HYPERHOMOCYSTKINEiViJA AS A RISK FACTOR FOR DEEP-VF IN THROMBOSIS 759 HYPERHOMOCYSTEINEMIA AS A RISK FACTOR FOR DEEP-VEIN THROMBOSIS

Background Previous studies have suggest­ ed that hyperhomocysteinemia may be a risk factor for venous thrombosis. To assess the risk of venous throm­ bosis associated with hyperhomocysteinemia, we stud­ ied plasma homocysteine levels in patients with a first episode of deep-vein thrombosis and in normal control subjects. Methods. We measured plasma homocysteine levels in 269 patients with a first, objectively diagnosed epi­ sode of deep-vein thrombosis and in 269 healthy con­ trols matched to the patients according to age and sex. Hyperhomocysteinemia was defined as a plasma ho­ mocysteine level above the 95th percentile in the control group (18.5 /xmol per liter). Results. Of the 269 patients, 28 (10 percent) had plas­ ma homocysteine levels above the 95th percentile for the controls, as compared with 13 of the controls (matched odds ratio, 2.5; 95 percent confidence interval, 1.2 to 5.2). The association between elevated homocysteine levels and venous thrombosis was stronger among women than among men and increased with age. The exclusion of subjects 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 af­ fect the risk estimates. Conclusions. High plasma homocysteine levels are a risk factor for deep-vein thrombosis in the general popu­ lation. (N Engl J Med 1996;334:759-62.) ©1996, Massachusetts Medical Society. M hyperhomocysteinemia is an established risk factor for atherosclerosis and vascular disease.1,2 In classic homocystinuria, half the vascular complica­ tions are of'venous origin,3 but until recently it has been unclear whether mild hyperhomocysteinemia is also a risk factor for venous thrombosis.2,1,3 In a case-control study. Falcon et al. found that hyperhomocysteinemia was a risk factor for thrombosis in people younger than 40 years of age. They reported that the difference in homocystcine levels between case patients and control subjects was particularly evident after methionine load­ ing (since methionine is a precursor of homocysteine). Recently, we found hyperhomocysteinemia to be a risk factor for recurrent venous thrombosis in patients be­ tween 20 and 70 years of age, as compared with controls from the general population.7 Although the results of these studies support the hypothesis that mild hyperho­ mocysteinemia is a risk factor fur venous thrombosis, the studies were not designed to estimate the risk in the general population. We measured homocysteine concentrations in patients and matched control subjects participating in the Leiden Thrombophilia Study.”'11 This is a population-based case-control study designed to measure the effect of sev­ eral acquired and genetic risk factors for thrombosis in the general population. Because of the data available on the study subjects, we were able to investigate wheth­ er the effect of hyperhomocysteinemia was independent of other well-established risk factors for thrombosis, such as a deficiency of protein G, protein S, or antithrombin; use of oral contraceptives; and pregnancy or From the Department o f Hematology, Municipal Hospital Leyenburg, The Hague (M.H., G.M.J.B.); the Departments o f 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, Univer­ sity Hospital, Nijmegen (H.J.I3.) — all in the Netherlands. Address reprint re­ quests to Dr. c!en Heijer at (he Department o f Hematology, Municipal Hospital Leyenburg, P.O. Box 40551, 2504 LN The Hague, the Netherlands. Supported by grants from the Prevention Fund of the Netherlands (28-22631) and the Netherlands Heart Foundation (89.063). recent childbirth. Recently, resistance to activated pro­ tein G caused by a single point mutation in the factor V gene (factor V Leiden) has been reported to be the most common hereditary cause of venous thrombosis.1" Since hyperhomocysteinemia also appears to be com­ mon, w7e examined the risk of thrombosis in persons with both abnormalities.