Published online before print February 8, 2007, doi: 10.1161/01.STR.0000258076.04860.8e
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(Stroke. 2007;38:1069.)
© 2007 American Heart Association, Inc.
Research Reports |
The Factor V Leiden, Prothrombin Gene 20210GA, Methylenetetrahydrofolate Reductase 677CT and Platelet Glycoprotein IIIa 1565TC Mutations in Patients With Acute Ischemic Stroke and Atrial Fibrillation
From the Haematological Research Laboratory (E.B., E.C.S., K.K.H., M.T., P.M.S.), Department of Haematology and R&D Group (K.B.F.H.), Department of Clinical Chemistry, Ullevaal University Hospital, Oslo, Norway.
Correspondence to Dr Eivind Berge, Department of Internal Medicine, Ullevaal University Hospital, NO-0407 Oslo, Norway. E-mail eivind.berge{at}medisin.uio.no
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Abstract |
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Background and Purpose— We wanted to investigate whether common prothrombotic mutations are more prevalent in patients with atrial fibrillation who have had a stroke than in healthy controls. We also wanted to assess whether early recurrent ischemic cerebrovascular events were more frequent among carriers of the factor V Leiden or the prothrombin gene mutations than among others.
Methods— We used a case-control design with 367 patients with acute ischemic stroke and atrial fibrillation (cases) and 482 healthy blood donors (controls). All mutations were detected with conventional polymerase-chain reaction protocols.
Results— The odds ratios for carriers of the factor V Leiden, prothrombin gene 20210GA, methylenetetrahydrofolate reductase 677CT, or platelet glycoprotein IIIa 1565TC (PlA2) mutation were 0.91, (95% CI, 0.51 to 1.59), 2.25 (95% CI, 0.61 to 8.90), 0.83 (0.61 to 1.13), and 0.79 (0.57 to 1.10), respectively. Early recurrent ischemic stroke and total recurrent ischemic cerebrovascular events were slightly more frequent among carriers of the factor V Leiden mutation than among noncarriers: odds ratio 1.45 (95% CI, 0.41 to 5.1), and 1.59 (0.61 to 4.1), respectively. None of the patients with recurrent ischemic cerebrovascular events had the prothrombin gene mutation.
Conclusion— These mutations are not important risk factors for thromboembolic stroke associated with atrial fibrillation. Carriers of the factor V Leiden mutation had a small, nonsignificantly higher risk of early recurrent ischemic cerebrovascular events.
Key Words: atrial fibrillation • ischemic stroke • prothrombotic gene mutations
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Introduction |
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Patients with atrial fibrillation have a 5-fold increased risk of thromboembolic stroke, probably attributable to activation of blood coagulation. We wanted to investigate whether common prothrombotic mutations are more prevalent in patients with atrial fibrillation who have had a thromboembolic stroke than in healthy controls. We also wanted to investigate whether, among patients with acute ischemic stroke and atrial fibrillation, early recurrent ischemic cerebrovascular events were more frequent in carriers of the most important of these gene mutations than in noncarriers.
We chose to screen for the factor V Leiden, prothrombin gene 20210GA, methylenetetrahydrofolate reductase (MTHFR) 677CT, and platelet glycoprotein (GP) IIIa 1565TC mutations. The factor V Leiden and the prothrombin gene mutations are associated with increased risk of venous thromboembolism1,2 and possibly myocardial infarction and stroke.3 The MTHFR mutation increases plasma homocysteine, which has emerged as a potential risk factor for cardiovascular diseases, including stroke.4 The mutant PlA2 allele in the platelet GPIIIa gene is associated with increased risk of coronary thrombosis5 and stroke in young patients.6
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Materials and Methods |
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Cases were 367 patients with acute ischemic stroke and atrial fibrillation, of which 355 had been included in the Heparin in Acute Embolic Stroke Trial (HAEST).7 Controls were unselected healthy subjects recruited from the Blood Bank at Ullevaal University Hospital. Of the 355 patients included in HAEST, 28 had a recurrent ischemic stroke and 54 had a recurrent ischemic cerebrovascular event (recurrent ischemic stroke or "progressive" stroke). In a separate analysis the prevalence of the factor V Leiden and prothrombin gene mutations in these cases were compared with the prevalence in the rest of the 355 patients (controls).
The factor V Leiden and prothrombin gene mutations were detected by conventional polymerase-chain reaction protocols.2,8 The MTHFR and GPIIIa mutations were detected using hybridization-based polymerase-chain reaction in a LightCycler real-time system.9,10 We used stratification to control for the presence of other potentially confounding variables. Relative risks were calculated as the odds of having the gene mutation for cases, compared with the odds for controls, with 95% CI for the odds ratios.
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Results |
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Table 1 shows the prevalence of the mutations in patients and controls. No patients were homozygous for the factor V Leiden or the prothrombin gene mutation. The odds ratio for carriers of the factor V Leiden, the prothrombin gene, the MTHFR (homo- and heterozygotes) and the GPIIIa mutations (PlA2/A2 and PlA1/A2) were 0.91, (95% CI, 0.51 to 1.59), 2.25 (0.61 to 8.90), 0.83 (0.61 to 1.13) and 0.79 (0.57 to 1.10), respectively. Early recurrent ischemic stroke and total recurrent ischemic cerebrovascular events were slightly more frequent among carriers of the factor V Leiden mutation than among noncarriers: odds ratio 1.45 (95% CI, 0.41 to 5.1) and 1.59 (0.61 to 4.1), respectively. Of the 54 patients who had an early recurrent ischemic cerebrovascular event, none had the prothrombin gene mutation, compared with 8 of 301 (2.7%) among controls (Table 2).
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Discussion |
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Our results indicate that none of these prothrombotic gene mutations are important risk factors for ischemic stroke in patients with atrial fibrillation. This means that these mutations cannot be used to identify patients with atrial fibrillation who are at particularly high risk of ischemic stroke, or to select patients for oral anticoagulant treatment. These results are consistent with previous findings in unselected patients with ischemic stroke.3,11,12
We cannot completely rule out the possibility of an association. First, although this is a relatively large study of these mutations in this high-risk population, the sample size is still limited and the confidence intervals relatively wide. Secondly, confounding from other prognostic variables may have played a role. Although we performed a number of stratification analyses, we may not have been able to control for all variables of prognostic significance.
To our knowledge no other studies have investigated whether the factor V Leiden or prothrombin gene mutations are risk factors for recurrent ischemic cerebrovascular events in the acute phase of stroke. We found a small, nonsignificant trend toward a higher risk of recurrent ischemic cerebrovascular events among patients who were carriers of the factor V Leiden mutation. If this is true, more intensive antithrombotic therapy may be warranted in acute stroke patients who are carriers of this mutation. Unfortunately, HAEST was too small for a subgroup analysis of patients with the factor V Leiden mutation to be informative.
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Acknowledgments |
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We thank the following persons for skillful technical assistance: Irene Ditmansen Schanche (Department of Medical Genetics), Anne Været (Haematological Research Laboratory, Department of Haematology), and Berit S. Brusletto (R&D Group, Department of Clinical Chemistry).
Sources of Funding
HAEST was financially supported by grants from the Norwegian Research Council (project no 118583/320) and the Norwegian Council on Cardiovascular Diseases and by unconditional grants from Pharmacia and Upjohn, Stockholm, Sweden, and Nycomed, Oslo, Norway.
Disclosures
None.
Received June 20, 2006; revision received September 24, 2006; accepted October 11, 2006.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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1. Svensson PJ, Dahlback B. Resistance to activated protein C as basis for venous thrombosis. N Engl J Med. 1994; 330: 517–522.
2. Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3'-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood. 1996; 88: 3698–3703.
3. Lalouschek W, Schillinger M, Hsieh K, Endler G, Tentschert S, Lang W, Cheng S, Mannhalter C. Matched case-control study on factor V Leiden and the prothrombin G20210A mutation in patients with ischemic stroke/transient ischemic attack up to the age of 60 years. Stroke. 2005; 36: 1405–1409.
4. Kim RJ, Becker RC. Association between factor V Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase C677T mutations and events of the arterial circulatory system: a meta-analysis of published studies. Am Heart J. 2003; 146: 948–957.[CrossRef][Medline] [Order article via Infotrieve]
5. 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.
6. Carter AM, Catto AJ, Bamford JM, Grant PJ. Platelet GP IIIa PlA and GP Ib variable number tandem repeat polymorphisms and markers of platelet activation in acute stroke. Arterioscler Thromb Vasc Biol. 1998; 18: 1124–1131.
7. Berge E, Abdelnoor M, Nakstad PH, Sandset PM. Low molecular-weight heparin versus aspirin in patients with acute ischaemic stroke and atrial fibrillation: a double-blind randomised study. Lancet. 2000; 355: 1205–1210.[CrossRef][Medline] [Order article via Infotrieve]
8. Bertina RM, Koeleman BP, Koster T, Rosendaal FR, Dirven RJ, de Ronde H, van der Velden PA, Reitsma PH. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature. 1994; 369: 64–67.[CrossRef][Medline] [Order article via Infotrieve]
9. Nauck MS, Gierens H, Nauck MA, Marz W, Wieland H. Rapid genotyping of human platelet antigen 1 (HPA-1) with fluorophore-labelled hybridization probes on the LightCycler. Br J Haematol. 1999; 105: 803–810.[CrossRef][Medline] [Order article via Infotrieve]
10. von Ahsen N, Schutz E, Armstrong VW, Oellerich M. Rapid detection of prothrombotic mutations of prothrombin (G20210A), factor V (G1691A), and methylenetetrahydrofolate reductase (C677T) by real-time fluorescence PCR with the LightCycler. Clin Chem. 1999; 45: 694–696.
11. Hankey GJ, Eikelboom JW, van B, Lofthouse E, Staples N, Baker RI. Inherited thrombophilia in ischemic stroke and its pathogenic subtypes. Stroke. 2001; 32: 1793–1799.
12. Go AS, Reed GL, Hylek EM, Phillips KA, Liu L, Henault LE, Selby JV, Singer DE. Factor V Leiden and risk of ischemic stroke in nonvalvular atrial fibrillation: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. J Thromb Thrombolysis. 2003; 15: 41–46.[CrossRef][Medline] [Order article via Infotrieve]
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