The risk of venous and arterial thrombosis in hyperhomocysteinaemia is low and mainly depends on concomitant thrombophilic defects

Willem M. Lijfering; Michiel Coppens; Marlène H. W. van de Poel; Saskia Middeldorp; Karly Hamulyák; Ivan Bank; Nic J. G. M. Veeger; Martin H. Prins; Harry R. Büller; Jan van der Meer

doi:10.1160/TH07-02-0138

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2007; 98(02): 457-463
DOI: 10.1160/TH07-02-0138

New Technologies, Diagnostic Tools and Drugs

Schattauer GmbH

The risk of venous and arterial thrombosis in hyperhomocysteinaemia is low and mainly depends on concomitant thrombophilic defects

Willem M. Lijfering

¹Division of Haemostasis, Thrombosis and Rheology, Department of Hematology, University Medical Center Groningen, Groningen, The Netherlands

,

Michiel Coppens

²Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands

,

Marlène H. W. van de Poel

¹Division of Haemostasis, Thrombosis and Rheology, Department of Hematology, University Medical Center Groningen, Groningen, The Netherlands

,

Saskia Middeldorp

²Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands

,

Karly Hamulyák

³Department of Hematology, University Hospital Maastricht, Maastricht, The Netherlands

,

Ivan Bank

²Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands

,

Nic J. G. M. Veeger

¹Division of Haemostasis, Thrombosis and Rheology, Department of Hematology, University Medical Center Groningen, Groningen, The Netherlands

,

Martin H. Prins

⁴Department of Clinical Epidemiology and Medical Technology Assessment, University Hospital Maastricht, Maastricht, The Netherlands.

,

Harry R. Büller

²Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands

,

Jan van der Meer

¹Division of Haemostasis, Thrombosis and Rheology, Department of Hematology, University Medical Center Groningen, Groningen, The Netherlands

› Author Affiliations

Abstract

Summary

As homocysteine-lowering treatment has not reduced the risk of recurrent thrombosis in recent clinical trials, we hypothesized that mild hyperhomocysteinaemia is an epiphenomenon or associated with a low absolute risk of thrombosis. In this retrospective study, we enrolled 478 evaluable first-degree relatives of consecutive patients with venous thrombosis or premature atherosclerosis, and hyperhomocysteinemia. Absolute risks of thrombosis and effects of concomitant thrombophilic defects were compared. Relative risks were adjusted for clustering in families, age, sex, and atherosclerotic risk factors, where appropriate. Annual incidence of venous thrombosis was 0.16% (95% confidence interval [CI], 0.08–0.30) in hyperhomocysteinemic relatives versus 0.11% (CI, 0.05–0.20) in normohomocysteinemic relatives; adjusted relative risk 1.6 (CI, 0.6–4.5). Annual incidences of arterial thrombosis were 0.34% (CI, 0.21–0.52) and 0.24% (CI, 0.15–0.37) in hyperhomocysteinemic and normohomocysteinemic relatives, respectively; adjusted relative risk 1.5 (CI, 0.6–3.5). Concomitance of multiple thrombophilic risk factors increased the risk of venous thrombosis in hyperhomocysteinemic relatives 20 fold, but a comparable effect was demonstrated in normohomocysteinemic relatives. We conclude that hyperhomocysteinaemia is associated with a low absolute risk of venous and arterial thrombosis. Concomitant thrombophilic defects are probably main determinants on the risk of venous thrombosis, rather than hyperhomocysteinaemia itself.

Keywords

Clinical studies - risk factors - venous thrombosis - arterial thrombosis - thrombophilia

Full Text

References

References
1 Undas A, Brozek J, Szczeklik A. Homocysteine and thrombosis: from basic science to clinical evidence. Thromb Haemost 2005; 94: 907-915.
2 Ray JG. Meta-analysis of hyperhomocysteinemia as a risk factor for venous thromboembolic disease. Arch Intern Med 1998; 158: 2101-2106.
3 Homocysteine Studies Collaboration.. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. J Am Med Assoc 2002; 288: 2015-2022.
4 Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. Br Med J 2002; 325: 1202.
5 den Heijer M, Rosendaal FR, Blom HJ, Gerrits WB, Bos GM. Hyperhomocysteinemia and venous thrombosis: a meta-analysis. Thromb Haemost 1998; 80: 874-877.
6 Selhub J, Jacques PF, Wilson PW, Rush D, Rosenberg IH. Vitamin status and in take as primary determinants of homocysteinemia in an elderly population. J Am Med Assoc 1993; 270: 2693-2698.
7 Toole JF, Malinow MR, Chambless LE. et al. Lowering homocysteine in patients with is chemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. J Am Med Assoc 2004; 291: 565-575.
8 Bonaa KH, Njolstad I, Ueland PM. et al NORVIT Trial Investigators.. Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med 2006; 354: 1578-1588.
9 den Heijer M, Willems HP, Blom HJ. et al. Homocysteine lowering by B vitamins and the secondary prevention of deep-vein thrombosis and pulmonary embolism. A randomized, placebo-controlled, double blind trial. Blood 2007; 109: 139-144.
10 Frezzato M, Tosetto A, Rodeghiero F. Validated questionnaire for the identification of previous personal or familial venous thromboembolism. Am J Epidemiol 1996; 143: 1257-1265.
11 Araki A, Sako Y. Determination of free and total homocysteine in human plasma by high-performance liquid chromatography with fluorescence detection. J Chromatogr 1987; 422: 43-52.
12 vander Griend R, Haas FJ, Duran M, Biesma DH, Meuwissen OJ, Banga JD. Methionine loading test is necessary for detection of hyperhomocysteinemia. J Lab Clin Med 1998; 132: 67-72.
13 Bertina RM, Koeleman BP, Koster T. et al. Mutationin blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64-67.
14 Danneberg J, Abbes AP, Bruggeman BJ, Engel H, Gerrits J, Martens A. Reliable genotyping of the G-20210-A mutation of coagulation factor II (prothrombin). Clin Chem 1998; 44: 349-351.
15 Koster T, Blann AD, Briet E, Vandenbroucke JP, Rosendaal FR. Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis. Lancet 1995; 345: 152-155.
16 Bank I, Libourel EJ, Middeldorp S. et al. Elevated levels of FVIII: C within families are associated with an increased risk for venous and arterial thrombosis. J Thromb Haemost 2005; 3: 79-84.
17 Rees DC, Cox M, Clegg JB. World distribution of factor V Leiden. Lancet 1995; 346: 1133-1134.
18 Nordstrom M, Lindblad B, Bergqvist D, Kjellstrom T. A prospective study of the incidence of deep-vein thrombosis within a defined urban population. J Intern Med 1992; 232: 155-160.
19 Anderson Jr FA, Wheeler HB, Goldberg RJ, Hosmer DW, Forcier A. The prevalence of risk factors for venous thromboembolism among hospital patients. Arch Intern Med 1992; 152: 1660-1664.
20 den Heijer M, Koster T, Blom HJ. et al. Hyperhomocysteinemia as a risk factor for deep-vein thrombosis. N Engl J Med 1996; 344: 759-761.
21 Rosendaal FR. Venous thrombosis: a multicausal disease. Lancet 1999; 353: 1167-1173.
22 Thom TJ, Kannel WB, Silbershatz H, D’Agostino RB. Incidence, prevalence, and mortality of cardiovascular diseases in the United States. In: Hurst’s the Heart. 9^th ed. McGraw-Hill; 1998. p 3-17.
23 Hofmann MA, Lalla E, Lu Y. et al. Hyperhomocysteinemia enhances vascular inflammation and accelerates atherosclerosis in a murine model. J Clin Invest 2001; 107: 675-683.
24 Zhou J, Moller J, Danielsen CC. et al. Dietary supplementation with methionine and homocysteine promotes early atherosclerosis but not plaque rupture in ApoE-deficient mice. Arterioscler Thromb Vasc Biol 2001; 21: 1470-1476.
25 Woo KS, Chook P, Lolin YI. et al. Hyperhomocyst(e)inemia is a risk factor for arterial endothelial dysfunction in humans. Circulation 1997; 96: 2542-2544.
26 Tawakol A, Omland T, Gerhard M. et al. Hyperhomocyst(e)inemia is associated with impaired endothelium-dependent vasodilation in humans. Circulation 1997; 95: 1119-1121.
27 Woo KS, Chook P, Lolin YI. et al. Folate therapy and in-stent restenosis after coronary stenting. N Engl J Med 2004; 350: 2673-2681.
28 Marongiu F, Fenu L, Pisu G, Contu P, Barcellona D. Hyperhomocysteinemia: could the post-methionine oral loading test sometimes be avoided?. Haematologica 2003; 88: 186-191.