Relationship of Blood Coagulation and Fibrinolysis to Vital Exhaustion

WILLEM J. KOP, P H D , KARLY HAMULYAK, MD, P H D , CARINA PERNOT, MSC, AND AD APPELS, PHD

Objective: Acute physical and psychological stressors affect blood coagulation and fibrinolysis, but little is known about hemostatic factors associated with chronic psychological stress. Prolonged psychological stress may end in a state of vital exhaustion, which has been shown to be a risk factor for first myocardial infarction and recurrent events after coronary angioplasty. The present study tested the hypothesis that vital exhaustion resulting from chronic psychological stress is associated with impaired fibrinolytic capacity and increased coagulation factors. Methods: On the basis of a validated questionnaire and subsequent structured interview, a well-defined group of otherwise healthy exhausted men was recruited (N = 15) and compared with age-matched not-exhausted controls (N = 15). Fibrinolytic measures included tissue plasminogen activator (TPA) antigen and plasminogen activator inhibitor (PAI-1) activity, and as coagulation factors we examined factors VIIc, factor VIIIc, and fibrinogen. Control variables were: blood pressure, smoking status, triglycerides, cholesterol, and standard hematological measures. Samples were collected twice to correct for intraindividual fluctuations. Statistical analyses were performed using 2 X 2 mixed model analysis of variance with subsequent univariate testing. Results: Vital exhaustion was associated with significantly elevated levels of PAI-1 activity (p = .023). The higher PAI-1 activity in exhausted subjects (median = 13.0 U/ml vs. 6.0 U/ml) was not accounted for by smoking status or serum lipids. No significant differences were observed in TPA antigen, factor Vile, factor VIIIc, and fibrinogen. The groups did not differ in blood pressure, smoking status, triglycerides, cholesterol, or standard hematological measures. Conclusion: These data suggest a reduced fibrinolytic capacity in exhausted individuals. Therefore, the relationship between vital exhaustion and risk of myocardial infarction may be mediated in part by an imbalance between blood coagulation and fibrinolysis. Key words: fibrinolysis, coagulation, vital exhaustion, psychological stress, hemostasis.

BP = blood pressure; DSM = Diagnostic and Statistical Manual of Mental Disorders; EDTA = ethylenediaminetetraacetic; ELISA = enzyme-linked immunosorbent assay; GGT = y-glutamyl transpeptidase; LDH = lactate dehydrogenase; MIVE = Maastricht Interview for Vital Exhaustion; MQ = Maastricht Questionnaire; PAI = plasminogen activator inhibitor; SCL-90 = Symptom Check List-90; SGOT = serum glutamic oxaloacetic transaminase; SGPT = serum glutamic pyruvic transaminase; TPA = tissue plasminogen activator.

INTRODUCTION
Thrombus formation in the coronary arteries is purported to be one of the pathophysiological pathways by which psychological stressors may lead to cardiac events (1, 2). Acute psychological stress has been shown to affect blood coagulation, fibrinolysis, and platelet activity (3-7). Both physical and mental stressors are reported to trigger transient cardiac ischemia, unstable angina, myocardial infarction, and sudden cardiac death (8-10). In contrast to acute stressors, the effects of chronic psychological stress on the blood clotting process is not well understood. Several prospective studies have shown that psychosocial factors reflecting prolonged psychological stress significantly increases the risk of myocardial infarction (11-14). It has been demonstrated, both in animal models (15) and in humans who suffered myocardial infarction (16), that prolonged uncontrol-

From the Department of Medical and Clinical Psychology (W.J.K.), Uniformed Services University of the Health Sciences, Bethesda, MD, Department of Internal Medicine (K.H., C.P.) and Medical Psyschology (W.J.K., A.A.), Cardiovascular Research Institute Maastricht, University of Limburg, Maastricht, the Netherlands. Address reprint requests to: Willem J. Kop, PhD, Department of Medical and Clinical Psychology, Uniformed Services University of Ihe Health Sciences, 4301 Jones Bridge Rd., Bethesda, 20814 MD. Received for publication November 20, 1996; revision received September 16, 1997. The opinions and assertions expressed herein are those of the authors and should not be construed as reflecting those of the United States Public Health Service or of the United Slates Department of Defense.

lable psychological distress ultimately may result in a state of exhaustion. It is, therefore, of relevance that extreme tiredness and fatigue are among the most prevalent premonitory symptoms of myocardial infarction (17-20). This state has been labeled as vital exhaustion and consists of three typical characteristics: lack of energy, increased irritability, and demoralization (21). We have demonstrated previously that vital exhaustion is an independent predictor of first myocardial infarction in a prospective study of 3877 healthy men (22). In addition, feelings of exhaustion in patients undergoing coronary angioplasty are associated with a two-fold increased risk of developing subsequent cardiac events within 1.5 years after the initially successful intervention (23). The pathophysiological mechanisms accounting for the relationship between vital exhaustion and future cardiac events are not well understood, but may include factors related to the blood clotting process, such as platelet aggregation (24), increased coagulation factors, and impaired fibrinolysis (25). Epidemiological investigations have demonstrated that coagulation and fibrinolytic factors contribute to the development of myocardial infarction (26-31). A dynamic balance exists between the coagulation factors that generate fibrin and the removal of fibrin by the fibrinolytic system. Normally, both components of the clotting process are activated by stress, resulting in a balanced response (3). Most studies that have investigated the influence of physical and mental stress on blood clotting have examined acute experimental stressors. For example, Jem et al. (3) used a laboratory mental stress task, physical exercise, and epinephrine infusion as stressors. An acute reaction was observed with an increase in clotting factors (von Willebrand factor, factors VII and VIII), fibrinogen, and indicators of fibrinolysis (tissue plasminogen activator activity, and plasminogen activator antigen) with all three stressors. An adrenergic mechanism is probably responsible for the relationship between acute psychological stress and coagulation and fibrinolysis, because as mental stress resulted in the same effects on hemostasis as did epinephrine infusion and physical exercise. In support of central nervous system involvement in the clotting process, it has been demonstrated that electrical stimulation of the hypothalamus and the reticular formation results in a subsequent increase in plasma concentration of factor VIII (32).

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0033-3174/98/6003-0352$03.00/0 Copyright 1998 by the American Psychosomatic

BLOOD COAGULATION AND FIBRINOLYSIS RELATIONSHIP TO VITAL EXHAUSTION The relationship between chronic psychological stress and blood-clotting tendency has not been widely investigated. There is some evidence that in case of sustained mental arousal, clotting tendency increases (factor VIII and fibrinogen) for several hours after a stressful task, and then decreases to normal levels over time (33). However, this study involved a stressful experimental situation with a duration of 3 days, which may differ in intensity, character, and duration from chronic stress that occurs in daily life. Another observation in support of a relationship between chronic psychological stress and hematological parameters is that people with high job strain and low socioeconomic status have relatively high levels of fibrinogen and factor VII (34, 35). Social class and job strain are rather crude measures of psychological stress, because they do not provide information regarding the psychological consequences of these environmental factors. Recently, Raikkonen et al. (25) observed significant associations between feelings of exhaustion and impaired fibrinolytic capacity. However, coagulation factors were not included in that study and assessment of psychological characteristics was limited by the use of questionnaire assessments only. Therefore, the present study investigates whether a well-defined group of healthy male subjects who are exhausted as a result of chronic psychological stress are characterized by reduced fibrinolytic capacity and increased coagulation factors. of 15 exhausted subjects. The not-exhausted control group of 15 men was recruited from the same population matching for age, because higher levels of factor VIIc, factor VIIIc, and PAI are associated with older age (38-40). The study was approved by the Institutional Review Board at the university and all subjects gave informed consent.

Assessment of Vital Exhaustion

Vital exhaustion was initially assessed by mailed questionnaire (Maastricht Questionnaire (22, 41)) and subsequently validated by using a structured interview (37). The MQ is a 21-item questionnaire and has been used to assess vital exhaustion in cardiac patients (23, 42, 43) as well as in healthy populations (normal MQ mean 8.8 8.7; possible score range = 0 to 42; Cronbach's a = 0.80) (22, 43). To confirm the MQ classification of exhaustion, potential candidates were invited for a structured interview if the MQ score was ^ 1 6 (probable exhausted), or s 6 (probable not-exhausted). The structured interview consisted of the MIVE (37) and the Diagnostic Interview Schedule (44, 45). The reliability and validity of the MIVE are described in detail elsewhere (37). Briefly, the MIVE has 23 items derived from the MQ and inquires about the presence and duration of symptoms of exhaustion. The correlation between MQ and MIVE scores is 0.74 and the MIVE reliability is good (Cronbach's a = 0.86 in healthy men) with satisfactory interrater reliability (kappa = .91) (37). Subjects were classified as exhausted if: a) more than 7 of the 23 MIVE items revealed a positive response; and b) at least one of the elements of exhaustion (lack of energy, irritability, or demoralization) showed an increase in intensity over the year before examination (37). It was additionally required that a psychologically stressful situation (eg, family- or job-related problems) precipitated the increase in feelings of exhaustion. This procedure has been shown to effectively exclude falsepositives of the questionnaire assessment of vital exhaustion in cardiac patients as well as healthy controls (37). After the MIVE, a previously validated abbreviated version of the Diagnostic Interview Schedule was administered to specifically assess depressive disorders following DSM-III-R criteria (44, 45). Subjects with complaints of exhaustion as the result of a major depression or dysphoric disorder were excluded from the study. In addition to the interview, subjects completed the SCL-90 (46, 47). This 90-item scale has a total score range of 0 to 360 with a normal population mean of 117.2 27.3 and was used as a marker of severity of psychological distress.

METHODS Subject Selection

Subjects were recruited from a previously sampled cohort of 451 men who participated in a study examining the relationship between vital exhaustion, sleep complaints, and depression (36). These 451 subjects were reinvited to participate in the current study, using a screening questionnaire mailed at 4 years after the initial study. Of the 451 subjects approached, 334 (74%) responded, 9 (2%) died, 49 (11%) did not return the screening questionnaire, and 59 (13%) were lost to follow-up. The screening questionnaire included: a) the Maastricht Questionnaire, which inquires about feelings of exhaustion (22); and b) a short health status inventory designed for the purposes of this study to evaluate current diagnosed diseases, medications used, smoking status, and alcohol consumption. On the basis of the 334 returned screening questionnaires, subjects were excluded for the following medical reasons: cardiac disease (N = 55), diabetes mellitus (N = 9), renal or liver disease (N = 6), hypertension (N = 31), rheumatic arthritis (N = 6), or no information volunteered (N = 21). Questionnaires of the remaining 206 candidates revealed 57 patients who had MQ scores S16 (potentially exhausted) and 94 patients with an MQ score < 6 (potentially not-exhausted). Potentially exhausted subjects (JV = 57) were contacted by telephone to make an appointment for the structured interview and medical evaluation. Twenty-two candidates were excluded at that time for various medical conditions (eg, severe obstructive pulmonary disease, thyroid dysfunction, severe physical handicap) or psychiatric reasons (eg, use of antipsychotic medication, current psychiatric treatment); of the remaining 35 potentially exhausted subjects, 13 (37%) were willing to come to the hospital for a clinical interview and blood collection. Subjects were invited to the hospital for clinical examination and to confirm the presence or absence of exhaustion by a structured psychological interview (37). One subject with a MQ score S16 was excluded because of major depression and two were excluded because the interview revealed insufficient symptoms of exhaustion. Given this low number of available exhausted subjects (N = 10), five additional exhausted subjects were recruited from a different project of our research group (37). The classification criteria for vital exhaustion are described below and resulted in a final study sample

Blood Sampling and Biochemical Assays

After the psychological assessment, blood samples were collected on two occasions from each subject. The first sample was collected within 2 weeks after the psychological interview and, to correct for intraindividual fluctuations of clotting factors, a second sample was obtained within 3 months. All blood specimens were collected after an overnight fast between 8:30 and 10:00 AM to control for circadian variations (40). Subjects were instructed to refrain from alcohol use starting the evening before study and not drink caffeinated beverages during the morning of study. After the subject had rested for at least 15 minutes, venipuncture was performed, using a 1.2-mm needle with minimal stasis applied to the upper arm. EDTA blood was used for routine blood chemistry determinations. For the determination of fibrinolytic and coagulation parameters, citrated blood (3.8 Na + ; pH = 8.10; at 1:10 mixture) was used. Samples were immediately centrifuged at 4C and aliquots of platelet-free plasma were snap frozen and stored at 70C until additional analysis. Control blood chemistry variables were measured using a Dimension automate (Dupont, Wilmington, DE); measurements included the level of triglycerides and total cholesterol, as well as creatinine, alkaline phosphatase, GGT, SGOT, SGPT, LDH, and bilirubin. Routine hematological parameters were measured immediately after blood-sampling, using the HI automate (Bayer, West Haven CT),

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W . J. KOP et al. and included hematocrit value, platelet count, leukocyte count, and differential. Measures of fibrinolysis included PAI-1 activity, which was measured with a chromogenic assay from Kabi (Nikoping, Sweden) in accordance with the manufacturer's prescription, and TPA antigen was measured with an ELISA technique, using a kit from Innogenetics (Antwerp, Belgium). All assays were analyzed in one run to prevent interassay variation. The activity of coagulation factors Vile and VIIIc was measured with a one-stage clotting assay, using immunodepleted factor deficient reagents obtained from Instrumentation Laboratory (Milano, Italy). Data are presented as percentages of values found with normal pool plasma. Fibrinogen was estimated in accordance with the method of Clauss (48). The laboratory personnel was blinded with respect to the psychological status of the subjects. Statistical Analysis Initial analyses examined group differences in control variables (age, blood pressure, smoking status, triglycerides, total cholesterol, and routine blood chemistry). For continuous variables, t tests were used; x1 tests were used for categorical variables. Bivariate associations of clotting factors with triglycerides and cholesterol were examined, using product-moment correlations. Differences between exhausted vs. not-exhausted subjects in measures of blood fibrinolysis and coagulation were examined, using analyses of variance. A 2 X 2 mixed model was used with exhaustion status as a two-level between-subjects factor and the two occasions of blood sampling as a two-level within-subject factor. Data for the five clotting factors (PAI-1 activity, TPA antigen, factor VIIc, factor VIIIc, and fibrinogen) were examined separately. Natural logarithmic transformations were applied if variables were not normally distributed (49). Increased factor VII, fibrinogen, and PAI-1 levels are related to smoking status (50, 51). Therefore, analyses were repeated with smokers excluded. To evaluate whether differences between exhausted vs. not-exhausted subjects were due to triglycerides and cholesterol levels, the 2 X 2 mixed models were repeated, adding these variables as separate covariates.

RESULTS
Values of control variables for exhausted and not-exhausted subjects are shown in Table 1 and indicated that the groups did not significantly differ in usual alcohol consumption, smoking status, or blood pressure, and that the matching for age was successful. No differences were found between the exhausted and the not-exhausted subjects in triglycerides, total cholesterol, nor in any of the other routine blood chemistry measurements (Table 1). Vital exhaustion was significantly associated with higher SCL-90 total scores (mean 149.9 39.4), compared with not-exhausted controls (104.8 9.4), which validates that the exhausted group experienced more psychological distress (t = 4.13; p < .01) than not-exhausted controls. With respect to blood clotting factors, fibrinolytic measures (PAI-1 activity and TPA antigen) were significantly correlated (r = .62), whereas coagulation factors (VIIc and VIIIc) and fibrinogen did not reveal significant interrelationships (r values < .25). Significant associations were found between TPA antigen and clotting factor VIIc (r = .51) and between both PAI-1 activity and TPA antigen with factor VIIIc (r values .49 and .51, respectively). Analysis of variance revealed significantly higher levels of PAI-1 activity in exhausted subjects (between-subjects main effect: p = .023; Table 2). In addition, exhausted subjects tended to have higher levels of TPA antigen (p = .086) and factor VIIc (p = .079). Variations over the two occasions of blood collection were observed for factor VIIIc [p = .014) and fibrinogen (p = .003) (higher levels at the second time), and

TABLE 1. Relationship Between Control Variables and Vital Exhaustion Not Exhausted Mean + SD Mean Age (yr) Alcohol consumption (/V/day) Current cigarette use (/V/day) Systolic BP (mm Hg) Diastolic BP (mm Hg) Triglycerides (mmol/1) Cholesterol (mmol/1) Hematocrit (1/1) Thrombocyte (nl~') Neutrophils (%) Creatinine (/xmolfl) Alkaline phosphatase (U/l) GGT (U/l) SGOT (U/l) SGPT (U/l) LDH (U/l) Bilirubin (^imol/1) Smoking status Never Stopped > 2 yr Stopped 2 yr Currently smoking
0

Exhausted P SD 9.7 1.2 21.6 12.7 10.0 1.03 0.90 0.03 71.6 7.9 8.3 20.9 9.5 3.4 5.6 54.2 8.5 26.7C 33.3 13.3 26.7 Mean 49.3 1.6 9.0 121.7 78.7 1.96 6.47 0.45 233.3 56.3 81.6 80.7 28.3 18.5 28.5 323.4 10.3 4b 5 0 6 SD 7.3 2.2 13.9 17.3 7.4 0.94 0.89 0.03 47.9 7.1 13.7 28.3 13.5 4.1 5.1 63.3 2.1 26.7 33.3 0.0 40.0 NS" NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS

54.2 1.5 13.0 120.3 77.7 1.47 6.06 0.44 232.8 53.6 84.7 67.9 23.1 19.9 27.7 316.5 13.5
4

5 2 4

NS

NS = not significant (p > .1); BP = blood pressure; GGT = 7-glutamyl transpeptidase; SGOT = serum glutamic oxaloacetic transminase; SPGT = serum glutamic pyruvic transminase; LDH = lactic dehydronase. Number. c Percent.
b

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TABLE 2. Association of Vital Exhaustion With Fibrinolytic and Coagulation Factors Blood Sampling Time 1 Not Exhausted PAI-1" activity (au/ml) TPA antigen (ng/ml) Factor VIIc (%) Factor VIIIc (%) Fibrinogen (g/l) 6.4 (3.3) 8.7 (2.9) 103.5(18.6) 118.5(32.6) 2.8 (0.6) Exhausted 12.5 (2.5)* 10.4(3.9) 107.5(14.1) 119.1 (31.5) 2.9 (0.4) Not Exhausted 5.7 (4.0) 7.8 (2.3) 94.0(14.2) 136.1 (30.6) 3.1 (0.6) Time 2 Exhausted 12.5(2.7)*" 10.2 (3.9)* 108.2 (9.6)**"' 129.7(33.2) 3.0 (0.5)c

1 PAI = plasminogen activator inhibitor; TPA = tissue plasminogen activator; ANOVA = analysis of variance. ' ANOVA main between-subjects effect (exhausted vs. not exhausted) p < .05. : ANOVA main within-subject (time) effect p < .05. 1 ANOVA interaction term (exhaustion by time of assessment) p < .05. " p < .05; ** p < .01 (exhausted vs. not exhausted; for separate time points).

factor VIIc (p - .016) (lower levels at the second time). There was also an interaction between vital exhaustion and time of assessment for factor VIIc, indicating that not-exhausted subjects showed a decrease over time, whereas exhausted subjects did not (p inte,.action = .006). As is shown in Figure I, PAI-1 activity was significantly higher in the exhausted group (median = 13 U/ml) than in not-exhausted controls (median = 6 U/ml; p = .025). Although a substantial overlap in the distribution of PAI-1 activity in the two groups was observed (Figure 1), all PAI-1 activity levels of the exhausted subjects were above the median of the not-exhausted subjects and in the upper range of normal PAI-1 activity values. The possible influence of control variables was examined by repeating the analyses of variance while adjusting for smoking status, triglycerides, and serum cholesterol. As is shown in Table 1, no associations were found between vital exhaustion and these control variables. When current smokers 35 30

were excluded, analyses of the remaining 20 subjects revealed essentially the same results. PAI-1 activity was higher in the exhausted group than in the not-exhausted group (p = .016), although there were no significant differences in TPA antigen and coagulation factors. Triglyceride levels correlated significantly with PAI-1 activity (r = .50), TPA antigen (r = .47), and factor VIIc (r = .43). In the present sample, cholesterol levels were correlated only with PAI-1 activity (r = .36). Analyses of covariance revealed that PAI-1 activity continued to be somewhat higher in exhausted subjects after covarying for triglycerides (p = .069) and cholesterol {p = .062).

DISCUSSION
Fibrinolytic processes have been reported to be dysfunctional in patients with coronary artery disease and also affect prognosis in patients with unstable angina and after successful coronary angioplasty (31, 52-55). The present study revealed significantly higher PAI-1 activity levels in a well-defined group of exhausted subjects. This finding suggests a reduced fibrinolytic capacity in exhausted individuals, which is congruent with previous observations (25). However, exhaustion was not consistently related to fibrinogen and coagulation factors (VIIc, VIIIc). This may suggest that a disequilibrium between the fibrinolytic and coagulation systems in response to prolonged psychological stress could promote the risk for thrombus formation and myocardial infarction (3). Classification of vital exhaustion was based on a standardized questionnaire (22, 23, 41) and subsequent confirmative structured interview (37). Subjects were excluded if exhaustion was a consequence of a somatic or psychiatric disorder, such as major depression. For classification purposes, vital exhaustion had to be present as the result of a failure to cope with prolonged psychological stress. Therefore, it was required that there was an increase in at least one of the three characteristics of exhaustion: lack of energy, irritability, or demoralization in the year before examination. The characteristics of vital exhaustion are to some extent the same as those of depression and the divergent validity of these two constructs requires additional investigation. Preliminary analyses has indicated, however, that "lack of energy" is the most important aspect of vital exhaustion, inasmuch as that component showed the strongest predictive value for future cardiac events after coronary angioplasty compared with irritability and demoralization (56). In addition, previous

% 25
D

20 >

i10
5 Not Exhausted Exhausted
Figure 1. Fibrinolysis and coagulation as related to vital exhaustion. Higher levels of plasminogen activator inhibitor (PAI-1) activity were observed in exhausted subjects ( = median = 13 U/ml) compared with not-exhausted controls ( = median = 6 U/ml). This difference between exhausted vs. not-exhausted subjects was statistically significant (p = .03), despite the overlap of the data distribution between the two groups.

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W . J. KOP et al.

studies showed that exhausted subjects have elevated fatigue scores on the Profile of Mood States, whereas no increased sadness scores were observed (36). In the present study, we explicitly excluded clinically depressed subjects on the basis of DSM-11I-R criteria. Therefore, the results of this study may not necessarily apply to depression, although impaired fibrinolytic activity has been observed in depression as well (57). Significant fluctuations over time were observed for measures of coagulation. Because these variations were not uniform (factor VIIIc and fibrinogen increased, whereas factor VUc decreased), we cannot draw firm interpretations of this finding from the present data. Repeated blood samples were obtained within 3 months, which precludes major confounding by seasonal changes, and biochemical analyses were performed at the same time to avoid interassay variation. The observation in the present study indicating that only notexhausted subjects displayed a decrease over time in factor VUc, might reflect a chronic elevation of this variable and a failure to habituate in exhausted subjects. The present study demonstrates that repeated assessments of fibrinolytic and coagulation factors are needed to reliably examine relationships between hemostatic measures and chronic psychological stress. Acute physiological and psychological stressors can increase coagulation and fibrinolytic activity (3-8), which confirms early observations of Cannon (58). Some evidence exists that stress-induced increases in platelet aggregation are elevated in exhausted individuals (24). On the basis of findings of Jem et al. (3), it could be argued that elevated levels of PA1-1 activity in exhausted subjects reflect an increased acute phase reaction to exogenous stressors. However, no distinction between the exhausted and not-exhausted groups was observed in platelet count, which is an indicator of acute phase reaction. Therefore, it is not likely that the higher PAI-1 activity resulted from increased responsiveness to the blood collection procedures among the exhausted subjects. The present study revealed a positive association between fibrinolytic measures (PAI-1 activity and TPA antigen). This result is congruent with similar observations in healthy subjects (59, 60) and patients with coronary artery disease (61). Evidence suggests that TPA antigen predominantly reflects TPA/PAI-1 complex (61) and higher TPA antigen levels are associated with reduced clot lysis time (60). However, the present study revealed only an overall trend for higher TPA antigen levels in exhausted subjects (p = .086), which was mainly explained by higher levels at the second occasion of blood sampling. A generalized altered fibrinolytic function has been suggested to occur secondary to atherosclerotic disease as a result of endothelial dysfunction (52). Future studies are needed to assess whether endothelial dysfunction could have accounted for the observed reduced fibrinolytic function in exhausted subjects. Study Limitations The specific criteria applied in this study for selection of exhausted subjects resulted in a relatively small sample size. Although a definite advantage of the procedure lies in the validation of the psychological assessments, the trade-off is that a lack of statistical power could have been responsible for the absence of significant between-group differences in TPA antigen, coagulation factors, and serum lipids. In addition, a substantial overlap was found in the distributions of PAI-1

activity of the two groups, which may indicate that other factors besides exhaustion also contributed to the high PAI-1 activity levels. However, PAI-1 activity was, nonetheless, significantly elevated in exhausted subjects and all PAI-1 activity levels of the exhausted subjects were above the median of the not-exhausted subjects. Given the small sample size, we were limited in our options to control multivariately for known correlates of hemostatic factors, such as smoking status and serum lipids. However, the exhausted and not-exhausted groups did not differ in smoking status, and similar findings on PAI-1 activity were found if smoking subjects were excluded from statistical analyses. Triglycerides and cholesterol were related to PAI-1 activity, but not to exhaustion. The significance level of elevated PAI-1 activity in exhausted subjects became marginal (p < .07) when these measures of serum lipids were entered as covariates. Larger samples are needed to disentangle the association between exhaustion, serum lipids, and measures of blood coagulation and fibrinolysis. A limited set of parameters was used to assess fibrinolytic capacity, which may confine the implications of the observed findings. Although both TPA and PAI-1 activity are adequate indicators of fibrinolytic function, the present study did not examine products of fibrinolytic activity, such as D-dimer or TPA/PAI complex. Similarly, a more complete picture of coagulation would have been obtained if thrombin fragments (F| +2 ) were measured. Therefore, the present study provides only a partial representation of the complex processes involved in blood coagulation and fibrinolysis. Clinical Implications Exhaustion and negative affective states, such as depression (62) or increases in depressive symptoms (63), are important risk factors for myocardial infarction and sudden cardiac death. The current data suggest that vital exhaustion influences fibrinolysis more than coagulation. Some evidence indicates that vital exhaustion is associated with markers of the insulin-resistance syndrome (hypertension, dyslipidemia, obesity, and hyperinsulinemia) (64). The insulin-resistance syndrome has hemostatic correlates (especially fibrinolytic factors) (65) and is associated with an increased risk for coronary artery disease (for review, see Ref. 66). The present study did not reveal significant association of vital exhaustion with triglycerides and cholesterol, which is congruent with our previous observations in cardiac patients (23), but other evidence suggests a relationship between vital exhaustion and serum lipids (67). Altered adrenocortical responsiveness may account in part for the relationship between vital exhaustion and the insulin-resistance syndrome (64). Therefore, future studies may examine the extent to which neurohormonal concomitants of exhaustion and risk factors for coronary artery disease may affect the relationship between blood clotting factors and vital exhaustion. Recent studies reveal that acute mental stress is a potent trigger of transient cardiac ischemia and myocardial infarction (9, 10, 68). It is also known that acute mental stress affects coagulation, fibrinolysis, and platelet function (3-8). Cardiac events result from multiple factors, one of which involves the blood clotting process. It is undetermined to what extent the elevated cardiac risk associated with vital exhaustion is accounted for by an increase in number or intensity of acute psychological stressors during daily life, or whether a rela-

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BLOOD COAGULATION AND FIBRINOLYSIS RELATIONSHIP TO VITAL EXHAUSTION tively invariable underlying pathophysiological vulnerability accounts for the predictive value of vital exhaustion for future cardiac events (69). The present study suggests a decreased fibrinolytic function in vital exhaustion, which could possibly result in a disequilibrium of coagulation and fibrinolytic factors. This may be one of the pathophysiological mechanisms relating vital exhaustion to future cardiac events. This research was supported in part by of the Dutch Organization for Scientific Research Grant 559-029, the National Institutes of Health Grant HL47337, and the Dutch Heart Foundation Grant 94-098. The authors would like to thank Drs. D. S. Krantz and R. H. Howell for valuable comments on an earlier version of this manuscript.
in the work environment, and acute myocardial infarction in adult men. J Psychosom Res 36:777-786, 1992 Klaboe G, Otterstad JE, Winsness T, et al: Predictive value of prodromal symptoms in myocardial infarction. Acta Med Scand 222:27-30, 1987 Kuller L, Cooper M, Perper J: Epidemiology of sudden death. Arch Intern Med 129:714-719, 1972 Fraser GE: Sudden death in Auckland. Aust N Z J Med 8:490-499, 1978 Rissanen V, Romo M, Sittanen P: Premonitory symptoms and stress-factors preceding sudden death from ischemic heart disease. Acta Med Scand 20:389-396, 1978 Appels A: Mental precursors of myocardial infarction. Br J Psychiatry 156:465-471, 1990 Appels A, Mulder P: Excess fatigue as a precursor of myocardial infarction. Eur Heart J 9:758-764, 1988 Kop WJ, Appels A, Mendes de Leon CF, et al: Vital exhaustion predicts new cardiac events after successful coronary angioplasty. Psychosom Med 56:281-287, 1994 Lulofs R: Stress reactivity, Type A Behavior and Vital Exhaustion. Maastricht, Datawyse, 1990 Raikkonen K, Lassila R, Keltikangas-Jarvinen L, et al: Association of chronic stress with plasminogen activator inhibitor-1 in healthy middle-aged men. Arterioscler Thromb Vase Biol 16: 363-367, 1996 Meade TW, Brozovid M, Chakrabarti R, et al: Haemostatic function and ischemic heart disease; principal results of the Northwick Park Heart Study. Lancet 11:533-537, 1986 Kannel WB, Wolf PA, Castelli WP, et al: Fibrinogen and risk of cardiovascular disease; the Framingham study. J Am Med Assoc 258:1183-1186, 1987 Stone MC, Thorp JM: Plasma fibrinogen; a major coronary risk factor. J R Coll Gen Pract 35:565-569, 1985 Hamsten A, Walldius G, Szamosi A, et al: Plasminogen activator inhibitor in plasma; risk factor for recurrent myocardial infarction. Lancet 11:3-9, 1987 Wilhelmsen L, Svardsudd K, Korsan-Bengtsen K, et al: Fibrinogen as a risk factor for stroke and myocardial infarction. N Engl J Med 311:501-505, 1984 Anzar J, Estell6s A, Tormo G, et al: Plasminogen activator inhibitor activity and other fibrinolytic variables in patients with coronary artery disease. Br Heart J 59:535-541, 1988 Gunn CG, Hampton JW. CNS influence on plasma levels of factor VIII activity. Am J Physio! 12:124-30, 1967 Palmblad J, Blomback M, Egberg N, et al: Experimentally induced stress in man; effects on blood coagulation and fibrinolysis. J Psychosom Res 21:87-92, 1977 Markowe HLJ, Marmot MG, Shipley MJ, et al. Fibrinogen; a possible link between social class and coronary heart disease. Br Med J 291:1312-1314, 1985 M0ller L, Kristensen TS: Plasma fibrinogen and ischemic heart disease risk factors. Arterioscler Thromb 11:344-350, 1991 van Diest R, Appels A: Vital exhaustion and depression: A conceptual study. J Psychosom Res 35:535-544, 1991 Meesters C, Appels A: An interview to measure vital exhaustion I and II: Development and comparison with the Maastricht Questionnaire. Psychol Health 11:557-581, 1996 Tracy RP, Bovill EG: Hemostasis and risk of ischemic disease: Epidemiologic evidence with emphasis on the elderly. In Califf RM, Mark DB, Wagner GS (eds), Acute Coronary Care. 2nd Edition. St. Louis, Mosby, 1995, 27-43

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