Published Online
on July 6, 2004

A more recent version of this article appeared on July 20, 2004

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Submitted on September 27, 2003
Revised on March 25, 2004
Accepted on March 26, 2004

Tissue Plasminogen Activator Antigen and D-Dimer as Markers for Atherothrombotic Risk Among Healthy Postmenopausal Women

Aruna D. Pradhan MD, MPH^*, Andrea Z. LaCroix PhD, Robert D. Langer MD, MPH, Maurizio Trevisan MD, MS, Cora E. Lewis MD, MSPH, Judith A. Hsia MD, Albert Oberman MD, MPH, Jane M. Kotchen MD, MPH, and Paul M Ridker MD, MPH

From the Divisions of Preventive Medicine and Cardiology (A.D.P., P.M.R.), the Donald M. Reynolds Center for Cardiovascular Research (A.D.P., P.M.R.), and Leducq Center for Molecular and Genetic Epidemiology of Cardiovascular Disorders (P.M.R.), Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass; Women’s Health Initiative Clinical Coordinating Center (A.Z.L.), Fred Hutchinson Cancer Research Center, Seattle, Wash; Department of Family and Preventive Medicine, Division of Epidemiology (R.D.L.), University of California, San Diego, Calif; Department of Social and Preventive Medicine (M.T.), School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY; Division of Preventive Medicine (C.E.L., A.O.), University of Alabama at Birmingham, Ala; Department of Medicine (J.A.H.), George Washington University, Washington, DC; and Departments of Medicine and Epidemiology (J.M.K.), Medical College of Wisconsin, Milwaukee, Wis.

^* To whom correspondence should be addressed. E-mail: apradhan{at}partners.org.

Background--Plasma markers of fibrinolytic function are associated with incident coronary events among several, but not all, prospective epidemiologic investigations of healthy individuals. Few studies have evaluated this relationship in women. In addition, although menopausal hormone therapy (HT) may alter markers of fibrinolytic function, the relevance of this effect for coronary risk assessment has not been studied.

Methods and Results--In a prospective, nested case-control study among 75 343 postmenopausal women without prior cardiovascular disease or cancer, we evaluated the relationships of elevated tissue plasminogen activator (tPA) antigen and D-dimer with subsequent first coronary heart disease events over a median period of 2.9 years. Baseline levels of both biomarkers were higher among 304 cases compared with 304 controls matched on age, smoking status, ethnicity, and length of follow-up; median values were 9.0 versus 7.4 ng/mL (P<0.001) for tPA antigen and 27.6 versus 23.4 ng/mL (P=0.001) for D-dimer. In matched-pairs analyses, the odds ratio in the highest versus lowest quartile of tPA antigen was 3.5 (95% CI, 2.1 to 5.8; P trend <0.001) and for D-dimer was 2.0 (95% CI, 1.2 to 3.2; P trend=0.005). After adjustment for lipid and nonlipid risk factors, including C-reactive protein, tPA antigen remained a significant predictor. Multivariable-adjusted associations for D-dimer, although attenuated, largely remained statistically significant. When stratified by HT, the relationship between tPA antigen and incident coronary heart disease was similar among nonusers, estrogen-only users, and current users of any HT.

Conclusions--Elevated tPA antigen and, to a lesser extent, D-dimer are independently associated with incident coronary events among postmenopausal women. In analyses stratified by HT, tPA antigen remained a consistent marker of increased coronary risk.

Key words: coronary disease • thrombosis • fibrinolysis • women • epidemiology

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