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Psychosomatic Medicine 65:145-150 (2003)
© 2003 American Psychosomatic Society

ORIGINAL ARTICLES

Association of Negative Life Event Stress With Coagulation Activity in Elderly Alzheimer Caregivers

Roland von Känel, MD, Joel E. Dimsdale, MD, Thomas L. Patterson, PhD and Igor Grant, MD

From the Department of Psychiatry (R.v.W., J.E.D., T.L.P., I.G.), University of California, San Diego; and the San Diego Veterans Affairs Healthcare System (T.L.P., I.G.), La Jolla, California.

Address reprint requests to: Igor Grant, MD, Department of Psychiatry, UCSD, 9500 Gilman Drive, La Jolla, CA 92093-0680. Email igrant{at}ucsd.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
OBJECTIVE: Part of the excess coronary disease rate and overall mortality reported with caregiving stress could relate to a hypercoagulable state. Physiological responses to the chronic distress of caregiving may involve hyperactive sympathetic nervous system responses to superimposed stressors. We wondered whether negative life stress might affect hemostatic function in caregivers.

METHODS: The three procoagulant measures thrombin-antithrombin III complex (TAT), fibrin D-dimer (DD), and von Willebrand factor (vWF) antigen were assessed in 54 spousal Alzheimer caregivers (mean age, 73 ± 6 years). Subjects completed a semistructured interview (Psychiatric Epidemiologic Research Interview, PERI) that assessed for non–caregiving-related life stress (ie, number of negative life events) over the 4-week period before blood sampling.

RESULTS: Caregivers reported an average of 2.6 negative life events (range, 0–6). The number of negative life events showed a direct association with plasma DD levels (p = .010). In multiple regression analyses, body mass index (BMI) and life stress were the only significant predictors of DD. Together, BMI, hypertension status, gender, and depression accounted for 23% of the variance in DD (p = .022). After these variables had been controlled for, life stress explained an additional 9% (p = .021) of the variance in DD. On the other hand, the number of life-events did not significantly predict TAT or vWF.

CONCLUSIONS: The findings suggest that superimposed life stress on top of the chronic stress of Alzheimer caregiving may elicit a hypercoagulable state that could contribute to coronary disease and to increased overall mortality in this population.

Key Words: psychological stress • life events • Alzheimer caregivers • hypercoagulable state • D-dimer • cardiovascular disease.

Abbreviations: BMI = body mass index; CAD = coronary artery disease; DD = fibrin D-dimer; Ham-D = Hamilton Rating Scale for Depression; TAT = thrombin-antithrombin III complex; vWF = von Willebrand factor.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
Alzheimer’s disease is the most prevalent form of irreversible dementia, affecting approximately four million patients and their caregivers in the United States (1). Healthcare professionals are increasingly aware that the burden of caregiving for a relative with Alzheimer’s disease poses enormous psychological and physical challenges for families. Among spousal Alzheimer caregivers, interviewer-rated depressive disorders are more frequent and physical health is substantially poorer than among the elderly in the general population (2). Caregiving strain, even at lower levels than usually encountered in dementia care providers, is an independent risk factor for overall mortality (3). Some of this increased mortality might relate to the high cardiovascular risk profile, which could accelerate atherosclerosis progression in dementia caregivers; caregiving distress may elicit hypertension (4), hyperlipidemia (5), hyperglycemia and hyperinsulinemia (6), as well as reduced physical activity (7). Consistent with this reasoning, it has been recently demonstrated that Alzheimer caregivers have a relatively increased rate of coronary events as compared with noncaregivers (8).

It is important to note that caregivers are not immune to other life stressors also experienced by the elderly noncaregiving population; life stressors, which may have little to do with caregiving, predict additional variance in burden beyond caregiver stressors (9). Physiological adaptation to chronic stress may render humans susceptible to increased sympathomedullary responses to superimposed stressors (10). Indeed, Alzheimer caregivers may show increased cardiovascular reactivity to mental stressors (11). In addition, our group found that caregivers who reported more life events had higher plasma norepinephrine levels than those who experienced fewer life events (12). Sympathetic hyperactivity and the associated plasma catecholamine surge with life stress may affect the risk of coronary artery disease (CAD) in a number of ways, such as by inducing coronary vasospasm (13) or by kindling procoagulant changes (13–15); the latter plays a crucial role in atherosclerosis and complicates coronary thrombosis (16). Changes in fibrin D-dimer (DD) and in von Willebrand factor (vWF), even within the "normal" range, may predict coronary events in both apparently healthy individuals and CAD patients (17–20).

This study measured markers of thrombin formation (thrombin-antithrombin III complex, TAT) (21), of fibrin turnover (DD) (22), and of endothelial cell damage (vWF) (23) in plasma in 54 elderly spousal Alzheimer caregivers. We hypothesized that added life stressors over and beyond chronic caregiving distress would promote hypercoagulability, an intermediate end-point measure of CAD. Because of comorbidity of life stress with depression (24), high prevalence of depression in caregivers (2), and increased procoagulant activity in depression (14), we also assessed depressive mood to disentangle potential interactions of stress and depression on hemostasis.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
Subjects and Study Design
Caregivers were 54 spouses of patients with Alzheimer’s disease participating in a longitudinal study of biological and psychosocial adaptation to caregiving. Data reported in this report were obtained on study entry, when all caregivers were providing home care for the patient. The University of California, San Diego (UCSD) Institutional Review Board approved the protocol, and all subjects gave written consent. Caregiver/patient dyads were recruited from the UCSD Alzheimer Disease Research Center or were obtained through community support groups or physician referrals. A research nurse conducted a structured medical history that included information on medication use based on subjects’ self-report.

Assessment of Life Stress and Depressed Mood
A trained interviewer conducted a semistructured interview to assess stressful life circumstances based on the Life Events and Difficulties Schedule (LEDS) method of Brown and Harris (24), as modified by Grant et al. (25) The interview probes systematically for the total number of stressful life circumstances that occurred within the 4-week period before the interview. Characteristic examples of negative life events reported independent from the caregiving situation were "pregnant daughter moved back in with caregiver," "death of a daughter who suffered from cancer," or "a son who had legal problems regarding his use of illicit drugs moved into the home of the caregiver and the patient." Depressed mood symptoms were assessed with the interviewer administrated Hamilton Rating Scale for Depression (Ham-D) (26).

Hemostasis Variables
Venous blood samples were obtained at 8:00 AM after the subject had rested for 20 minutes in a sitting position. The first 2 ml of blood was discarded, and 10 ml of blood was subsequently drawn through an indwelling 22-gauge venous forearm catheter into sterile ethylenediaminetetraacetic acid Vacutainer tubes. Plasma samples were obtained by centrifugation at 3000 g at 4°C for 10 minutes and immediately stored in plastic tubes at -80° C until assayed. Plasma levels of hemostatic molecules were measured by enzyme-linked immunosorbent assay as per the manufacturer (TAT, Enzyme Research Laboratories; DD, Diagnostica Stago) and as per a previous method for vWF antigen (27), using antibodies from DAKO Corporation (Carpinteria, CA) and substrate from Bio-Rad Laboratories (Hercules, CA). Interassay coefficients of variation for vWF antigen, TAT, and DD were 4.6%, 5.9%, and 5.5%, respectively. The respective intraassay coefficients of variation were 2.6%, 4.9%, and 2.2%.

Statistical Analysis
For statistical analyses, subjects were grouped on the basis of self-reported conditions potentially associated with hemostasis ("yes" or "no"): 1) "vascular disease," ie, coronary artery or cerebrovascular disease; 2) "hypertension"; 3) "cancer"; 4) type II diabetes; 5) former or current smoker; and 6) hypercholesterolemia. Subjects were also classified in terms of medications taken: 1) "nonsteroidal anti-inflammatory drugs" (NSAIDs), including aspirin; 2) "antihypertensives"; and 3) "hormone replacement therapy" with estrogen derivatives. Subjects with overt phlebitis and those taking anticoagulant therapy or ß-blocking agents were excluded from this study.

Data were analyzed using SPSS (version 9.0) statistical software (Chicago, IL). Results were considered statistically significant at the p <= .05 level; all tests were two-tailed. To approximate a normal distribution, hemostasis variables and Ham-D scores were log10 transformed. To test for differences in dichotomized variables, a 2 x 2 chi-square analysis was performed (Fisher’s exact test). Testing of continuous variables between groups used either one-way analysis of variance or Student’s t test. Fisher’s least significant difference was applied for post hoc testing. Univariate analysis of variance was performed with hemostatic measures, life event scores, or Ham-D scores being the dependent variables and with gender and either medical disorders, cardiovascular risk factors, or medication being the fixed factors. Correlations were estimated using Pearson’s correlation coefficient. Multiple linear regression was used to estimate the unique variance in hemostasis variables explained by variables significantly associated with hemostatic measures in univariate correlation analyses.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
Table 1 shows demographic data and the proportions of various medical disorders and medications in this older population. In terms of accuracy of health information obtained by caregivers’ self-report, we computed a 2 x 2-table of hypertension (yes/no) vs. antihypertensive medication (yes/no), which showed a good degree of agreement between self-reported disease and drug intake (Table 2). Only 4% of caregivers reported no medical disorder of clinical relevance, and only 4% received no prescribed drugs. With the exceptions of a higher body mass index (BMI) in women than in men (mean ± SD, 27.4 ± 4.4 vs. 24.7 ± 2.4 kg/m2, p = .008) and with hormone replacement therapy (p = .004), there were no gender differences in any variable from Table 1. Women receiving hormone replacement therapy did not significantly differ from women not taking hormone replacement therapy in any variable of interest and hemostasis measures in particular (data not shown).


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  		TABLE 1. Health Factors of 54 Spousal Caregivers Studieda
 

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  		TABLE 2. Self-Reported Hypertensive Disease vs. Self-Reported Antihypertensive Drug Intake
 
Subjects reported a mean ± SD of 2.6 ± 1.8 life events (range, 0–6). Table 3 shows that women scored higher in both life events (p = .001) and depressive symptoms (p = .001) than men. Smokers had higher depression scores than nonsmokers (mean ± SD, 5.6 ± 4.6 vs. 2.7 ± 3.2, p = .005). Life stress scores were associated with BMI (r = 0.29, p = .044), but they were not significantly associated with having a medical disorder or being on medication. vWF antigen was higher in men than in women (p = .027, Table 2), and it was, rather unexpectedly, lower in subjects reporting vascular diseases as compared with those with a negative vascular disease history (median, interquartile range: 92, 61%–143% vs. 122, 100%–144%, p = .045). DD was higher in hypertensive than in normotensive caregivers (median, interquartile range, 641, 463–862 ng/ml vs. 444, 359–642 ng/ml, p = .019); DD was also associated with BMI (r = 0.43, p = .002).


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  		TABLE 3. Psychosocial Scales and Hemostasis Variables
 
There was a significant correlation between total number of life events and Ham-D scores (r = 0.34, p = .013). DD showed a positive association with total number of life events (r = 0.35, p = .010), whereas vWF was inversely related to both number of life-events (r = -0.32, p = .018) and Ham-D scores (r = -0.27, p = .048). TAT showed no significant relationship with either the number of life events or Ham-D scores.

We then performed multiple linear regression analyses with DD and vWF as the dependent variables and with the variables significantly correlated with DD and vWF in univariate analyses as the independent variables. Ham-D scores and gender, which both were significantly related to life events (cf, above), were also forced into the equation. In particular, gender was considered because overall mortality with caregiving and coronary disease rate in Alzheimer caregivers both are higher in men than in women (3, 8). Table 4 shows that the number of negative life events and BMI emerged as significant predictors of DD, whereas none of the variables predicted vWF with significance.


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  		TABLE 4. Multiple Linear Regression Models for D-Dimer and von Willebrand Factora
 
To compute the unique variance in DD accounted for by life stressors, hypertension status, gender, and depression scores together were forced into the regression equation in a first step; BMI and number of life events were subsequently entered in a second and third step, respectively. Hypertension status, gender, and depression together accounted for 12% ({Delta}R2 = 0.12, {Delta}F(3,45) = 1.9, NS), BMI for 11% ({Delta}R2 = 0.11, {Delta}F(1,44) = 6.3, p = .016), and the number of negative life events for an additional 9% ({Delta}R2 = 0.09, {Delta}F(1,43) = 5.8, p = .021) of the variance in DD, respectively.

For further analysis, the 1 subject who indicated no life event was grouped along with the 22 subjects reporting 1 life event, and the 3 subjects with 5 life events were grouped together with the 6 caregivers reporting 6 life events. Figure 1 depicts log10 mean ± SE of DD values for the five caregiver groups categorized by the number of life events. DD was significantly different between groups (F(4,49) = 2.6, p = .049). In post hoc analyses, caregivers who reported 5 or 6 life events had significantly higher DD than those reporting 0 or 1 life event (median, interquartile range: 631, 445–1004 ng/ml vs. 439, 283–598 ng/ml, p = .007). In addition, there were trends for higher DD in caregivers with 4 life events as compared with those with either 0 or 1 life event (p = .052) and in caregivers with 5 or 6 life events as compared with those with 3 life events (p = .059). Also, the 18 caregivers with >=4 life events had 43% higher DD than the 36 caregivers with <4 life events (666, 447–910 ng/ml vs. 467, 351–632 ng/ml, p = .006).



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  		Fig. 1. Plasma D-dimer levels showed a direct association with number of negative life events (r = 0.35, p = .010). Caregivers with >=4 negative life events had significantly higher D-dimer than those with <4 life events (p = .006).

 
Even though Figure 1 suggests a departure from linearity, Spearman rank correlation analyses between the number of life events and hemostasis factors as well as regression analyses using ranked DD or ranked vWF as the dependent variables showed essentially the same p values, suggesting that assumptions about linearity were not violated.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
ACKNOWLEDGMENTS
 REFERENCES
 
The burden and distress of providing care for a close relative suffering from dementia may have health hazards including increased risk for overall mortality (2, 3). Part of this increased mortality might relate to the high cardiovascular risk profile (4–7) and to the excess rate of CAD events (8) in Alzheimer caregivers. Also, caregiving distress elicits hyperactive sympathetic responses to added distress (11, 12). In highly stressed dementia caregivers, a hypercoagulable state in response to superimposed life stressors could constitute a plausible intermediate end-point measure of cardiovascular disease.

Before discussing our results, we acknowledge that studying an elderly population entails difficult-to-control variables that are associated with aging and declining health, independent of whatever risks might be attendant on caregiving distress. We also acknowledge that our sample was limited and heterogeneous. In the present instance most subjects had histories of various medical conditions, and many of them were taking various medications. Given the sample size, for statistical analyses we were forced to make compromises in controlling for these factors. For example, we were not able to take into account potential differences in hemostatic effects of the several categories of antihypertensive drugs. We attempted to control for histories suggestive of clinical atherosclerosis, but given the age and high prevalence of cardiovascular risk factors in our subjects, we may have missed undiagnosed atherosclerosis. Even though we found good agreement between self-reports of hypertension and antihypertensive medication (Table 2), the use of medical records to document health factors might have rendered more appropriate information on caregivers’ health conditions (28). We also are unable to state whether the stress-procoagulability relationship is unique for the Alzheimer caregiving population since our study design did not include a noncaregiving elderly control group.

Acknowledging such limitations, we found a positive relationship between quantity-of-life stress within a 4-week period and plasma levels of DD, a widely used clinical marker of a hypercoagulable state (22). Even though Figure 1 does not allow a statement on a linear relationship between number of life events (likely because of the small numbers of subjects and thus high variance in DD across life event categories), we may argue that caregivers who experienced relatively more life stress, as tapped by a cutoff value of 4 negative life events, were more liable for a hypercoagulable state.

Life stress explained 9% of the variance in DD after controlling for its traditional biological correlates BMI (29) and hypertension (30) (parenthetically, the amount of variance explained by life stress was similar to that explained by BMI and higher than that explained by hypertension). Given that even within a "normal" range, elevated DD may predict coronary events (17, 19, 31, 32), our results support the notion that changes in hemostatic function could mediate part of the association between life change variables and CAD (13). Our finding is compatible with the observations by Kario et al. (33), who found increased DD in elderly persons after a most intense life event (major earthquake) and who also found an increased rate of acute coronary events in the earthquake area.

We found no significant relationship between life stress and TAT, the second hypercoagulability marker measured in our study. In part, this might be explained by the substantially different half-life of TAT, which is only a few minutes (34), as compared with that of DD, which is up to 48 hours (22). Even though TAT increases in response to acute sympathetic challenges (14, 15), the kinetics of fibrin turnover with fluctuating life stress intensity may make DD a more relevant indicator of life stress–related coagulation changes than TAT (30).

Similarly, life stress was not a significant predictor of vWF in regression analyses, and the association of life events with vWF in univariate analyses may be confounded by mutually correlated variables. Although intense forms of acute sympathetic stimuli may trigger rises of vWF levels in plasma in healthy subjects (14, 15) and in elderly hypertensive individuals (33), the comparatively more subtle sympathetic activation in the present study did not elicit increase in vWF in our caregivers

Sympathetic mechanisms underlying hemostatic changes are to some extent speculative. Nonetheless, elevated plasma norepinephrine levels in caregivers with high life stress scores (12) may promote a series of procoagulant and anticoagulant changes (15). In patients with atherosclerotic disease and concomitantly impaired endothelial anticoagulant function, procoagulant mechanisms seem to outweigh anticoagulant processes in response to sympathetic stressors (14, 15, 34–37). The high prevalence of clinical (and subclinical) atherosclerosis in our caregivers may be a harmful "breeding ground" for hypercoagulable changes with negative life stress.

In summary, there is evidence that superimposed negative life stress may elicit hypercoagulability in chronically stressed Alzheimer caregivers. Together with increased prevalence of cardiovascular risk factors, a hypercoagulable state could help explain the increased coronary risk in dementia caregivers. Such a mechanism might contribute to excess mortality in this highly stressed population.


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
REFERENCES
 
This work was supported by Grants MH42840 and HL36005 from the National Institutes of Health (to I.G. and J.E.D.), by fellowship 81BE-56155 from the Swiss National Science Foundation (to R.v.K.), and by an educational grant from Novartis Foundation, Switzerland (to R.v.K.). The authors thank Dr. Richard Mayou for serving as action editor in the evaluation of this manuscript. The authors wish to thank Chris Archuleta, MS, Carolyn Swenerton, RN, and Sharyn Wilensky, RN for their assistance in the conduct of this study.

Received for publication April 23, 2001.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 

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B. T. Mausbach, J. E. Dimsdale, M. G. Ziegler, P. J. Mills, S. Ancoli-Israel, T. L. Patterson, and I. Grant
Depressive Symptoms Predict Norepinephrine Response to a Psychological Stressor Task in Alzheimer's Caregivers
Psychosom Med, July 1, 2005; 67(4): 638 - 642.
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