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• W2108387519 abstract "Venous thrombosis is considered as a multicausal disease. Hyperhomocysteinemia is considered as one of the risk factors for venous thrombosis [1Den Heijer M. Lewington S. Clarke R. Homocysteine, MTHFR and risk of venous thrombosis: a meta‐analysis of published epidemiological studies.J Thromb Haemost. 2005; 3: 292-9Abstract Full Text Full Text PDF PubMed Scopus (368) Google Scholar]. Because homocysteine levels are strongly influenced by the intake and concentrations of B vitamins, it is worthwhile to assess the role of these vitamins as a risk factor for venous thrombosis. Venous thrombosis is considered as a multicausal disease. Hyperhomocysteinemia is considered as one of the risk factors for venous thrombosis [1Den Heijer M. Lewington S. Clarke R. Homocysteine, MTHFR and risk of venous thrombosis: a meta‐analysis of published epidemiological studies.J Thromb Haemost. 2005; 3: 292-9Abstract Full Text Full Text PDF PubMed Scopus (368) Google Scholar]. Because homocysteine levels are strongly influenced by the intake and concentrations of B vitamins, it is worthwhile to assess the role of these vitamins as a risk factor for venous thrombosis. What are B vitamins? The name vitamin was first used in the beginning of the 20th century. They were categorized according to their chemical characteristics into vitamin A, B, C, D, E, and K. Vitamin B was distinguished from the other vitamins because it is soluble in water [2Truswell S. Milne R. The B vitamins.in: Mann J Truswell AS Essentials of Human Nutrition. Oxford University, 2002: 209-30Google Scholar]. Later it was shown that B vitamin is not one chemical substance but a group of different agents: vitamin B1 (thiamin), vitamin B2 (riboflavin), vitamin B3 (niacin), vitamin B5 (panthothenic acid), vitamin B6 (pyridoxin), vitamin B11 (folate) and vitamin B12 (cobalamin). For most of these vitamins several chemical forms are described with different bioactivities. Although vitamins play different roles, the most common role is their function as a co‐factor for enzymes. To answer the question whether B vitamins are a risk factor for venous thrombosis, we should make clear which vitamins we are speaking about. A ‘PubMed’‐search yielded no meaningful hits for thiamin and venous thrombosis, or panthothenic acid and thrombosis. Niacin (nicotinic acid) increases high‐density lipoprotein cholesterol and is therefore of interest in atherosclerosis, but there is no literature concerning venous thrombosis. The remaining B vitamins folate, pyridoxine, cobalamin and riboflavin are all related to homocysteine metabolism. So, in the remainder of this paper, we should focus our attention on the question: are homocysteine‐related B vitamins a risk factor for venous thromboembolism? The term B vitamins could refer to plasma concentration, intracellular function (often referred to as status), intake, or supplementation. Because there are no studies on vitamin intake and also no published trials on vitamin supplementation, we restrict our enquiry to the question: are plasma concentrations (or markers of status) of homocysteine‐related vitamins a risk factor for venous thrombosis? This question is important because it is related to the question of causality of homocysteine with respect to venous thrombosis. My very first paper on homocysteine metabolism precisely deals with this question and was entitled ‘Will a decrease of blood homocysteine by vitamin supplementation reduce the risk for vascular disease?’ [3Den Heijer M. Bos G.M.J. Gerrits W.B.J. Blom H.J. Will a decrease of blood homocysteine by vitamin supplementation reduce the risk for vascular disease.Fibrinolysis. 1994; 8: 91-2Crossref Scopus (12) Google Scholar]. In this paper, I discussed the observation in our study on recurrent venous thrombosis [4Den Heijer M. Blom H.J. Gerrits W.B. Rosendaal F.R. Haak H.L. Wijermans P.W. Bos G.M. Is hyperhomocysteinaemia a risk factor for recurrent venous thrombosis.Lancet. 1995; 345: 882-5Crossref PubMed Scopus (364) Google Scholar] that homocysteine concentrations were higher in patients and could be interpreted as a risk factor, but concentrations of folate and vitamin B12 were not lower in patients compared with control subjects, which pleads against a beneficial effect of these vitamins in the prevention of thrombosis. In addition to the criteria of Sir Bradford Hill [5Bradford Hill A. The environment and disease: association or causation.Proc Royal Soc Med. 1966; 58: 295Crossref Scopus (7360) Google Scholar], one could formulate that if a certain factor is a cause of a disease then it could be supposed that, in principle, every determinant of that cause in itself should be a cause (risk factor) for that disease. This statement is gently extended for genetic determinants of metabolic risk factor in the theory of ‘Mendelian randomization’ [6Davey Smith G. Ebrahim S. Mendelian randomization: can genetic epidemiology contribute to understanding environmental determinants of disease.Int J Epidemiol. 2003; 32: 1-22Crossref PubMed Scopus (2586) Google Scholar], but is to some extent also true for non‐genetic determinants (although the relation with these non‐genetic determinants is of course much more sensitive to confounding). So if plasma homocysteine concentration is associated with venous thrombosis and plasma homocysteine is determined by the concentration of B vitamins, the finding that B vitamins are a risk factor for venous thrombosis supports the view that homocysteine is causally related to venous thrombosis, where the absence of such an effect pleads against a causal relationship. If B vitamins are not a risk factor for thrombosis then it is very unlikely that supplementation of B vitamins will reduce the risk of venous thrombosis. All studies regarding B vitamins and venous thrombosis are studies on homocysteine and venous thrombosis, and in these studies folate, vitamin B12 and vitamin B6 concentrations are measured. No studies on vitamin B2 concentration and venous thrombosis have been found. Regarding folate, vitamin B12 and vitamin B6, several papers have presented only mean or median vitamin B concentrations. [4Den Heijer M. Blom H.J. Gerrits W.B. Rosendaal F.R. Haak H.L. Wijermans P.W. Bos G.M. Is hyperhomocysteinaemia a risk factor for recurrent venous thrombosis.Lancet. 1995; 345: 882-5Crossref PubMed Scopus (364) Google Scholar, 7Brattstrom L. Tengborn L. Lagerstedt C. Israelsson B. Hultberg B. Plasma homocysteine in venous thromboembolism.Haemostasis. 1991; 21: 51-7PubMed Google Scholar, 8Gemmati D. Previati M. Serino M.L. Moratelli S. Guerra S. Capitani S. Forini E. Ballerini G. Scapoli G.L. Low folate levels and thermolabile methylenetetrahydrofolate reductase as primary determinant of mild hyperhomocystinemia in normal and thromboembolic subjects.Arterioscler Thromb Vasc Biol. 1999; 19: 1761-7Crossref PubMed Scopus (70) Google Scholar, 9D'Angelo A. Coppola A. Madonna P. Fermo I. Pagano A. Mazzola G. Galli L. Cerbone A.M. 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: 563-70Crossref PubMed Scopus (105) Google Scholar]. Surprisingly, most of these studies reported higher mean or median folate and vitamin B12 levels in patients. However, a difference in mean or median vitamin level in patients and control subjects is not a very sensitive measure of risk. Only five studies give risk estimates for low vitamin levels. The first study was published by Cattaneo et al. [10Cattaneo M. Lombardi R. Lecchi A. Bucciarelli P. Mannucci P.M. Low plasma levels of vitamin B(6) are independently associated with a heightened risk of deep‐vein thrombosis.Circulation. 2001; 104: 2442-6Crossref PubMed Scopus (72) Google Scholar] who did a case–control study in 397 patients with previous venous thrombosis and 585 control subjects. Next to homocysteine, folate vitamin B12 and vitamin B6 were measured and stratified in quartiles. There was an increased risk for the lowest compared with the highest vitamin B6 quartile [OR 1.5 (95% CI 1.0–2.1)], which remained after the adjustment for other risk factors and even after adjustment for the other vitamins and homocysteine concentration [OR 1.8 (95% CI 1.2–2.8)]. No effect was found for folate or vitamin B12 in the lowest quartile. The second study was published by Quere et al. [11Quere I. Perneger T.V. Zittoun J. Bellet H. Gris J.C. Daures J.P. Schved J.F. Mercier E. Laroche J.P. Dauzat M. Bounameaux H. Janbon C. De Moerloose P. Red blood cell methylfolate and plasma homocysteine as risk factors for venous thromboembolism: a matched case–control study.Lancet. 2002; 359: 747-52Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar] who did a matched case–control study in 243 patients with venous thrombosis. Next to homocysteine, folate and vitamin B12 in serum and 5‐methyltetrahydrofolate, and total folate were measured in red blood cells. A strong effect was found for low 5‐methyltetrathydrofolate in red bloods cells [OR 4.49 (95%CI 2.48–8.14) for the bottom vs. top quartile], which remained after adjustment for homocysteine while the effect of homocysteine itself disappeared. The third study was published by Diaz de Tuesta et al. [12Diaz de Tuesta A.M. Ribo M.D. Belinchon O. Marchena P.J. Bruscas M.J. Val E. Cortes A. Nieto J.A. Low levels of vitamin B12 and venous thromboembolic disease in elderly men.J Intern Med. 2005; 258: 244-9Crossref Scopus (13) Google Scholar]. They studied 101 patients with venous thrombosis and 101 control subjects matched for age and sex. Homocysteine was higher and folate somewhat lower in patients compared with control subjects, but the difference in vitamin B12 levels was stronger. After stratification in quartiles, the risk for the bottom vs. top quartile was 3.82 (95%CI 1.44–10.18). This effect of folate and vitamin B12 was also reported by Obeid et al. [13Obeid R. Hakki T. Jouma M. Herrmann W. The risk of venous thromboembolism associated with the factor V Leiden mutation and low B‐vitamin status.Clin Chem Lab Med. 2003; 41: 1357-62Crossref PubMed Scopus (9) Google Scholar] in a study of 78 patients with venous thrombosis and 98 control subjects. Finally, Cantu et al. [14Cantu C. Alonso E. Jara A. Martinez L. Rios C. Fernandez Mde L. Garcia I. Barinagarrementeria F. Hyperhomocysteinemia, low folate and vitamin B12 concentrations, and methylene tetrahydrofolate reductase mutation in cerebral venous thrombosis.Stroke. 2004; 35: 1790-4Crossref PubMed Scopus (101) Google Scholar] reported that low folate and vitamin B12 concentrations are a risk factor for cerebral venous thrombosis in a study of 45 patients and 90 control subjects. So, there is some evidence that a low B vitamins concentration is a risk factor for venous thrombosis, but studies are sparse. Unfortunately, several studies did not measure all the relevant B vitamins. Except the study of Cattaneo et al., no studies measured vitamin B6 concentrations. It is surprising that some studies found folate, some found vitamin B12, and others found vitamin B6 to be the critical B vitamin. With this small number of studies, it might be that this is a matter of change. On the other hand, it might be hypothesized that this is influenced by the geographical (nutrional) status. In other words, it might be that in an area that is borderline sufficient for folate and sufficient for vitamin B12 and vitamin B6, folate is the key B vitamin associated with thrombotic risk while in an other area in which, for instance, vitamin B6 is borderline sufficient, this vitamin turns out to be the key risk factor. Next to the question whether homocysteine‐related B vitamins are a risk factor for venous thrombosis, the question arises whether B vitamins are a risk factor independently of homocysteine. This is suggested by the studies of Cattaneo et al. [10Cattaneo M. Lombardi R. Lecchi A. Bucciarelli P. Mannucci P.M. Low plasma levels of vitamin B(6) are independently associated with a heightened risk of deep‐vein thrombosis.Circulation. 2001; 104: 2442-6Crossref PubMed Scopus (72) Google Scholar] and Quere et al. [11Quere I. Perneger T.V. Zittoun J. Bellet H. Gris J.C. Daures J.P. Schved J.F. Mercier E. Laroche J.P. Dauzat M. Bounameaux H. Janbon C. De Moerloose P. Red blood cell methylfolate and plasma homocysteine as risk factors for venous thromboembolism: a matched case–control study.Lancet. 2002; 359: 747-52Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar] In fact, this is an unexpected finding, because the question about B vitamins and venous thrombosis arose from the fact that homocysteine is a risk factor and homocysteine is influenced by certain B vitamins. So, if we find an effect of B vitamins, it is most likely that this effect would be mediated by homocysteine concentrations. Nevertheless, the papers mentioned above do show that the effect is independent of homocysteine. The question then is: what do we mean by independent. The conclusion of independent effect is based on the results of regression analysis. The general opinion is that a factor is independent from another factor if the corresponding coefficient in a regression model does not change materially after including the other factor in the model. In the studies of Cattaneo et al. and Quere et al., this seems to be true. However, these studies did not take into account that homocysteine and B vitamin concentrations are correlated and that both are measured with (probably different) error and biological variation. Furthermore, the dose–response relationship between homocysteine and thrombosis and B vitamins and thrombosis might be different, which might affect the multivariate analysis. In conclusion, some studies do report that low B vitamin concentration is a risk factor for venous thrombosis. However, the number of studies is very limited and they are conflicting regarding which B vitamin is a risk factor. Martin den Heijer is recipient of a VENI‐grant from the Netherlands Foundation of Scientific Research." @default.
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• W2108387519 title "Are B vitamins a risk factor for VTE? Perhaps" @default.
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