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(Circulation. 1997;95:1777-1782.)
© 1997 American Heart Association, Inc.

Articles

Interrelation of Hyperhomocyst(e)inemia, Factor V Leiden, and Risk of Future Venous Thromboembolism

Paul M. Ridker, MD; Charles H. Hennekens, MD; Jacob Selhub, PhD; Joseph P. Miletich, MD; M. Rene Malinow, MD; Meir J. Stampfer, MD

From the Division of Preventive Medicine (P.M.R., C.H.H.), the Cardiovascular Division (P.M.R.), and the Channing Laboratory (M.J.S.), Department of Medicine, Brigham and Women's Hospital, and the Department of Ambulatory Care and Prevention (C.H.H.), Harvard Medical School, Boston, Mass; the Departments of Nutrition (M.J.S.) and Epidemiology (M.J.S., C.H.H.), Harvard School of Public Health, Boston, Mass; the Laboratory Medicine Division (J.P.M.), Washington University School of Medicine, St Louis, Mo; the Oregon Regional Primate Research Center (M.R.M.), Beaverton; and the Jean Mayer Human Nutrition Research Center at Tufts University (J.S.), Boston, Mass.

Correspondence to Paul M. Ridker, Department of Medicine, Brigham and Women's Hospital, 900 Commonwealth Ave E, Boston, MA 02115. E-mail PMRIDKER{at}BICS.BWH.HARVARD.EDU

Background Because patients with rare familial homocystinuria who also carry factor V Leiden have an increased incidence of venous thromboembolism (VTE), we hypothesized an interrelation of moderate hyperhomocyst(e)inemia, factor V Leiden, and risk of VTE in the general population.

Methods and Results In a large prospective cohort, we determined total homocysteine level and factor V Leiden mutation in baseline blood samples from 145 initially healthy men who subsequently developed VTE and among 646 men who remained free of vascular disease during a 10-year follow-up period. Hyperhomocyst(e)inemia was defined as a total homocysteine level above the 95th percentile (17.25 µmol/L). Compared with men with normal total homocysteine levels, those with hyperhomocyst(e)inemia had no increase in risk of any VTE but were at increased risk of idiopathic VTE (relative risk [RR]=3.4, P=.002). Compared with men without Leiden mutation, those with mutation were at increased risk of developing any VTE (RR=2.3, P=.005) as well as idiopathic VTE (RR=3.6, P=.0002). Compared with men with neither abnormality, those affected by both disorders had a 10-fold increase in risk of any VTE (RR=9.65, P=.009) and a 20-fold increase in risk of idiopathic VTE (RR=21.8, P=.0004).

Conclusions Apparently healthy men with coexistent hyperhomocyst(e)inemia and Leiden mutation are at substantially increased risk of developing future VTEs, particularly those events considered idiopathic. In these data, the risk of VTE among doubly affected individuals was far greater than the sum of the individual risks associated with either abnormality alone.

Key Words: factor V Leiden • thrombosis, venous • homocysteine • embolism, pulmonary