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Effects of psychosocial stress on the fibrinolytic system in man
Fibrinolysis (1990) 4. supp: 2,110-l 8 Longman Group UK Ltd 1990
KM-9499/90/0004-0110/$10.00
12
Effects of Psychosocial Stress on the Fibrinolytic System in Man
L. Tengborn, C. Jem, E. Briksson, B. Risberg, H. Wadenvik, S. Jem SUMMARY. In our study exposure to standardized acute mental stress in healthy volunteers caused similar alterations in fibrinolysis, although less pronounced, as physical exercise and adrenaline infusion. Thus, tPA:Ag and activity were significantly increased and PAL1 activity had a tendency to decrease in response to mental stress. However, the effects of long-term mental stress on fibrinolysis in healthy persons and patients are, so far, not known. KEYWORDS. Psychosocial stress. Mental stress. Fibrinolysis
It has repeatedlybeen suggestedthat psychosocialstress may play a role in the development of cardiovascular disorders.’However, the precise mechanismsby which psychophysiological reactions may promote vascular lesions remain unclear. A number of hypotheseshave beenproposed,invoking a variety of haemodynamicand neuroendocrinefactors, but the possible effects of stress on fibrinolysis and plasma coagulation have hitherto receivedlittle attention.’I2 Regarding for example coronary heart disease, severalstudieshave demonstratedstatistical associations between myocardial infarction and/or coronary atherosclerosisand environmental stress or personality factors (e.g. type A behaviour).3’4 More recently, evidencehas beenobtainedthat indicate that this relation may’in fact be causal.In their eloquentanimal models of non-human primates studied, Clarkson and co-workers have demonstratedthat psychosocial stress caused by repeatreorganizationpromotesdevelopmentof coronary atherosclerosis.5 Early Studies A variety of early studies have suggestedthat emotional activation may induce changes in the coagulation and fibrinolytic systemsof the blood. In an interesting study from 195@ a protocol with cyclic occupational stress with excessive “drive”, competition, economic stress, and meeting deadlineswas used. During the period with heavy occupational stressthe participants worked about 70 hours per week for 3.5 months. This was compared L. Tengbom, Coagulation Laboratory, Sahlgren’s Hospital C. Jem, H. Wadenvik, S. Jem, Department of Clinical Physiology, &-a Hospital E. Eriksson, B. l&berg, Department of Surgery, &a and Sahlgren’s Hospitals, University of Gdteborg, Gbteborg, Sweden
110
with a “lull” period, working only 30 hours per week and without any stress moments. Serum cholesterol was determinedevery fortnight and Lee-White clotting time every month. Each subject’s highest serum cholesterol and shortest clotting time consistently occurred during severestress and the lowest at times of minimal stress. These results could not be ascribed to any changesof weight, exercise or diet. Unfortunately, fibrinolysis was not determined in this study with prolonged stress. However, recently a positive correlation between cholesterol and the plasminogen activator inhibitor of endothelialcell type (PAI-1) was found.7 Consequently, one could speculateif this fairly long-term stressmight have producedan impairment of the fibrinolysis. In an early study by Macfarlane & Biggs8concerning minor surgical procedures such as endoscopy, fibrinolysis was assayedas diluted clot lysis time. They found that fibrinolysis occurred not only after surgical operations,but also immediately before them in about fifty per cent of the cases. The drugs used for premeditation might have been responsible for some cases of preoperative fibrinolytic activity. Fear of impending operationsappearedto have causeda further proportion of positive results. Ogston et al9 observed a group of patients after comparatively minor anxiety-provoking stimuli such as information that a test was to be carried out. In some of the patientsthe coagulationtime measuredas recalcified plasma clotting time was shortenedand the fibrinolytic activity was increased. Sherry et al.” thoroughly studied the tibrinolysis (whole blood clot analysis,euglobulin clot lysis, diluted clot lysis, fibrin plate assay,lysis of radiolabelledclots) in various conditions e.g. after moderate emotional experience,such as diatribe to staff. No alterationsin the
Fibrinolysis
fibrinolysis were found. The stress utilized in their study was rather m ild, and, for that reason,may have failed to elicit an increasein activity. Effects of Standardized Short Term Mental Stress Apart from the fact that fibrlnolysis was determinedwith a variety of methods, the stress situations in the mentioned investigations, were not adequately standardized.One of the important aspectsin studies of psychosocialstressis related to the fact that mental stress challengers are difficult to define and standardize. Therefore, great caution must be exercisedin the choice of stresstasks and the technics involved. In a recent study we investigatedthe effect of mental stresson the fibrinolytic system in a well defined sample of young healthy non-smoking subjects without any medication.” We also comparedthe reactionswith those obtained during physical exercise and adrenergic stimulation, i.e. infusion of adrenaline. Two strictly standardizedexperimentalstressorswere used: the Stroop colour word test and mental arithmetic. Both of these stmssors have been used for a number of years in our laboratory and elicit highly reproducible haemodynamicand endocrine responsepatterns, which are similar to the defence-alarmreaction.‘1T’2 After a 30minute resting period in the sitting position, the stress experimentstarted with a pre-stressbaselineperiod of 10 m inutes. The subject then performed a video-display colour word test (Stroop test) for 10 m inutes, immediately followed by mental arithmetic for another 10 m inutes. Then the subject was left alone for a 10 m inutes post-stress baseline period. Heart rate, systolic and diastolic blood pressure were monitored continuously. Non-traumatic venipunchrres were performed, using Butterfly needles without venous occlusion at the end of the pre-stress baseline period, stressperiod and post-stressbaseline,respectively. Tissue plasminogen activator (t-PA) antigen was determined using a kit from Biopool (Sweden). t-PA activity and PAI- activity were assessed using pob&sine as a stimulator according to Eriksson et al. ’ Factor VIII and factor VII clotting activity were determined with one-stage clotting assays. von Willebrand factor antigen and factor VII antigen were measuredusing ELISAs. During mental stress heart rate increased by 26% (66.4k2.6 vs 83.6k3.8 beats per m in; P
111
in PAI- activity; mental stresscauseda decreaseby 6% (2.24fl.65 vs 2.11ti.9 U/ml). Moreover, mental stress caused a significant increase in von Willebrand factor antigen as well as in factor VIII and factor VII clotting activity. There was only a m inimal increase in haemoconcentration,3%, during mental stress. We concluded from this shadythat mental stress has effects of both fibrinolysis and coagulation. In addition, in a previous study, we observed increased peripheral platelet and white blood cell count during mental stress.15 A Study with Prolonged Stress An important aspect which is even more difficult to standardize and define is the response to long-term psychosocial stress. In one of the few studies available on this subject, Palmblad et all6 investigatedthe effects of longer stress, a vigil for 77 h. The protocol was originally designedfor officers and soldiersconsisting of long periods of shooting with electronic rifles, simulating a prolonged ground combat. In this study, no effect’ was observed in fibrinolysis measured as euglobulin clot lysis time. In the contrary to the short-term stress situation,” they observeda decreasein various coagulation factors (factors V, VIII, IX and fibrinogen), which was interpreted as a conceivable adaptationto the prolonged stressorexposure.However, it should be stressed that in this particular study the subjects were not only exposed to psychologically stressful situations but also to a number of biological changes - such as alterations in diurnal rhythm. Therefore, the conclusions should be interpreted with caution as regardsthe psychosocial stress. Mental Stress Disorders?
Causative of
Cardiovascular
Concerningthe possiblepathophysiologicalimplications of the findings often observedin responseto stress, e.g. elevation both of fibrinolysis and clotting activity, it could be arguedthat these simultaneousincreaseswould tend to counteracteach other, resulting in an unchanged coagulation-fibrinolysisequilibrium. In healthy subjectsthere is generally a good response in fibrinolytic activity to laboratory stimuli like short-term and prolonged exercise and adrenaline infusion, b$trsthere is also a small group of poor responders. ’ It is possible that patients with cardiovascular diseases are such poor responders and may be more susceptibleto a state of disequilibrium in favour of coagulation. Interestingly, Hamsten et al” observedin patients, who had had myocardial infarction before 45 years of age, an associationbetweendecreased fibrinolytic capacity (determinedas plasminogenactivity on fibrin plates and as PAI- activity) and recurrency of myocardial infarction.
112
Effects of Psychosocial Stress on Fibrinolysis
CONCLUSION The knowledge about the effects of mental stress on fibrinolysis is scanty. One of the main obstacles is to select a suitable standardizedstressor in order to study both healthy subjects and patients. Using a strictly standardized protocol we observed that short-term mental stress caused an increased activity of the fibrinolytic system. For the time being we can only speculatethat mental stress and impaired fibrinolysis may play a role in the pathogenesisof cardiovasculardisorders and thrombosis. REFERENCES 1. Eliot RS, Buell JC, Dembroski TM 1982 Bio-behavioural perspectives on coronary heart disease, hypertension and sudden cardiac death. Acta Med Stand (Suppl) 660: 203-213 2. Clarkson TB, We&and KW, Kaplan JR, Adams MR 1987 Mechanisms of atherogenesis. Circ 76 (supplI):20-28 3. Wolfs 1969 Psychosocial forces in myocardial infarction and sudden death. Circ 40 (suppl4): 74-83 4. Matthews KA, Haynes SG 1986 Type A behavior pattern and coronary disease risk: Update and critical evaluation. Am J Epidemiol123: 923-960 5. Clarkson TB, Kaplan JR, Adams MR, Manuck SB 1987 Psychosocial influences on the pathogenesis of atherosclerosis among nonhuman primates. Circ 76 (suppl 1): 29-40 6. Friedman M, Rosemnan RH, Carroll V 1958 changes in the serum cholesterol and blood clotting time in men subjected to cyclic variation of occupational stress. Circ 17: 852-861 7. Landin K, Tengbom L, Smith U 1990 Elevated fibrinogen and plasminogen activator inhibitor @‘AI-l) in hypertension are related to metabolic risk factors for cardiovascular disease. J
Jntem Med 227: 273-278 8. Macfarlane RG, Biggs R 1946 Observations on tibrinolysis spontaneous activity associated with surgical operations, trauma, & c. Lancet 251:2: 862-864 9. Ogston D, McDonald GA, Fullerton HW 1962 The influence of anxiety in tests of blood coagulability and fibrinolytic activity. Lancet 2: 521-523 10. Sherry S, Lindemeyer RI, Fletcher AP, Alkjaemig N 19.59Studies on enhanced fibrinolytc activity in man. J Clin Invest 38: 810-822 11. Jem C, Eriksson E, Tengbom L, Risberg B, Wadenwik H, Jem S 1989 Changes of plasma coagulation and fibrinolysis in response to mental stress. Thromb and Haemost 62(2): 767-771 12. Jem S, Pilhall M, Jem C, Carlsson SG 1990 Short-term reproducibility of mental stress tests. Submitted for publication. 13. Eriksson E, Risberg B 1987 Measurement of tissue plasminogen activator in plasma: A comparison of three methods and description of a new improved technique. Thromb Res 46: 213-223 14. Eriksson E, Riinby M, Gyzander E, Risberg B 1988 Determination of plasminogen activator inhibitor in plasma using t-PA and a chromgenic single point poly-D-lysine stimulated assay. Thromb Res50: 91-101 15. Jem C, Wadenvik H, Mark H, Hallgmn J, Jem S 1989 Haemotological changes during acute mental stress. Br J Haemotol71: 153-156 16. Pahnblad J, Blomblck M, Egberg N, F&erg J, Karlsson C-G, Levi L 1977 Experimentally induced stress in man: effects on blood coagulation and tibrinolysis. J Psychosomatic Res 21: 87-92 17. Cash JD, Allan AGE 1967 The tibrinolytic response to moderate exercise and intravenous adrenaline in the same subjects. Br J Haemat 13: 376-378 18. Cash JC, Woodfield DG 1967 Fibrinolytic response to moderate, exhaustive and prolonged exercise in normal subjects. Nature 215: 628-629 19. Hamsten A, DeFaire U, Walldius G, Dahlen G, Szamosi A, Landou C, Blomback M, Wiman B 1987 Plasminogen activator inhibitor in plasma: risk factor for recurrent myocsrdial infarction. Lancet 2: 3-9
KM-9499/90/0004-0110/$10.00
12
Effects of Psychosocial Stress on the Fibrinolytic System in Man
L. Tengborn, C. Jem, E. Briksson, B. Risberg, H. Wadenvik, S. Jem SUMMARY. In our study exposure to standardized acute mental stress in healthy volunteers caused similar alterations in fibrinolysis, although less pronounced, as physical exercise and adrenaline infusion. Thus, tPA:Ag and activity were significantly increased and PAL1 activity had a tendency to decrease in response to mental stress. However, the effects of long-term mental stress on fibrinolysis in healthy persons and patients are, so far, not known. KEYWORDS. Psychosocial stress. Mental stress. Fibrinolysis
It has repeatedlybeen suggestedthat psychosocialstress may play a role in the development of cardiovascular disorders.’However, the precise mechanismsby which psychophysiological reactions may promote vascular lesions remain unclear. A number of hypotheseshave beenproposed,invoking a variety of haemodynamicand neuroendocrinefactors, but the possible effects of stress on fibrinolysis and plasma coagulation have hitherto receivedlittle attention.’I2 Regarding for example coronary heart disease, severalstudieshave demonstratedstatistical associations between myocardial infarction and/or coronary atherosclerosisand environmental stress or personality factors (e.g. type A behaviour).3’4 More recently, evidencehas beenobtainedthat indicate that this relation may’in fact be causal.In their eloquentanimal models of non-human primates studied, Clarkson and co-workers have demonstratedthat psychosocial stress caused by repeatreorganizationpromotesdevelopmentof coronary atherosclerosis.5 Early Studies A variety of early studies have suggestedthat emotional activation may induce changes in the coagulation and fibrinolytic systemsof the blood. In an interesting study from 195@ a protocol with cyclic occupational stress with excessive “drive”, competition, economic stress, and meeting deadlineswas used. During the period with heavy occupational stressthe participants worked about 70 hours per week for 3.5 months. This was compared L. Tengbom, Coagulation Laboratory, Sahlgren’s Hospital C. Jem, H. Wadenvik, S. Jem, Department of Clinical Physiology, &-a Hospital E. Eriksson, B. l&berg, Department of Surgery, &a and Sahlgren’s Hospitals, University of Gdteborg, Gbteborg, Sweden
110
with a “lull” period, working only 30 hours per week and without any stress moments. Serum cholesterol was determinedevery fortnight and Lee-White clotting time every month. Each subject’s highest serum cholesterol and shortest clotting time consistently occurred during severestress and the lowest at times of minimal stress. These results could not be ascribed to any changesof weight, exercise or diet. Unfortunately, fibrinolysis was not determined in this study with prolonged stress. However, recently a positive correlation between cholesterol and the plasminogen activator inhibitor of endothelialcell type (PAI-1) was found.7 Consequently, one could speculateif this fairly long-term stressmight have producedan impairment of the fibrinolysis. In an early study by Macfarlane & Biggs8concerning minor surgical procedures such as endoscopy, fibrinolysis was assayedas diluted clot lysis time. They found that fibrinolysis occurred not only after surgical operations,but also immediately before them in about fifty per cent of the cases. The drugs used for premeditation might have been responsible for some cases of preoperative fibrinolytic activity. Fear of impending operationsappearedto have causeda further proportion of positive results. Ogston et al9 observed a group of patients after comparatively minor anxiety-provoking stimuli such as information that a test was to be carried out. In some of the patientsthe coagulationtime measuredas recalcified plasma clotting time was shortenedand the fibrinolytic activity was increased. Sherry et al.” thoroughly studied the tibrinolysis (whole blood clot analysis,euglobulin clot lysis, diluted clot lysis, fibrin plate assay,lysis of radiolabelledclots) in various conditions e.g. after moderate emotional experience,such as diatribe to staff. No alterationsin the
Fibrinolysis
fibrinolysis were found. The stress utilized in their study was rather m ild, and, for that reason,may have failed to elicit an increasein activity. Effects of Standardized Short Term Mental Stress Apart from the fact that fibrlnolysis was determinedwith a variety of methods, the stress situations in the mentioned investigations, were not adequately standardized.One of the important aspectsin studies of psychosocialstressis related to the fact that mental stress challengers are difficult to define and standardize. Therefore, great caution must be exercisedin the choice of stresstasks and the technics involved. In a recent study we investigatedthe effect of mental stresson the fibrinolytic system in a well defined sample of young healthy non-smoking subjects without any medication.” We also comparedthe reactionswith those obtained during physical exercise and adrenergic stimulation, i.e. infusion of adrenaline. Two strictly standardizedexperimentalstressorswere used: the Stroop colour word test and mental arithmetic. Both of these stmssors have been used for a number of years in our laboratory and elicit highly reproducible haemodynamicand endocrine responsepatterns, which are similar to the defence-alarmreaction.‘1T’2 After a 30minute resting period in the sitting position, the stress experimentstarted with a pre-stressbaselineperiod of 10 m inutes. The subject then performed a video-display colour word test (Stroop test) for 10 m inutes, immediately followed by mental arithmetic for another 10 m inutes. Then the subject was left alone for a 10 m inutes post-stress baseline period. Heart rate, systolic and diastolic blood pressure were monitored continuously. Non-traumatic venipunchrres were performed, using Butterfly needles without venous occlusion at the end of the pre-stress baseline period, stressperiod and post-stressbaseline,respectively. Tissue plasminogen activator (t-PA) antigen was determined using a kit from Biopool (Sweden). t-PA activity and PAI- activity were assessed using pob&sine as a stimulator according to Eriksson et al. ’ Factor VIII and factor VII clotting activity were determined with one-stage clotting assays. von Willebrand factor antigen and factor VII antigen were measuredusing ELISAs. During mental stress heart rate increased by 26% (66.4k2.6 vs 83.6k3.8 beats per m in; P
111
in PAI- activity; mental stresscauseda decreaseby 6% (2.24fl.65 vs 2.11ti.9 U/ml). Moreover, mental stress caused a significant increase in von Willebrand factor antigen as well as in factor VIII and factor VII clotting activity. There was only a m inimal increase in haemoconcentration,3%, during mental stress. We concluded from this shadythat mental stress has effects of both fibrinolysis and coagulation. In addition, in a previous study, we observed increased peripheral platelet and white blood cell count during mental stress.15 A Study with Prolonged Stress An important aspect which is even more difficult to standardize and define is the response to long-term psychosocial stress. In one of the few studies available on this subject, Palmblad et all6 investigatedthe effects of longer stress, a vigil for 77 h. The protocol was originally designedfor officers and soldiersconsisting of long periods of shooting with electronic rifles, simulating a prolonged ground combat. In this study, no effect’ was observed in fibrinolysis measured as euglobulin clot lysis time. In the contrary to the short-term stress situation,” they observeda decreasein various coagulation factors (factors V, VIII, IX and fibrinogen), which was interpreted as a conceivable adaptationto the prolonged stressorexposure.However, it should be stressed that in this particular study the subjects were not only exposed to psychologically stressful situations but also to a number of biological changes - such as alterations in diurnal rhythm. Therefore, the conclusions should be interpreted with caution as regardsthe psychosocial stress. Mental Stress Disorders?
Causative of
Cardiovascular
Concerningthe possiblepathophysiologicalimplications of the findings often observedin responseto stress, e.g. elevation both of fibrinolysis and clotting activity, it could be arguedthat these simultaneousincreaseswould tend to counteracteach other, resulting in an unchanged coagulation-fibrinolysisequilibrium. In healthy subjectsthere is generally a good response in fibrinolytic activity to laboratory stimuli like short-term and prolonged exercise and adrenaline infusion, b$trsthere is also a small group of poor responders. ’ It is possible that patients with cardiovascular diseases are such poor responders and may be more susceptibleto a state of disequilibrium in favour of coagulation. Interestingly, Hamsten et al” observedin patients, who had had myocardial infarction before 45 years of age, an associationbetweendecreased fibrinolytic capacity (determinedas plasminogenactivity on fibrin plates and as PAI- activity) and recurrency of myocardial infarction.
112
Effects of Psychosocial Stress on Fibrinolysis
CONCLUSION The knowledge about the effects of mental stress on fibrinolysis is scanty. One of the main obstacles is to select a suitable standardizedstressor in order to study both healthy subjects and patients. Using a strictly standardized protocol we observed that short-term mental stress caused an increased activity of the fibrinolytic system. For the time being we can only speculatethat mental stress and impaired fibrinolysis may play a role in the pathogenesisof cardiovasculardisorders and thrombosis. REFERENCES 1. Eliot RS, Buell JC, Dembroski TM 1982 Bio-behavioural perspectives on coronary heart disease, hypertension and sudden cardiac death. Acta Med Stand (Suppl) 660: 203-213 2. Clarkson TB, We&and KW, Kaplan JR, Adams MR 1987 Mechanisms of atherogenesis. Circ 76 (supplI):20-28 3. Wolfs 1969 Psychosocial forces in myocardial infarction and sudden death. Circ 40 (suppl4): 74-83 4. Matthews KA, Haynes SG 1986 Type A behavior pattern and coronary disease risk: Update and critical evaluation. Am J Epidemiol123: 923-960 5. Clarkson TB, Kaplan JR, Adams MR, Manuck SB 1987 Psychosocial influences on the pathogenesis of atherosclerosis among nonhuman primates. Circ 76 (suppl 1): 29-40 6. Friedman M, Rosemnan RH, Carroll V 1958 changes in the serum cholesterol and blood clotting time in men subjected to cyclic variation of occupational stress. Circ 17: 852-861 7. Landin K, Tengbom L, Smith U 1990 Elevated fibrinogen and plasminogen activator inhibitor @‘AI-l) in hypertension are related to metabolic risk factors for cardiovascular disease. J
Jntem Med 227: 273-278 8. Macfarlane RG, Biggs R 1946 Observations on tibrinolysis spontaneous activity associated with surgical operations, trauma, & c. Lancet 251:2: 862-864 9. Ogston D, McDonald GA, Fullerton HW 1962 The influence of anxiety in tests of blood coagulability and fibrinolytic activity. Lancet 2: 521-523 10. Sherry S, Lindemeyer RI, Fletcher AP, Alkjaemig N 19.59Studies on enhanced fibrinolytc activity in man. J Clin Invest 38: 810-822 11. Jem C, Eriksson E, Tengbom L, Risberg B, Wadenwik H, Jem S 1989 Changes of plasma coagulation and fibrinolysis in response to mental stress. Thromb and Haemost 62(2): 767-771 12. Jem S, Pilhall M, Jem C, Carlsson SG 1990 Short-term reproducibility of mental stress tests. Submitted for publication. 13. Eriksson E, Risberg B 1987 Measurement of tissue plasminogen activator in plasma: A comparison of three methods and description of a new improved technique. Thromb Res 46: 213-223 14. Eriksson E, Riinby M, Gyzander E, Risberg B 1988 Determination of plasminogen activator inhibitor in plasma using t-PA and a chromgenic single point poly-D-lysine stimulated assay. Thromb Res50: 91-101 15. Jem C, Wadenvik H, Mark H, Hallgmn J, Jem S 1989 Haemotological changes during acute mental stress. Br J Haemotol71: 153-156 16. Pahnblad J, Blomblck M, Egberg N, F&erg J, Karlsson C-G, Levi L 1977 Experimentally induced stress in man: effects on blood coagulation and tibrinolysis. J Psychosomatic Res 21: 87-92 17. Cash JD, Allan AGE 1967 The tibrinolytic response to moderate exercise and intravenous adrenaline in the same subjects. Br J Haemat 13: 376-378 18. Cash JC, Woodfield DG 1967 Fibrinolytic response to moderate, exhaustive and prolonged exercise in normal subjects. Nature 215: 628-629 19. Hamsten A, DeFaire U, Walldius G, Dahlen G, Szamosi A, Landou C, Blomback M, Wiman B 1987 Plasminogen activator inhibitor in plasma: risk factor for recurrent myocsrdial infarction. Lancet 2: 3-9