The MESA cohort at risk and with complete baseline information included 3013 men and 3378 women, with a mean age of 62 years at study enrollment (range 45–84 y). Their ethnic composition was 2434 (38%) white, 1779 (28%) African American, 1410 (22%) Hispanic, and 768 (12%) Chinese American. None had clinically recognized atherosclerotic disease (by design), but 7.8% reported a history of cancer not currently treated by radiation or chemotherapy. Median (interquartile range) values for D-dimer, factor VIIIc, and PAP were 0.20 (0.24) µg/mL, 93 (46) %, and 4.4 (2.2) nM, respectively. Unadjusted Pearson correlations between these factors were r = 0.25 for D-dimer and PAP, r = 0.10 for D-dimer and factor VIIIc, and r = 0.21 for PAP and factor VIIIc.
As shown in , D-dimer was positively associated with age, was lower in men than women, and varied by ethnicity and several other risk factors. D-dimer was also associated positively but modestly with fibrinogen (unadjusted r = 0.15), IL-6 (r = 0.12), and CRP (r = 0.13). Supplemental Tables I
[RECOMMENDED FOR THE JOURNAL’S WEBSITE] similarly show risk factor relations with factor VIIIc
and PAP. Both factor VIIIc
and PAP were positively associated with age, female gender, African American ethnicity. Factor VIIIc
was also notably associated positively with body mass index and diabetes and negatively with current smoking. PAP was associated positively with LDL and HDL cholesterol levels and inversely with body mass index, systolic blood pressure, statin use, and diabetes. Traditional risk factors were therefore taken into account when examining the independent association of the hemostatic factors with clinical outcomes. Factor VIIIc
was modestly correlated with fibrinogen (unadjusted r = 0.26), IL-6 (r = 0.17), and CRP (r = 0.15), and so was PAP (r = 0.38 with fibrinogen, r = 0.16 with IL-6, and r = 0.19 with CRP).
Baseline Risk Factor Levels (Mean (SEM) or Percent) by Quartile of D-Dimer, MESA, 2000–2002
Over a mean of 4.6 years of follow-up, we identified 307CVD events, 207 hard CHD events, and 210 deaths (22 deaths had underlying cause coded as CHD, 19 other CVD, 93cancer, 13 accidental, 55 other cause, and 8 unknown). Although D-dimer was positively associated with incidence of CVD and hard CHD in crude models, it was not associated independent of age, race, and sex, or other risk factors (). Age, by far, explained most of the association (data not shown). A similar pattern was observed when D-dimer was alternatively modeled as a continuous variable or by examining the highest 10 percentile versus lowest 90 percentile. However, D-dimer was associated positively and strongly with risk of all cause mortality. In the risk factor adjusted model, hazard ratios for mortality were 1.00, 1.62, 1.91, and 2.57 across quartiles of D-dimer (). This association was attenuated, but still significant, even after adjustment for fibrinogen, IL-6, and CRP. Numbers were too sparse for analysis of CVD-specific mortality, but in the risk factor adjusted model, hazard ratios for cancer mortality were 1.00, 1.47 (95% CI = 0.61–3.52), 3.03 (1.41–6.51), and 3.07 (1.41–6.68) across D-dimer quartiles.
Hazard Ratio and 95% Confidence Interval for Study Endpoints by Quartile of D-Dimer, MESA, 2000–2006
Factor VIIIc () and PAP () similarly showed no relation with CVD or hard CHD, independent of age and to a lesser degree sex and race. This was true for factor VIIIc or PAP modeled as categorical or continuous variables. Yet, both factor VIIIc and PAP were associated with total mortality, with approximately 2-fold gradients in risk factor adjusted mortality from quartile 1 to quartile 4 ( and ). For cancer mortality, hazard ratios in the risk factor adjusted model were 1.00, 1.32 (95% CI = 0.66–2.67), 1.55 (0.79–3.04), and 1.89 (0.98–3.64) across factor VIIIc quartiles. However, there was no association of cancer mortality with PAP: hazard ratios were 1.0, 1.89 (0.92–3.89), 1.29 (0.59–2.81), 1.62 (0.75–3.48) across PAP quartiles. When the three hemostatic factor quartiles were modeled as ordinal variables, adjusted for risk factors but not each other, total mortality was greater by 33% (95% CI = 15–54%) for each quartile increment of D-dimer, 26% (95% CI = 11–44%) for factor VIIIc, and 20% (95% CI = 4–38%) for PAP.
Hazard Ratio and 95% Confidence Interval for Study Endpoints by Quartile of Factor VIIIc, MESA, 2000–2006
Hazard Ratio and 95% Confidence Interval for Study Endpoints by Quartile of Plasmin-Antiplasmin (PAP) Complex, MESA, 2000–2006
There was no effect modification between hemostatic factors and subclinical atherosclerosis measures in relation to CVD or hard CHD. All tests for multiplicative (and additive) interaction between a hemostatic factor and either CAC or IMT were statistically non-significant (p>0.05) in models adjusted for other risk factors and multiple testing. Correspondingly, there was no association between hemostatic factors and CVD or CHD within strata of CAC or IMT.