Hyperhomocysteinemia as a Risk Factor for Deep-Vein Thrombosis
Martin den Heijer, M.D., Ted Koster, M.D., Henk J. Blom, Ph.D., Gerard M.J. Bos, M.D., Ernest Briët, M.D., Pieter H. Reitsma, Ph.D., Jan P. Vandenbroucke, M.D., and Frits R. Rosendaal, M.D.
Background Previous studies have suggested that hyperhomocysteinemiamay be a risk factor for venous thrombosis. To assess the riskof venous thrombosis associated with hyperhomocysteinemia, westudied plasma homocysteine levels in patients with a firstepisode of deep-vein thrombosis and in normal control subjects.
Methods We measured plasma homocysteine levels in 269 patientswith a first, objectively diagnosed episode of deep-vein thrombosisand in 269 healthy controls matched to the patients accordingto age and sex. Hyperhomocysteinemia was defined as a plasmahomocysteine level above the 95th percentile in the controlgroup (18.5 µmol per liter).
Results Of the 269 patients, 28 (10 percent) had plasma homocysteinelevels above the 95th percentile for the controls, as comparedwith 13 of the controls (matched odds ratio, 2.5; 95 percentconfidence interval, 1.2 to 5.2). The association between elevatedhomocysteine levels and venous thrombosis was stronger amongwomen than among men and increased with age. The exclusion ofsubjects with other established risk factors for thrombosis(e.g., a deficiency of protein C, protein S, or antithrombin;resistance to activated protein C; pregnancy or recent childbirth;or oral-contraceptive use) did not materially affect the riskestimates.
Conclusions High plasma homocysteine levels are a risk factorfor deep-vein thrombosis in the general population.
Mild hyperhomocysteinemia is an established risk factor foratherosclerosis and vascular disease.1,2 In classic homocystinuria,half the vascular complications are of venous origin,3 but untilrecently it has been unclear whether mild hyperhomocysteinemiais also a risk factor for venous thrombosis.2,4,5 In a case–controlstudy, Falcon et al. found that hyperhomocysteinemia was a riskfactor for thrombosis in people younger than 40 years of age.6They reported that the difference in homocysteine levels betweencase patients and control subjects was particularly evidentafter methionine loading (since methionine is a precursor ofhomocysteine). Recently, we found hyperhomocysteinemia to bea risk factor for recurrent venous thrombosis in patients between20 and 70 years of age, as compared with controls from the generalpopulation.7 Although the results of these studies support thehypothesis that mild hyperhomocysteinemia is a risk factor forvenous thrombosis, the studies were not designed to estimatethe risk in the general population.
We measured homocysteine concentrations in patients and matchedcontrol subjects participating in the Leiden Thrombophilia Study.8,9,10,11This is a population-based case–control study designedto measure the effect of several acquired and genetic risk factorsfor thrombosis in the general population. Because of the dataavailable on the study subjects, we were able to investigatewhether the effect of hyperhomocysteinemia was independent ofother well-established risk factors for thrombosis, such asa deficiency of protein C, protein S, or antithrombin; use oforal contraceptives; and pregnancy or recent childbirth. Recently,resistance to activated protein C caused by a single point mutationin the factor V gene (factor V Leiden) has been reported tobe the most common hereditary cause of venous thrombosis.12Since hyperhomocysteinemia also appears to be common, we examinedthe risk of thrombosis in persons with both abnormalities.
Methods
The methods by which blood samples were obtained and interviewdata were collected have been described elsewhere.8,9,10,11The study protocol was approved by the local ethics committee,and all participants gave their informed consent. Briefly, consecutivepatients younger than 70 years of age who had a first episodeof deep-vein thrombosis, objectively confirmed (by impedanceplethysmography, Doppler ultrasonography, compression ultrasonography,or contrast venography), between 1988 and 1993 and who had noknown cancer were selected from the files of three anticoagulationclinics in the Netherlands (in Leiden, Amsterdam, and Rotterdam).These clinics monitor the anticoagulant treatment of virtuallyall patients in well-defined geographic areas. Each patientwas asked to find his or her own healthy control subject ofthe same sex and age (within five years) by asking neighborsor friends. We restricted the present analysis to case patientsand controls who were seen at the Leiden Anticoagulation Clinicand whose blood samples were processed and frozen on site withminimal delay. (Blood samples from participants in Amsterdamand Rotterdam were also processed in Leiden, which caused delaysof several hours, and homocysteine measurements were thereforeless accurate than those measured in samples from subjects inLeiden.13)
The total homocysteine concentration was measured in citratedplasma by automated high-performance liquid chromatography withreverse-phase separation and fluorescent detection (with a Gilson232-401 sample processor, Spectra-Physics 8800 solvent-deliverysystem, and Spectra-Physics LC 304 fluorometer). We used themethod described by Fiskerstrand et al.13 with some modifications.14If not otherwise stated, hyperhomocysteinemia was defined asa homocysteine level above the 95th percentile in the controlgroup (18.5 µmol per liter).
We calculated matched odds ratios as estimates of the relativerisk of thrombosis for homocysteine values above a given point,with the matching factor taken into account. The univariatematched odds ratio is the ratio of the number of pairs of casepatients and controls in which the homocysteine value for thecase patient was above the specified level and the value forthe control was below that level to the number of pairs in whichthe homocysteine value for the control was above the specifiedlevel and the value for the case patient was below that level.The 95 percent confidence intervals were calculated from a conditionallogistic-regression algorithm by the maximum-likelihood method,with Egret software. We also investigated a possible dose–responserelation by calculating odds ratios for several ranges of homocysteineconcentrations in a conditional logistic model. In addition,we calculated odds ratios for men and women separately and forseveral age groups in order to study possible differences inrisk among these subgroups.
We further explored the differences in risk between men andwomen by taking risk factors specific to women into account— specifically, the use of oral contraceptives, pregnancy,and recent childbirth. We analyzed the risk of thrombosis amongwomen less than 50 years old, both with and without the inclusionof women with these risk factors, by calculating unmatched oddsratios. The use of unmatched odds ratios was necessary becausein the restricted groups many matched pairs would not have beencomplete. Since the matched and unmatched odds ratios did notdiffer substantially in any of our analyses, we considered thisapproach justified.
We also assessed whether the increased risk associated withhyperhomocysteinemia in both sexes was confounded by other riskfactors, such as a deficiency of protein C, protein S, or antithrombin.We repeated the analysis after excluding subjects with abnormallylow levels of these proteins (measured, as previously reported,with a single test8) and estimated the risk associated withhyperhomocysteinemia in persons with normal protein C, proteinS, and antithrombin levels.
Finally, we looked at the possibility of an interaction betweenhyperhomocysteinemia and heterozygosity (carrier status) forfactor V Leiden, a rather common defect that causes resistanceto activated protein C. We analyzed this interaction by calculatingunivariate odds ratios for thrombosis in persons with both oreither of these risk factors, as compared with persons withneither risk factor.
Results
The ratio of male to female subjects among both the case patientsand the controls was 1:1.3, and the mean age was 44 years (range,16 to 70 for the case patients and 16 to 71 for the controls);both these variables were used in matching the case patientsand the controls.
The median plasma homocysteine level in the patients was 12.9µmol per liter (range, 4.8 to 60.2), and that in the controlswas 12.3 µmol per liter (range, 6.4 to 37.5). The homocysteineconcentrations of individual case patients and controls areshown in Figure 1.
Figure 1. Plasma Homocysteine Levels in 269 Patients with Deep-Vein Thrombosis and 269 Controls.
Values shown have been rounded.
The 95th percentile of the homocysteine levels in the controlgroup was 18.5 µmol per liter. Of the 269 patients, 28(10 percent) exceeded this cutoff, as compared with 13 (5 percent,by definition) in the control group. The matched odds ratiofor deep-vein thrombosis in subjects with a homocysteine concentrationabove the 95th percentile, as compared with those whose homocysteinelevels were at or below that value, was 2.5 (95 percent confidenceinterval, 1.2 to 5.2). When the cutoff was set at the 90th percentile,the matched odds ratio was 1.9 (95 percent confidence interval,1.1 to 3.3); it was 4.0 (95 percent confidence interval, 1.4to 12.0) when the cutoff was the 97.5th percentile (Table 1).
Table 1. Pairwise Distribution of Plasma Homocysteine Values in 269 Case Patients and Their Matched Controls, According to Various Definitions of Hyperhomocysteinemia.
In order to evaluate the possibility of a dose–responserelation, we stratified the patients and controls accordingto their homocysteine concentrations and calculated odds ratiosfor thrombosis in the patients at the higher levels as comparedwith those at the lowest level. As Figure 2 shows, the riskof thrombosis did not increase among subjects with homocysteinelevels up to 18 µmol per liter; the risk was greatly increasedabove 22 µmol per liter, however, indicating a thresholdeffect rather than a continuous dose–response relation.
Figure 2. Odds Ratio for Thrombosis According to Plasma Homocysteine Level.
The reference category was the subjects with plasma homocysteine values of <12 µmol per liter.
Odds ratios for several age groups and for men and women separatelyare shown in Table 2. For both sexes, there was a sharp increasein the risk of thrombosis associated with hyperhomocysteinemiaat increasing ages. The overall odds ratio for thrombosis associatedwith hyperhomocysteinemia in women was 7.0 (95 percent confidenceinterval, 1.6 to 30.8), and in men it was 1.4 (95 percent confidenceinterval, 0.6 to 3.4), with the cutoff set at the 95th percentileof the homocysteine levels in the control group (P = 0.067 forthe comparison between the sexes). When we calculated the 95thpercentile of the distribution of homocysteine levels for menand women separately, we found a 95th percentile of 17.1 µmolper liter among women and 20.0 µmol per liter among menin the control group. Using these cutoffs for hyperhomocysteinemia,we found an odds ratio for thrombosis of 3.8 (95 percent confidenceinterval, 1.4 to 10.2) for women and 1.8 (95 percent confidenceinterval, 0.6 to 5.4) for men.
Table 2. Odds Ratios for Thrombosis Associated with Hyperhomocysteinemia, According to Age and Sex.
The higher rate of hyperhomocysteinemia in women than in menwas present at all ages, making it unlikely that the differencewas due to risk factors specific to women, such as the use oforal contraceptives, recent childbirth, or pregnancy. Indeed,when we excluded women with these risk factors, the unmatchedodds ratio for thrombosis that was associated with hyperhomocysteinemia(with the 95th percentile for both sexes — 18.5 µmolper liter — as the cutoff for hyperhomocysteinemia) amongwomen under the age of 50 was 11.3 (95 percent confidence interval,2.7 to 46.0), whereas it was 2.8 (95 percent confidence interval,0.9 to 8.7) for all women, both those with and those withoutthese risk factors, under the age of 50.
Of the 269 patients, 15 had protein C deficiency, 7 had proteinS deficiency, and 10 had antithrombin deficiency. In the controlgroup, four had protein C deficiency, eight had protein S deficiency,and eight had antithrombin deficiency. After excluding thesesubjects, we found a matched odds ratio for deep-vein thrombosisof 2.6 (95 percent confidence interval, 1.2 to 5.9), as comparedwith 2.5 (95 percent confidence interval, 1.2 to 5.2) when thosesubjects were included; this result shows that the effect ofhomocysteine is largely independent of these deficiencies inclotting-factor inhibitors.
With respect to the combination of factor V Leiden and hyperhomocysteinemia,we calculated odds ratios for thrombosis in subjects with bothrisk factors or either one in relation to subjects with neither.A total of 47 of the patients carried the factor V Leiden mutation,as compared with 7 of the controls. The small number with bothdefects made the results statistically unstable and somewhatsensitive to the cutoff chosen for elevated homocysteine levels.When the 90th percentile was used as the cutoff, the odds ratiofor thrombosis associated with the presence of both risk factors(factor V Leiden and hyperhomocysteinemia) was 3.5 (95 percentconfidence interval, 0.7 to 16.9); the odds ratios for thrombosisassociated with factor V Leiden alone and hyperhomocysteinemiaalone, calculated separately, were 9.5 and 2.2, respectively.With the 95th percentile used as the cutoff, the odds ratiofor the combination of risk factors was 2.0 (95 percent confidenceinterval, 0.4 to 10.9), whereas the odds ratios for each riskfactor separately remained virtually unchanged. The statisticaluncertainty of results based on these data is reflected in thewide confidence intervals, which do not exclude a relative riskas high as 16.9.
Discussion
Our study shows that hyperhomocysteinemia is a risk factor fordeep-vein thrombosis in the general population. Moreover, ourresults suggest that the association between mild hyperhomocysteinemiaand venous thrombosis is similar in degree to that reportedfor hyperhomocysteinemia and arterial vascular disease.15,16An unexpected finding was the substantial increase in the riskof thrombosis at the highest plasma homocysteine levels. Ourdata suggest that there may be a threshold level above whichhomocysteine has a thrombogenic effect.
Falcon et al. reported that hyperhomocysteinemia was a riskfactor for juvenile thrombosis.6 Our data imply that hyperhomocysteinemiais a risk factor for thrombosis in adult subjects as well, sincewe found an increasing odds ratio with increasing age.
When we analyzed men and women separately, we found a differencein the risk of thrombosis associated with hyperhomocysteinemia.Even when we used different cutoff points for hyperhomocysteinemiain men and women by calculating the 95th percentiles of theirhomocysteine distributions in the control group separately,we found that the odds ratio was roughly twice as high for womenas for men. This suggests that women may be more susceptibleto the pathologic effects of elevated homocysteine levels, eventhough their homocysteine levels are in general lower than thoseof men.1 This effect cannot be explained by risk factors specificto women (such as pregnancy, recent childbirth, and oral-contraceptiveuse); an effect of these risk factors was unlikely in any casebecause the difference between men and women who did not havesuch risk factors was even more pronounced.
Hyperhomocysteinemia remained a risk factor for deep-vein thrombosisafter we excluded subjects with other well-established riskfactors; that is, the association with thrombosis was not explainedby the presence of other hereditary risk factors for thrombosis,such as a deficiency of protein C, protein S, or antithrombin.The same was true of the most common hereditary risk factorfor deep venous thrombosis, resistance to activated proteinC, since hyperhomocysteinemia also increased the risk of thrombosisin those without this abnormality. We investigated a possibleinteraction between resistance to activated protein C (factorV Leiden) and hyperhomocysteinemia. Although we found that therisk of thrombosis may be higher in carriers of the mutationwho have hyperhomocysteinemia than in noncarriers with hyperhomocysteinemia,the combined effect in our subjects seemed smaller than forfactor V Leiden alone. Because of the small numbers involved,the only reasonable conclusion is that the two factors do notpotentiate each other.
Many hypotheses have been proposed to explain how hyperhomocysteinemiamay lead to venous thrombosis and atherosclerosis. One hypothesisis that homocysteine has a toxic effect on the vascular endotheliumand on the clotting cascade.1,2 Several in vitro studies seemto support this view.17,18 However, virtually all these studiesused amounts of homocysteine that produced higher-than-physiologicconcentrations. Alternatively, hyperhomocysteinemia may reflectabnormal methionine metabolism that affects the methylationof DNA and cell membranes.19
Elevated homocysteine levels may result from low levels of folicacid, vitamin B6, or vitamin B12. Moreover, several geneticalterations in enzymes involved in homocysteine metabolism havebeen described.20,21,22 It remains unclear whether hyperhomocysteinemiaof different causes entails the same risk of thrombosis. Nevertheless,it is well known that vitamin supplementation lowers homocysteineconcentrations in almost all subjects with hyperhomocysteinemia,regardless of the underlying cause.
We conclude that mild hyperhomocysteinemia is a risk factorfor deep-vein thrombosis in the general population. The nextquestion to be answered is whether homocysteine-lowering therapy— folic acid, vitamin B6, or vitamin B12 — contributesto the prevention of recurrent venous thrombosis.23,24,25
Supported by grants from the Prevention Fund of the Netherlands(28-2263-1) and the Netherlands Heart Foundation (89.063).
We are indebted to Mrs. T. Visser, Mrs. A. van Beek, Mrs. M.T.W.B.te Poele-Pothoff, and Mrs. A. de Graaf-Hess for their excellentassistance.
Source Information
From the Department of Hematology, Municipal Hospital Leyenburg, The Hague (M.H., G.M.J.B.); the Departments of Clinical Epidemiology (T.K., J.P.V., F.R.R.) and Hematology (E.B., P.H.R., F.R.R.), University Hospital, Leiden; and the Laboratory of Pediatrics and Neurology, Department of Pediatrics, University Hospital, Nijmegen (H.J.B.) — all in the Netherlands.
Address reprint requests to Dr. den Heijer at the Department of Hematology, Municipal Hospital Leyenburg, P.O. Box 40551, 2504 LN The Hague, the Netherlands.
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