Correspondence
Hyperhomocysteinemia as a Risk Factor for Deep-Vein Thrombosis
N Engl J Med 1996; 335:974-976September 26, 1996
- Article
To the Editor:
The article by den Heijer et al. (March 21 issue)1 supports our finding that hyperhomocysteinemia is a risk factor for deep-vein thrombosis that is independent of coexisting abnormalities of naturally occurring anticoagulants.2 This important confirmation challenges the suggestion by Mandel et al., in their article in the same issue,3 that hyperhomocysteinemia increases the risk of thrombosis only if the elevation in homocysteinemia is associated with the presence of factor V Leiden.
Unlike our study of patients with early-onset deep-vein thrombosis2 and their previous study of patients with recurrent deep-vein thrombosis,4 the current study by den Heijer et al. reports on patients with a first episode of deep-vein thrombosis who were younger than 70 years of age, in order to estimate the risk in the general population. Den Heijer et al. may have underestimated the actual risk, because they measured homocysteine levels only in the fasting state. Patients with abnormalities of homocysteine metabolism, particularly those with abnormalities of the vitamin B6–dependent transsulfuration pathway, may have normal homocysteine levels in the fasting state but abnormal levels after oral methionine loading.5 Patients with hyperhomocysteinemia after methionine loading are at increased risk for early-onset2 and recurrent4 deep-vein thrombosis, and a substantial proportion (39 to 53 percent) have normal homocysteine levels in the fasting state. It therefore remains to be established whether patients with hyperhomocysteinemia after methionine loading are also at increased risk for a first episode of deep-vein thrombosis.
We measured plasma homocysteine levels before and after oral methionine loading (3.8 g per square meter of body-surface area) in 89 consecutive patients with a first episode of objectively confirmed deep-vein thrombosis and in 89 age- and sex-matched healthy controls. No subject had decreased serum concentrations of folate or vitamin B12. Homocysteine was measured in EDTA-treated plasma by high-performance liquid chromatography and electrochemical detection.2 There was a higher prevalence of hyperhomocysteinemia in the fasting state and after methionine loading in the patients with deep-vein thrombosis than in the controls (Table 1Table 1
Prevalence of Hyperhomocysteinemia in the Fasting State and after Methionine Loading in 89 Patients with a First Episode of Deep-Vein Thrombosis and 89 Controls.). The data in Table 1 also show that since many of the patients with hyperhomocysteinemia after methionine loading had normal homocysteine levels in the fasting state, the combination of the two tests identified a larger number of patients with thrombosis and impaired homocysteine metabolism than either test alone. The detection of deep-vein thrombosis in patients with hyperhomocysteinemia after methionine loading has important clinical implications, since the metabolic abnormality may be corrected by vitamin supplements containing a high dose of vitamin B6, in addition to folate and vitamin B12.5 ReferencesMarco Cattaneo, M.D.
Ida Martinelli, M.D.
Pier Mannuccio Mannucci, M.D.
University of Milan, 20122 Milan, Italy1
den Heijer M ,Koster T ,Blom HJ , et al. Hyperhomocysteinemia as a risk factor for deep-vein thrombosis. N Engl J Med 1996;334:759-762
Full Text | Web of Science | Medline2
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;14:1080-1083
CrossRef | Medline3
Mandel H ,Brenner B ,Berant M , et al. Coexistence of hereditary homocystinuria and factor V Leiden -- effect on thrombosis. N Engl J Med 1996;334:763-768
Full Text | Web of Science | Medline4
den Heijer M ,Blom HJ ,Gerrits WB , et al. Is hyperhomocysteinaemia a risk factor for recurrent venous thrombosis? Lancet 1995;345:882-885
CrossRef | Web of Science | Medline5
Rees MM ,Rodgers GM . Homocysteinemia: association of a metabolic disorder with vascular disease and thrombosis. Thromb Res 1993;71:337-359
CrossRef | Web of Science | Medline
To the Editor:
In their case–control study, den Heijer et al. found mildly elevated plasma homocysteine levels among 269 patients with deep-vein thrombosis. They concluded that plasma hyperhomocysteinemia is a risk factor for deep-vein thrombosis. The authors note that elevated homocysteine levels may result from low levels of folate, vitamin B6, or vitamin B12. They fail to mention, however, that deficiencies in these vitamins represent potential confounders in their study.
All the patients with deep-vein thrombosis were recruited from anticoagulation clinics and were presumably given warfarin, unlike the controls. Patients taking warfarin are commonly instructed to avoid foods high in vitamin K. Although vitamin K is the focus of these recommendations, subtle deficiencies in other nutrients may also occur. If the patients in the study by den Heijer et al. had deficiencies in folate, vitamin B6, or vitamin B12 as a result of dietary modification, the result would be an elevation in the plasma homocysteine level, contaminating the results of the study.
Michael W. Jacobson, M.D., M.P.H.
Lenox Hill Hospital, New York, NY 10021Author/Editor Response
The authors reply:
To the Editor: Cattaneo et al. comment on the place of the methionine-loading test in the definition of hyperhomocysteinemia. The methionine-loading test was intended to identify heterozygotes for a deficiency of cystathionine-β-synthase (CS) — a key enzyme in the transsulfuration pathway.1 Patients with homozygous CS deficiency (classic homocystinuria) have severe vascular disease and thrombosis at an early age. On the basis of this observation, it was hypothesized that heterozygosity for CS deficiency may initiate or exacerbate atherosclerosis. Therefore, many case–control studies were performed with a methionine-loading test, and an abnormal result was frequently considered to indicate heterozygous homocystinuria.
Recent research shows that abnormal results of the loading tests cannot be explained — or can only partly be explained — by heterozygosity for CS.2 In contrast, many patients with abnormal results of the loading test had mutated methylenetetrahydrofolate reductase, an enzyme that functions in the remethylation pathway.2,3 We therefore believe that the common view that the homocysteine level in the fasting state reflects the remethylation pathway (dependent on folate, vitamin B12, and methylenetetrahydrofolate reductase) and the homocysteine level after methionine loading reflects the transsulfuration pathway (dependent on vitamin B6 and CS) needs correction.
The need to correct this view is supported by the data, presented by Cattaneo and colleagues, on homocysteine levels in the fasting state and after methionine loading in patients with first-time venous thrombosis and in healthy controls. The odds ratios associated with elevated levels in the fasting state and after methionine loading are very similar, indicating that the postloading test has little additional value. The slightly higher odds ratio for patients with elevated levels during fasting or after methionine loading may be the result of the natural and assay-specific variation in homocysteine levels: repeated measurements with one or the other test, or both, increase the overall sensitivity (regression dilution bias).4
Indeed, our findings are at variance with those of Mandel and colleagues, who found thrombosis only in patients with homozygous CS deficiency who were also carriers of the factor V Leiden mutation.5 Mandel et al. reported on highly consanguineous pedigrees, in which only 6 patients had thrombosis (of 11 with homozygous CS deficiency). Classic homocystinuria (i.e., CS deficiency) is an uncommon disorder and, as noted above, may be a different entity from mild hyperhomocysteinemia.
In our study, we found that the risk of thrombosis associated with hyperhomocysteinemia was not affected by the concomitant presence of factor V Leiden. Few subjects in our study had both abnormalities. Although we are confident that hyperhomocysteinemia is associated with an increased risk of thrombosis in persons without factor V Leiden, much larger studies will be needed to obtain reliable estimates of the risk in those with both abnormalities.
We thank Dr. Jacobson for pointing out that in case–control studies, one should always be aware of possible differences between cases and controls that may confound the results. We do not think that dietary recommendations made during anticoagulation therapy could have affected our findings, since most patients (90 percent) were seen several months to years after the cessation of therapy. Also, anticoagulation clinics in the Netherlands do not provide dietary recommendations concerning vitamin K intake.
5 ReferencesMartin den Heijer, M.D.
Leyenburg Hospital, 2545 CH The Hague, the NetherlandsHenk J. Blom, Ph.D.
University Hospital, 6531 HC Nijmegen, the NetherlandsFrits R. Rosendaal, M.D.
University Hospital, 2333 AL Leiden, the Netherlands1
Fowler B ,Sardharwalla IB ,Robins AJ . The detection of heterozygotes for homocystinuria by oral loading with L-methionine. Biochem J 1971;122:23P-24P
Web of Science | Medline2
Kluijtmans LA ,van den Heuvel LP ,Boers GH , et al. Molecular genetic analysis in mild hyperhomocysteinemia: a common mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for cardiovascular disease. Am J Hum Genet 1996;58:35-41
Web of Science | Medline3
Frosst P ,Blom HJ ,Milos R , et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995;10:111-113
CrossRef | Web of Science | Medline4
Law MR ,Wald NJ ,Wu T ,Hackshaw A ,Bailey A . Systematic underestimation of association between serum cholesterol concentration and ischaemic heart disease in observational studies: data from the BUPA study. BMJ 1994;308:363-366
CrossRef | Web of Science | Medline5
Mandel H ,Brenner B ,Berant M , et al. Coexistence of hereditary homocystinuria and factor V Leiden -- effect on thrombosis. N Engl J Med 1996;334:763-768
Full Text | Web of Science | Medline
- Citing Articles (20)
Citing Articles
1
Silvio Danese, Alfredo Papa, Simone Saibeni, Alessandro Repici, Alberto Malesci, Maurizio Vecchi. (2007) Inflammation and Coagulation in Inflammatory Bowel Disease: The Clot Thickens.. The American Journal of Gastroenterology 102:1, 174-186
CrossRef2
Massimo Primignani, Ida Martinelli, Paolo Bucciarelli, Tullia Battaglioli, Raffaella Reati, Federica Fabris, Alessandra Dell'Era, Emanuela Pappalardo, Pier Mannuccio Mannucci. (2005) Risk factors for thrombophilia in extrahepatic portal vein obstruction. Hepatology 41:3, 603-608
CrossRef3
M. DEN HEIJER, S. LEWINGTON, R. CLARKE. (2005) Homocysteine, MTHFR and risk of venous thrombosis: a meta-analysis of published epidemiological studies. Journal of Thrombosis and Haemostasis 3:2, 292-299
CrossRef4
Wolfgang Herrmann. (2003) Where Are We Standing in Homocysteine Research?. Clinical Chemistry and Laboratory Medicine 41:11, 1389-1391
CrossRef5
Albert W. Tsai, Mary Cushman, Michael Y. Tsai, Susan R. Heckbert, Wayne D. Rosamond, Nena Aleksic, N. David Yanez, Bruce M. Psaty, Aaron R. Folsom. (2003) Serum homocysteine, thermolabile variant of methylene tetrahydrofolate reductase (MTHFR), and venous thromboembolism: Longitudinal investigation of thromboembolism etiology (LITE). American Journal of Hematology 72:3, 192-200
CrossRef6
James O’Donnell, David J Perry. (2002) Pharmacotherapy of hyperhomocysteinaemia in patients with thrombophilia. Expert Opinion on Pharmacotherapy 3:11, 1591-1598
CrossRef7
T. B. Domagala, L. Adamek, E. Nizankowska, M. Sanak, A. Szczeklik. (2002) Mutations C677T and A1298C of the 5,10-methylenetetrahydrofolate reductase gene and fasting plasma homocysteine levels are not associated with the increased risk of venous thromboembolic disease. Blood Coagulation & Fibrinolysis 13:5, 423-431
CrossRef8
Martin den Heijer, Miranda B.A.J. Keijzer. (2001) Hyperhomocysteinemia as a Risk Factor for Venous Thrombosis. Clinical Chemistry and Laboratory Medicine 39:8, 710-713
CrossRef9
R. Junker, Ulrike Nowak-Göttl, M. Fobker. (2001) Der Methylentetrahydrofolat-Reduktase (MTHFR) C677T- Polymorphismus und andere genetische Ursachen der Hyperhomocysteinämie bei venösen Gefäßverschlüssen. The Methyienetetrahydrofolate-reductase (MTHFR) C677T-Polymorphism and Other Genetic Causes of Hyperhomocysteinemia in Venous Thrombosis. LaboratoriumsMedizin 25:7-8, 239-253
CrossRef10
Marco Cattaneo. (2001) Hyperhomocysteinemia and thrombosis. Lipids 36:S1, S13-S26
CrossRef11
Mojca Božič, Mojca Stegnar, Isabella Fermo, Anka Ritonja, Polona Peternel, Janez Stare, Armando D'Angelo. (2000) Mild Hyperhomocysteinemia and Fibrinolytic Factors in Patients with History of Venous Thromboembolism. Thrombosis Research 100:4, 271-278
CrossRef12
John C. Wood, Sunita Maheshwari, William E. Hellenbrand. (2000) Pulmonary thrombosis, homocysteinemia, and reperfusion edema in an adolescent. Catheterization and Cardiovascular Interventions 50:1, 59-62
CrossRef13
Hironobu Fujimura, Tomio Kawasaki, Toshiyuki Sakata, Hideo Ariyoshi, Hisao Kato, Morito Monden, Toshiyuki Miyata. (2000) Common C677T Polymorphism in the Methylenetetrahydrofolate Reductase Gene Increases the Risk for Deep Vein Thrombosis in Patients with Predisposition of Thrombophilia. Thrombosis Research 98:1, 1-8
CrossRef14
O. Nygard, S. E. Vollset, H. Refsum, L. Brattstrom, P. M. Ueland. (1999) Total homocysteine and cardiovascular disease. Journal of Internal Medicine 246:5, 425-454
CrossRef15
Sherri A. Zimmerman, Russell E. Ware. (1998) Inherited DNA mutations contributing to thrombotic complications in patients with Sickle cell disease. American Journal of Hematology 59:4, 267-272
CrossRef16
Monica Nordström, Thomas Kjellström. (1998) Age and cystathionine β-synthase activity in cultured fibroblasts from patients with arterial and venous vascular disease. Atherosclerosis 139:2, 231-236
CrossRef17
JACOB SELHUB, ARMANDO D'ANGELO. (1998) Relationship Between Homocysteine and Thrombotic Disease. The American Journal of the Medical Sciences 316:2, 129-141
CrossRef18
H. Refsum, MD, P. M. Ueland, MD, O. Nygård, MD, S. E. Vollset, MD, Dr.PH. (1998) HOMOCYSTEINE AND CARDIOVASCULAR DISEASE. Annual Review of Medicine 49:1, 31-62
CrossRef19
M. Cattaneo. (1997) Hyperhomocysteinemia: A risk factor for arterial and venous thrombotic disease. International Journal of Clinical & Laboratory Research 27:2-4, 139-144
CrossRef20
(1997) Plasma Homocysteine Levels and Mortality in Patients with Coronary Artery Disease. New England Journal of Medicine 337:22, 1631-1633
Full Text
