Elevated hemostasis markers after pneumonia increases one-year risk of all-cause and cardiovascular deaths

Abstract

Background: Acceleration of chronic diseases, particularly cardiovascular disease, may increase long-term mortality after community-acquired pneumonia (CAP), but underlying mechanisms are unknown. Persistence of the prothrombotic state that occurs during an acute infection may increase risk of subsequent atherothrombosis in patients with pre-existing cardiovascular disease and increase subsequent risk of death. We hypothesized that circulating hemostasis markers activated during CAP persist at hospital discharge, when patients appear to have recovered clinically, and are associated with higher mortality, particularly due to cardiovascular causes.

Methods: In a cohort of survivors of CAP hospitalization from 28 US sites, we measured D-Dimer, thrombin-antithrombin complexes [TAT], Factor IX, antithrombin, and plasminogen activator inhibitor-1 at hospital discharge, and determined 1-year all-cause and cardiovascular mortality.

Results: Of 893 subjects, most did not have severe pneumonia (70.6% never developed severe sepsis) and only 13.4% required intensive care unit admission. At discharge, 88.4% of subjects had normal vital signs and appeared to have clinically recovered. D-dimer and TAT levels were elevated at discharge in 78.8% and 30.1% of all subjects, and in 51.3% and 25.3% of those without severe sepsis. Higher D-dimer and TAT levels were associated with higher risk of all-cause mortality (range of hazard ratios were 1.66-1.17, p = 0.0001 and 1.46-1.04, p = 0.001 after adjusting for demographics and comorbid illnesses) and cardiovascular mortality (p = 0.009 and 0.003 in competing risk analyses).

Conclusions: Elevations of TAT and D-dimer levels are common at hospital discharge in patients who appeared to have recovered clinically from pneumonia and are associated with higher risk of subsequent deaths, particularly due to cardiovascular disease.

Figure 1. Subject disposition for the entire Genetic and Inflammatory Markers of Sepsis (GenIMS) cohort.

CAP indicates community-acquired pneumonia.

Figure 2. Varying hazard ratios with 95% confidence intervals (CI) for circulating thrombin-antithrombin (TAT) complexes, D-dimer, plasminogen activator inhibitor (PAI)-1, and interleukin (IL)-6 concentrations measured at hospital discharge and mortality over 1 year.

The hazard ratios are shown over ten time intervals based on the Grays' model. For TAT, D-dimer, and IL-6, the lower bounds of the CI are above 1 for the first 111 days. For PAI-1, the lower bounds of the 95% CI are above 1 for the first 44 days.

Figure 3. Failure plots for high and low concentrations (25^th and 75^th percentiles of marker concentrations) of thrombin-antithrombin (TAT) complexes, D-dimer, plasminogen activator inhibitor (PAI)-1, and interleukin (IL)-6 concentrations measured at hospital discharge and mortality over 1 year.

Using the Gray's model, the hazard ratios are estimated at ten intervals over 1 year and hazard ratios over five representative periods are shown. P values are obtained from the Grays' survival model.