Published online before print August 26, 2004, doi: 10.1161/01.STR.0000141978.33388.eb
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(Stroke. 2004;35:2282.)
© 2004 American Heart Association, Inc.
Original Contributions |
Platelet GP IIIa Polymorphism HPA-1 (PlA) Protects Against Subarachnoid Hemorrhage
From the Hematology and Oncology Service (R.G.-C., V.V., J.C.), Centro Regional de Hemodonación, Universidad de Murcia, Spain; the Neurology Section (J.A.I.), Hospital General Universitario, Murcia, Spain; and the Neurosurgery Service (C.P.), Hospital Virgen de la Arrixaca, Murcia, Spain.
Correspondence to Dr Javier Corral, Centro Regional de Hemodonación, C/Ronda de Garay s/n, Murcia 30003, Spain. E-mail jcc{at}um.es
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Abstract |
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Background and Purpose— Few genetic modifications have been identified to be associated with subarachnoid hemorrhage (SAH), most of them playing a role in the formation or size of aneurysms.
Methods— We evaluated the role of common and functional polymorphisms affecting the main platelet adhesive glycoproteins (GP) (GPIIIa: HPA-1; GPIa: HPA-5 and C807T; GPIb
: HPA-2 and VNTR) in the risk for development of the disease and in the severity of the onset. The study was performed in 103 patients with SAH, 103 matched controls, and 473 subjects from the general population.
Results— The HPA-1b (PlA2) allele significantly protected against SAH (OR, 0.48; 95% CI, 0.24 to 0.96; P=0.037). Interestingly, patients carrying this allele displayed larger aneurysms, but the extension of their hemorrhage and the clinical grade at presentation was significantly lower when compared with patients HPA-1 a/a (11.9±2.8 mm versus 8.8±2.2 mm, P=0.0001. Fisher grade 
2: 68.4% versus 20%; P=0.0001; Hunt and Hess score <IV; 84.2% versus 53.8%; P=0.0187, respectively). The protection of the HPA-1b allele seemed to be exacerbated by the simultaneous presence of the HPA-2b allele. Thus, no patient carried this combination, which was present in 7.8% of controls (P=0.007).
Conclusions— We present the first evidence suggesting a protective role for the platelet GPIIIa HPA-1b allele in SAH. The suggested platelet hyper-reactivity determined by this allele could reduce the risk to suffer SAH, specially if the aneurysm is small, attenuate the severity of the hemorrhage, and reduce the clinical grade at presentation. This effect might be amplified by the simultaneous combination with the GPIb HPA-2b allele.
Key Words: aneurysm • genetics • hemostasis • subarachnoid hemorrhage
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Introduction |
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Subarachnoid hemorrhage (SAH) accounts for 10% of cerebrovascular disease and has an annual incidence of 10 to 15 per 100 000. SAH continues to have a substantial impact on mortality and has long-lasting effects on the functional status and quality of life of patients who survive.1 The high frequency of SAH with family history suggests that a genetic component might be involved in this disease.1,2 Previous reports have shown contradictory results about the role of polymorphisms affecting the
1-antitrypsin and matrix metalloproteinases in the development of intracranial aneurysms.2,3 The endothelial nitric oxide synthase T-786C single nucleotide polymorphism has been suggested to play a significant role in the size of ruptured aneurysm, although it seems to have a minor effect in the risk for SAH.4
Platelets play a key role in generating the protective hemostatic plug that prevents blood loss at sites of vascular injury. Therefore, modifications of platelet reactivity might favor thrombotic or hemorrhagic disorders.5 The identification of functional prothrombotic polymorphisms during the past decade encouraged the study of common polymorphisms affecting platelet glycoproteins (GP) in arterial thrombotic disorders. The most frequent platelet polymorphisms evaluated in these studies are those affecting the structure or levels of adhesive receptors. First, GPIIIa HPA-1 (from human platelet alloantigen), also named PlA, is responsible for a structural change (Leu33Pro) in this key platelet protein.6 From the report of Weiss et al in 1996 suggesting a prothrombotic role in myocardial infarction,7 this is the platelet polymorphism more studied in arterial thrombosis. Second, GPIa C807T and HPA-5 (Glu505Lys) polymorphisms associate with the levels of the high-affinity collagen receptor.8 Third, GPIb HPA-2 (Thr145Met) are genetically linked to a VNTR (variable number of tandem repeats) polymorphism. These polymorphisms cause a significant structural change in the Ib subunit, affecting the binding of von Willebrand factor.9
The role of these polymorphisms in arterial thrombosis is conflictive, but all have been suggested to be prothrombotic.10 We recently observed that prothrombotic polymorphisms such as the factor V Leiden and prothrombin G20210A might protect against cerebral hemorrhage,11 supporting that prothrombotic polymorphisms could protect against hemorrhage. However, only 2 reports analyzed the effect of platelet GP polymorphisms in small groups of patients with intracranial hemorrhage, finding no significant effect.12,13
The aim of this study was to evaluate the role of common functional polymorphisms affecting relevant platelet GP that have been involved in arterial thrombosis in the development and severity of SAH.
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Subjects and Methods |
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A prospective study was performed on all patients admitted to the Arrixaca Hospital and University General Hospital (Murcia, Spain) with aneurysmal and spontaneous nonaneurysmal SAH during a 3-year period. The study was approved by the hospital institutional review board and conducted in accordance with the Helsinki Declaration. Blood samples were obtained via venipuncture for other routine blood tests. Informed consent from patients or their next of kin was obtained before blood samples were taken. Patients are eligible if they are older than age 18 years. The diagnosis of SAH was established by the admission computed tomography (CT) scan or by xanthochromia of the cerebrospinal fluid if the CT was not diagnostic.
The selection of patients and controls was designed to avoid interference of other factors and to determine the role of common polymorphisms that predisposed to or protected against SAH. First, patients at high risk for SAH (patients with SAH caused by trauma, brain tumor, arteriovenous malformation rupture, vasculitis, and other structural lesions, as well as patients in antithrombotic treatment) were excluded. One hundred three patients were finally recruited in our study. All patients underwent standard hematologic screening tests (platelet count, activated partial thromboplastin time and prothrombin time). We recorded baseline demographic data (age, sex, and ethnicity). Moreover, the presence of selected risk factors for SAH (hypertension, smoking history, and alcohol consumption) and the personal history of arterial ischemic events were obtained from clinical data and direct interview of patients. Confounding risk factors of those patients unable to give a meaningful clinical history were obtained from family members. The frequency of deaths within 30 days of the first episode was also recorded (Table 1). The presence and size of the aneurysm was determined on the basis of radiological findings (including cerebral angiography in each case). Severity of SAH on admission CT scan was classified according to the grading system of Fisher (Fisher grades 1 to 4).14 Neurological status on admission was assessed with the Hunt and Hess Scale.15
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Second, to avoid overrepresentation of classic hemorrhagic risk factors among patients, their respective controls were selected to match for age, race, sex, and selected risk factors for SAH. Thus, we selected 103 matched controls during the same period of time by reviewing the charts of traumatology and ophthalmology (Table 1). Controls had neither documented history of vascular disease nor personal history of thromboembolic or hemorrhagic disease and were not undergoing antithrombotic therapy.
Finally, the frequency of these polymorphisms in the general population from our region was analyzed in 473 additional healthy unrelated white subjects, mainly blood donors (Table 1).
DNA Studies
Genomic DNA was extracted from whole blood (Wizard genomic DNA purification system; Promega). Genotyping of the studied polymorphisms was performed as described elsewhere.7,8,16
Statistical Analysis
Results are expressed as mean±SD for continuous variables and as percentages for categorical variables. Comparisons between 2 groups were performed by the unpaired t test. Categorical data were compared using the 
2 test, and a Fisher exact test was performed. The differences with a 2-tailed P<0.05 were considered significant. The strength of the association of major risk factors and the polymorphism with the occurrence of disease was estimated by calculation of the odds ratio with the EpiInfo software and the Cornfield method for the calculation of 95% CI. Gene–gene interactions were determined by comparing the prevalence of combined carrier for 2 gene variants in patients and controls by analysis of the distribution of 1 chosen gene variant in subgrouped patients and controls who carry another gene variant as genetic background.
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Results |
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Characteristics of the Study Population
The general characteristics of patients and controls are shown in Table 1. We did not detect significant differences in coagulation tests or in number of platelets between patients and controls (Table 1).
Table 1 shows the survival percentage 30 days after admission to the hospital, which is slightly higher than that described in previous reports.17
Prevalence of Polymorphisms in the Case Control Study
The genotypic frequencies for the analyzed polymorphisms in the case control study are shown in Table 2. The frequencies of these polymorphisms in the control group were similar to those identified in the general population from our region (Table 2) and did not differ from those previously reported in other white populations.18 There was no statistical deviation from Hardy–Weinberg equilibrium for all polymorphisms in all groups of subjects.
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We observed no significant differences in the distribution of HPA-2, VNTR, C807T, and HPA-5 genotypes between cases and controls (Table 2). However, the prevalence of the GPIIIa HPA-1 polymorphism differed significantly in these 2 groups. The percentage of subjects carrying the HPA-1b allele (PlA2) was significantly lower in patients than in controls (18.4% versus 32.0%, respectively; P=0.037). According to these results, carriers of the HPA-1b allele (a/b+b/b) showed almost a 2-fold decreased risk for SAH than those lacking the genetic variant under the same environmental risk factors (OR, 0.48; 95% CI, 0.24 to 0.96). The protection observed in heterozygous was significantly higher (a/b versus a/a: OR, 0.43; 95% CI, 0.22 to 0.85; P=0.0191), whereas the b/b genotype did not protect against SAH (b/b versus a/a: OR, 1.25; 95% CI, 0.21 to 7.70).
Association of Polymorphisms With Clinical Features of SAH
We observed no significant association between HPA-2, VNTR, HPA-5, and C807T polymorphisms and clinical features of SAH (data not shown). However, we identified interesting associations concerning the HPA-1 genotype. As indicated in Table 3, we did not find significant differences in age, sex, platelet counts, activated partial thromboplastin time, prothrombin time, presence of aneurysm, smoking, alcohol consumption, and hypertension status according to the HPA-1 genotype. Patients carrying the HPA-1b allele had more previous arterial ischemic events than those with HPA-1 a/a genotype (31.6% versus 7.1%, respectively; P=0.008). Intriguingly, we observed a significant association of the HPA-1 genotype with the aneurysm size. Patients carrying the HPA-1b allele had aneurysms with size significantly higher than that found in patients with HPA-1 a/a genotype (11.9±2.8 mm versus 8.8±2.2 mm, respectively; P=0.0001). In contrast, the severity of SAH, determined on admission CT scan according to the grading system of Fisher (Fisher grade 1 to 4), indicated that patients carrying the HPA-1b allele had smaller hemorrhage than patients with HPA-1 a/a genotype (68.4% of patients carrying the HPA-1b allele had a Fisher’s grade 2, in contrast to the 20% of patients with HPA-1 a/a genotype; P=0.0001). Interestingly, the HPA-1b allele also associated with a milder clinical grade at presentation according to the Hunt and Hess score (Hunt–Hess I to III: 84.2% in carriers of the HPA-1b allele versus 53.8% in patients with HPA-1 a/a genotype; P=0.0187).
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Finally, this polymorphism did not seem to affect significantly the incidence of early mortality, at least in those patients reaching the hospital. However, there is a trend toward an increase in the survival 30 days after admission to the hospital in those patients carrying the HPA-1b allele (79.0% versus 65.5%; Table 3).
Synergism Between Polymorphisms
The studied polymorphisms are common in the white population. Therefore, it was possible to test any association between polymorphisms despite the relative small size of our sample. Only the association between HPA-1 and HPA-2 deserved our attention. No patient simultaneously carried these 2 polymorphisms but 8 controls did (7.8%; a similar percentage was found in the general population [7.5%]). Accordingly, the combination of these 2 polymorphisms strongly increase the protection against the development of SAH (P=0.007).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Exquisitely regulated hemostatic mechanisms have evolved within the animal kingdom to protect against the ever-present danger of fatal hemorrhage. Platelets and coagulation factors interact to generate the protective hemostatic plug that prevents blood loss at sites of vascular injury. During the past decade, numerous studies have investigated the role of polymorphisms affecting platelet GP in arterial thrombosis with conflictive results.10,18 However, few reports have analyzed the significance of these polymorphisms in hemorrhage. Our report is the first one showing a protective role of a platelet polymorphism in spontaneous SAH. We found that the HPA-1b allele (PlA2) of platelet GPIIIa significantly reduces the risk of SAH. This result is consistent with the suggested platelet hyper-reactivity and high thrombotic risk associated with this variant.10,18
The association we found between the size of the aneurysm and the HPA-1 genotype probably does not indicate that this polymorphism is related to the cause and pathogenesis of intracranial aneurysm (although the HPA-1 is also expressed on vascular endothelial cells),19 but could be an additional result supporting the mild protective effect of the HPA-1b allele in hemorrhage. Thus, patients carrying the HPA-1b allele were protected for bleeding if the size of the aneurysm is small or medium (<9 mm), but the influence of a mild and common polymorphism cannot avoid hemorrhage in patients with large aneurysms (>9 mm). Because size is the most important factor influencing the possibility of aneurysmal rupture,20 the HPA-1b variant could protect only subjects with small aneurysms.
The role of the platelet HPA-1 polymorphism in SAH is not restricted to the risk of disease; it is also involved in the severity of the onset. In agreement with the protective role identified in the case control study, the HPA-1b allele also seems to reduce the severity of the disease. Thus, the extension of the hemorrhage (measured by the grading system of Fisher) and the clinical grade at presentation (determined by the Hunt and Hess score) are significantly lower in carriers of the HPA-1b allele than in patients with HPA-1 a/a genotype. This is especially relevant considering that patients carrying the HPA-1b allele presented large aneurysms, which have been consistently identified as predictors of mortality and poor functional outcome after SAH.21 Accordingly, the HPA-1b allele seems to be a potent factor reducing the severity of SAH. These data are supported by the high 30-day survival observed in patients carrying the HPA-1b allele (79%).
Our data support previous studies reporting the protective role of prothrombotic polymorphisms (factor V Leiden, prothrombin G20210A, or GPIa C807T) in congenital or acquired bleeding diseases (von Willebrand disease, hemophilia, partum, menstruation, or cerebral hemorrhage).11 Remarkably, the HPA-1b allele also seems to reduce the severity of bleeding in patients with Glanzmann thrombasthenia.22 These results support that a polymorphism may play mild but opposite roles in the pathogenesis of thrombotic and hemorrhagic disorders, suggesting an explanation for the high frequency of these polymorphisms in the general population. Interestingly, the HPA-1b allele is almost absent in the Japanese population,23 which is a population with extremely high incidence of SAH (22.1 per 100 000).24
Finally, because SAH is a polygenic and multifactorial disorder, the genetic components in this disease may be a combined effect of a number of genes, with each playing only a small role. A recent article suggests a role for certain endothelial nitric oxide synthase polymorphisms in predicting susceptibility toward SAH and post-SAH vasospasm.25 The predisposition imparted by individual genes may act independently or interact with other genes to result in an additive effect or a synergistic co-effect. Synergism between polymorphisms has been identified in other diseases, including hemostatic disorders,26,27 and also involves the HPA-1 polymorphism.28 Our data support that the combination of 2 polymorphisms affecting the most important platelet adhesive receptors, GPIIIa (HPA-1) and GPIb (HPA-2), strongly increases the protection of the HPA-1b allele in SAH.
In conclusion, we presented the first evidence to our knowledge suggesting a protective role for the platelet GPIIIa HPA-1b allele in SAH. The suggested platelet hyper-reactivity determined by the GPIIIa Pro33 variant could reduce the risk of SAH, especially if the aneurysm is small, and attenuate the severity of the hemorrhage. This effect might be amplified by the simultaneous combination with the GPIb HPA-2b allele. The sample size is relatively small, but the frequency of the polymorphism is high. Thus, our matched case control sample has a power of 58% to detect a relative risk of 0.48 for the HPA-1 polymorphism with a statistical significance of 5%. The power becomes higher (67%) considering the general population, which shows similar distribution of genotypes that selected controls. Moreover, the conflictive functional and thrombotic role of the GPIIIa HPA-1 polymorphism encourage the performance of further studies including more patients from other populations in association with other polymorphism to confirm whether the HPA-1b allele or the HPA-1 a/b genotype provides protection against SAH or other hemorrhagic disorders.
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Acknowledgments |
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J.C. and R.G.-C. are Investigadores Ramón y Cajal from University of Murcia. We are deeply grateful to Dr. Vanessa Roldán for statistical analysis. We acknowledge Antonia Miñano and Mari Luz del Rey for providing excellent technical assistance. This study has been supported by SAF2003-00840 (Ministerio de Ciencia Y Tecnologia and Fondo Europeo para el Desarrollo Estructural de las Regiones).
Received April 28, 2004; revision received June 16, 2004; accepted July 7, 2004.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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- Zhang B, Fugleholm K, Day LB, Ye S, Weller RO, Day INM. Molecular pathogenesis of subarachnoid haemorrhage. Int J Biochem Cell Biol. 2003; 35: 1341–1360.[CrossRef][Medline] [Order article via Infotrieve]
- Kissela BM, Sauerbeck L, Woo D, Khoury J, Carrozzella J, Pancioli A, Jauch E, Moomaw CJ, Shukla R, Gebel J, Fontaine R, Boderick J. Subarachnoid hemorrhage. A preventable disease with a heritable component. Stroke. 2002; 33: 1321–1326.
[Abstract/Free Full Text] - Zhang B, Dhillon S, Geary I, Howell WM, Iannotti F, Day I, Ye S. Polymorphisms in matrix metalloproteinase-1, -3, -9, and -12 genes in relation to subarachnoid hemorrhage. Stroke. 2001; 32: 2198–2202.
[Abstract/Free Full Text] - Khurana VG, Youvraj RS, Mangrum WI, McClelland RL, O'Kane DJ, Meyer FB, Meissner I. Endothelial nitric oxide synthase T-786C single nucleotide polymorphism. A putative genetic marker differentiating small versus large ruptured intracranial aneurysms. Stroke. 2003; 34: 2555–2559.
[Abstract/Free Full Text] - Ni H, Freedman J. Platelets in hemostasis and thrombosis: role of integrins and their ligands. Transfus Apheresis Sci. 2003; 28: 257–264.[CrossRef][Medline] [Order article via Infotrieve]
- Calvete JJ. Platelet integrin GPIIb/IIIa: structure-function correlations. An update and lessons from other integrins. Proc Soc Exp Biol Med. 1999; 222: 29–38.
[Abstract/Free Full Text] - Weiss EJ, Bray PF, Tayback M, Schulman SP, Kickler TS, Becker LC, Weiss JL, Gerstenblith G, Goldschmidt-Clermont PJ. A polymorphism of a platelet glycoprotein receptor as an inherited risk factor for coronary thrombosis. N Engl J Med. 1996; 334: 1090–1094.
[Abstract/Free Full Text] - Corral J, Rivera J, González-Conejero R, Vicente V. The number of platelet glycoprotein Ia molecules is associated with the genetically linked 807 C/T and HPA-5 polymorphisms. Transfusion. 1999; 39: 372–378.[CrossRef][Medline] [Order article via Infotrieve]
- Ulrichts H, Vanhoorelbeke K, Cauwenberghs S, Vauterin S, Kroll H, Santoso S, Deckmyn H. von Willebrand factor but not alpha-thrombin binding to platelet glycoprotein Ibalpha is influenced by the HPA-2 polymorphism. Arterioscler Thromb Vasc Biol. 2003; 23: 1302–1307.
[Abstract/Free Full Text] - Bray PF. Platelet glycoprotein polymorphisms as risk factors for thrombosis. Curr Opin Hematol. 2000; 7: 284–289.[CrossRef][Medline] [Order article via Infotrieve]
- Corral J, Iniesta JA, González-Conejero R, Villalón M, Vicente V. Polymorphisms of clotting factors modify the risk of primary intracranial hemorrhage. Blood. 2001; 97: 2979–2982.
[Abstract/Free Full Text] - Reiner AP, Kumar PN, Schwartz SM, Long-streth WT Jr., Pearce RM, Rosendaal FR, Psaty BM, Siscovick DS. Genetic variants of platelet glycoprotein receptors and risk of stroke in young women. Stroke. 2000; 31: 1628–1633.
[Abstract/Free Full Text] - Iniesta JA, Corral J, González-Conejero R, Piqueras C, Vicente V. Polymorphisms of platelet adhesive receptors: do they play a role in primary intracerebral hemorrhage?. Cerebrov Dis. 2003; 15: 51–55.
- Fischer CM, Kistler JP, Davis JM. Relation of cerebral vasospasm to subarachnoid hemorrhage visualized by CT scanning. Neurosurgery. 1980; 6: 1–9.[Medline] [Order article via Infotrieve]
- Hunt WE, Hess RM. Surgical risk as related to time of intervention in the repair of intracranial aneurysms. J Neurosurg. 1968; 28: 14–20.[Medline] [Order article via Infotrieve]
- González-Conejero R, Lozano ML, Rivera J, Corral J, Iniesta JA, Moraleda JM, Vicente V. Polymorphisms of platelet membrane glycoprotein Ib associated with arterial thrombotic disease. Blood. 1998; 92: 2771–2776.
[Abstract/Free Full Text] - Hop JW, Rinkel GJ, Algra A, van Gijn J. Case-fatality rates and functional outcome after subarachnoid hemorrhage: a systematic review. Stroke. 1997; 28: 660–664.
[Abstract/Free Full Text] - Kunicki TJ, Nugent DJ. The influence of platelet glycoprotein polymorphisms on receptor function and risk for thrombosis. Vox Sang. 2002; 83 Suppl 1: 85–90.[Medline] [Order article via Infotrieve]
- Kieffer N, Phillips DR. Platelet membrane glycoproteins: functions in cellular interactions. Annu Rev Cell Biol. 1990; 6: 329–357.[CrossRef][Medline] [Order article via Infotrieve]
- The International Study of Unruptured Intracranial Aneurysms Investigators. Unruptured intracranial aneurysms: risk of rupture and risks of surgical intervention. N Engl J Med. 1998; 339: 1725–1733.
[Abstract/Free Full Text] - Sundt TM Jr., Piepgras DG, Fode NC, Meyer FB. Giant intracranial aneurysms. Clin Neurosurg. 1991; 37: 116–154.[Medline] [Order article via Infotrieve]
- Ghosh K, Kulkarni B, Nair S, Shetty S, Mohanty D. Human platelet alloantigen polymorphism in Glanzmann’s thrombasthenia and its impact on the severity of the disease. Br J Haematol. 2002; 119: 348–353.[CrossRef][Medline] [Order article via Infotrieve]
- Tanaka S, Ohnoki S, Shibata H, Okubo Y, Yamaguchi H, Shibata Y. Gene frequencies of human platelet antigens on glycoprotein IIIa in Japanese. Transfusion. 1996; 36: 813–817.[CrossRef][Medline] [Order article via Infotrieve]
- Ohkuma H, Fujita S, Suzuki S. Incidence of aneurysmal subarachnoid hemorrhage in Shimokita, Japan, from 1989 to 1998. Stroke. 2002; 33: 195–199.
[Abstract/Free Full Text] - Khurana VG, Sohni YR, Mangrum WI, McClelland RL, O’Kane DJ, Meyer FB, Meissner I. Endothelial nitric oxide synthase gene polymorphisms predict susceptibility to aneurysmal subarachnoid hemorrhage and cerebral vasospasm. J Cereb Blood Flow Metab. 2004; 24: 291–297.[Medline] [Order article via Infotrieve]
- Reich LM, Bower M, Key NS. Role of the geneticist in testing and counseling for inherited thrombophilia. Genet Med. 2003; 5: 133–143.[Medline] [Order article via Infotrieve]
- Butt C, Zheng H, Randell E, Robb D, Parfrey P, Xie YG. Combined carrier status of prothrombin 20210 A and factor XIII-A Leu34 alleles and a strong risk factor for myocardial infarction: evidence of a gene-gene interaction. Blood. 2003; 101: 3037–3041.
[Abstract/Free Full Text] - Schwartz E, Demidova D, Sirotkina O, Kudinov S. The combination of glycoprotein IIIa PlA polymorphism with polymorphism of serotonin transporter as an independent strong risk factor for the occurrence of coronary thrombosis. Mol Genet Metab. 2003; 79: 229–230.[CrossRef][Medline] [Order article via Infotrieve]
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