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

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.