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The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 55:M649-M657 (2000)
© 2000 The Gerontological Society of America

Age, Functional Status, and Racial Differences in Plasma D-Dimer Levels in Community-Dwelling Elderly Persons

Carl F. Piepera,b,c, K. Murali K. Raod, Mark S. Curried,e, Tamara B. Harrisf and Harvey J. Cohena,c,d

a Center for the Study of Aging and Human Development
b Department of Community and Family Health, Division of Biometry
c Claude D. Pepper Older Americans Independence Center, Duke University Medical Center, Durham, North Carolina
d Duke University Medical Center, Geriatric Research, Education, and Clinical Center, VA Medical Center, Durham, North Carolina
e Lewis-Gale Clinic, Salem, Virginia
f The National Institute on Aging, National Institutes of Health, Washington, DC.

Carl F. Pieper, Box 3003, Center for Aging and Human Development, DUMC, Durham, NC 27710 E-mail: cfp{at}geri.duke.edu.

Decision Editor: William B. Ershler, MD


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
Background.

Dysregulation of immunologic and coagulation systems is common in elderly persons and is associated with many diseases of aging. Thrombotic events are a major cause of morbidity and mortality in the elderly population. This study assesses whether D-dimer, a marker of fibrinolytic activity, varies systematically by demographic, health, and functional measures, and derives a prediction model for factors related to D-dimer in a sample of community-dwelling elderly persons.

Methods.

D-dimer levels were assessed in a random sample of 1,727 community-dwelling elderly persons from five rural and urban counties in North Carolina in 1992, as part of the Established Populations for the Epidemiologic Studies of the Elderly (Duke University). All subjects were 72 years or older at the time of the blood draw. In addition, all subjects were surveyed yearly by telephone or in person each year from 1986 to 1992 for a variety of health, functional, and social factors. Levels of D-dimer in 1992 were related cross-sectionally to demographics (age, race, education, income, gender, smoking), function (Nagi, Rosow-Breslau, Katz, Older Americans Resources and Services procedures instrumental activities of daily living), life satisfaction and self-rated health, self-reported diseases (heart attack, cancer, stroke, diabetes, and hypertension), and weight change from 1986 to 1992.

Results.

D-dimer levels increased with increasing age and functional disability. Among the health variables, only high blood pressure was predictive of D-dimer level. D-dimer levels were dramatically higher in blacks. Blacks were nearly four times more likely to have an extreme value of D-dimer (>600 µg/l) than whites when high D-dimer (yes/no) was analyzed, and blacks had an average level that was nearly 40% higher than whites in analyses of the continuous version of the outcome. This racial effect was not substantively affected in multivariable analyses with demographic and socioeconomic variables controlled. Race, age, functional status, current smoking, high blood pressure, and weight loss were related to level of D-dimer, and race, age, and functional status were related to the presence of a high D-dimer level (in the top 10% of the sample).

Conclusions.

Black, older, and functionally impaired persons had significantly higher levels of D-dimer in this sample of community-dwelling elderly persons. The findings for race were particularly striking and persisted even after controlling for smoking and other factors known to be related to thrombosis and were not mediated by social factors. This result may contribute to our understanding of the increased levels of thrombotic events found in these groups.

IMMUNOLOGIC processes and coagulation play an important role in the genesis of thrombosis and atherosclerosis (1)(2). Thrombotic events are a major cause of morbidity in the elderly population. In epidemiologic studies of atherosclerotic patients, as well as healthy subjects, baseline abnormalities of fibrinogen (3)(4)(5), antithrombin III (6)(7), coagulation factor VII (8), and platelet reactivity (9) have been associated with increased risk of acute thrombotic disorders, and there have been numerous studies demonstrating aging effects for hemostatic and inflammatory variables in elderly populations (10)(11)(12)(13)(14).

D-dimer is the primary degradation product of cross-linked fibrin. The assay was originally developed to assess the presence and/or risk of thrombosis. Plasma D-dimer levels remain stable over long periods in individual subjects, and a single measurement may be adequate to assess the fibrinolytic status (15). In a limited sample of community-dwelling elderly persons, we have shown that racial/ethnic differences in plasma D-dimer levels are related to age and functional status, with some suggestion of a racial association (16)(17). Such changes may also be a harbinger of future adverse events, as suggested by a recent study that demonstrated that activation of the endogenous fibrinolytic system occurs many years in advance of coronary arterial occlusion (18).

In this study, we had the opportunity to measure D-dimer levels in over 1,700 subjects in a community-based population of diverse racial composition, Duke University's Established Populations for Epidemiologic Studies of the Elderly (EPESE). In addition to D-dimer, there was an extensive collection of survey information on demographics, social, health, and functional conditions. We assessed the correlates to D-dimer in this sample of community-dwelling subjects measured across a range of functional, health, racial, social, and demographic factors.


   Methods
Top
 Abstract
 Methods
Results
 Discussion
 References
 
Subject Population
Our subjects were obtained from Duke University's component of the National Institute on Aging–funded EPESE. The populations for the four sites—for the Duke University study and for the subpopulation sampled for the blood draw—have been described elsewhere in detail (19)(20). The study enrolled 4,162 subjects, aged 65 years and older in 1986, selected as a random household sample in a five-county area, including and adjacent to Durham, North Carolina. Blacks were oversampled in the sample to allow for comparison by racial group. The initial in-person survey, conducted in 1986, included extensive information on a variety of health status indicators including cognitive and functional status, nutrition, depression, life satisfaction, exercise, social interaction and functioning, presence of chronic health conditions, and drug and medical use. The group was followed up in each subsequent year by telephone (1986–1987, 1990–1991) or in-person (1986, 1989, 1992) interview. In year 6 of the study, at the third in-person interview in 1992, blood samples were drawn on all subjects who were able to consent and who agreed to the blood draw, with the purpose of assessing a variety of routine hematologic and blood chemistry variables, including D-dimer. This was the only blood draw obtained in all waves of the sample. In addition, at the point of this follow-up interview, information on functioning, health status, cognitive status, and quality of life was obtained again.

At the time of the blood draw, there were 2,569 interviews conducted with the remaining members of the cohort (or their proxies). All subjects were older than 70 years at the time of this interview. Among those interviewed, 67% (1) had a successful blood draw for D-dimer and are the subject of this report. Those not having a blood draw were, in general, either unable to give consent, usually due to cognitive impairment (n 269); were able to give consent, but refused to have blood drawn; were residing too distant for an in-person interview; or had technical difficulties in blood draw (n 573).

Measures
Variables that did not change over time were collected at the baseline in-person interview (1986). Time-varying measures were re-collected at the time of the third in-person interview (1992). Information was collected on variables in the following domains.

Demographics and smoking status..-- Information on self-reported age, race, marital status, urban status, education, income, and smoking status were collected at baseline (1986). At the time of the third in-person interview in 1992, current smoking status and marital status were assessed.

Body mass index and change in weight.-- Height and weight were measured at the baseline and third in-person interviews to derive body mass index (BMI) (kg/m2). Change in weight was defined as the percentage change in weight over the 6-year period between interviews. Weight loss was defined as loss of more than 5% of body weight since 1986.

Activities of daily living and instrumental activities of daily living..-- Activities of daily living (ADLs) and instrumental activities of daily living (IADLs) measure the ability of the individual to perform generally required tasks (e.g., stooping, walking, lifting, dressing, toileting). Three ADL tasks were measured at the third in-person interview: Nagi (21), Rosow-Breslau (22), and Katz (23). IADLs were assessed by the Older Americans Resources and Services procedures (OARS) (24).

Cognitive impairment and depression..-- Cognitive impairment was assessed at the third in-person interview by the Short Portable Mental Status Questionnaire (25). Depression was assessed by the Center for Epidemiologic Studies–Depression Scale (26). Both of these scales have extensive use in epidemiologic settings as screens for dementia and depression.

Life satisfaction and self-rated health..-- Life satisfaction and self-rated health were assessed by single questions ("How would you say you find life" and "Overall, how would you rate your health") at the third in-person interview.

Prevalent diseases..-- The third in-person interview obtained self-reported diseases ("Did a doctor ever tell you that you had ...") for six comorbidities: cancer, arthritis, heart disease, stroke, diabetes, and hypertension.

Laboratory methods..-- Blood was collected in ethylenediaminetetraacetic acid-containing vacutainer tubes, placed on ice and taken to the laboratory and centrifuged, and plasma was stored at –70°C in 0.5 mL aliquots. D-dimers were measured by an enzyme-linked immunosorbent assay (ELISA; Dimertest Tripwell EIA kit, American Diagnostica, Greenwich, CT) according to the instructions provided with the kit as previously described (15)(16). We have also previously reported the characteristics and reliability of the assay (15)(16).

Statistical Analyses
The relationship of D-dimer with demographics, health status, health behaviors, and level of function was assessed. Analyses proceeded in several stages. In the first set of analyses, the distribution of D-dimer was assessed in an attempt to develop a transformation for the data, which could affect approximate normality, and to discover multiple modes that would be possibly indicative of increased risk. In the presence of unimodality, the data were then assessed to discern some reasonable threshold in order to define an "at-risk" group. As in our previous work with interleukin-6 (IL-6) (20), we chose the highest 10% to represent this high-risk group.

Second, the bivariate relationship of D-dimer with demographics, level of functioning, health behaviors, and health status variables was assessed. For each indicator, two statistics are reported: (i) for each independent variable, the mean of the logarithm of D-dimer level is calculated at each level of the independent variable; and (ii) the percent of subjects above some threshold level at each level of the independent variable is reported. Statistical significance is reported by analysis of variance, the Kruskall-Wallis test, or the chi-squared test of association. For variables measured at the ordinal level, a Spearman rank order correlation was calculated.

Finally, to arrive at a final multivariable model, we performed a forward stepwise regression for logarithm of D-dimer and a forward stepwise logistic regression for the D-dimer threshold variable. Because of their potential importance as covariates, age (in decades), gender, and race were forced into each of these final models. In addition, in an effort to unconfound the effects of race from the social effects that are correlated with race, education and income were also forced into these models. For the nearly one third of subjects who did not answer the income question (mostly because of refusal), we imputed the mean income value and computed an indicator variable for missing or not missing into the equation. This allowed us to analyze the effect of income and the effect of refusal on the outcome. The remaining variables were assessed individually as potential entry variables (p < .05 to enter, p < .05 to stay).


   Results
Top
 Abstract
 Methods
 Results
Discussion
 References
 
As shown in Table 1 , there were significant differences between the subjects for whom we obtained blood samples, for those requiring a proxy, and those for whom a blood draw did not occur. It was known that subjects with proxy interviews would be older, more cognitively impaired, more functionally impaired, have lower education, would more likely be black, and more diseased than their nonproxy counterparts. Of interest for the generalizability of the results was to assess if, relative to the group with valid blood samples, the nonproxy subjects who did not have a blood sample (refusers) were different. As shown in Table 1 , refusers were older on average (72.5 vs 71.6 years, p < .01), were more likely to be women (78.0% vs 65.0%, p < .001), had greater functional impairment (p < .01 for Nagi, Rosow-Breslau, Katz, and IADLs), and were more likely to be black (57.8% vs 52.3%, p < .05). However, the two groups did not differ statistically on percent urban, years of education, percent depressed, and presence of chronic diseases. We concluded that those unable to give blood for reasons of consent were older, sicker, and more impaired than those not having blood drawn and were, on average, somewhat older and more impaired than those for whom blood was sampled and studied. This result may impose some ceiling effect on the generalizability of the results to be reported, relative to the general population of over-70 year olds. Although the entire sample was randomly selected, the sample who had a blood draw were younger and healthier than the total population of over-70 year olds.


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  		Table 1. Distribution of Demographic, Health, Functional, Cognitive Impairment, and Depression Variables: Comparison of Refusals, Proxy, and Blood Draw Sample Groups (mean [SD] or percentage)

 
D-Dimer Distribution
D-dimer levels were measured in 1,727 subjects ranging in age from 72 to 101 years. The minimum and maximum values in this population were 13.8 and 6,831 µg/l. The mean value was 300 µg/l and the median was 202 µg/l. The data showed a non-Gaussian distribution. Because D-dimer demonstrated a strong right skew and appeared to be distributed approximately log normal, the D-dimer was transformed by the natural log, which brought about approximate normality (see Fig. 1). As can be seen, this transformation brought the data to near perfect normality and allowed the use of parametric statistics without the use of trimming or nonparametric techniques.



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  		Figure 1. Distribution of log (D-dimer) values for the North Carolina Established Populations for Epidemiologic Studies of the Elderly (EPESE; n 1727).

 
D-dimer did not show evidence of bimodality, the right skew could indicate extreme levels being associated with deleterious outcomes. We chose 600 µg/l as the cut point for a "high level," because this value demarcated approximately the highest 10% D-dimer level for the sample.

D-Dimer Associations With Demographic Variables
Table 2 shows the D-dimer values in this age group, divided on the basis of race, gender, age, rural-urban residence, smoking status, and weight change over 6 years. Age was positively correlated with high D-dimer levels (p .0001) by the Kruskall-Wallis test. In a set of follow-up analyses (not shown), the age correlation appeared to be applicable across the races and gender. D-dimer values were significantly higher in blacks (median value 242 µg/l) compared with whites (164 µg/l) and showed a trend towards statistical difference by gender (median value 188 for men and 210 for women, p .04 for levels of D-dimer). D-dimer levels were not related to smoking status, but were highly related to loss of 5% or more of body weight in the preceding 6 years. The relationship of D-dimer with race, gender, and age, simultaneously, is shown in Fig. 2.


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  		Table 2. Mean Log D-Dimer and Percentage Above 600 (µg/l) D-Dimer With Demographic, Smoking, and Weight Change Variables

 


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  		Figure 2. Distribution of median D-dimer level by age group, race, and gender. From the North Carolina Established Populations for Epidemiologic Studies of the Elderly (EPESE; n 1727).

 
D-Dimer Associations With Measures of General Health
Table 3 lists a number of health indicators that show a high degree of correlation with D-dimer level. High D-dimer levels were associated with increasing functional disability, as measured by ADL with Nagi, Katz, and Rosow-Breslau instruments. This was also reflected in the correlation (Spearman's rho 0.112) between high D-dimer levels and total IADL. In concordance with the above correlations, high D-dimers levels were associated with lower life satisfaction and poor self-rated health.


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  		Table 3. Mean and Percentage Above 600 (µg/l) D-Dimer With Functional Status Variables

 
D-Dimer Associations With Disease States
Table 4 shows the relationship of D-dimer with disease states. Among this aged population, 1,207 subjects had high blood pressure, determined by intake of antihypertensive medicines or a blood pressure greater than 160/90 mm Hg. There was a strong association between high blood pressure and high D-dimer values. The differences were significant when comparisons were made between mean log levels, median levels, or percent greater than 600 µg/l. Similarly, a correlation was found between a history of stroke and high D-dimer values. In this case, the difference was significant only when median values were compared, indicating either a generalized effect of stroke on D-dimer or, possibly, statistical vagaries in the findings. No correlation was found between D-dimer levels and a history of arthritis, heart attack, broken hip or bone, diabetes, or arthritis. There was a weak association with history of cancer. These findings held true when "in the last year" variables were utilized rather than "ever" (data not shown), indicating a lack of both an acute and chronic effect of D-dimer for these variables.


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  		Table 4. Mean Log D-Dimer, Median D-Dimer and Percentage Above 600 (µg/l) D-Dimer With "Ever" Disease Variables

 
Final Model
When the set of independent variables was used to predict log (D-dimer) using ordinary least squares regression (Table 5 ) and D-dimer >600 µg/l by logistic regression (Table 6 ), controlling for age, gender and race, both models revealed the importance of race and age in the association with D-dimers. The parameter estimates indicate that, in this sample, each decade of age was associated with a 25.9% elevation in level of D-dimer or a 1.8 increased odds of having a D-dimer >600 µg/l. Similarly, blacks had a greater than 30% increase (ß 0.306) in level of D-dimer relative to whites and a 3.94 increased odds of having an elevated D-dimer relative to whites. Because education and income were entered into the model, these race effects are independent of two of the common measures of socioeconomic status. Gender was a nonsignificant predictor in both models, but women demonstrated slightly lower values.


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  		Table 5. Stepwise Ordinary Least Squares Regression Estimates Log (D-Dimer) (µg/l)

 

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  		Table 6. Stepwise Logistic Regression Odds Ratios (D-Dimer >600 µg/l)

 
For the log (D-dimer) model, four additional variables were significantly related to D-dimer. Increased functional impairment as measured by the Rosow-Breslau instrument was related to elevated D-dimer level (p .0001). In addition, weight loss in the previous 6 years was related to increased D-dimer (p .002), and high blood pressure and current smoking were related to increased levels (p .04) for both variables. For the prediction of D-dimer above 600 µg/l, only ADL functioning, as measured by Rosow-Breslau, was related to D-dimer (p .0001).


   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
Aging is associated with increased morbidity due to a number of autoimmune, degenerative, and vascular diseases. Efforts are being focused to determine the biological markers that may show a correlation with functional status of elderly individuals. With this in mind, we measured two biological markers, namely, D-dimer and plasma IL-6 levels in a subpopulation of the Duke University's EPESE cohort. In this report, we present the associations between plasma D-dimer levels and a number of health parameters that are a part of the Duke University's EPESE database. The IL-6 analyses have been presented previously (20).

We found age is associated with high D-dimer values, even in this elderly cohort. This is consistent with several previous reports showing high D-dimer levels in elderly subjects (16)(27)(28)(29). In a previous study, we measured D-dimer levels in 315 elderly donors who were participants in the Duke University component of the MacArthur Foundation Network in Successful Aging Study of Community-dwelling Elderly (16). A majority of that group (89%) were in the upper third of health status and functional abilities for community-dwelling elderly persons, with no significant limitations in ability to perform routine physical tasks. The average D-dimer levels in that group were 153 µg/l, which are significantly lower than in the current group (300 µg/l). Several factors account for this difference in the mean D-dimer levels in the two cohorts: (i) the age range in the MacArthur cohort was restricted to 70–79 years; (ii) blacks constituted 43% of the population compared to 53% in the current cohort; and (iii) in the current cohort, 608 subjects (35%) had some functional defect as measured by OARS ADLs. As indicated by the current analysis, all these factors might have contributed to the high D-dimer levels in this population.

Thrombotic events are a major cause of morbidity in the elderly population. The risk factors associated with thrombotic events include age, smoking, and a history of high blood pressure. Several studies have examined relationships between these risk factors and assays of coagulation activity. Smoking has been shown to increase levels of both fibrinogen and platelets in plasma (3). An increased risk of ischemic disease and thrombotic events has been associated with elevated plasma levels of fibrinogen (3)(4), factor VII (7), and plasminogen activator inhibitor (30)(31). Increased D-dimer levels have been documented in patients experiencing unstable angina (32), and the D fragment may stimulate increased fibrinogen production (33)(34). Fibrin fragments also modulate function of neutrophils, monocyte/macrophages, and lymphocytes in vitro (35)(36)(37). Thus, the correlation between D-dimer levels and functional activity may indicate subclinical activation of coagulation and inflammatory cascades, which may lead to functional disability.

The link between activation of coagulation and inflammatory process has been noted many other times in the literature (38)(39)(40)(41). In correlating disease associations with D-dimer levels, we found no association between high D-dimer levels and a history of heart disease. This is consistent with the report that, although D-dimers are associated with increased risk of future myocardial infarction, it did not appear to be an independent predictor when other risk factors were considered (18). In contrast, we found a strong correlation between high D-dimer levels and another marker of heart disease, high blood pressure. A strong correlation was also observed between D-dimer levels and a history or diagnosis of stroke in bivariate analyses. It may be speculated that high blood pressure leads to endothelial cell damage and chronic activation of the fibrinolytic system, which might contribute to the incidence of stroke.

Because our subjects reflected a full spectrum of functional capacity, we had the ability to assess the contributions of this relationship with D-dimer levels by functional status, disease, and other demographic variables. This observation confirms our earlier report on the MacArthur cohort, where we found high D-dimer levels were associated with functional impairment (16). As a result, it was not unexpected to find that the self-rated health and life satisfaction indices were poorer in those subjects with high D-dimer levels, because these indices are associated with health and functional status. Thus, a consistent picture of poor health being associated with high D-dimer levels emerges from these data. It is worth noting that these same parameters were also highly associated with increased IL-6 levels in this data set (20), suggesting that the interface of inflammatory and coagulation factors may play an important role in these age and age-related phenomena. However, in this sample, D-dimer and IL-6 were only moderately correlated (Spearman's rank order correlation 0.24, p .0001), indicating potentially different pathways to pathogenesis.

One area in which there was discordance between the coagulation marker and our previous description of the inflammatory marker IL-6 was with respect to race. The Duke University's EPESE population is uniquely suited to establish such a relation, because African Americans were oversampled to ensure adequate numbers to address such issues. We have shown a striking relationship of race with D-dimer levels, with blacks having an average value nearly 40% greater than whites and nearly four times the odds of having a high D-dimer level. This racial effect was not mediated by any of the standard socioeconomic factors (education and income) commonly associated with race, was independent of hypertension status, and was unchanged in multivariable models that controlled for these factors as well as level of functioning. Thus, although it is true that blacks have lower levels of socioeconomic variables and higher levels of hypertension, our study suggests that there are factors independent of hypertension and class that result in blacks having higher D-dimer levels.

To what can we attribute this increase in D-dimer levels? The possibilities include intrinsically higher levels of reactivity in blacks because of stress (42), altered responsiveness of the coagulation system per se (43)(44)(45), including the possibility of enhanced production of tissue factor (TF) to a given level of cytokine stimulus from endothelial cells (46)(47)(48).

Future studies will be needed to assess TF gene expression in older subjects in samples with differing racial compositions. It would also be of interest to determine prospectively the impact of control of vascular phenomena, such as hypertension, on the level of D-dimers in blacks and whites. Regardless, our work suggests that one adverse risk factor for subsequent vascular events, D-dimer, is remarkably increased in elderly community-dwelling subjects and, especially, in older black subjects. In future studies, we plan to determine whether this risk factor is correlated with increased mortality, changes in function, and cardiovascular events. If so, it could serve an important role in the overall approach to geriatric assessment.


   Acknowledgments
 
The research was performed pursuant to contract NO1-AG1-2102, with the National Institute of Aging, and the Duke University Claude D. Pepper Older American Independence Center Grant NIH AG112618. The content of this publication does not necessarily reflect the views of the U.S. Department of Health and Human Services.

Received April 26, 1999

Accepted February 8, 2000


   References
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 Abstract
 Methods
 Results
 Discussion
 References
 

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