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ORIGINAL ARTICLES |
From the Departments of Psychiatry (P.J.M., J.E.D.) and Medicine (C.F.), University of California, San Diego, California and the Division of Psychosocial Medicine (R.v.K.), University Hospital, Zurich, Switzerland.
Address reprint requests to: Joel E. Dimsdale, MD, Department of Psychiatry, UCSD, 9500 Gilman Drive, La Jolla, CA 92093-0804. Email: jdimsdale{at}ucsd.edu
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPsychological Factors and CADBlood Coagulation and...Hemostatic Factors and CADMETHODSSUMMARY AND FUTURE DIRECTIONSACKNOWLEDGMENTSREFERENCES |
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METHODS: Literature on coagulation, anticoagulation, and fibrinolysis measures in conjunction with psychological factors (mental stress, psychosocial strain, and psychiatric disorders) was identified by MEDLINE search back to 1966 and through checking the bibliographies of these sources. Sixty-eight articles were critically reviewed.
RESULTS: In healthy subjects, acute mental stress simultaneously activates coagulation (ie, fibrinogen or von Willebrand factor) and fibrinolysis (ie, tissue-type plasminogen activator) within a physiological range. In patients with atherosclerosis and impaired endothelial anticoagulant function, however, procoagulant responses to acute stressors may outweigh anticoagulant mechanisms and thereby promote a hypercoagulable state. Chronic psychosocial stressors (job strain or low socioeconomic status) are related to a hypercoagulable state reflected by increased procoagulant molecules (ie, fibrinogen or coagulation factor VII) and by reduced fibrinolytic capacity. There is also some evidence that points to hypercoagulability in depression.
CONCLUSIONS: Different categories of psychological measures to varying extent are associated with characteristic patterns of coagulation and fibrinolysis activity. Associations between psychological factors and several coagulation and fibrinolysis variables related to atherosclerosis provide a plausible biobehavioral link to coronary artery disease.
Key Words: Psychological stress • personality • depressive disorder • blood coagulation • fibrinolysis • hemostasis
Abbreviations: CAD = coronary artery disease; FVII = clotting factor FVII; PAI-1 = type 1 plasminogen activator inhibitor; QS = quality score; t-PA = tissue-type plasminogen activator; vWF = von Willebrand factor.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPsychological Factors and CADBlood Coagulation and...Hemostatic Factors and CADMETHODSSUMMARY AND FUTURE DIRECTIONSACKNOWLEDGMENTSREFERENCES |
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Psychological Factors and CAD |
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TOPABSTRACTINTRODUCTIONPsychological Factors and CADBlood Coagulation and...Hemostatic Factors and CADMETHODSSUMMARY AND FUTURE DIRECTIONSACKNOWLEDGMENTSREFERENCES |
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Blood Coagulation and Fibrinolysis Pathways |
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TOPABSTRACTINTRODUCTIONPsychological Factors and CADBlood Coagulation and...Hemostatic Factors and CADMETHODSSUMMARY AND FUTURE DIRECTIONSACKNOWLEDGMENTSREFERENCES |
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on Figure) (17). It has to be noted, however, that this model is simplified, because there are multiple interactions of the clotting factors across the two pathways (18). The intrinsic, or contact activation, pathway is initiated by contact of clotting factor XII (FXII) with negatively charged surfaces ("surface factor"). The extrinsic, or tissue factor, pathway is triggered by the interaction of tissue factor—the major physiologic initiator of the coagulation cascade—with activated FVII that is continuously present in plasma at low levels. Tissue factor is a membrane-integrated protein that is not normally expressed on vascular cell surfaces. However, tissue factor is exposed on vascular cells on injury, or it may be expressed on monocytes and endothelial cells in response to a variety of stimuli. The role of tissue factor in coronary syndromes is emphasized by its presence in the matrix of the necrotic core of the atherosclerotic plaque (19).
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). On conversion of prothrombin to thrombin, prothrombin fragments 1 and 2 are released. Thrombin converts fibrinogen to soluble fibrin, whereby fibrinopeptide A is released (Figure 1, 
). Finally, soluble fibrin becomes stabilized to form a fibrin clot or thrombus.
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) (20, 21). Hemostatic function is closely related to vWF (Figure 1, 
) that is stored in endothelial cells and platelets. vWF is crucial for both platelet adhesion to injured subendothelial structures and platelet aggregation. In addition, vWF binds to and protects FVIII from proteolysis (22).
Termination of clot formation involves several anticoagulant mechanisms, such as binding of antithrombin III to thrombin, that inhibit thrombin activity in a thrombin-antithrombin III complex (Figure 1, 
) (17). The fibrinolytic system removes fibrin clots and thrombi by proteolitically degrading fibrin (and fibrinogen) into soluble fragments, so-called fibrinogen/fibrin degradation products, of which fibrin D-dimer is widest known (Figure 1, 
). These steps are triggered by t-PA, which converts fibrin-bound plasminogen to fibrin-cleaving plasmin (Figure 1, 
). Both PAI-1 and 
2-antiplasmin terminate fibrinolysis by inactivation of t-PA and plasmin in a t-PA/PAI-1 and plasmin-2-antiplasmin complex (Figure 1, 
), respectively (23, 24). Clotting factors, vWF, and fibrinolysis enzymes are either measured by immunological (ie, antigen level) or functional (ie, molecule activity) methods. Prothrombin fragments 1 and 2, thrombin-antithrombin III complex, fibrinopeptide A, fibrin degradation products, D-dimer, and plasmin-2-antiplasmin complex are so-called prethrombotic markers, because elevated levels indicate augmented coagulation activity (and subsequent fibrinolysis activation) without overt thrombosis (25, 26). These markers are more sensitive in detecting a hypercoagulable state than screening assays for coagulation (eg, prothrombin time), fibrinolysis (eg, euglobulin lysis time), and clotting factor activities (25, 26).
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Hemostatic Factors and CAD |
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TOPABSTRACTINTRODUCTIONPsychological Factors and CADBlood Coagulation and...Hemostatic Factors and CADMETHODSSUMMARY AND FUTURE DIRECTIONSACKNOWLEDGMENTSREFERENCES |
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2-antiplasmin complex (40). In turn, a decrease in fibrinolytic capacity reflected by low t-PA activity (41) and prolonged euglobulin clot lysis time (32), as well as low antithrombin III consumed in anticoagulant processes with severe atherosclerosis (42, 43), may all prospectively be associated with CAD events. Aside from its long-term adverse effect on vessel health, a procoagulant milieu also plays a crucial role in acute coronary events such as unstable angina, myocardial infarction, and sudden death, by rapidly promoting thrombus growth after plaque disruption and exposure of thrombotic plaque material, particularly tissue factor, to the blood flow (12, 44). The significance of increased coagulation activity for CAD morbidity and mortality is further established by the therapeutic benefits of anticoagulant (eg, heparin and warfarin), fibrinolytic (eg, recombinant tissue plasminogen activator), and platelet inhibitory therapy (eg, aspirin) administered either alone or in combination in both stable and acute coronary syndromes (45, 46).
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METHODS |
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TOPABSTRACTINTRODUCTIONPsychological Factors and CADBlood Coagulation and...Hemostatic Factors and CADMETHODSSUMMARY AND FUTURE DIRECTIONSACKNOWLEDGMENTSREFERENCES |
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.05) and nonsignificant hemostasis findings. 6) A control situation/group was required. 7) Patients had to be diagnosed appropriately. Studies were considered for review if they reached a minimum QS of four and five points in healthy subjects and patients, respectively. Sixty studies fulfilled this criterion. In addition, we included eight (seven acute and one chronic) stress studies with a lower QS because they provided otherwise remarkable (eg, historical) data. We provide the QS of the studies in the tables. For the few studies not listed in a table, the QS is in the text.
Sixty-four studies were in English, two in Russian, and one in Italian, so two of us (C.F. and R.v.K.) translated the non-English articles. The literature considering coagulation and fibrinolysis measures in conjunction with psychological factors was organized in three sections: 1) acute mental stress, 2) chronic psychological distress (ie, job strain and low socioeconomic status), and 3) psychiatric disorders (ie, depression and anxiety). Although we did not perform a formal meta-analysis, we weighted significant relationships (p .05) between stress and hemostasis according to the studies’ sample size whenever we located at least three studies about an individual hemostasis variable. In such instances, we multiplied each study’s percentage change by its sample size; we added these products together and divided by the total sample size across the studies of interest.
Acute Mental Stress
Table 2 depicts the wide range of changes in coagulation and fibrinolysis parameters in situations with short-term mental arousal in the field and in the laboratory. There emerges a fairly reliable coagulation and fibrinolysis pattern in response to acute mental stressors that may be distinct between healthy individuals and patients with cardiovascular disease. As described below, the literature suggests that short-term arousal activates the coagulation and fibrinolysis systems simultaneously. In healthy individuals, the hemostatic equilibrium between thrombosis and hemorrhage likely is maintained within a physiological range. Indeed, such perspective is consistent with the evolutionary paradigm of Cannon and Mendenhall, who, almost a century ago, proposed that hastening of blood coagulation (without overt thrombosis) in a "fight-flight" situation protects the organism from deadly bleeding in case of injury (47). In cardiovascular disease, however, stress-induced procoagulant changes appear to outweigh anticoagulant mechanisms because of impaired endothelial anticoagulant function in atherosclerotic vessels possibly enhancing patients’ odds of clinical thrombosis.
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In 1946, MacFarlane and Biggs (48) were the first to note increased fibrinolytic capacity with emotional distress related to fear of an impending operation. Stimulated fibrinolysis also was found after air-raid warning (49), with examinations (50), with announced blood tests (51, 58), and even by suggesting a state of mental agitation and anxiety under hypnosis (50). On the other hand, authors have also reported shortened blood clotting time in subjects attending an examination (52), in persons rated as being particularly anxious before blood drawing (51, 53), and in psychiatry patients scheduled for electroconvulsive therapy (54). A few authors challenged these findings by reporting unchanged blood clotting time before announced electroconvulsive therapy (55) and unchanged fibrinolytic activity with an examination (56) and with an unjustified diatribe to employees of being inefficient (57).
The coexistent coagulation and fibrinolysis activation by mental arousal in naturalistic studies is in line with recent findings in standardized laboratory stress protocols (59–66). However, there are few attempts to assess activation states of both systems at a time. One earlier study registered both shortened blood clotting time and increased fibrinolytic activity in male subjects anxiously expecting blood drawing (51). Jern et al. (59, 60) also found simultaneous increase in molecules of both coagulation pathways as well as of fibrinolysis across two studies in healthy subjects who underwent a standardized 20-minute stress protocol, although their results suggest that hemostatic reactivity might differ between sexes. Both procoagulant and anticoagulant molecules also increased 10 days after a major earthquake in highly stressed hypertensive individuals who had lost their homes (but not in the moderately stressed subjects still living in their homes) (67). Because of lack of a normotensive control group, however, these results may not be generalizable to a healthy population (67).
Regarding individual hemostasis molecules, there is some evidence that fibrinogen and vWF are the molecules with procoagulant properties and that t-PA is the enzyme with clot-dissolving properties susceptible to stimulation by mental arousal, though findings are not uniform. Five of seven studies showed elevated fibrinogen levels (mean increase 7%, range 3%–11%) in response to either a standardized or a naturalistic stressor (59–63, 67, 68). However, regarding all fibrinogen studies, two referred to positive findings in hypertensive individuals alone (63, 67), two studies were limited because of lack of a control group (67, 68), and four studies exclusively included either men (59, 68) or women (60, 61). There is also some inconsistency with respect to vWF, which increased in three studies for an average of 26% (range 25%–30%) with either laboratory or catastrophic stressors (59, 64, 67), whereas it remained unchanged in two other studies (60, 69). Female gender (60) and a relatively shorter stress period (69) could have accounted for part of the negative study findings.
Elevated t-PA with a standardized protocol and with naturalistic stressors in five (mean increase 50%, range 8%–96%) of seven studies (58–60, 65–67, 69), notably without change in its inhibitor PAI-1 in four of five studies (58, 59, 65, 67, 69), is consistent with increased fibrinolytic capacity triggered by acute mental stressors. Complex kinetics of fibrinolysis molecules may explain the puzzling observation that increased t-PA antigen was accompanied by nonsignificant change in t-PA activity in two studies (59, 65), whereas, in turn, elevated t-PA activity was accompanied by unchanged t-PA antigen in two other studies (60, 66). Because t-PA antigen measures predominantly t-PA/PAI-1 complexes (29), increased t-PA antigen may reflect the aftermath of an initial increase in t-PA activity that rapidly became inhibited by binding to PAI-1 (65). Indeed, stress-induced t-PA activity increased after five minutes when t-PA antigen (still) was unchanged (66), whereas t-PA antigen increased after 20 minutes when t-PA activity was unchanged (again) because the initial peak presumably had decreased (59, 65).
The few investigations on prethrombotic markers reflect their recent introduction into the routine hemostasis laboratory as a most efficient tool to sensitively monitor effects of mental arousal on coagulation and fibrinolysis pathways (Figure 1). Thrombin-antithrombin III complex significantly increased with aerotactical training in six combat pilots (70) and tended to increase in response to a 15-minute Stroop protocol in healthy subjects (71). D-dimer increased in hypertensive subjects exposed to an earthquake (67) but not in stressed military pilots (70). A small sample size in the latter study and impaired endothelial function in the hypertensive earthquake population both may have contributed to this difference.
From a kinetic point of view, these results suggest that amount of thrombin formed did not exceed amount of thrombin neutralized (eg, in thrombin-antithrombin III complexes) in the healthy pilots, whereas, in the earthquake population, the evident amount of thrombin was not inactivated and led to conversion of fibrinogen to fibrin, followed by its degradation reflected by increased D-dimer. Elevated plasmin-2-antiplasmin complex in the earthquake population (67) similarly suggests fibrin formation with the stressor, because fibrin is required to convert plasminogen to plasmin that subsequently becomes inactivated by forming a complex with its inhibitor 2-antiplasmin. In line with stimulated fibrin and eventually coronary thrombus formation with the catastrophic stressor, increased D-dimer was accompanied by 3.5-fold increased prevalence of angiographically confirmed myocardial infarction in the earthquake area during the 4 weeks after the disaster (Figure 2, a and b) (72).
Another study found that the cold pressor test was a sufficient sympathetic stimulus to elicit (soluble) fibrin formation, reflected by increase in fibrinopeptide A, in patients with certain types of diabetes (73). Some studies found unchanged prethrombotic markers (68, 71), although their different half-lives (67, 71) may have prevented detection of transient increase.
Studies in patients with cardiovascular disease. Excellent reviews emphasize the importance of several highly regulated endothelial anticoagulant pathways, which constrain the generation and activity of thrombin in the normal vasculature (74, 75). In atherosclerotic vessels, however, antithrombotic and fibrinolytic capacities, mainly endothelial release of t-PA, are both impaired and underlie gradual fibrin deposition and plaque growth (11, 74, 76). A number of studies suggest that mental arousal could critically shift the hemostatic equilibrium toward a hypercoagulable state in patients with clinical atherosclerosis because, unlike in normal subjects, endothelial dysfunction might underlie imperfect stress-induced activation of anticoagulant and fibrinolytic steps.
In hypertensive individuals, acute stressors led to increase in fibrinogen (63) and reduced fibrinolysis activation (63, 66) compared with normotensives. Patients with CAD showed longer recovery time of stress-induced decline in antithrombin III than normal controls (77). With the cold-pressor test, patients with certain forms of diabetes had significantly elevated fibrinopeptide A compared with healthy controls (73). These studies correspond to effects of sympathetic stimuli on platelets, which found more pronounced platelet activation with mental arithmetic in patients with CAD and with epinephrine infusion in hypertensive subjects than in normals (78, 79).
Type A personality. The primary cardiovascular risk of the type A behavior, and of its hostility-anger complex in particular, may involve endothelial damage and presumably hemostatic activation because of pronounced hemodynamic and neuroendocrine reactivity to environmental stressors in persons with high trait hostility and anger (80). Such reasoning guided us to review type A effects on coagulation and fibrinolysis using an acute stress paradigm, even though type A behavior as a personality trait is a chronic condition.
In their classical work, Friedman and Rosenman (81) found significant shortening of basal blood clotting time in subjects with fully developed type A behavior pattern (QS 4/6). One recent study found impaired fibrinolysis with intrinsic overcommitment at work that had emerged from the global type A pattern ([82]; Table 3). Two other studies found no association between type A behavior and basal PAI-1 antigen (QS 6/6) (83) and fibrinogen ([84]; Table 3), respectively. The few coagulation and fibrinolysis reactivity studies refer to type A behavior in general rather than to its hostility component. Nonetheless, they suggest that pursuing the reactivity avenue might track down important links between type A features and CAD.
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Neuroendocrine effects on hemostasis with acute stress. A variety of neuroendocrine responses to short-term mental stress in laboratory and real-life situations have been reported (89). Several reviewed studies measured increased plasma catecholamine levels in response to the sympathetic challenge (65, 66, 69, 71, 77, 87), although no study assessed plasma cortisol response. Although correlation does not imply causation, some found positive associations between plasma epinephrine levels and both fibrinogen (87) and fibrinolytic activity (65, 87). On the other hand, two studies found an inverse relationship between epinephrine and antithrombin III levels, which suggests its consumption in anticoagulant processes such as in thrombin-antithrombin III complexes (77, 87).
The relationships between stress-induced catecholamine spillover and changes in coagulation and fibrinolysis are in line with previously reviewed effects of adrenergic infusions and blockade on hemostasis molecules, where a 20- to 30-minute epinephrine infusion accelerated blood clotting time and stimulated fibrinolysis. Epinephrine also led to an increase in FVIII clotting activity, vWF antigen, and certain prethrombotic markers. Adrenoreceptor-blockade studies suggest that endothelial release of FVIII, vWF, and t-PA into circulation is most likely mediated by adrenergic stimulation of endothelial ß2 receptors (90).
Adrenergic mechanisms may provide a bridge to an important parallel line of investigation on acute stressor-induced expression of cellular adhesion molecules on leukocytes, which is also closely linked to the ß2 adrenoreceptor (91). Adhesion molecules are widely expressed on leukocytes, the endothelium, and platelets and mediate adhesive interactions of inflammatory and hemostatic processes in atherogenesis (92, 93). Procoagulant changes in response to acute stressors in turn might activate adhesion molecules, although this remains to be demonstrated. For example, thrombin, fibrin, and fibrin degradation products promote leukocyte tethering to the endothelium via induction of endothelial adhesion molecule expression (94–96).
Chronic Psychological Distress
Table 3 summarizes epidemiological studies on coagulation and fibrinolysis with chronic psychological stressors we conceptualized as per either job stress or (low) socioeconomic status. The distinction of the two concepts is helpful for discussion. We acknowledge, however, that some of the chronic stress constructs reach beyond "job strain," and that the term "socioeconomic status" in fact covers a wide range of measures such as education, income, and also the work environment (5). The 21 studies that did not reach the maximum QS of six provided no information on medications well known to interfere with hemostasis.
Job stress. Friedman et al. were in the vanguard of hemostasis research related to strain imposed by the occupational environment, when they noted in 1958 that tax accountants, subjected to a several-month period of increased workload, showed accelerated blood coagulation that eased off during periods of respite (97). Inspired by Karasek’s job strain model (3), several authors described hemostatic correlations with similar definitions of work stress. The 18 studies reviewed (82, 84, 97–112) suggest an association between high job stress and a thrombophilic milieu reflected by elevated procoagulant molecules (ie, fibrinogen and FVII) and reduced fibrinolytic capacity (ie, decreased t-PA activity and increased PAI-1). However, such reading is not straightforward in terms of procoagulant variables, given that the number of studies showing an increase (84, 97, 101–107) is virtually equal to the number of studies indicating unchanged or even decreased coagulation factors (82, 100, 107–112). On the other hand, impaired fibrinolysis is a fairly consistent finding across four of five investigations (82, 98–100, 108).
As compared with controls, the average increase in fibrinogen was 8% (range 4%–30%), and the average decrease in the fibrinolytic capacity was 47% (range 28%–107%) in six and four studies, respectively, which showed an independent association between the particular hemostasis variables and job stress items (82, 98, 99, 101–104, 106–108).
Socioeconomic status. Nineteen studies looked at the relation between different measures for socioeconomic status (5) and blood coagulation and fibrinolysis factors. There is substantial evidence that socioeconomic status is inversely related to plasma fibrinogen (84, 101, 103, 105, 108, 109, 113–122) and FVII levels (101, 114, 117, 121). Fibrinolysis seemed to be unchanged or even stimulated with low socioeconomic status, although this has been explored by only three studies (101, 123, 124). Major cardiovascular risk factors, demographics, and health related behavior accounted for part of the social gradient in fibrinogen and other hemostasis variables (84, 101, 115, 116, 118, 119); this risk factor confounding seems to be less strong in conjunction with job stress (82, 104, 106, 108). Nonetheless, just as through established cardiovascular risk factors (5), socioeconomic status might exert its adverse impact on vessel health through procoagulant hemostatic effects.
Neuroendocrine effects on hemostasis with chronic stress. Long-term mental stress is associated with increase in many stress hormone levels (125–127) akin to that reported with acute sympathetic stressors (89). Such rationale made several authors assume that catecholamine and cortisol surges also might underlie hypercoagulability observed with chronic psychological distress (82, 84, 99, 104, 106, 111). However, the few studies on chronic stress in this area do not support such assumption, because neither plasma cortisol nor catecholamine levels mediated the effects of chronic stress on fibrinogen levels (112, 122). In addition, during a 3-day vigil, fibrinogen and clotting activities of FV, FVIII, and FIX decreased, and euglobulin lysis time remained unchanged, despite elevated levels of serum cortisol, urinary epinephrine, and norepinephrine (100). However, the particularly sustained intensity of the latter stress protocol could have favored both depletion of storage pools and reduced synthesis of clotting factors, whereas the majority of other psychosocial stressors may allow periods of stress relief.
Sympathetic activation appears to modulate fibrinolysis through a ß2-mediated increase of fibrinolysis with acute stress as mentioned above (90) and a ß1-mediated decrease of fibrinolysis with chronic stress (128). It is theorized that chronic stress stimulates the ß1 adrenoreceptor in the vascular endothelium, leading to reduced intracellular prostacyclin synthesis. Reduced prostacyclin concentration eventually impairs the release of t-PA, which leads to impaired inhibition of circulating PAI-1 (128). In addition, chronic stress may downregulate ß2 adrenergic receptor function (129) such that fibrinolysis is ineffectively stimulated in response to acute stressors. For instance, a small study found that students lacked exercise-induced fibrinolysis stimulation during a 5-day examination, with prolonged effect beyond the stressful period (QS 3/6) (130). Taken together, a variety of features of a chronic stressor, namely intensity and continuity, may shape its impact on coagulation and fibrinolysis and underlying neurohumoral mechanisms.
Psychiatric Disorders
Considerable work from the periods of 1910 to 1950 deals with inconsistent alterations of the blood clotting time in a variety of psychiatric disorders (131). There is, however, a paucity of qualifying contemporary reports on coagulation and fibrinolysis with depression and anxiety; these studies are summarized in Table 4. Although well-defined psychiatric syndromes cannot be derived from scales screening for psychiatric symptoms, we do not emphasize this distinction because there is a graded relation between depression scores and future risk for CAD events (9) and because of the relatively small number of relevant studies.
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With respect to scarce data, there is evidence for a thrombophilic state in depression. Virtually all four studies looking at procoagulant measures found that they were increased (84, 133–135), whereas one study showed unchanged fibrinolysis (98). A hypercoagulable profile also is consistent with previous findings of increased platelet activity in depressed individuals (16). This interpretation becomes less powerful, considering that the association between depression scores and both D-dimer and fibrinogen may have been driven by cardiovascular risk factors in two epidemiological studies (84, 135). Moreover, one study counterintuitively found increased fibrinolytic capacity with several fibrinolysis assays in depressive syndromes (136).
Neuroendocrine effects on hemostasis with psychiatric disorders. Many depression studies have documented hyperactivity of the hypothalamic-pituitary-adrenocortical and sympathomedullary axis (16). Major depressive disorders have been associated with increase in plasma norepinephrine, cortisol, and arginine vasopressin levels (137–139). A serotoninergic deficit is another hallmark of altered neuroendocrine physiology in depressed individuals (140). With respect to attractive avenues for future research, neuroendocrine hormones relevant to depression have the potential to alter hemostatic activity, and their interaction effects on hemostasis could promote a hypercoagulable state.
Norepinephrine (90) and the synthetic arginine vasopressin analog desmopressin, the latter widely used in the treatment of bleeding disorders (141), both stimulate blood coagulation and fibrinolysis similar to that observed with acute psychological stress; they also could account for procoagulant changes and stimulated fibrinolysis observed in depressive disorders (134, 136). Likewise, hypercortisolism could elicit a hypercoagulable state in depressed subjects similar to that found with anti-inflammatory corticosteroids, which increase coagulation activity and decrease fibrinolytic activity (142, 143). Similarly, patients with Cushing’s syndrome show increase in FVIII and vWF, as well as defective fibrinolytic potential likely as a consequence of metabolic effects of endogenously elevated glucocorticoids on the endothelium (144, 145). In addition, one study suggested impaired fibrinolysis in terms of elevated t-PA antigen with low plasma serotonin levels in healthy subjects (146).
Another explanatory model suggests that increased fibrinogen in major depression reflects an acute phase response to inflammatory changes (133). Indeed, some have hypothesized that a common trigger such as viral infection precedes both depressive symptoms and atherosclerotic processes (9). The model further assumes that feelings of exhaustion before a CAD event form an adaptive response to proinflammatory cytokines (147).
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SUMMARY AND FUTURE DIRECTIONS |
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TOPABSTRACTINTRODUCTIONPsychological Factors and CADBlood Coagulation and...Hemostatic Factors and CADMETHODSSUMMARY AND FUTURE DIRECTIONSACKNOWLEDGMENTSREFERENCES |
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Because the first studies on this topic were published many decades ago, the field has generated considerable data with strikingly broad methodology. Future research might be more fruitful if it considered replication of previous findings with careful selection of study populations and by use of established psychological instruments. In addition, focusing on hemostatic changes, in particular on prethrombotic markers, in conjunction with measures of sympathetic nerve activity and of neuroendocrine hormone profiles, could tremendously advance current knowledge of the mechanisms underlying the link between psychological factors, hemostasis, and coronary artery disease.
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ACKNOWLEDGMENTS |
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TOPABSTRACTINTRODUCTIONPsychological Factors and CADBlood Coagulation and...Hemostatic Factors and CADMETHODSSUMMARY AND FUTURE DIRECTIONSACKNOWLEDGMENTSREFERENCES |
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Received for publication May 1, 2000.
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TOPABSTRACTINTRODUCTIONPsychological Factors and CADBlood Coagulation and...Hemostatic Factors and CADMETHODSSUMMARY AND FUTURE DIRECTIONSACKNOWLEDGMENTSREFERENCES |
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K. Aschbacher, R. von Kanel, P. J. Mills, S. Hong, S. K. Roepke, B. T. Mausbach, T. L. Patterson, M. G. Ziegler, J. E. Dimsdale, S. Ancoli-Israel, et al. Combination of Caregiving Stress and Hormone Replacement Therapy is Associated With Prolonged Platelet Activation to Acute Stress Among Postmenopausal Women Psychosom Med, November 1, 2007; 69(9): 910 - 917. [Abstract] [Full Text] [PDF]
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 D. H. Novack, O. Cameron, E. Epel, R. Ader, S. R. Waldstein, S. Levenstein, M. H. Antoni, and A. R. Wainer Psychosomatic Medicine: The Scientific Foundation of the Biopsychosocial Model Acad Psychiatry, October 1, 2007; 31(5): 388 - 401. [Abstract] [Full Text] [PDF]
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B. T. Mausbach, R. von Kanel, K. Aschbacher, S. K. Roepke, J. E. Dimsdale, M. G. Ziegler, P. J. Mills, T. L. Patterson, S. Ancoli-Israel, and I. Grant Spousal Caregivers of Patients With Alzheimer's Disease Show Longitudinal Increases in Plasma Level of Tissue-Type Plasminogen Activator Antigen Psychosom Med, October 1, 2007; 69(8): 816 - 822. [Abstract] [Full Text] [PDF]
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 S. Penckofer, C. E. Ferrans, B. Velsor-Friedrich, and S. Savoy The Psychological Impact of Living With Diabetes: Women's Day-to-Day Experiences The Diabetes Educator, July 1, 2007; 33(4): 680 - 690. [Abstract] [Full Text] [PDF]
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A. Sherwood, J. A. Blumenthal, R. Trivedi, K. S. Johnson, C. M. O'Connor, K. F. Adams Jr, C. S. Dupree, R. A. Waugh, D. R. Bensimhon, L. Gaulden, et al. Relationship of Depression to Death or Hospitalization in Patients With Heart Failure Arch Intern Med, February 26, 2007; 167(4): 367 - 373. [Abstract] [Full Text] [PDF]
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 P. Joshi, S. Islam, P. Pais, S. Reddy, P. Dorairaj, K. Kazmi, M. R. Pandey, S. Haque, S. Mendis, S. Rangarajan, et al. Risk Factors for Early Myocardial Infarction in South Asians Compared With Individuals in Other Countries JAMA, January 17, 2007; 297(3): 286 - 294. [Abstract] [Full Text] [PDF]
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W. Schobersberger, B. Schobersberger, M. Mittermayr, D. Fries, and W. Streif Air Travel, Hypobaric Hypoxia, and Prothrombotic Changes. JAMA, November 15, 2006; 296(19): 2313 - 2314. [Full Text] [PDF]
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P. H. Wirtz, U. Ehlert, L. Emini, K. Rudisuli, S. Groessbauer, J. Gaab, S. Elsenbruch, and R. von Kanel Anticipatory Cognitive Stress Appraisal and the Acute Procoagulant Stress Response in Men Psychosom Med, November 1, 2006; 68(6): 851 - 858. [Abstract] [Full Text] [PDF]
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 P C Strike, L Perkins-Porras, D L Whitehead, J McEwan, and A Steptoe Triggering of acute coronary syndromes by physical exertion and anger: clinical and sociodemographic characteristics Heart, August 1, 2006; 92(8): 1035 - 1040. [Abstract] [Full Text] [PDF]
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A. Steptoe and M. Marmot Psychosocial, Hemostatic, and Inflammatory Correlates of Delayed Poststress Blood Pressure Recovery Psychosom Med, July 1, 2006; 68(4): 531 - 537. [Abstract] [Full Text] [PDF]
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R. von Kanel, U. Hepp, C. Buddeberg, M. Keel, L. Mica, K. Aschbacher, and U. Schnyder Altered Blood Coagulation in Patients With Posttraumatic Stress Disorder Psychosom Med, July 1, 2006; 68(4): 598 - 604. [Abstract] [Full Text] [PDF]
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M. Hamer, E. Williams, R. Vuonovirta, P. Giacobazzi, E. L. Gibson, and A. Steptoe The Effects of Effort-Reward Imbalance on Inflammatory and Cardiovascular Responses to Mental Stress Psychosom Med, May 1, 2006; 68(3): 408 - 413. [Abstract] [Full Text] [PDF]
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 P. C. Strike, K. Magid, D. L. Whitehead, L. Brydon, M. R. Bhattacharyya, and A. Steptoe Pathophysiological processes underlying emotional triggering of acute cardiac events. PNAS, March 14, 2006; 103(11): 4322 - 4327. [Abstract] [Full Text] [PDF]
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J. A. Wagner, H. Tennen, G. A. Mansoor, and G. Abbott History of Major Depressive Disorder and Endothelial Function in Postmenopausal Women Psychosom Med, January 1, 2006; 68(1): 80 - 86. [Abstract] [Full Text] [PDF]
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 K. E. Innes, C. Bourguignon, and A. G. Taylor Risk Indices Associated with the Insulin Resistance Syndrome, Cardiovascular Disease, and Possible Protection with Yoga: A Systematic Review J Am Board Fam Med, November 1, 2005; 18(6): 491 - 519. [Abstract] [Full Text] [PDF]
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 J J C S Veldhuijzen van Zanten, C Ring, D Carroll, and G D Kitas Increased C reactive protein in response to acute stress in patients with rheumatoid arthritis Ann Rheum Dis, September 1, 2005; 64(9): 1299 - 1304. [Abstract] [Full Text] [PDF]
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S Vale Psychosocial stress and cardiovascular diseases Postgrad. Med. J., July 1, 2005; 81(957): 429 - 435. [Abstract] [Full Text] [PDF]
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E. B. Loucks, L. F. Berkman, T. L. Gruenewald, and T. E. Seeman Social Integration Is Associated With Fibrinogen Concentration in Elderly Men Psychosom Med, May 1, 2005; 67(3): 353 - 358. [Abstract] [Full Text] [PDF]
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J. A. Bosch, G. G. Berntson, J. T. Cacioppo, and P. T. Marucha Differential Mobilization of Functionally Distinct Natural Killer Subsets During Acute Psychologic Stress Psychosom Med, May 1, 2005; 67(3): 366 - 375. [Abstract] [Full Text] [PDF]
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C. M. O'Connor and K. E. Joynt Depression: are we ignoring an important comorbidity in heart failure? J. Am. Coll. Cardiol., May 5, 2004; 43(9): 1550 - 1552. [Full Text] [PDF]
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 D. B Panagiotakos, C. Pitsavos, C. Chrysohoou, E. Tsetsekou, C. Papageorgiou, G. Christodoulou, and C. Stefanadis Inflammation, coagulation, and depressive symptomatology in cardiovascular disease-free people; the ATTICA study Eur. Heart J., March 2, 2004; 25(6): 492 - 499. [Abstract] [Full Text] [PDF]
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M. J. Zellweger, R. H. Osterwalder, W. Langewitz, and M. E. Pfisterer Coronary artery disease and depression Eur. Heart J., January 1, 2004; 25(1): 3 - 9. [Abstract] [Full Text] [PDF]
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 R. von Kanel and J. E. Dimsdale Hemostatic Alterations in Patients With Obstructive Sleep Apnea and the Implications for Cardiovascular Disease Chest, November 1, 2003; 124(5): 1956 - 1967. [Abstract] [Full Text] [PDF]
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 R. S. Wilson, J. L. Bienias, C. F. Mendes de Leon, D. A. Evans, and D. A. Bennett Negative Affect and Mortality in Older Persons Am. J. Epidemiol., November 1, 2003; 158(9): 827 - 835. [Abstract] [Full Text] [PDF]
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A. Schins, A. Honig, H. Crijns, L. Baur, and K. Hamulyak Increased Coronary Events in Depressed Cardiovascular Patients: 5-HT2A Receptor as Missing Link? Psychosom Med, September 1, 2003; 65(5): 729 - 737. [Abstract] [Full Text] [PDF]
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 R. von Kanel, J. E. Dimsdale, K. A. Adler, E. Dillon, C. J. Perez, and P. J. Mills Effects of nonspecific beta -adrenergic stimulation and blockade on blood coagulation in hypertension J Appl Physiol, April 1, 2003; 94(4): 1455 - 1459. [Abstract] [Full Text] [PDF]
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 B. C. Sirois and M. M. Burg Negative Emotion and Coronary Heart Disease: A Review Behav Modif, January 1, 2003; 27(1): 83 - 102. [Abstract] [PDF]
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A. Steptoe, S. Kunz-Ebrecht, N. Owen, P. J. Feldman, A. Rumley, G. D. O. Lowe, and M. Marmot Influence of Socioeconomic Status and Job Control on Plasma Fibrinogen Responses to Acute Mental Stress Psychosom Med, January 1, 2003; 65(1): 137 - 144. [Abstract] [Full Text] [PDF]
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R. von Kanel, J. E. Dimsdale, T. L. Patterson, and I. Grant Association of Negative Life Event Stress With Coagulation Activity in Elderly Alzheimer Caregivers Psychosom Med, January 1, 2003; 65(1): 145 - 150. [Abstract] [Full Text] [PDF]
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 E.J. Brunner, H. Hemingway, B.R. Walker, M. Page, P. Clarke, M. Juneja, M.J. Shipley, M. Kumari, R. Andrew, J.R. Seckl, et al. Adrenocortical, Autonomic, and Inflammatory Causes of the Metabolic Syndrome: Nested Case-Control Study Circulation, November 19, 2002; 106(21): 2659 - 2665. [Abstract] [Full Text] [PDF]
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 B. A. Shaw and N. Krause Exposure to Physical Violence During Childhood, Aging, and Health J Aging Health, November 1, 2002; 14(4): 467 - 494. [Abstract] [PDF]
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" indicates inhibition steps of thrombin, plasmin, and t-PA. See text for description and explanation of circled numbers.