Coagulation and activation of inflammatory pathways in the development of functional decline and mortality in the elderly☆

Article Outline

• Abstract
• Methods
  • Subjects
  • Measures
  • Statistical analysis
• Results
  • Mortality
  • Functional status and incident diseases
• Discussion
• References
• Copyright

Abstract 

Purpose

This study was performed to determine the effects of markers of inflammation (interleukin 6) and coagulation (D-dimer) on mortality and functional status in older persons.

Methods

Subjects were selected for the Duke Established Populations for Epidemiologic Studies of the Elderly. In 1992, 2569 subjects (age >71 years) were interviewed, of whom 1723 had interleukin-6 and D-dimer measurements. Values of interleukin 6 and D-dimer were categorized into quartiles. Outcomes were mortality (through 5 years) and functional status (through 4 years). Relative risks were estimated with proportional hazards models that adjusted for potential confounders.

Results

The relative risk of mortality was 1.28 (95% confidence interval [CI]: 0.98 to 1.69; P = 0.06) for those with only interleukin-6 levels in the highest quartile, 1.53 (95% CI: 1.18 to 1.97; P = 0.001) for subjects with only D-dimer levels in the highest quartile, and 2.00 (95% CI: 1.53 to 2.62; P = 0.0001) for those with levels of both in the highest quartile, as compared with those who were not in either of the highest quartiles. Those with high interleukin-6 and high D-dimer levels had the greatest declines in all measures of function.

Conclusion

Activation of the coagulation and inflammatory pathways is associated with mortality and decline in function, and may be part of the explanation for the development of a frailty phenotype in the elderly.

Keywords:  inflammation, functional status, frailty, mortality, D-dimer, interleukin 6

Frailty, a decrease in function and an increased vulnerability that ultimately leads to death, is a major problem in the elderly 1, 2, 3. Markers of the activation of the chronic inflammatory and coagulation pathways, such as interleukin 6 and D-dimer, have been associated with aspects of the frailty phenotype (4). For example, levels of interleukin 6 and fibrin D-dimer both increase with age. Although these elevations are associated to some degree with disorders such as cardiovascular disease, there is also an independent association with decreased functional status 5, 6, 7.

Activation of the inflammatory pathway, marked by increases in the level of C-reactive protein, has been linked to the development of cardiovascular disease, suggesting an inflammatory basis for atherosclerosis 8, 9, 10, 11, 12, 13. Activation of the coagulation system, as marked by D-dimer elevations, has been associated with several cardiovascular outcomes in the elderly, including myocardial infarction, angina, and death 14, 15, 16, 17. The extent to which the inflammatory and coagulation pathways have synergistic or independent effects on survival and functional outcomes has not been determined 18, 19, 20, 21. Activation of the inflammatory pathway in the elderly has been linked to the development of disability and mortality 22, 23, 24, but the effect of coagulation pathway activation on these outcomes is not known. In this longitudinal study, we assessed the effects of interleukin-6 and D-dimer levels on mortality and functional status.

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Methods 

Subjects 

Subjects were participants in the Duke Established Populations for Epidemiologic Studies of the Elderly, a component of the four-site National Institute on Aging study 6, 7, 25, 26, 27. This study was approved by the Duke institutional review board, and informed consent was obtained from each participant or proxy. The study enrolled 4162 participants aged 65 years or older who were selected in a random household sample of a five-county area including and adjacent to Durham, North Carolina, in 1986.

Blacks were oversampled to allow for comparison by race. Participants were contacted annually. In 1992, at the sixth annual contact, 2569 interviews were conducted, and blood samples permitting determination of interleukin-6 and D-dimer levels were obtained on 1723 participants. Blood was not obtained from those who refused, from those who were unable to give consent because of cognitive impairment, when there were technical difficulties in the blood draw, or from those who had moved from the in-person interview area 6, 7. Those unable or refusing to give blood tended to be older and more impaired than those who gave blood (7). Four years later, in 1996, a follow-up in-person interview was conducted, and functional status was again determined. No interviews were conducted during this 4-year interval.

Measures 

Information on demographic characteristics was obtained at entry into the study. At the sixth annual follow-up interview, when the blood draw occurred, height and weight were measured, and body mass index (kg/m²) was calculated. At each interview, we obtained information on smoking status; self-report of cancer, stroke, myocardial infarction, and diabetes; and four measures of functional status: Katz (basic personal maintenance tasks, such as toileting and bathing), Nagi (primarily upper and lower body functioning), Rosow-Breslau (stamina and mobility), as well as instrumental activities of daily living (ability to function in society, such as shopping and handling money) 28, 29, 30, 31, 32. Interleukin-6 and D-dimer levels were measured using high-sensitivity enzyme-linked immunoabsorbent assays as previously described for this population 6, 7, 33. Death was determined by search of the National Death Index; death certificates were obtained to ascertain cause of death. All deaths identified as of January 1, 2000, are included in the current analyses.

Statistical analysis 

Both interleukin-6 and D-dimer levels were dichotomized so that the top quartile (25%) could be compared with the remainder of the participants. The sample was divided into four groups, designating the subjects in the upper quartile of levels for each assay as “high.” For interleukin-6 levels, the top 25% was 2.96 to 201 pg/mL and the lower 75% was 0.60 to 2.95 pg/mL. For D-dimer levels, the top 25% was 336 to 6831 μg/L and the lower 75% was 13.8 to 335 μg/L. We then created four mutually exclusive groups: high interleukin-6 levels only (top 25% of IL-6, lower 75% of D-dimer); high D-dimer levels only (top 25% of D-dimer, lower 75% of IL-6); both high interleukin-6 and D-dimer levels (top 25% of both); and neither (lower 75% of both interleukin 6 and D-dimer) as the reference group.

Three sets of analyses were performed. First, the associations between each interleukin-6/D-dimer group with the important covariates were assessed using analysis of variance for continuous variables or the chi-squared test for categorical variables. In the second set of analyses, the relation of each group with subsequent mortality was assessed with the proportional hazards model (34), adjusting for age, sex, race, body mass index, disease status, current and past smoking, and disability in basic and instrumental activities of daily living. In the third set of analyses, 4-year changes in performance on the four functional status measures (from 1992 to 1996) were assessed among survivors. The relation of each interleukin-6/D-dimer group with the change in function was assessed. These analyses were repeated, adjusting for age, sex, race, body mass index, smoking, baseline and incident diseases, and the baseline level of each functional measure. Hazard ratios are reported as relative risks. For each outcome, type I error was controlled by using an omnibus test for a group effect. If significant (P < 0.05), the reference group was compared with each of the three “high”- level combination groups.

We also tested the effects of treating interleukin-6 and D-dimer levels as continuous or categorical variables, as well as the interaction of interleukin-6 and D-dimer levels on outcomes. The assumption of linearity was met for the log versions of interleukin-6 and D-dimer levels, and the results for these transformations are reported. The correlation between variables was measured with the Spearman rank test.

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Results 

About two thirds of the subjects were women (Table 1). Subjects with elevated markers were older and more likely to be black than were those in the reference group (Table 1). Sex, weight, body mass index, and smoking were not associated with interleukin-6 or D-dimer category. The prevalence of cancer and stroke differed significantly among the interleukin-6/D-dimer categories. Higher levels of markers were associated with poorer functional status for each of the four measures (Table 1). Levels of interleukin 6 and D-dimer were weakly, but significantly, correlated (r = 0.24; P = 0.001).

Table 1. Baseline Characteristics of the Sample in 1992, by Interleukin-6 and D-dimer Levels

Mortality 

Both the high D-dimer group and the high IL-6/high D-dimer group had significantly increased mortality (Table 2; Figure). When interleukin-6 and D-dimer levels were analyzed as continuous variables, both were significantly associated with mortality (Table 2). There was no evidence of an interaction between interleukin-6 and D-dimer levels (P for interaction = 0.44).

Table 2. Associations between Levels of Interleukin 6 and D-dimer and 5-Year Mortality*

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• Figure. 

  Mortality by interleukin-6 and D-dimer category. For each marker, “high” refers to the upper quartile of the reported values. Adjusted for sex; race; age; current and past smoking; baseline cancer, stroke, myocardial infarction, or diabetes; body mass index; and functional status. See Table 1 for numbers of patients in each group.

In the sample as a whole, 96 patients (20.1%) died of cancer, 114 (23.8%) of myocardial infarction, 110 (23%) of other circulatory conditions, 31 (6.5%) of stroke, and 63 (13.1%) of respiratory/chronic obstructive pulmonary disease. The high interleukin-6/high D-dimer group had a slightly higher proportion (33%) of deaths due to myocardial infarction and a lower proportion (5.7%) due to respiratory/chronic obstructive pulmonary disease.

Functional status and incident diseases 

All four interleukin-6/D-dimer groups had increasing functional dependency after 4 years of follow-up (Table 3). However, only change in Katz activities of daily living and instrumental activities of daily living were associated with interleukin-6 and D-dimer levels. The incidence of reported cancer, and perhaps heart attack, varied by interleukin-6/D-dimer categories (Table 3).

Table 3. Unadjusted Associations between Interleukin-6 and D-dimer Categories, and Disease Incidence and Changes in Functional Status, from 1992 to 1996

In multivariable analyses that adjusted for potential confounders, including incident disease, there were overall differences among the interleukin-6/D-dimer groups that were significant for each of the four functional measures (Table 4). Compared with the reference category of participants without high levels of either interleukin 6 or D-dimer, the decline in function was significant for those in the high interleukin-6/high D-dimer group for all measures. These effects were especially prominent among subjects without baseline impairment (Table 4). There was no evidence of interaction between interleukin 6 and D-dimer as continuous variables or as discrete variables with functional outcomes (all P >0.2).

Table 4. Adjusted 4-Year Changes in Functional Status by D-dimer and Interleukin-6 Category, by Presence or Absence of Baseline Disabilities*

When interleukin-6 and D-dimer levels were treated as continuous measures (after log transformation), higher levels were associated with greater functional decline, which was significant for two of the measures (Table 5).

Table 5. Effects of Interleukin 6 and D-dimer as Continuous, Log-Transformed Variables on 4-Year Functional Status Change*

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Discussion 

Inflammatory markers, in particular C-reactive protein and interleukin 6, have been associated with the risk of coronary heart disease, as well as with adverse outcomes among patients with coronary heart disease, leading to the theory that inflammation affects the development and evolution of atherosclerosis 8, 11, 35, 36. In these studies, fibrinogen and other markers of coagulation and fibrinolysis were found to show similar relations and were considered to be other markers of inflammation 14, 16, 17, 37, 38. More recently, it has been suggested that these pathways may have independent effects on cardiovascular disease. One study suggested that measures of inflammation and fibrinolysis might yield additive information in predicting the risk of myocardial infarction (14). We, as well as others, have extended this concept to the broader aspect of frailty in the elderly, and have demonstrated that inflammatory markers such as interleukin 6 and C-reactive protein are associated with age, decreased functional status, and disability. They also predict functional decline and mortality 5, 6, 22, 24. We have also shown in cross-sectional studies that fibrin D-dimer, a coagulation marker, is associated with poor functional status (7).

The results of the current study indicate that higher levels of D-dimer, and to a lesser extent, interleukin 6, are associated with greater functional decline and mortality. These effects are independent of age, sex, race, smoking, body mass index, health status, and initial functional status. Moreover, the effects of each marker were independent of each other. Simultaneous activation of both pathways is associated with greater decline in function and substantially greater mortality.

Although the effects on mortality were clear-cut, the effects on function are less certain. Of the four functional measures studied, only declines in Katz activities of daily living and instrumental activities of daily living were associated with marker elevations in univariate analysis. These two measures are hierarchical, whereas the others are not (39). Thus, they may be more likely to reflect sequential changes associated with increasing intensity of an underlying cause. Other recent studies have also indicated that not all functional outcomes are affected to the same degree 3, 40. Moreover, in multivariable analysis, the high interleukin-6 plus high D-dimer category was associated with declines in all four measures. The most striking association was seen in subjects without baseline functional impairment, suggesting that these markers may be early indicators, even in otherwise healthy people, of impending functional decline.

The lack of an independent effect of interleukin 6 alone on functional decline at first glance differs from that reported previously among a high-functioning group (22). That study did not measure D-dimer levels. Our results are consistent with a recent report that noted a substantially greater correlation of multiple markers of inflammation with functional change than with interleukin 6 alone (41), suggesting that, as is often true in the elderly, the sum of several small effects may matter.

Both interleukin-6 and D-dimer levels may be dysregulated with age, independent of disease status 6, 7. Our current findings that the age-related increases in interleukin-6 and D-dimer levels are related to subsequent functional decline and mortality, largely independent of disease status, suggest that this may be an important component of age-related physiological dysregulation, leading to portions of the frailty phenotype and subsequent death. However, we cannot exclude the effect of diseases that we did not record, or of subclinical inflammatory diseases, such as periodontitis or diverticulitis, on subsequent outcomes.

Products of inflammatory activation have pleiotropic effects that are relevant to declines in health (12). Excessive activation of the cytokine network has detrimental effects on the neuroendocrine system, skeletal muscle, bone, the central nervous system, and the vascular tree 4, 13, 42, 43, 44, perhaps via increased production of oxygen free radicals that produce oxidative tissue damage leading to subsequent organ damage and systemic functional decline (45). D-dimers result from fibrinolysis of cross-linked fibrin. Thus, the effects of D-dimer levels on functional decline could be related to activation of any part of the coagulation pathway. Because we did not measure markers of fibrinolysis, we cannot exclude increased fibrinolysis. There are several interactions between the inflammatory and coagulation pathways, suggesting that activation of one may lead to activation of the other 18, 19, 20, 21. Activation of the coagulation system and production of D-dimers has direct effects that could explain the effects on functional decline and mortality independent of the effects of interleukin-6 production. These include modulating the function of immunocytes to produce other mediators and cytokines 19, 21, 36, 46, 47, and roles in cell migration, vascular remodeling, and endothelial cell activation 16, 38. In addition, long-standing low levels of coagulant activation could result in systemic events as a subclinical manifestation of diffuse vascular thrombotic disease.

There may be a unifying theme for the relations that we observed as a chronic analogue of the multiple organ dysfunction syndrome, which is seen in close to half of critically ill patients, most characteristically with sepsis, and which is a leading cause of death in intensive care units (48). It is related to age and characterized by excessive, often massive, activation of both the inflammatory and coagulation pathways 48, 49, 50. In this syndrome, micro-thrombi are seen in multiple organs, leading to failure and ultimately death (49). It is possible that frailty is a type of chronic multiple organ dysfunction syndrome with low-level activation of, and imbalance in, inflammatory and coagulant pathways. Our data suggest that activation of these systems may be independent mechanisms through which several antecedent factors lead to agerelated functional decline and death.

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