Relationship of Blood Coagulation and Fibrinolysis to Vital ExhaustionWILLEM J. KOP, PHD, KARLY HAMULYAK, MD, PHD, CARINA PERNOT, MSC, AND AD APPELS, P H D

Objective: Acute physical and psychological stressors affect blood coagulation and fibrinolysis, but little is known about hemostaticfactors associated with chronic psychological stress. Prolonged psychological stress may end in a state of vital exhaustion, whichhas been shown to be a risk factor for first myocardial infarction and recurrent events after coronary angioplasty. The present studytested the hypothesis that vital exhaustion resulting from chronic psychological stress is associated with impaired fibrinolyticcapacity 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-exhaustedcontrols (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: bloodpressure, smoking status, triglycerides, cholesterol, and standard hematological measures. Samples were collected twice to correctfor intraindividual fluctuations. Statistical analyses were performed using 2 X 2 mixed model analysis of variance with subsequentunivariate testing. Results: Vital exhaustion was associated with significantly elevated levels of PAI-1 activity (p = .023). Thehigher PAI-1 activity in exhausted subjects (median = 13.0 U/ml vs. 6.0 U/ml) was not accounted for by smoking status or serumlipids. No significant differences were observed in TPA antigen, factor Vile, factor VIIIc, and fibrinogen. The groups did not differin blood pressure, smoking status, triglycerides, cholesterol, or standard hematological measures. Conclusion: These data suggesta reduced fibrinolytic capacity in exhausted individuals. Therefore, the relationship between vital exhaustion and risk of myocardialinfarction 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 StatisticalManual of Mental Disorders; EDTA =ethylenediaminetetraacetic; ELISA = enzyme-linkedimmunosorbent assay; GGT = y-glutamyltranspeptidase; LDH = lactate dehydrogenase; MIVE =Maastricht Interview for Vital Exhaustion; MQ =Maastricht Questionnaire; PAI = plasminogen activatorinhibitor; SCL-90 = Symptom Check List-90; SGOT =serum glutamic oxaloacetic transaminase; SGPT =serum glutamic pyruvic transaminase; TPA = tissueplasminogen activator.

INTRODUCTIONThrombus formation in the coronary arteries is purported to

be one of the pathophysiological pathways by which psycho-logical stressors may lead to cardiac events (1, 2). Acutepsychological stress has been shown to affect blood coagula-tion, fibrinolysis, and platelet activity (3-7). Both physical andmental stressors are reported to trigger transient cardiacischemia, unstable angina, myocardial infarction, and suddencardiac death (8-10). In contrast to acute stressors, the effectsof chronic psychological stress on the blood clotting process isnot well understood.

Several prospective studies have shown that psychosocialfactors reflecting prolonged psychological stress significantlyincreases the risk of myocardial infarction (11-14). It has beendemonstrated, both in animal models (15) and in humans whosuffered myocardial infarction (16), that prolonged uncontrol-

From the Department of Medical and Clinical Psychology (W.J.K.), UniformedServices University of the Health Sciences, Bethesda, MD, Department of InternalMedicine (K.H., C.P.) and Medical Psyschology (W.J.K., A.A.), Cardiovascular Re-search Institute Maastricht, University of Limburg, Maastricht, the Netherlands.

Address reprint requests to: Willem J. Kop, PhD, Department of Medical and ClinicalPsychology, Uniformed Services University of Ihe Health Sciences, 4301 Jones BridgeRd., 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 theUnited Slates Department of Defense.

lable psychological distress ultimately may result in a state ofexhaustion. It is, therefore, of relevance that extreme tirednessand fatigue are among the most prevalent premonitory symp-toms of myocardial infarction (17-20). This state has beenlabeled as vital exhaustion and consists of three typicalcharacteristics: lack of energy, increased irritability, anddemoralization (21). We have demonstrated previously thatvital exhaustion is an independent predictor of first myocar-dial infarction in a prospective study of 3877 healthy men(22). In addition, feelings of exhaustion in patients undergoingcoronary angioplasty are associated with a two-fold increasedrisk of developing subsequent cardiac events within 1.5 yearsafter the initially successful intervention (23). The pathophys-iological mechanisms accounting for the relationship betweenvital exhaustion and future cardiac events are not well under-stood, but may include factors related to the blood clottingprocess, such as platelet aggregation (24), increased coagula-tion factors, and impaired fibrinolysis (25).

Epidemiological investigations have demonstrated that co-agulation and fibrinolytic factors contribute to the develop-ment of myocardial infarction (26-31). A dynamic balanceexists between the coagulation factors that generate fibrin andthe removal of fibrin by the fibrinolytic system. Normally,both components of the clotting process are activated bystress, resulting in a balanced response (3). Most studies thathave investigated the influence of physical and mental stresson blood clotting have examined acute experimental stressors.For example, Jem et al. (3) used a laboratory mental stresstask, physical exercise, and epinephrine infusion as stressors.An acute reaction was observed with an increase in clottingfactors (von Willebrand factor, factors VII and VIII), fibrin-ogen, and indicators of fibrinolysis (tissue plasminogen acti-vator activity, and plasminogen activator antigen) with allthree stressors. An adrenergic mechanism is probably respon-sible for the relationship between acute psychological stressand coagulation and fibrinolysis, because as mental stressresulted in the same effects on hemostasis as did epinephrineinfusion and physical exercise. In support of central nervoussystem involvement in the clotting process, it has beendemonstrated that electrical stimulation of the hypothalamusand the reticular formation results in a subsequent increase inplasma concentration of factor VIII (32).

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

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BLOOD COAGULATION AND FIBRINOLYSIS RELATIONSHIP TO VITAL EXHAUSTION

The relationship between chronic psychological stress andblood-clotting tendency has not been widely investigated.There is some evidence that in case of sustained mentalarousal, clotting tendency increases (factor VIII and fibrino-gen) for several hours after a stressful task, and then decreasesto normal levels over time (33). However, this study involveda stressful experimental situation with a duration of 3 days,which may differ in intensity, character, and duration fromchronic stress that occurs in daily life. Another observation insupport of a relationship between chronic psychological stressand hematological parameters is that people with high jobstrain and low socioeconomic status have relatively highlevels of fibrinogen and factor VII (34, 35). Social class andjob strain are rather crude measures of psychological stress,because they do not provide information regarding the psy-chological consequences of these environmental factors. Re-cently, Raikkonen et al. (25) observed significant associationsbetween feelings of exhaustion and impaired fibrinolyticcapacity. However, coagulation factors were not included inthat study and assessment of psychological characteristics waslimited by the use of questionnaire assessments only. There-fore, the present study investigates whether a well-definedgroup of healthy male subjects who are exhausted as a resultof chronic psychological stress are characterized by reducedfibrinolytic capacity and increased coagulation factors.

METHODSSubject SelectionSubjects were recruited from a previously sampled cohort of 451

men who participated in a study examining the relationship betweenvital exhaustion, sleep complaints, and depression (36). These 451subjects were reinvited to participate in the current study, using ascreening questionnaire mailed at 4 years after the initial study. Ofthe 451 subjects approached, 334 (74%) responded, 9 (2%) died, 49(11%) did not return the screening questionnaire, and 59 (13%) werelost to follow-up. The screening questionnaire included: a) theMaastricht Questionnaire, which inquires about feelings of exhaus-tion (22); and b) a short health status inventory designed for thepurposes of this study to evaluate current diagnosed diseases,medications used, smoking status, and alcohol consumption. On thebasis of the 334 returned screening questionnaires, subjects wereexcluded 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 informationvolunteered (N = 21). Questionnaires of the remaining 206 candi-dates revealed 57 patients who had MQ scores S16 (potentiallyexhausted) and 94 patients with an MQ score

W. J. KOP et al.

and included hematocrit value, platelet count, leukocyte count, anddifferential.

Measures of fibrinolysis included PAI-1 activity, which wasmeasured with a chromogenic assay from Kabi (Nikoping, Sweden)in accordance with the manufacturer's prescription, and TPA antigenwas measured with an ELISA technique, using a kit from Innoge-netics (Antwerp, Belgium). All assays were analyzed in one run toprevent interassay variation. The activity of coagulation factors Vileand VIIIc was measured with a one-stage clotting assay, usingimmunodepleted factor deficient reagents obtained from Instrumen-tation Laboratory (Milano, Italy). Data are presented as percentagesof values found with normal pool plasma. Fibrinogen was estimatedin accordance with the method of Clauss (48). The laboratorypersonnel was blinded with respect to the psychological status of thesubjects.

Statistical AnalysisInitial analyses examined group differences in control variables

(age, blood pressure, smoking status, triglycerides, total cholesterol,and routine blood chemistry). For continuous variables, t tests wereused; x1 tests were used for categorical variables. Bivariate associ-ations of clotting factors with triglycerides and cholesterol wereexamined, using product-moment correlations.

Differences between exhausted vs. not-exhausted subjects inmeasures of blood fibrinolysis and coagulation were examined, usinganalyses of variance. A 2 X 2 mixed model was used with exhaustionstatus as a two-level between-subjects factor and the two occasions ofblood sampling as a two-level within-subject factor. Data for the fiveclotting factors (PAI-1 activity, TPA antigen, factor VIIc, factorVIIIc, and fibrinogen) were examined separately. Natural logarithmictransformations were applied if variables were not normally distrib-uted (49). Increased factor VII, fibrinogen, and PAI-1 levels arerelated to smoking status (50, 51). Therefore, analyses were repeatedwith smokers excluded. To evaluate whether differences betweenexhausted vs. not-exhausted subjects were due to triglycerides and

cholesterol levels, the 2 X 2 mixed models were repeated, addingthese variables as separate covariates.

RESULTSValues of control variables for exhausted and not-ex-

hausted subjects are shown in Table 1 and indicated that thegroups did not significantly differ in usual alcohol consump-tion, smoking status, or blood pressure, and that the matchingfor age was successful. No differences were found betweenthe exhausted and the not-exhausted subjects in triglycerides,total cholesterol, nor in any of the other routine bloodchemistry measurements (Table 1). Vital exhaustion wassignificantly 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 groupexperienced 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 betweenTPA antigen and clotting factor VIIc (r = .51) and betweenboth PAI-1 activity and TPA antigen with factor VIIIc(r values .49 and .51, respectively).

Analysis of variance revealed significantly higher levels ofPAI-1 activity in exhausted subjects (between-subjects maineffect: p = .023; Table 2). In addition, exhausted subjectstended to have higher levels of TPA antigen (p = .086) andfactor VIIc (p = .079). Variations over the two occasions ofblood collection were observed for factor VIIIc [p = .014) andfibrinogen (p = .003) (higher levels at the second time), and

TABLE 1. Relationship Between Control Variables and Vital Exhaustion

Mean + SD

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

NeverStopped > 2 yrStopped 2 yrCurrently smoking

Not Exhausted

Mean

54.21.5

13.0120.3

77.71.476.060.44

232.853.684.767.923.119.927.7

316.513.5

4 b

524

SD

9.71.2

21.612.710.0

1.030.900.03

71.67.98.3

20.99.53.45.6

54.28.5

26.7C33.313.326.7

Exhausted

Mean

49.31.69.0

121.778.7

1.966.470.45

233.356.381.680.728.318.528.5

323.410.3

4b506

SD

7.32.2

13.917.37.40.940.890.03

47.97.1

13.728.313.54.15.1

63.32.1

26.733.30.0

40.0

P

NS"NSNSNSNSNSNSNSNSNSNSNSNSNSNSNSNS

NS

0 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.b Number.

c Percent.

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TABLE 2. Association of Vital Exhaustion With Fibrinolytic and Coagulation Factors

PAI-1" activity (au/ml)TPA antigen (ng/ml)Factor VIIc (%)Factor VIIIc (%)Fibrinogen (g/l)

Not Exhausted

6.4 (3.3)8.7 (2.9)

103.5(18.6)118.5(32.6)

2.8 (0.6)

Time 1

Exhausted

12.5 (2.5)*10.4(3.9)

107.5(14.1)119.1 (31.5)

2.9 (0.4)

Blood Sampling

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). Therewas also an interaction between vital exhaustion and time ofassessment for factor VIIc, indicating that not-exhaustedsubjects showed a decrease over time, whereas exhaustedsubjects 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 innot-exhausted controls (median = 6 U/ml; p = .025). Al-though a substantial overlap in the distribution of PAI-1activity in the two groups was observed (Figure 1), all PAI-1activity levels of the exhausted subjects were above themedian of the not-exhausted subjects and in the upper range ofnormal PAI-1 activity values.

The possible influence of control variables was examinedby repeating the analyses of variance while adjusting forsmoking status, triglycerides, and serum cholesterol. As isshown in Table 1, no associations were found between vitalexhaustion and these control variables. When current smokers

35

30

% 25D20>

i 1 05

Not Exhausted ExhaustedFigure 1. Fibrinolysis and coagulation as related to vital exhaustion. Higherlevels of plasminogen activator inhibitor (PAI-1) activity were observed inexhausted subjects ( = median = 13 U/ml) compared with not-exhaustedcontrols ( = median = 6 U/ml). This difference between exhausted vs.not-exhausted subjects was statistically significant (p = .03), despite theoverlap of the data distribution between the two groups.

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

DISCUSSIONFibrinolytic processes have been reported to be dysfunc-

tional in patients with coronary artery disease and also affectprognosis in patients with unstable angina and after successfulcoronary angioplasty (31, 52-55). The present study revealedsignificantly higher PAI-1 activity levels in a well-definedgroup of exhausted subjects. This finding suggests a reducedfibrinolytic capacity in exhausted individuals, which is con-gruent with previous observations (25). However, exhaustionwas not consistently related to fibrinogen and coagulationfactors (VIIc, VIIIc). This may suggest that a disequilibriumbetween the fibrinolytic and coagulation systems in responseto prolonged psychological stress could promote the risk forthrombus formation and myocardial infarction (3).

Classification of vital exhaustion was based on a standard-ized questionnaire (22, 23, 41) and subsequent confirmativestructured interview (37). Subjects were excluded if exhaus-tion was a consequence of a somatic or psychiatric disorder,such as major depression. For classification purposes, vitalexhaustion had to be present as the result of a failure to copewith prolonged psychological stress. Therefore, it was re-quired that there was an increase in at least one of the threecharacteristics of exhaustion: lack of energy, irritability, ordemoralization in the year before examination. The character-istics of vital exhaustion are to some extent the same as thoseof depression and the divergent validity of these two con-structs requires additional investigation. Preliminary analyseshas indicated, however, that "lack of energy" is the mostimportant aspect of vital exhaustion, inasmuch as that com-ponent showed the strongest predictive value for futurecardiac events after coronary angioplasty compared withirritability and demoralization (56). In addition, previous

Psychosomatic Medicine 60:352-358 (1998)

W. J. KOP et al.

studies showed that exhausted subjects have elevated fatiguescores on the Profile of Mood States, whereas no increasedsadness scores were observed (36). In the present study, weexplicitly excluded clinically depressed subjects on the basisof DSM-11I-R criteria. Therefore, the results of this study maynot necessarily apply to depression, although impaired fibrino-lytic activity has been observed in depression as well (57).

Significant fluctuations over time were observed for mea-sures of coagulation. Because these variations were notuniform (factor VIIIc and fibrinogen increased, whereas factorVUc decreased), we cannot draw firm interpretations of thisfinding from the present data. Repeated blood samples wereobtained within 3 months, which precludes major confoundingby seasonal changes, and biochemical analyses were per-formed at the same time to avoid interassay variation. Theobservation in the present study indicating that only not-exhausted subjects displayed a decrease over time in factorVUc, might reflect a chronic elevation of this variable and afailure to habituate in exhausted subjects. The present studydemonstrates that repeated assessments of fibrinolytic andcoagulation factors are needed to reliably examine relation-ships between hemostatic measures and chronic psychologicalstress.

Acute physiological and psychological stressors can in-crease coagulation and fibrinolytic activity (3-8), whichconfirms early observations of Cannon (58). Some evidenceexists that stress-induced increases in platelet aggregation areelevated in exhausted individuals (24). On the basis offindings of Jem et al. (3), it could be argued that elevatedlevels of PA1-1 activity in exhausted subjects reflect anincreased acute phase reaction to exogenous stressors. How-ever, no distinction between the exhausted and not-exhaustedgroups was observed in platelet count, which is an indicator ofacute phase reaction. Therefore, it is not likely that the higherPAI-1 activity resulted from increased responsiveness to theblood collection procedures among the exhausted subjects.

The present study revealed a positive association betweenfibrinolytic measures (PAI-1 activity and TPA antigen). Thisresult is congruent with similar observations in healthy sub-jects (59, 60) and patients with coronary artery disease (61).Evidence suggests that TPA antigen predominantly reflectsTPA/PAI-1 complex (61) and higher TPA antigen levels areassociated with reduced clot lysis time (60). However, thepresent study revealed only an overall trend for higher TPAantigen levels in exhausted subjects (p = .086), which wasmainly explained by higher levels at the second occasion ofblood sampling. A generalized altered fibrinolytic functionhas been suggested to occur secondary to atheroscleroticdisease as a result of endothelial dysfunction (52). Futurestudies are needed to assess whether endothelial dysfunctioncould have accounted for the observed reduced fibrinolyticfunction in exhausted subjects.

Study LimitationsThe 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 thevalidation of the psychological assessments, the trade-off isthat a lack of statistical power could have been responsible forthe absence of significant between-group differences in TPAantigen, coagulation factors, and serum lipids. In addition, asubstantial overlap was found in the distributions of PAI-1

activity of the two groups, which may indicate that otherfactors besides exhaustion also contributed to the high PAI-1activity levels. However, PAI-1 activity was, nonetheless,significantly elevated in exhausted subjects and all PAI-1activity levels of the exhausted subjects were above themedian of the not-exhausted subjects.

Given the small sample size, we were limited in our optionsto control multivariately for known correlates of hemostaticfactors, such as smoking status and serum lipids. However, theexhausted and not-exhausted groups did not differ in smokingstatus, and similar findings on PAI-1 activity were found ifsmoking 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-1activity in exhausted subjects became marginal (p < .07)when these measures of serum lipids were entered as covari-ates. Larger samples are needed to disentangle the associationbetween exhaustion, serum lipids, and measures of bloodcoagulation and fibrinolysis.

A limited set of parameters was used to assess fibrinolyticcapacity, which may confine the implications of the observedfindings. Although both TPA and PAI-1 activity are adequateindicators of fibrinolytic function, the present study did notexamine products of fibrinolytic activity, such as D-dimer orTPA/PAI complex. Similarly, a more complete picture ofcoagulation would have been obtained if thrombin fragments(F|+2) were measured. Therefore, the present study providesonly a partial representation of the complex processes in-volved in blood coagulation and fibrinolysis.

Clinical ImplicationsExhaustion and negative affective states, such as depres-

sion (62) or increases in depressive symptoms (63), areimportant risk factors for myocardial infarction and suddencardiac death. The current data suggest that vital exhaustioninfluences fibrinolysis more than coagulation. Some evidenceindicates that vital exhaustion is associated with markers ofthe insulin-resistance syndrome (hypertension, dyslipidemia,obesity, and hyperinsulinemia) (64). The insulin-resistancesyndrome has hemostatic correlates (especially fibrinolyticfactors) (65) and is associated with an increased risk forcoronary artery disease (for review, see Ref. 66). The presentstudy did not reveal significant association of vital exhaustionwith triglycerides and cholesterol, which is congruent with ourprevious observations in cardiac patients (23), but otherevidence suggests a relationship between vital exhaustion andserum lipids (67). Altered adrenocortical responsiveness mayaccount in part for the relationship between vital exhaustionand the insulin-resistance syndrome (64). Therefore, futurestudies may examine the extent to which neurohormonalconcomitants of exhaustion and risk factors for coronaryartery disease may affect the relationship between bloodclotting factors and vital exhaustion.

Recent studies reveal that acute mental stress is a potenttrigger of transient cardiac ischemia and myocardial infarction(9, 10, 68). It is also known that acute mental stress affectscoagulation, fibrinolysis, and platelet function (3-8). Cardiacevents result from multiple factors, one of which involves theblood clotting process. It is undetermined to what extent theelevated cardiac risk associated with vital exhaustion isaccounted for by an increase in number or intensity of acutepsychological stressors during daily life, or whether a rela-

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tively invariable underlying pathophysiological vulnerabilityaccounts for the predictive value of vital exhaustion for futurecardiac events (69). The present study suggests a decreasedfibrinolytic function in vital exhaustion, which could possiblyresult in a disequilibrium of coagulation and fibrinolyticfactors. This may be one of the pathophysiological mecha-nisms relating vital exhaustion to future cardiac events.

This research was supported in part by of the DutchOrganization for Scientific Research Grant 559-029, theNational Institutes of Health Grant HL47337, and the DutchHeart Foundation Grant 94-098. The authors would like tothank Drs. D. S. Krantz and R. H. Howell for valuablecomments on an earlier version of this manuscript.

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