9 de junio de 2012

Effects of Psychological Stress and Psychiatric Disorders on Blood Coagulation and FibrinolysisA Biobehavioral Pathway to Coronary Artery Disease?

Fuente original: http://www.psychosomaticmedicine.org/content/63/4/531.full
Roland von Känel, MD, Paul J. Mills, PhD, Claudia Fainman, MD and Joel E. Dimsdale, MD

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.

Abstract

OBJECTIVE: A hypercoagulable state before overt thrombosis resulting from an imbalance between the coagulation and fibrinolysis systems is related to cardiovascular disease progression and acute coronary syndromes. Psychological stressors and depressive and anxiety disorders also are associated with coronary artery disease. This review explores whether changes in blood coagulation, anticoagulant, and fibrinolytic activity may constitute psychobiological pathways that link psychological factors with coronary syndromes.

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.

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.

Numerous psychological factors have been associated with CAD (1–10)⇓⇓⇓⇓⇓⇓⇓⇓⇓. In addition, there is growing evidence that disturbances between procoagulant and anticoagulant hemostasis molecules and the hypercoagulable milieu they may create are crucial in both atherosclerosis progression and acute coronary syndromes (11–13)⇓⇓. We and others have previously reviewed how hemostatic function could reflect a psychobiological pathway linking psychological factors with CAD, given that mental stress, hostility, and depressive disorders are accompanied by increased platelet activity (14–16)⇓⇓. This article reviews psychobiological research in terms of the three other hemostasis components (ie, blood coagulation, anticoagulation, and fibrinolysis) and discusses implications for cardiovascular disease, in particular CAD. Before critically delineating the literature in the field, we provide an introductory overview of psychological measures and of hemostatic disturbances related to CAD, as well as a concise presentation of blood coagulation and fibrinolysis pathways.

Psychological Factors and CAD

Widespread epidemiological data highlight the negative impact of emotional stress, psychosocial strains, unfavorable personality patterns, and certain psychiatric disorders on evolution and prognosis in CAD. The harmful potential of emotional stress on the cardiovascular system has been reviewed extensively (1, 2). Constructs like “job strain” (3), “vital exhaustion” (4), and low socioeconomic status, the latter actually referring to a wide range of socioeconomic measures (5), have all been suggested as independent risk factors for cardiovascular disease. “Anger” and “hostility,” which emerged from type A coronary behavior pattern, also appear to have a detrimental influence on the cardiovascular system (6, 7). Several studies have found increased mortality from CAD and a poorer outcome in the aftermath of a coronary event among depressed individuals (8, 9). Recent literature also points to a possible link between anxiety disorders and cardiovascular events, with the strongest evidence for phobic anxiety (9, 10).

Blood Coagulation and Fibrinolysis Pathways

Figure 1 shows that two pathways of blood clotting have been identified that are referred to as intrinsic and extrinsic coagulation pathways ( 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).

In a progressive cascade, intrinsic and extrinsic pathways converge to form a common pathway that comprises activation of FX in presence of FV and activated platelets (cf. below) and, subsequently, thrombin formation (Figure 1, ). 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.



In response to vessel wall injury, alterations of blood flow (“shear stress”), or chemical stimuli (eg, thrombin or catecholamines), platelets manifest a series of linked functional responses (ie, adhesion, secretion, and aggregation). The surface of activated platelets expresses procoagulant phospholipids and binding sites for FV and FVIII that constitute the platelet coagulation activity referred to as platelet factor 3 (Figure 1, ) (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 α2-antiplasmin terminate fibrinolysis by inactivation of t-PA and plasmin in a t-PA/PAI-1 and plasmin-α2-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-α2-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).

Hemostatic Factors and CAD

Although the current concept of normal hemostasis physiology suggests that procoagulant and anticoagulant mechanisms exist in a balanced equilibrium (27), hemostatic variables and the prothrombotic tendency they may create play an important role in pathogenesis of cardiovascular disease (28). Table 1 gives an overview of laboratory markers of coagulation, anticoagulation and fibrinolytic activity and their implications in terms of a hypercoagulable state. With respect to laboratory assessment of the fibrinolytic capacity, complex kinetics explain distinct meanings of elevated t-PA antigen and elevated t-PA activity. Decreased fibrinolytic activity, demonstrated by a prolonged euglobulin clot lysis time, is accompanied by elevated levels of PAI-1 (antigen and activity) and of t-PA antigen, the latter predominantly reflecting t-PA/PAI-1 complexes and PAI-1 activity, respectively. On the other hand, enhanced fibrinolytic activity, demonstrated by shortened euglobulin lysis time, is accompanied by low PAI-1 (antigen and activity) levels and elevated t-PA activity (29).

Hypercoagulability underlies chronic CAD progression by promoting gradual deposition of fibrin within atherosclerotic plaques (11). In spite of the active debate whether hypercoagulability merely indicates an underlying atherosclerotic process or is also a cause of atherosclerosis and thrombosis (30), increased levels of the following hemostasis variables have shown predictive value for coronary artery syndromes in patients with CAD and in apparently healthy individuals: fibrinogen (31, 32), FVII clotting activity (32), FVIII clotting activity (33, 34), vWF antigen (34, 35), t-PA antigen (29, 36), PAI-1 antigen (29, 37), D-dimer (38–40)⇓⇓, and plasmin-α2-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).

METHODS

Literature on humans was located through use of a MEDLINE/HEALTHSTAR search (California Digital Library) back to 1966 and through checking the bibliographies of these sources. The following key words were used for searching: psychological stress, personality, depressive disorder, anxiety, hemostasis, blood coagulation, fibrinolysis, and cardiovascular disease. The wide methodological variability across studies in terms of psychological and hemostasis variables precluded a formal meta-analysis. Alternatively, we choose the most rigorous analytical approach possible for a narrative review by systematically subjecting the located studies to a quality filter (8) by considering the following six (items 1–6) or seven (items 1–7) issues in healthy subjects and patients, respectively. 1) The study population (without controls) had to comprise at least 10 subjects. 2) Standard blood processing methods had to be used. 3) Hemostatic assay(s) had to be either described or cited. 4) Medical conditions (eg, cardiovascular disorders) and drugs (eg, platelet inhibitory and anticoagulant therapy) potentially interfering with hemostasis had to be controlled for. 5) A p value obtained by either parametric or nonparametric statistics distinguished between significant (p ≤ .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.

Integration of naturalistic and laboratory findings. Inspired by Cannon’s classical experiments (47), short-term effects of mental arousal on hemostasis have attracted investigators throughout the 20th century (Table 2). Investigators’ tools to assess coagulation and fibrinolytic activity decades ago were largely restricted to insensitive assays (48–57)⇓⇓⇓⇓⇓⇓⇓⇓⇓, and, moreover, some early studies raise quality concerns (49, 50, 53, 57)⇓⇓⇓. Nonetheless, a number of naturalistic studies, predominantly dating between the 1940s and 1960s, suggest that emotional states of anxiety, fear, insecurity, and tension trigger both the coagulation and fibrinolysis systems (48–54, 58)⇓⇓⇓⇓⇓⇓⇓.

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-α2-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 α2-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.

In the 1950s, Schneider et al. reported that emotional states of anger and hostility, elicited by stressful interviews during psychotherapy on topics of intrapersonal conflicts, hastened blood clotting time (QS 3/6) (85, 86). Although not directly related to arterial thrombosis, the authors also attributed to patients with recurrent thrombophlebitis, what would be called “anger-in style” nowadays (86). In addition, two studies from Russia, which has long-running tradition of behavioral research in hemostasis, sustain Schneider’s case reports. In the first study, 101 patients with stable CAD and 25 controls underwent a protocol consisting of an arithmetic task under time pressure and punishment by light and sound in case of failure. After five minutes, patients with CAD who had type A personality showed significantly accelerated blood coagulation and lower antithrombin III levels than individuals with type B personality and normal controls (QS 7/7) (87). In the second study, fibrinolytic activity increased in 125 subjects when two stress tasks characterized by either demands of intellectual activity at rapid work pace or by conflictual interpersonal interaction patterns elicited self-rated feelings of aggressiveness and emotional tension (QS 6/6) (88).

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 β2 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 β2 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 β2-mediated increase of fibrinolysis with acute stress as mentioned above (90) and a β1-mediated decrease of fibrinolysis with chronic stress (128). It is theorized that chronic stress stimulates the β1 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 β2 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.

In line with the observation that acute state anxiety may concurrently activate coagulation and fibrinolysis systems (48–54, 58)⇓⇓⇓⇓⇓⇓⇓, fibrinogen was higher in patients with chronic anxiety disorders than in normals (132). Moreover, fibrinogen correlated directly with trait anxiety scores in healthy young adults, which, however, was insignificant when restricted to nonsmokers (83).

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).

SUMMARY AND FUTURE DIRECTIONS

Although this review cannot exclude the possibility of a publication bias, the evidence for an association between psychological factors and several hemostatic variables related to CAD is abundant. Moreover, some psychological factors appear to show a characteristic pattern of coagulation and fibrinolysis activity. Concomitant activation of coagulation and fibrinolysis pathways in response to acute mental stressors may be harmless or even of evolutionary benefit in healthy individuals. On the other hand, by eliciting procoagulant changes due to impaired endothelial anticoagulant function, mental arousal could contribute to CAD progression and acute coronary syndromes in patients with cardiovascular disease. Much evidence also points to a hypercoagulable state comprising increased procoagulant molecules and, to a certain extent, impaired fibrinolytic capacity, with chronic psychological distress in particular job strain and low socioeconomic status. These associations (ie, with fibrinogen) are partially mediated by cardiovascular risk factors and demographics. More studies are needed to confirm thrombophilic changes in depressive disorders and to verify occasional reports on increased hemostatic reactivity with type A features (ie, hostility and anger).

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.

Acknowledgments

This work was supported by fellowship 81BE-56155 from the Swiss National Science Foundation (R.vK.), by an educational grant from Novartis Foundation, Switzerland (R.vK.), and by Grants HL44915, HL36005, and HL57265 from the National Institutes of Health (J.D. and P.M.). The authors thank Dr. David Krantz, action editor for this manuscript and the anonymous reviewers for their comments. Received May 1, 2000. © 2001 American Psychosomatic Society