Associations of D-Dimer with Computed Tomographic Lung Abnormalities, Serum Biomarkers of Lung Injury, and Forced Vital Capacity: MESA Lung Study

Abstract

Rationale: The coagulation cascade may play a role in the pathogenesis of interstitial lung disease through increased production of thrombin and fibrin deposition. Whether circulating coagulation cascade factors are linked to lung inflammation and scarring among community-dwelling adults is unknown. Objectives: To test the hypothesis that higher baseline D-dimer concentrations are associated with markers of early lung injury and scarring. Methods: Using the MESA (Multi-Ethnic Study of Atherosclerosis) cohort (n = 6,814), we examined associations of baseline D-dimer concentrations with high attenuation areas from examination 1 (2000-2002; n = 6,184) and interstitial lung abnormalities from examination 5 computed tomographic (CT) scans (2010-2012; n = 2,227), and serum MMP-7 (matrix metalloproteinase-7) and SP-A (surfactant protein-A) from examination 1 (n = 1,098). We examined longitudinal change in forced vital capacity (FVC) from examinations 3-6 (2004-2018, n = 3,562). We used linear logistic regression and linear mixed models to examine associations and adjust for potential confounders. Results: The mean (standard deviation) age of the cohort was 62 (10) years, and the D-dimer concentration was 0.35 (0.69) ug/ml. For every 10% increase in D-dimer concentration, there was an increase in high attenuation area percentage of 0.27 (95% confidence interval (CI), 0.08-0.47) after adjustment for covariates. Associations were stronger among those older than 65 years (P values for interaction < 0.001). A 10% increase in D-dimer concentration was associated with an odds ratio of 1.05 for interstitial lung abnormalities (95% CI, 0.99-1.11). Higher D-dimer concentrations were associated with higher serum MMP-7 and a faster decline in FVC. D-dimer was not associated with SP-A. Conclusions: Higher D-dimer concentrations were associated with a greater burden of lung parenchymal abnormalities detected on CT scan, MMP-7, and FVC decline among community-dwelling adults.

Keywords: D-dimer; coagulation cascade; interstitial lung disease; lung function; smoking.

Figure 1.

Study flow diagram. DHA = docosahexaenoic acid; FEV₁ = forced expiratory volume in 1 second; FVC = forced vital capacity; HAA = high attenuation area; HDL = high-density lipoprotein; IL-6 = interleukin-6; ILA = interstitial lung abnormality; MMP-7 = matrix metalloproteinase-7; SP-A = surfactant protein-A.

Figure 2.

Forest plots of multivariable-adjusted associations of D-dimer concentrations with (A) high attenuation areas (HAAs) and (B) interstitial lung abnormalities (ILAs) stratified by smoking status, sex, age, BMI, and race/ethnicity. Model 1 was unadjusted for ILAs and adjusted for study site, radiation dose, and lung volume imaged for HAAs. Model 2 adjusted for age, sex, race/ethnicity, smoking status, cigarette pack-years, height, weight, education attainment, cancer history, statin use, hypertension medication use, docosahexaenoic acid concentration, high-density lipoprotein cholesterol concentration, total cholesterol concentration, and emphysema percentage. Model 3 was the same as model 2, with additional adjustment for interleukin-6 concentration. Stratified analyses are based on model 3 and include interaction terms (e.g., “D-dimer × smoking status”). P values for stratified analyses are P values for interaction. Results are reported per 10% increase in D-dimer concentration. Boxes represent the effect estimates, and horizontal lines represent their 95% CIs. BMI = body mass index; CI = confidence interval; OR = odds ratio.

Figure 3.

Forest plots of multivariable-adjusted associations of D-dimer concentrations with (A) MMP-7 and (B) SP-A overall and stratified by smoking status, sex, age, BMI, and race/ethnicity. Model 1 was unadjusted. Model 2 adjusted for age, sex, race/ethnicity, smoking status, cigarette pack-years, height, weight, education attainment, cancer history, statin use, hypertension medication use, docosahexaenoic acid concentration, high-density lipoprotein cholesterol concentration, total cholesterol concentration, and glomerular filtration rate. Model 3 was the same as model 2, with additional adjustment for interleukin-6 concentration. Stratified analyses are based on model 3 and include interaction terms (e.g. “D-dimer × smoking status”). P values for stratified analyses are P values for interaction. Results are reported per 10% increase in D-dimer concentration. Boxes represent the effect estimates and horizontal lines represent their 95% CIs. BMI = body mass index; CI = confidence interval; MMP-7 = matrix metalloproteinase-7; SP-A = surfactant protein-A.