Ann Hematol (2002) 81:616–621 DOI 10.1007/s00277-002-0560-6 ORIGINAL ARTICLE A. F. Remacha · J. C. Souto · E. Rµmila · G. Perea · M. P. Sarda · J. Fontcuberta Enhanced risk of thrombotic disease in patients with acquired vitamin B 12 and/or folate deficiency: role of hyperhomocysteinemia Received: 18 June 2002 / Accepted: 7 October 2002 / Published online: 9 November 2002 # Springer-Verlag 2002 Abstract A number of studies have identified elevated levels of homocysteine (Hcy) as a risk factor for thrombosis. Given the relationship between Hcy and thrombosis, a high prevalence of thrombosis would be expected in patients with megaloblastic anemia. The aim of our study was to determine whether an acquired vitamin B 12 /folate deficiency is a risk factor for throm- bosis. A retrospective case and control study was performed that included 193 cases with reduced levels ofvitaminB 12 /folate. The cases were divided initially into two groups (105 with serum vitamin B 12 £150 pmol/l and/ or low red cell folate £450 nmol/l and 88 with serum vitamin B 12 between 150 and 200 pmol/l and/or red cell folate between 450 and 590 nmol/l). The control group consisted of 87 additional patients who had normal levels of serum vitamin B 12 , red cell folate, and normal renal function. Serum Hcy, thrombotic events, and risk factors were evaluated in all participants. Eight patients (9%) in the control group had had previous vascular events although only three of these events (37.5%) were observed between the vitamin study and 2 years prior to the study. In the case group, 20% of the patients had a history of thrombosis. In contrast with controls, 85% of cases suffered thrombosis between the time they were diagnosed and 2 years prior to the time they were diagnosed as showing a vitamin deficiency. Multivariate analysis demonstrated that vitamin deficiency was a significant risk factor for arterial thrombosis [adjusted odds ratio (OR) 3.3, confidence interval (CI) 1.1–10.2]. However, when hyperhomocysteinemia was included in the analysis, vitamin deficiency was no longer a risk factor, suggesting that hyperhomocysteinemia was re- sponsible for arterial thrombotic risk in these patients (adjusted OR 2.5, CI 1.1–5.8). As a consequence of hyperhomocysteinemia, patients with acquired vitamin deficiency of vitamin B 12 /folate had a high risk of thrombosis. However, a more extensive study that controls risk variables and genetic factors is needed to sort out the various contributing factors. Keywords Vitamin B 12 · Folate · Homocysteine · Thrombosis Introduction A number of studies have indicated that elevated levels of homocysteine (Hcy) are a risk factor for thromboembo- lism [1]. In addition, a negative relationship has been found between Hcy levels and vitamin B 12 /folate levels. This might be expected since both vitamins are involved in the metabolism of Hcy [2, 3]. Most of these studies have focused attention on cardiovascular epidemiology, with special emphasis on thrombosis and nutrition. In a meta-analysis procedure, Boushy et al. concluded that a reduction in the Hcy level of 5 1mol/l after dietary supplementation with folate provides significant cardiovascular protection [4]. An extensive European multicenter study reported that the incidence of vascular pathology was related to the amount of plasma Hcy [5]. In our previous study, 23% of the patients with venous thrombosis had hyperhomocysteine- mia [6]. However, it should be pointed out that in these studies the increase of Hcy was moderate [1, 7]. In megaloblastic anemias the degree of hyperhomo- cysteinemia has been reported as more pronounced than in studies of cardiovascular disease, since vitamin B 12 and folate are enzyme cofactors involved in Hcy metabolism [8]. In addition to thrombophilia assessment, Hcy mea- surement is useful in inherited disorders of vitamin B 12 / folate metabolism [9, 10, 11] and in atypical cases of megaloblastosis [12]. Given the relationship between high levels of Hcy and thrombosis, an increased prevalence of thromboembolism would be expected in patients with megaloblastic anemia. A.F. Remacha ( ) )·J.C.Souto·E.Rµmila·G.Perea·M.P.Sarda· J. Fontcuberta Department of Hematology, Hospital de la Santa Creu i Sant Pau, Avda. Padre Claret 167, Barcelona 08025, Spain e-mail: aremacha@hsp.santpau.es Tel.: +34-93-2919290 Fax: +34-93-2919192