Homocysteine, MTHFR and risk of venous thrombosis: a meta‐analysis of published epidemiological studies
2005; Elsevier BV; Volume: 3; Issue: 2 Linguagem: Inglês
10.1111/j.1538-7836.2005.01141.x
ISSN1538-7933
AutoresMartin den Heijer, Sarah Lewington, Robert Clarke,
Tópico(s)Blood Coagulation and Thrombosis Mechanisms
ResumoJournal of Thrombosis and HaemostasisVolume 3, Issue 2 p. 292-299 Free Access Homocysteine, MTHFR and risk of venous thrombosis: a meta-analysis of published epidemiological studies M. DEN HEIJER, M. DEN HEIJER Department of Endocrinology and Epidemiology and Biostatistics, Radboud University Nijmegen Medical Centre, Nijmegen, the NetherlandsSearch for more papers by this authorS. LEWINGTON, S. LEWINGTON Clinical Trial Service Unit and Epidemiological Studies Unit, Radcliffe Infirmary, University of Oxford, Oxford, UKSearch for more papers by this authorR. CLARKE, R. CLARKE Clinical Trial Service Unit and Epidemiological Studies Unit, Radcliffe Infirmary, University of Oxford, Oxford, UKSearch for more papers by this author M. DEN HEIJER, M. DEN HEIJER Department of Endocrinology and Epidemiology and Biostatistics, Radboud University Nijmegen Medical Centre, Nijmegen, the NetherlandsSearch for more papers by this authorS. LEWINGTON, S. LEWINGTON Clinical Trial Service Unit and Epidemiological Studies Unit, Radcliffe Infirmary, University of Oxford, Oxford, UKSearch for more papers by this authorR. CLARKE, R. CLARKE Clinical Trial Service Unit and Epidemiological Studies Unit, Radcliffe Infirmary, University of Oxford, Oxford, UKSearch for more papers by this author First published: 25 January 2005 https://doi.org/10.1111/j.1538-7836.2005.01141.xCitations: 281 M. den Heijer, Department of Endocrinology (531), Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, the Netherlands. Tel.: +31 24 3614599; fax: +31 24 3618809; e-mail: m.denheijer@endo.umcn.nl AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Abstract Summary. Context: It has been suggested that elevated total plasma homocysteine levels are associated with the risk of venous thrombosis. Objective: To assess the relationship of homocysteine and the MTHFR 677TT genotype and the risk of venous thrombosis by conducting a meta-analysis of all relevant studies. Data sources and selection: Studies (case–control or nested case–control) were identified by searches of electronic literature for relevant reports published before July 2003 on homocysteine and the MTHFR 677TT genotype and venous thrombosis as an end-point, by hand-searching reference lists of original articles (including meta-analyses) on this topic and by contact with investigators in the field. Data extraction: A meta-analysis of 24 retrospective (n = 3289 cases) and three prospective studies (n = 476 cases) was carried out to examine the association of homocysteine with venous thrombosis. A meta-analysis of 53 studies (n = 8364 cases) of the MTHFR 677TT genotype (that increases homocysteine) was carried out to assess if this association is causal. Data synthesis: A 5 µmol L−1 higher measured homocysteine level was associated with a 27% (95% CI: 1–59) higher risk of venous thrombosis in prospective studies and a 60% (95% CI: 10–134) higher risk in retrospective studies. The 677TT genotype was associated with a 20% (95% CI: 8–32) higher risk of venous thrombosis compared with the 677CC genotype. In contrast with non-American studies, the 677TT genotype had no effect on venous thrombosis in North America, due probably to the higher intake of folate and riboflavin in North America. Conclusion: This meta-analysis of prospective and retrospective studies demonstrates a modest association of homocysteine with venous thrombosis. The elevated risk associated with the MTHFR 677TT genotype provides some support for causality. Introduction Venous thrombosis, including deep-vein thrombosis and pulmonary embolism, is an important cause of morbidity and mortality, particularly in older people [1]. Most cases of venous thrombosis arise due to prolonged immobilization, major surgery, trauma or cancer, but genetic or acquired hemostatic abnormalities, including elevated plasma homocysteine levels, have also been implicated [2]. The initial epidemiological evidence that examined the association between homocysteine and venous thrombosis was derived from retrospective case–control studies (in which blood for homocysteine measurements was collected after onset of thrombotic events in cases) [3-7], but it was not possible to ascertain whether the higher homocysteine levels caused the thrombotic event or was a consequence of it. Subsequently, prospective studies (in which blood for homocysteine measurements was collected before the onset of the thrombotic events) appeared to confirm these findings, but the weaker results raised questions about causality [8-10]. Elucidation of an association between a genetic variant associated with elevated homocysteine levels and venous thrombosis might be informative about the hypothesis that higher levels of homocysteine plays a causal role in the occurrence of venous thrombosis [11]. Studies of genetic variants that affect homocysteine levels would reflect long-term differences in homocysteine, and be independent of confounding and concerns about reverse causality [11]. A common polymorphism exists in the gene that encodes the catalytic domain of the MTHFR enzyme, in which a C > T substitution at position 677 (referred to as 677TT) results in a substitution of alanine to valine [12]. The single amino acid substitution results in impaired folate binding and reduced activity of the MTHFR enzyme [12]. About 10–12% of Caucasians of Northern European descent carry the 677TT genotype for MTHFR and have about 25% higher homocysteine levels than those with the 677CC genotype. The effect of the MTHFR 677TT genotype on homocysteine levels varies according to folate status, whereby the difference in homocysteine levels between those with TT vs. CC genotypes is greater among those with low folate or riboflavin status than in those with normal or high levels of these vitamins [13, 14]. Individual studies and a previous meta-analysis included too few cases to produce reliable evidence for or against an association of this polymorphism with venous thrombosis [15, 16]. The aim of this study was to examine the association between homocysteine and venous thrombosis by conducting a meta-analysis of epidemiological studies on this topic and to assess if such associations are causal by conducting a meta-analysis of studies of the MTHFR 677TT genotype and venous thrombosis. Methods Data sources and study selection Eligible studies were identified by searching the electronic literature (MEDLINE) for relevant reports published between 1990 and July 2003 (using the terms homocysteine, hyperhomocysteinemia, MTHFR, methylenetetrahydrofolate reductase and venous thrombosis, pulmonary embolism, deep vein thrombosis or venous thromboembolism), by hand-searching reference lists of original articles (including meta-analyses) on this topic and by personal contact with relevant investigators in the field. The MEDLINE search yielded 443 studies and 70 retrospective or prospective studies were eligible for inclusion [4, 6, 8-10, 17-81]. Studies that primarily involved cerebral vein thrombosis or Budd–Chiari syndrome were excluded, as were studies carried out in diseased populations (e.g. inflammatory bowel syndrome, systemic lupus erythematosis or Behçet's syndrome). Studies with incomplete data or zero observations in cases or controls were excluded [3, 5, 26, 82-88]. Among the 70 individual studies that were eligible, 27 provided data on homocysteine and venous thrombosis, 53 additional studies provided data on the MTHFR C677T genotype and venous thrombosis and 10 studies that had data on homocysteine also provided data on MTHFR. It was not possible to distinguish studies that included first-time or recurrent venous thrombosis from the published reports. Data extraction and data synthesis For the meta-analysis of homocysteine and venous thrombosis, information was extracted from each report on: the odds ratio (or risk ratio) and its confidence interval; the study design — prospective (or nested case–control) or retrospective (case–control) — and the number of cases and controls. If the odds ratios (and 95% CI) were not provided, they were calculated from the number of cases and controls above and below a particular cut-off point using Woolf's method [89]. Different studies reported odds ratios on the basis of different cut-off levels, including comparisons of top and bottom thirds, quarters, fifths and top 95th vs. the rest. To estimate the log odds ratio for 5 µmol L−1 increase in homocysteine, information about the normal distribution was used to calculate the expected mean level of homocysteine in the groups being compared. For example, the mean value in the top fifth of a normal distribution is 1.4 standard deviations (SD) above the mean, and the mean in the bottom fifth is 1.4 SD below the mean. Hence, the odds ratio comparing the top vs. the bottom fifth is also the odds ratio for a 2.8 SD difference in homocysteine. Most of the studies reported odds ratios for the top 95th percentile vs. the rest, giving an odds ratio for a 2.17 SD difference in homocysteine levels [90, 91]. Wherever possible, the SD in controls was used to estimate the difference in µmol L−1 between the groups being compared in a study, but if this was not reported then a weighted average of the SDs from the studies that did report it was used. Assuming the association was log-linear, it was then possible to calculate the odds ratio for a unit change in homocysteine and hence for a 5 µmol L−1 increase in homocysteine. None of the analyses were corrected for the effects of regression dilution; that is, they relate risk to the measured values of homocysteine, rather than to the long-term average (i.e. ‘usual’) homocysteine level [92, 93], because of the limited data reported on the time between the thrombotic event and blood collection. Thus, all analyses estimate the odds ratio for a 5 µmol L−1 increase in measured homocysteine, which is approximately equivalent to a 3.5 µmol L−1 increase in usual homocysteine (i.e. after correction for regression dilution) for prospective studies (assuming a mean time to event of 5 years) and about 4.5 µmol L−1 for retrospective studies (assuming an interval between the event and blood collection of less than 1 year) [93]. For analyses of MTHFR C677T and venous thrombosis, data were collected on the frequency of CC, CT and TT genotypes in cases and controls (or calculated from the allele frequency), and the odds ratios (and 95% CI) for TT compared with CC genotypes for MTHFR were estimated using Woolf's method [89]. The studies were classified by continent as a surrogate for folate status (because the folate status of the North American population is more favorable compared with that in Europe or elsewhere) [94, 95]. For all analyses, summary estimates were obtained by taking an inverse variance weighted average of the log odds ratios from individual studies. Heterogeneity was assessed using standard χ2 tests. Results Homocysteine and venous thrombosis Data were obtained from 24 retrospective studies (n = 3289 cases) [4, 6, 15, 21-41] and three prospective or ‘nested’ case–control studies (n = 476 cases) [8-10]. Figure 1 shows the odds ratios of venous thrombosis associated with a 5 µmol L−1 increase in measured plasma total homocysteine, separately for individual studies and subtotals for prospective and retrospective studies when taken together. There was significant heterogeneity between the results of retrospective studies ( = 45.2; P = 0.004), but there was no heterogeneity between the results of prospective studies ( = 1.87; P =0.39), although with only three studies there was limited power with which to detect this. A 5 µmol L−1 increase in measured homocysteine was associated with a 27% (OR 1.27; 95% CI: 1.01–1.59) increased risk of venous thrombosis in prospective studies and a 60% (OR 1.60; 95% CI: 1.10–1.34) increased risk in retrospective studies. Figure 1Open in figure viewerPowerPoint The odds ratio of venous thrombosis for a 5 µmol L−1 increase in the measured concentration of plasma total homocysteine in individual studies. The combined odds ratio for the subtotals for each study design and their 95% CI are indicated by the diamonds. While data for three studies has been excluded in the graph of individual studies [31, 35, 37], the data from these studies are included in the subtotals. The size of the diamond is inversely proportional to the variance of the log odds ratio and the width of the diamond represents the 95% CI. MTHFR and venous thrombosis Data on the C677T polymorphism were obtained from 53 studies involving 8364 cases with venous thrombosis and 12 468 controls [10, 27, 28, 30, 35-37, 40-81]. Figure 2 shows the results of individual studies and when taken together in groups of studies classified by continent of origin as Europe, North America and elsewhere. The individual studies within each subgroup are ordered by the number of cases to evaluate publication bias. The absence of asymmetry in the distribution of the odds ratios in each continent (whereby smaller studies might yield more extreme results) excludes evidence of publication bias. Figure 2Open in figure viewerPowerPoint The odds ratio of venous thrombosis for TT vs. CC genotype for MTHFR. The symbols and convention are the same as for Fig. 1. Among the 53 studies, 30 were carried out in Europe, 11 in North America and 12 were carried out elsewhere. Overall, the 677TT genotype was associated with a 20% (OR 1.2; 95% CI 1.08–1.32) higher risk of venous thrombosis compared with the 677CC genotype, with no significant differences between the 53 studies ( = 55.2; P = 0.36). However, although not statistically significant there was an apparent difference between the studies carried out in Europe, North America or elsewhere. The 677TT genotype was associated with a 15% (OR 1.15; 95% CI: 1.02–1.30) increased risk of venous thrombosis in Europe and a 60% (OR 1.60; 95% CI: 1.27–1.02) increased risk in studies carried out elsewhere, but had no effect on venous thrombosis in North America (OR 1.03; 95% CI: 0.82–1.29). Discussion This meta-analysis of prospective and retrospective epidemiological studies demonstrates an association between an elevated plasma total homocysteine level and venous thrombosis. The odds ratio of 27% higher risk of venous thrombosis for a 5 µmol L−1 increase in homocysteine observed in prospective studies was only half as extreme as that in retrospective studies. As is the case for coronary heart disease and stroke [92], the results of prospective (or nested case–control) studies are likely to provide more reliable estimates of the risks of venous thrombosis associated with differences in homocysteine levels than the retrospective studies. However, it is likely that the 27% higher risk of venous thrombosis for a 5 µmol L−1 increase in homocysteine observed in prospective studies may be underestimated due to the effects of regression dilution (where the measured homocysteine levels may not reflect the usual homocysteine level during an observation period of about 10 years) to a greater extent compared with retrospective studies [92-94]. Both prospective and retrospective studies are influenced by confounding due to age, sex, smoking and body mass index. In this meta-analysis, the unadjusted odds ratios were abstracted from each report because the adjusted odds ratios were not routinely provided. Hence, it was not possible to control for confounding factors (as data were not available for individuals), but most of the studies had selected controls that were approximately age- and sex-matched. Analysis of individual studies where this information was provided suggests that the extent of confounding due to body mass index or smoking was not substantial. For the same reason it was not possible to distinguish between type of thrombosis (deep-vein thrombosis or pulmonary embolism) or even first-time and recurrent thrombosis. While most studies focused on first-time thrombosis, some included recurrent venous thrombosis or both recurrent and first-time thrombosis. Genetic variants affecting homocysteine levels precede the onset of disease and reflect long-term differences in homocysteine levels that are not influenced by reverse causality. Moreover, apart from effect modification by dietary intake of folate and riboflavin, it is unlikely that the effects of these genotypes on venous thrombosis will be influenced by lifestyle or other confounders [11, 95]. This meta-analysis demonstrated that the 677TT genotype was associated with a 20% increased risk of venous thrombosis. If the studies just from outside North America are combined (to minimize the effect of folate and riboflavin supplementation), the overall result is little altered [OR (95% CI) 1.23 (1.11–1.37)]. Most studies included in this meta-analysis involved less than a few hundred cases, and so the confidence intervals around the odds ratios were wide. The present meta-analysis includes more than twice the number of cases with venous thrombosis compared with those which were included in previous meta-analyses on this topic [15, 16] and provides more reliable evidence about the importance of the 677TT genotype for venous thrombosis. The odds ratios of venous thrombosis for the approximately 2.5 µmol L−1 (i.e. 25%) difference in measured levels of homocysteine associated with the TT vs. CC genotypes are approximately equivalent to the estimates derived from prospective or nested case–control studies for a 3.5 µmol L−1 difference in usual homocysteine levels. The concordance of the risk estimates from prospective (nested case–control) studies and genetic studies of venous thrombosis support the hypothesis that the association of homocysteine with venous thrombosis is causal. The risk estimates for 677TT genotype and venous thrombosis obtained from studies carried out in North America differed from those carried out in Europe and elsewhere, which may be explained by the higher dietary intake of folate and riboflavin in North America compared with Europe [20, 95, 96]. Hence, in addition to providing support for a causal association between homocysteine and venous thrombosis, the genetic studies demonstrating effect modification in North America suggest that higher vitamin intake may have a protective effect, but these inferences require confirmation in large randomized trials. A meta-analysis of the short-term trials of folic acid-based vitamin supplements showed that a daily dose of folic acid of between 0.5 and 5 mg was associated with a reduction in homocysteine levels of 25% and that vitamin B12 was associated with a further reduction of about 7%[97]. This difference in homocysteine of 25% that is typically achieved with folic acid supplements is comparable to the difference in homocysteine between 677TT and 677CC genotypes. If it could be shown that folic acid supplementation reduced the risk of venous thrombosis by 20%, this could be of substantial relevance for clinical practice and for public health. In clinical practice, measurement of homocysteine levels (and subsequent determination of folate and vitamin B12 levels if homocysteine levels are elevated) may be indicated for individuals with unexplained idiopathic venous thrombosis or recurrent venous thrombosis, or venous thrombosis occurring at early age or at an unusual site [98]. Vitamin supplements may be indicated for those individuals who are identified with evidence of folate or vitamin B12 deficiency [98], but whether such supplements may reduce the risk of recurrent venous thrombosis is not known. Large trials of folic acid-based vitamin supplements are currently testing whether lowering homocysteine levels may reduce the risk of vascular disease and further evidence is required to assess the relevance of folic acid supplementation for the prevention of venous thrombosis [99, 100]. Acknowledgements We thank Paul Sherliker for producing the figures. Robert Clarke and Sarah Lewington are supported by grants from the British Heart Foundation and Medical Research Council, European Union BIOMED (BMH4-98–3549). Martin den Heijer is recipient of a VENI-grant from the Netherlands Organization for Scientific Research. References 1 White RH. The epidemiology of venous thromboembolism. Circulation 2003; 107 (Suppl. I): I– 4–I-8. Google Scholar 2 Anderson FA, Spencer FA. Risk factors for venous thromboembolism. Circulation 2003; 107 (Suppl. I): I– 9–I-16. Google Scholar 3 Bienvenu T, Ankri A, Chadefaux B, Kamoun P. Plasma homocysteine assay in the exploration of thrombosis in young subjects. Presse Med 1991; 20: 985– 8. CASPubMedWeb of Science®Google Scholar 4 Brattstrom L, Tengborn L, Lagerstedt C, Israelsson B, Hultberg B. Plasma homocysteine in venous thromboembolism. Haemostasis 1991; 21: 51– 7. PubMedWeb of Science®Google Scholar 5 Falcon CR, Cattaneo M, Panzeri D, Martinelli I, Mannucci PM. High prevalence of hyperhomocyst(e)inemia in patients with juvenile venous thrombosis. Arterioscler Thromb 1994; 14: 1080– 3. CrossrefCASPubMedWeb of Science®Google Scholar 6 Den Heijer M, Blom HJ, Gerrits WB, Rosendaal FR, Haak HL, Wijermans PW, Bos GM. Is hyperhomocysteinaemia a risk factor for recurrent venous thrombosis? Lancet 1995; 345: 882– 5.DOI: 10.1016/S0140-6736(95)90008-X CrossrefPubMedGoogle Scholar 7 Den Heijer M, Koster T, Blom HJ, Bos GM, Briet E, Reitsma PH, Vandenbroucke JP, Rosendaal FR. Hyperhomocysteinemia and venous thrombosis: a meta-analysis. Thromb Haemost 1998; 80: 874– 7. CASPubMedWeb of Science®Google Scholar 8 Ridker PM, Hennekens CH, Selhub J, Miletich JP, Malinow MR, Stampfer MJ. Interrelation of hyperhomocyst(e)inemia, factor V Leiden, and risk of future venous thromboembolism. Circulation 1997; 95: 1777– 82. CrossrefCASPubMedWeb of Science®Google Scholar 9 Eichinger S, Stumpfen A, Hirschl M, Bialonczyk C, Herkner M, Stain M, Schneider, B, Pabinger I, Lechner K, Kyrle PA. Hyperhomocysteinemia is a risk factor of recurrent thromboembolism. Thromb Haemost 1998; 80: 566– 9. CASPubMedWeb of Science®Google Scholar 10 Tsai AW, Cushman M, Tsai MY, Heckbert SR, Rosamond WD, Aleksic NN, Yanez D, Psaty BM, Folsom AR. Serum homocysteine, thermolabile variant of methylene tetrahydrofolate reductase (MTHFR), and venous thromboembolism: longitudinal investigation of thromboembolism (LITE). Am J Hematol 2003; 72: 192– 200.DOI: 10.1002/ajh.10287 Wiley Online LibraryCASPubMedWeb of Science®Google Scholar 11 Davey Smith G, Ebrahim S. ‘Mendelian randomization’: can genetic epidemiology contribute to understanding environmental determinants of disease? Int J Epidemiol 2003; 32: 1– 22.DOI: 10.1093/ije/dyg070 CrossrefPubMedWeb of Science®Google Scholar 12 Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJH, Den Heijer M, Kluijtmans LAJ, Van Den Heuvel LP, Rozen R. A candidate genetic risk factor for vascular disease: a common mutation in methylene tetrahydrofolate reductase. Nature Genet 1995; 10: 111– 13.DOI: 10.1038/ng0595-111 CrossrefCASPubMedWeb of Science®Google Scholar 13 Jacques PF, Bostom AG, Williams RR, Ellison RC, Eckfeldt JH, Rosenberg IH, Selhub J, Rosen R. Relation between folate status, a common mutation between methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation 1996; 93: 7– 9. CrossrefCASPubMedWeb of Science®Google Scholar 14 Hustad S, Ueland PM, Vollset SE, Zhang Y, Bjorke-Monsen AL, Schneede J. Riboflavin as a determinant of plasma total homocysteine: effect modification by methylenetetrahydrofolate reductase C677T polymorphism. J Clin Chem 2000; 46: 1065– 71. CASPubMedWeb of Science®Google Scholar 15 Ray JG, Shmorgun D, Chan WS. Common C677T polymorphism of the methylenetetrahydrofolate reductase gene and the risk of venous thromboembolism: meta-analysis of 31 studies. Pathophysiol Haemost Thromb 2002; 32: 51– 8.DOI: 10.1159/000065076 CrossrefCASPubMedWeb of Science®Google Scholar 16 Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ 2002; 325: 1202– 8. CrossrefPubMedWeb of Science®Google Scholar 17 Arruda VR, Von Zuben PM, Chiaparini LC, Annichino-Bizzacchi JM, Costa FF. The mutation Ala677→Val in the methylene tetrahydrofolate reductase gene: a risk factor for arterial disease and venous thrombosis. Thromb Haemost 1997; 77: 818– 21. CASPubMedWeb of Science®Google Scholar 18 Tosetto A, Missiaglia E, Frezzato M, Rodeghiero F. The VITA project: C677T mutation in the methylene-tetrahydrofolate reductase gene and risk of venous thromboembolism. Br J Haematol 1997; 97: 804– 6.DOI: 10.1046/j.1365-2141.1997.1422957.x Wiley Online LibraryPubMedWeb of Science®Google Scholar 19 Salden A, Keeney S, Hay CR, Cumming AM. The C677T MTHFR variant and the risk of venous thrombosis. Br J Haematol 1997; 99: 472. CASPubMedWeb of Science®Google Scholar 20 Cattaneo M, Tsai MY, Bucciarelli P, Taioli E, Zighetti ML, Bignell M, Mannucci PM. A common mutation in the methylenetetrahydrofolate reductase gene (C677T) increases the risk for deep-vein thrombosis in patients with mutant factor V (factor V:Q506). Arterioscler Thromb Vasc Biol 1997; 17: 1662– 6. CrossrefCASPubMedWeb of Science®Google Scholar 21 Amundsen T, Ueland PM, Waage A. Plasma homocysteine levels in patients with deep venous thrombosis. Arterioscler Thromb Vasc Biol 1995; 15: 1321– 3. CrossrefCASPubMedWeb of Science®Google Scholar 22 Fermo I, Vigano'D'Angelo S, Paroni R, Mazzola G, Calori G, D'Angelo A. Prevalence of moderate hyperhomocysteinemia in patients with early-onset venous and arterial occlusive disease. Ann Intern Med 1995; 123: 747– 53. CrossrefPubMedWeb of Science®Google Scholar 23 Den Heijer M, Koster T, Blom HJ, Bos GM, Briet E, Reitsma PH, Vandenbroucke JP, Rosendaal FR. Hyperhomocysteinemia as a risk factor for deep-vein thrombosis. N Engl J Med 1996; 334: 759– 62.DOI: 10.1056/NEJM199603213341203 CrossrefPubMedWeb of Science®Google Scholar 24 Cattaneo M, Martinelli I, Mannucci PM. Hyperhomocysteinemia as a risk factor for deep-vein thrombosis. N Engl J Med 1996; 335: 974– 5. CrossrefPubMedWeb of Science®Google Scholar 25 Simioni P, Prandoni P, Burlina A, Tormene D, Sardella C, Ferrari V, Benedetti L, Girolami A. Hyperhomocysteinemia and deep-vein thrombosis. A case–control study. Thromb Haemost 1996; 76: 883– 6. CrossrefCASPubMedWeb of Science®Google Scholar 26 Vargas M, Soto I, Pinto CR, Urgelles MF, Coto E. Mild hyperhomocysteinemia and MTHFR C677T do not increase the risk for venous thrombosis in a Spanish population. Blood Coagul Fibrinolysis 1998; 9: 555– 6. CrossrefCASPubMedWeb of Science®Google Scholar 27 Quere I, Chasse JF, Dupuy E, Bellet E, Molho-Sabatier P, Tobelem G, Janbon C. Homocysteine, 5,10-methylenetetrahydrofolate reductase and deep venous thrombosis. Survey of 120 patients in internal medicine. Rev Med Interne 1998; 19: 29– 33.DOI: 10.1016/S0248-8663(97)83696-X CrossrefCASPubMedWeb of Science®Google Scholar 28 Gemmati D, Previati M, Serino ML, Moratelli S, Guerra S, Capitani S, Forini E, Ballerini G, Scapoli GL. Low folate levels and thermolabile methylenetetrahydrofolate reductase as primary determinant of mild hyperhomocystinemia in normal and thromboembolic subjects. Arterioscler Thrombvasc Biol 1999; 19: 1761– 7. CrossrefCASPubMedWeb of Science®Google Scholar 29 Bozic M, Stegnar M, Fermo I, Ritonja A, Peternel P, Stare J, D'Angelo A. Mild hyperhomocysteinemia and fibrinolytic factors in patients with history of venous thromboembolism. Thromb Res 2000; 100: 271– 8. CrossrefCASPubMedWeb of Science®Google Scholar 30 De Franchis R, Fermo I, Mazzola G, Sebastio G, Di Minno G, Coppola A, Andria G, D'Angelo A. Contribution of the cystathionine betasynthase gene (844ins68) polymorphism to the risk of early-onset venous and arterial occlusive disease and of fasting hyperhomocysteinemia. Thromb Haemost 2000; 84: 576– 82. CASPubMedWeb of Science®Google Scholar 31 De Stefano V, Zappacosta B, Persichilli S, Rossi E, Casorelli I, Paciaroni K, Chiusolo P, Leone AM, Giardina B, Leone G. Prevalence of mild hyperhomocysteinaemia and association with thrombophilic genotypes (factor V Leiden and prothrombin G20210A) in Italian patients with venous thromboembolic disease. Br J Haematol 1999; 106: 564– 8.DOI: 10.1046/j.1365-2141.1999.01613.x Wiley Online LibraryCASPubMedWeb of Science®Google Scholar 32 D'Angelo A, Coppola A, Madonna P, Fermo I, Pagano A, Mazzola G, Galli L, Cerbone AM. The role of vitamin B12 in fasting hyperhomocysteinemia and its interaction with the homozygous C677T mutation of the methylenetetrahydrofolate reductase (MTHFR) gene. A case–control study of patients with early-onset thrombotic events. Thromb Haemost 2000; 83: 563– 70. CASPubMedWeb of Science®Google Scholar 33 Langman LJ, Ray JG, Evrovski J, Yeo E, Cole DE. Hyperhomocyst(e)inemia and the increased risk of venous thromboembolism: more evidence from a case–control study. Arch Intern Med 2000; 160: 961– 4.DOI: 10.1001/archinte.160.7.961 CrossrefCASPubMedWeb of Science®Google Scholar 34 Cattaneo M, L
Referência(s)