Platelet-monocyte aggregate formation and mortality risk in older patients with severe sepsis and septic shock

Abstract

Background: Aging-related changes in platelet and monocyte interactions may contribute to adverse outcomes in sepsis but remain relatively unexamined. We hypothesized that differential platelet-monocyte aggregate (PMA) formation in older septic patients alters inflammatory responses and mortality.

Methods: We prospectively studied 113 septic adults admitted to the intensive care unit with severe sepsis or septic shock. Patients were dichotomized a priori into one of two groups: older (age ≥ 65 years, n = 28) and younger (age < 65 years, n = 85). PMA levels were measured in whole blood via flow cytometry within 24 hours of admission. Plasma levels of IL-6 and IL-8, proinflammatory cytokines produced by monocytes upon PMA formation, were determined by commercial assays. Patients were followed for the primary outcome of 28-day, all-cause mortality.

Results: Elevated PMA levels were associated with an increased risk of mortality in older septic patients (hazard ratio for mortality 5.64, 95% confidence interval 0.64-49.61). This association remained after adjusting for potential confounding variables in multivariate regression. Receiver operating curve analyses demonstrated that PMA levels greater than or equal to 8.43% best predicted 28-day mortality in older septic patients (area under the receiver operating curve 0.82). Plasma IL-6 and IL-8 levels were also significantly higher in older nonsurvivors. In younger patients, neither PMA levels nor plasma monokines were significantly associated with mortality.

Conclusions: Increased PMA formation, and associated proinflammatory monokine synthesis, predicts mortality in older septic patients. Although larger studies are needed, our findings suggest that heightened PMA formation in older septic patients may contribute to injurious inflammatory responses and an increased risk of mortality.

Keywords: Inflammation; Mortality.; Platelet; Platelet–monocyte aggregates; Sepsis.

© The Author 2014. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Figures

Figure 1.

Increased levels of platelet–monocyte aggregates (PMAs) in older patients correlate with a greater risk of mortality. (A) Levels of PMA in whole blood were significantly higher in older, nonsurviving, septic patients (n = 7), compared with older, surviving, septic patients (n = 21, p ≤ .05). PMA levels did not differ between younger septic nonsurvivors (n = 71) and survivors (n = 14, p = NS). Values represent the mean ± SEM. (B) Interaction analyses confirmed that higher PMA levels in older septic patients were significantly associated with a greater risk of mortality (*p ≤ .05). In younger septic patients, there was no significant interaction between PMA levels and mortality.

Figure 2.

Receiver operating characteristic (ROC) analyses demonstrated that platelet–monocyte aggregate (PMA) levels in older septic patients were a sensitive marker for subsequent mortality. (A) In older septic patients, a PMA level ≥ 8.43% provided the best performance for discriminating between survivors and nonsurvivors. At this cutoff, the area under the ROC curve was 0.82 with a sensitivity of 83%, specificity of 68%, positive likelihood ratio of (LR+) 2.62, and negative likelihood ratio of (LR−) 0.24. (B) PMA levels were neither a sensitive nor specific marker of mortality in younger patients (area under the ROC curve 0.52, sensitivity 35% LR+ 1.15, specificity 69%, LR− 0.93). (C) In older septic patients, elevated PMA levels (PMA ≥ 8.43%) were associated with almost a sixfold higher risk of mortality (hazard ratio 5.64, 95% confidence interval 0.64–49.61). (D) In contrast, PMA levels were not associated with mortality in younger septic patients (hazard ratio 0.89, 95% confidence interval 0.30–2.68).

Figure 3.

Proinflammatory plasma monokines were higher in older septic nonsurvivors compared with survivors. Plasma levels of IL-6 and IL-8, which are commonly synthesized upon platelet–monocyte aggregate (PMA) formation, were determined from the same blood sample used for PMA measurements by flow cytometry. (A) In older septic patients, levels of IL-6 and IL-8 were higher in nonsurvivors compared with survivors. (B) In comparison, in younger septic patients, levels of IL-6 and IL-8 were not significantly different between survivors and nonsurvivors. The solid bar shown represents the median value (**p ≤ .05).