen were determined as previously described.^{17 19}

Categorical variables were compared by ² test. The degree of linkage disequilibrium between the HPA-3 and Pl^A polymorphisms was estimated with a method described by Weir and Cockerham²⁰ based on a maximum likelihood iteration described by Hill²¹ to overcome the difficulty of estimating the haplotype distribution of those subjects heterozygous at both loci. Genotype differences in survival were assessed by the Kaplan-Meier log rank statistic. The association of genotype with survival after acute stroke, with classic risk factors taken into account, was assessed by Cox regression analysis; results are presented as relative risk (RR) with 95% CIs. Interaction terms were created in the Cox regression models to assess possible gene-environment and gene-gene interactions. All statistical analyses were performed with the use of the SPSS statistics package version 7.0 (SPSS Inc).

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The characteristics of the patients and control subjects are presented in Table 1. There was a greater proportion of men, hypertensives, smokers, and subjects with atrial fibrillation and diabetes in the patient group compared with the controls. In addition, the patients had higher levels of fibrinogen and ß-TG compared with the control subjects, as previously described.^{17 19} There was no significant difference in the GPIIIa Pl^A genotype distributions between patients and controls.¹⁷

View this table: [in this window] [in a new window]   Table 1. Characteristics of Patients With Acute Ischemic Stroke and Healthy Control Subjects

The genotype distributions of patients with ischemic stroke and healthy control subjects did not differ significantly from Hardy-Weinberg equilibrium. The HPA-3 polymorphism was not in linkage disequilibrium with the Pl^A polymorphism (D'=8%; P=0.2).

There was no significant difference in the HPA-3 genotype distributions of patients (aa=40.7%, ab=47.5%, bb=11.8%) and healthy control subjects (aa=44.2%, ab=43.3%, bb=12.5%). In addition, there was no significant difference in the genotype distributions of patients with small-vessel disease (aa=36.1%, ab=53.3%, bb=10.7%) compared with those with large-vessel disease (aa=41.4%, ab=46.0%, bb=12.6%). There was no significant association of HPA-3 genotype with levels of fibrinogen or ß-TG in either the patients or the healthy control subjects (data not shown), nor was there any significant association of HPA-3 with any other factor presented in Table 1 in either group (data not shown). In addition, there was no difference in the association of HPA-3 with survival when subjects were classified into those taking aspirin or warfarin compared with those not taking these medications (data not shown).

A total of 231 deaths had been notified by March 31, 1998, representing a median follow-up of 2.8 (95% CI, 0.7 to 4.0) years. Of these, 151 (65%) were due to the acute stroke event, subsequent stroke, or stroke-related complications; 41 (18%) were due to ischemic heart disease (IHD); and 39 (17%) were due to other causes, as stated on the death certificate. The characteristics of patients surviving and those dying are presented in Table 2. Those dying were significantly older than those still alive, with a greater incidence of atrial fibrillation, previous stroke, and previous MI, a lower incidence of smoking, and elevated levels of fibrinogen and ß-TG.

View this table: [in this window] [in a new window]   Table 2. Characteristics of Patients With Acute Stroke Subsequently Dying and Those Remaining Alive Until March 30, 1998

By ² analysis, there was a significant difference in the genotype distributions of those still alive (n=284; aa=37.0%, ab=48.2%, bb=14.8%) compared with those who had died (n=231; aa=45.0%, ab=46.8%, bb=8.2%) (P=0.03). Further analyses confirmed that HPA-3 genotype was significantly associated (P=0.006) with survival after ischemic stroke, with poorer survival in those of aa and ab genotypes compared with those homozygous for the b allele, as indicated in the Kaplan-Meier survival curves presented in Figure 1. When patients who had died were classified by cause of death, only the HPA-3 genotype distributions of those who had died of stroke or stroke-related complications was significantly different from those who were still alive, as shown in Table 3. HPA-3 a allele remained significantly associated with poststroke mortality in this group by Kaplan-Meier survival analysis, with 80% of subjects of bb genotype surviving compared with 68% of those with ab genotype and 58% of those with aa genotype (P=0.001).

View larger version (16K): [in this window] [in a new window]   Figure 1. Kaplan-Meier survival curves for subjects with acute ischemic stroke characterized by HPA-3 genotype during 2.8 years of follow-up. Patients possessing the a allele demonstrated the poorest poststroke survival compared with those homozygous for the b allele. Crosses indicate censored cases.

View this table: [in this window] [in a new window]   Table 3. Genotype Distributions of Patients Who Had Died, Classified by Cause of Death as Indicated on Death Certificate, Compared With Patients Who Were Still Alive

In a backward stepwise Cox regression model, when we excluded those who had died from IHD and other causes, including HPA-3, Pl^A, age, sex, smoking history, atrial fibrillation, stroke subtype, previous stroke, and previous MI as covariates, possession of the a allele remained independently associated with poststroke mortality. The RRs for those homozygous and heterozygous for the a allele compared with those homozygous for the b allele were 2.42 (95% CI, 1.24 to 4.71) and 2.13 (95% CI, 1.09 to 4.17), respectively. RRs for other factors independently related to poststroke mortality were as follows: 1.85 (95% CI, 1.55 to 2.20) for an increase of 10 years in age; 3.08 (95% CI, 1.95 to 4.88) for those with large-vessel disease compared with those with small-vessel disease; and 1.56 (95% CI, 1.08 to 2.26) for those with atrial fibrillation compared with those in sinus rhythm. If fibrinogen was also included in this model (thus restricting the number of subjects in the analyses to 315), HPA-3 genotype remained independently predictive of poststroke mortality (RR for aa compared with bb: 3.28 [95% CI, 1.39 to 7.71]; RR for ab compared with bb: 2.35 [95% CI, 1.00 to 5.50]), as did age, stroke subtype, previous stroke (data not shown), and fibrinogen (RR for those with fibrinogen levels in the highest tertile compared with the lowest tertile: 1.95 [95% CI, 1.17 to 3.25]). If ß-TG was also included in the model (thus further restricting the number of subjects in the analyses to 232), again HPA-3 remained independently associated with poststroke mortality, with RR for aa compared with bb of 4.29 (95% CI, 1.50 to 12.32) and for ab compared with bb of 2.89 (95% CI, 1.01 to 8.32). Age, stroke subtype, and previous stroke were the other factors independently associated with poststroke mortality in this model (data not shown).

Finally, interaction terms were created between HPA-3 and the other factors included in the final model (which included HPA-3, Pl^A, age, sex, smoking history, atrial fibrillation, stroke subtype, previous stroke, previous MI, fibrinogen, and ß-TG as covariates) to identify any interactions independently associated with poststroke mortality. Each interaction term was entered separately, and the only terms found to be significantly associated with poststroke mortality were HPA-3*Pl^A (P=0.002) and HPA-3*fibrinogen (P=0.01). On further investigation of these interactions, it was found that HPA-3 was significantly associated with poststroke mortality in those with fibrinogen levels in the highest tertile (P=0.04), with only 39% of subjects with aa genotype surviving compared with 75% of those with bb genotype, but not significantly associated with mortality in those with levels in tertiles 1 and 2, as shown in Figure 2A. Similarly, HPA-3 was significantly associated with poststroke mortality in those homozygous for Pl^A1 (P=0.003), with 55% of those with aa genotype surviving compared with 82% of those with bb genotype, whereas no significant difference in survival by HPA-3 genotype was observed in those possessing Pl^A2 (P=0.6), as shown in Figure 2B. Finally, if the 3-way interaction between HPA-3, Pl^A, and fibrinogen was included, this term was independently associated with mortality (P=0.05). The results from the Cox regression models described above were not greatly influenced by the inclusion of those patients dying from IHD and other causes, except for a slight diminishing in the RR for HPA-3 (although it remained significant in all models) and the inclusion of atrial fibrillation as an independent predictor of mortality in all models (data not shown).

View larger version (64K): [in this window] [in a new window]   Figure 2. Interactions of HPA-3 with fibrinogen and the GPIIIa PlA polymorphism in relation to poststroke mortality. There was a significant interaction between HPA-3 and PlA (P=0.002) and fibrinogen (P=0.01) in a backward stepwise Cox regression model including classic risk factors. A, There was no significant difference in the proportion of survivors by HPA-3 genotype in patients with fibrinogen levels in tertiles 1 and 2, whereas in patients with levels of fibrinogen in the highest tertile, the proportion of subjects surviving decreased with increasing number of a alleles. B, Similarly, in patients possessing PlA2, there was no significant difference in the proportion of survivors by HPA-3 genotype, whereas in patients homozygous for PlA1, the proportion of subjects surviving decreased with increasing number of a alleles.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Platelet hypersensitivity to aggregating agents has been associated with IHD and ischemic stroke^{1 4} and with total and cardiovascular mortality in middle-aged healthy men during 13.5 years of follow-up.² We have previously found elevated levels of ß-TG in these subjects compared with healthy control subjects that were independently related to poststroke mortality.¹⁷ The Pl^A polymorphism of GPIIIa has been related to coronary thrombosis¹¹ and coronary stent thrombosis.¹³ We have found associations of Pl^A with premature ischemic stroke and MI but no association with poststroke mortality.^{17 22} These findings have served to highlight the importance of platelet activation and aggregation, as well as the role of GPIIb/IIIa, in acute thrombotic disorders.

In the present study, although there was no significant difference in the HPA-3 genotype distributions of patients and healthy control subjects, there was a significant difference in survival after acute ischemic stroke when patients were considered by genotype. This was related to poorer survival in patients possessing the a allele compared with those homozygous for the b allele. Further classification of patients according to cause of death indicated a significant association of HPA-3 only in those dying of stroke or stroke-related complications, and this association remained after we accounted for covariates. The ascertainment of cause of death from death certificates is, however, fraught with problems, but we found that HPA-3 remained independently associated with mortality in all analyses even if deaths from all causes were included.

The functional significance of the HPA-3 polymorphism is unclear since it does not occur within a region of GPIIb identified as important for binding of fibrinogen or Arg-Gly-Asp peptides.¹⁰ However, Shadle et al¹⁶ found the PMI-1 antibody, which binds to GPIIb within the region of base pairs 844 to 859, gave a >80% inhibition of platelet-collagen adhesion. This suggests a potential role of this region of GPIIb in platelet adhesion, although the relevance of GPIIb/IIIa adhesion to collagen in vivo remains controversial.²³ Ligand binding to GPIIb/IIIa gives rise to conformational changes in GPIIb/IIIa, and the binding of PMI-1 is enhanced by ligand binding, suggesting that this is 1 of the regions that undergoes a conformational change.¹⁵ Ligand binding to GPIIb/IIIa also initiates a series of intracellular signaling pathways, known as outside-in signaling, which give rise to a number of events, including reorganization of the cytoskeleton and clot retraction.²⁴ Thus, it is possible that HPA-3 may influence these postfibrinogen binding events and in some way modulate the stability of platelet-fibrinogen interactions and subsequent clot resolution. Alternatively, HPA-3 may be a nonfunctional polymorphism that is in linkage disequilibrium with a functional polymorphism elsewhere.

Fibrinogen is the primary circulating ligand for GPIIb/IIIIa in vivo and has itself been associated with increased risk of IHD²⁵ and stroke²⁶ and with coronary and all-cause mortality.²⁷ In the present study, when both fibrinogen and HPA-3 were included in the Cox regression model, both factors remained independently associated with poststroke mortality after we accounted for covariates. In addition, when the interaction between HPA-3 and fibrinogen was also included in the model, this interaction term was independently associated with mortality, and further analyses indicated a significant association of HPA-3 with mortality only in those with fibrinogen levels in the highest tertile. This may merely reflect the increased number of deaths in those with fibrinogen levels in the highest tertile or may suggest enhanced binding of fibrinogen to HPA-3a–positive platelets compared with HPA-3bb platelets in the presence of higher levels of plasma fibrinogen.

Despite the close proximity of the genes encoding GPIIb and GPIIIa on chromosome 17, the HPA-3 and Pl^A polymorphisms were not in linkage disequilibrium, and Pl^A was not associated with mortality. However, in the present study if Pl^A, HPA-3, and the interaction between these 2 polymorphisms were included in the Cox regression model, the interaction term HPA-3*Pl^A was independently associated with mortality. Further analyses indicated a significant association of HPA-3 with mortality only in those homozygous for Pl^A1. In addition, the 3-way interaction between HPA-3, Pl^A, and fibrinogen was also significant, suggesting that in subjects homozygous for Pl^A1 with high plasma fibrinogen, possession of HPA-3a predisposes to poorer outcome after stroke relative to those homozygous for the b allele.

It is unclear why this polymorphism should be related to poststroke mortality when we found no association with the acute event itself or to stroke subtype. The observed association may merely represent a type I statistical error; however, the fact that HPA-3 remained independently associated with mortality even in subgroup analyses suggests that this is less likely. It is also possible that HPA-3 may influence the stability of platelet/fibrinogen interactions rather than affecting thrombus formation per se and may lead to the formation of a more stable clot that is more resistant to lysis, thereby increasing the risk of death and disability. Unfortunately, data are not available in these patients regarding long-term disability, and therefore we were unable to test this hypothesis. Further studies are therefore required both in vitro and in vivo to confirm the present findings and to determine the effect of the HPA-3 polymorphism on GPIIb/IIIa function and the stability of platelet/fibrinogen interactions.

	Acknowledgments

 
This study was funded by the UK Stroke Association.

Received October 15, 1998; revision received March 8, 1999; accepted August 25, 1999.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

1. Elwood PC, Renaud S, Sharp DS, Beswick AD, O’Brien JR, Yarnell JW. Ischemic heart disease and platelet aggregation: the Caerphilly Collaborative Heart Disease Study. Circulation.. 1991;83:38–44.[Abstract/Free Full Text]
2. Thaulow E, Erikssen J, Sandvik L, Stormorken H, Cohn PF. Blood platelet count and function are related to total and cardiovascular death in apparently healthy men. Circulation. 1991;84:613–617.[Abstract/Free Full Text]
3. Shah AB, Beamer N, Coull BM. Enhanced in vivo platelet activation in subtypes of ischemic stroke. Stroke. 1985;16:643–647.[Abstract/Free Full Text]
4. Uchiyama S, Takeuchi M, Osawa M, Kobayashi I, Maruyama S, Aosaki M, Hirosawa K. Platelet function tests in thrombotic cerebrovascular disorders. Stroke. 1983;14:511–517.[Abstract/Free Full Text]
5. Konstantopoulos K, Grotta JC, Sills C, Wu KK, Hellums JD. Shear-induced platelet aggregation in normal subjects and stroke patients. Thromb Haemost. 1995;74:1329–1334.[Medline] [Order article via Infotrieve]
6. Jang Y, Lincoff AM, Plow EF, Topol EJ. Cell adhesion molecules in coronary artery disease. J Am Coll Cardiol. 1994;24:1591–1601.[Abstract]
7. Bennett JS. Structural biology of glycoprotein IIb-IIIa. TCM. 1996;6:31–37.
8. Tcheng JE. Platelet glycoprotein IIb/IIIa integrin blockade: recent clinical trials in interventional cardiology. Thromb Haemost. 1997;78:205–209.[Medline] [Order article via Infotrieve]
9. Bray PF, Barsh G, Rosa JP, Luo XY, Magenis E, Shuman MA. Physical linkage of the genes for platelet membrane glycoproteins IIb and IIIa. Proc Natl Acad Sci U S A. 1988;85:8683–8687.[Abstract/Free Full Text]
10. Nurden AT. Polymorphisms of human platelet membrane glycoproteins: structure and clinical significance. Thromb Haemost. 1995;74:345–351.[Medline] [Order article via Infotrieve]
11. Bray PF, Weiss EJ, Tayback M, Goldschmidt-Clermont PJ. Pl^A1/A2 polymorphism of platelet glycoprotein IIIa and risk of cardiovascular disease. Lancet. 1997;349:1100–1101.
12. Carter AM, Ossei-Gerning N, Wilson IJ, Grant PJ. Association of the platelet Pl^A 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.[Abstract/Free Full Text]
13. Walter DH, Schachinger V, Elsner M, Dimmeter S, Zeiner AM. Platelet glycoprotein IIIa polymorphism and risk of coronary stent thrombosis. Lancet. 1997;350:1217–1219.[Medline] [Order article via Infotrieve]
14. Ridker PM, Hennekens CH, Schmitz C, Stampfer MJ, Lindpaintner K. Pl^A1/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]
15. Lyman S, Aster RH, Visentin GP, Newman PJ. Polymorphism of human platelet membrane glycoprotein IIb associated with the Bak^a/Bak^b alloantigen system. Blood. 1990;75:2343–2348.[Abstract/Free Full Text]
16. Shadle PJ, Ginsberg MH, Plow EF, Barondes SH. Platelet-collagen adhesion: inhibition by a monoclonal antibody that binds glycoprotein IIb. J Cell Biol. 1984;99:2056–2060.[Abstract/Free Full Text]
17. Carter AM, Catto AJ, Bamford JM, Grant PJ. Platelet GPIIIa Pl^A and GPIb variable number tandem repeat (VNTR) polymorphisms and markers of platelet activation in acute stroke. Arterioscler Thromb Vasc Biol. 1998;18:1124–1131.[Abstract/Free Full Text]
18. Unkelbach K, Kalb R, Santoso S, Kroll H, Mueller-Eckhardt C, Kiefel V. Genomic RFLP typing of human platelet alloantigens Zw(PlA), Ko, Bak and Br (HPA-1, 2, 3, 5). Br J Haematol. 1995;89:169–176.[Medline] [Order article via Infotrieve]
19. Carter AM, Catto AJ, Bamford JM, Grant PJ. Gender specific associations of the fibrinogen Bß 448 polymorphism, fibrinogen levels and acute cerebrovascular disease. Arterioscler Thromb Vasc Biol. 1997;17:589–594.[Abstract/Free Full Text]
20. Weir B, Cockerham C. Estimation of linkage disequilibrium in randomly mating populations. Heredity. 1979;42:105–111.
21. Hill WG. Estimation of linkage disequilibrium in randomly mating populations. Heredity. 1974;1974:33:229–239.
22. 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]
23. Sixma JJ, van Zanten GH, Saelman EU, Verkleij M, Lankhof H, Nieuwenhuis HK, de Groot PG. Platelet adhesion to collagen. Thromb Haemost. 1995;74:454–459.[Medline] [Order article via Infotrieve]
24. Du X, Ginsberg MH. Integrin alpha IIb beta 3 and platelet function. Thromb Haemost. 1997;78:96–100.[Medline] [Order article via Infotrieve]
25. Meade TW, Mellows S, Brozovic M, Miller GJ, Chakrabarti RR, North WR, Haines AP, Stirling Y, Imeson JD, Thompson SG. Haemostatic function and ischaemic heart disease: principal results of the Northwick Park Heart Study. Lancet. 1986;2:533–537.[Medline] [Order article via Infotrieve]
26. Wilhelmsen L, Svärdsudd K, Korsan-Bengtsen K, Larsson B, Welin L, Tibblin G. Fibrinogen as a risk factor for stroke and myocardial infarction. N Engl J Med. 1984;311:501–505.[Abstract]
27. Tunstall-Pedoe H, Woodward M, Tavendale R, A’Brook R, McCluskey MK. Comparison of the prediction by 27 different factors of coronary heart disease and death in men and women of the Scottish Heart Health Study: cohort study. BMJ. 1997;315:722–729.[Abstract/Free Full Text]

This article has been cited by other articles:

				G. G. Leblanc, J. F. Meschia, D. T. Stuss, and V. Hachinski Genetics of Vascular Cognitive Impairment: The Opportunity and the Challenges Stroke, January 1, 2006; 37(1): 248 - 255. [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]

				J. F. Meschia Clinically Translated Ischemic Stroke Genomics Stroke, November 1, 2004; 35(11_suppl_1): 2735 - 2739. [Abstract] [Full Text] [PDF]

				T. J. Kunicki, A. B. Federici, D. R. Salomon, J. A. Koziol, S. R. Head, T. S. Mondala, J. D. Chismar, L. Baronciani, M. T. Canciani, and I. R. Peake An association of candidate gene haplotypes and bleeding severity in von Willebrand disease (VWD) type 1 pedigrees Blood, October 15, 2004; 104(8): 2359 - 2367. [Abstract] [Full Text] [PDF]

				G.J. Hademenos, M.J. Alberts, I. Awad, M. Mayberg, T. Shephard, A. Jagoda, R.E. Latchaw, H.W. Todd, K. Viste, R. Starke, et al. Advances in the genetics of cerebrovascular disease and stroke Neurology, April 24, 2001; 56(8): 997 - 1008. [Abstract] [Full Text] [PDF]

				A. P. Reiner, P. N. Kumar, S. M. Schwartz, W. T. Longstreth Jr, R. M. Pearce, F. R. Rosendaal, B. M. Psaty, and D. S. Siscovick Genetic Variants of Platelet Glycoprotein Receptors and Risk of Stroke in Young Women Stroke, July 1, 2000; 31(7): 1628 - 1633. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Carter, A. M. Articles by Grant, P. J. Search for Related Content PubMed PubMed Citation Articles by Carter, A. M. Articles by Grant, P. J. Related Collections Acute Stroke Syndromes Genetics of Stroke Risk Factors for Stroke