Anthony W. Austin

Stress and hemostasis: an update.

Numerous naturalistic, experimental, and mechanistic studies strongly support the notion that-as part of fight-or-flight response-hemostatic responses to acute psychosocial stress result in net hypercoagulability, which would protect a healthy organism from bleeding in case of injury. Sociodemographic factors, mental states, and comorbidities are important modulators of the acute prothrombotic stress response. In patients with atherosclerosis, exaggerated and prolonged stress-hypercoagulability might accelerate coronary thrombus growth following plaque rupture. Against a background risk from acquired prothrombotic conditions and inherited thrombophilia, acute stress also might trigger venous thromboembolic events. Chronic stressors such as job strain, dementia caregiving, and posttraumatic stress disorder as well as psychological distress from depressive and anxiety symptoms elicit a chronic low-grade hypercoagulable state that is no longer viewed as physiological but might impair vascular health. Through activation of the sympathetic nervous system, higher order cognitive processes and corticolimbic brain areas shape the acute prothrombotic stress response. Hypothalamic-pituitary-adrenal axis and autonomic dysfunction, including vagal withdrawal, are important regulators of hemostatic activity with longer lasting stress. Randomized placebo-controlled trials suggest that several cardiovascular drugs attenuate the acute prothrombotic stress response. Behavioral interventions and psychotropic medications might mitigate chronic low-grade hypercoagulability in stressed individuals, but further studies are clearly needed. Restoring normal hemostatic function with biobehavioral interventions bears the potential to ultimately decrease the risk of thrombotic diseases.

Hemoconcentration and hemostasis during acute stress: interacting and independent effects

BackgroundAcute psychological stress can produce significant hemoconcentration as well as prothrombotic changes in blood, both of which may have potentially harmful effects on the cardiovascular system. It is unclear whether these effects are independent or have influence on each other.PurposeThis review discusses research investigating the effects of acute psychological stress on hemoconcentration and hemostasis and explores future directions for psychohematology research. Physiology, associations with cardiovascular disease, and relationships between acute psychological stress are discussed independently for hemoconcentration and hemostasis, followed by an examination of the effects of stress-hemoconcentration on hemostasis.ConclusionsTraditional methods of adjusting for stress-hemoconcentration effects (e.g., calculated plasma volume or hematocrit level corrections) may not be appropriate when examining stress-induced changes in hemostasis. The effects of acute stress on hemostasis should be examined in conjunction with hemoconcentration.

Stress-Induced Alterations in Coagulation: Assessment of a New Hemoconcentration Correction Technique

Objective For the examination of psychological stress effects on coagulation, the Dill and Costill correction (DCC) for hemoconcentration effects has been used to adjust for stress-induced plasma volume changes. Although the correction is appropriate for adjusting concentrations of various large blood constituents, it may be inappropriate for time-dependent or functional coagulation assays. Two new plasma reconstitution techniques for correcting hemoconcentration effects on stress-induced changes in coagulation were compared with the DCC. Methods Blood was collected from 31 men during baseline, the Trier Social Stress Test (TSST), and after 20-minute recovery. For the reconstitution techniques, TSST plasma samples were reconstituted with either baseline plasma or physiological saline equal to the amount of plasma lost during stress. Results Uncorrected activated partial thromboplastin time (APTT) decreased, whereas fibrinogen, factor VIII clotting activity (FVIII:C), D-dimer and prothrombin time (PT%) increased significantly during the TSST. The DCC produced a significantly greater decrease in APTT during stress compared to uncorrected APTT, a significant decrease in PT% compared to uncorrected PT%, and stress D-dimer and fibrinogen and FVIII:C being no different than baseline. APTT, fibrinogen, D-dimer and PT% after saline reconstitution were not different from baseline, whereas FVIII:C after saline reconstitution remained elevated. APTT, PT%, fibrinogen and D-dimer after plasma reconstitution were no different from uncorrected values, whereas FVIII:C remained significantly elevated. Conclusions The observed changes in coagulation are likely in part a consequence of stress and hemoconcentration, but the DCC seems to be an inappropriate hemoconcentration correction technique of time-dependent assays. The saline reconstitution technique may be more biologically relevant when examining stress-hemoconcentration effects on coagulation. Abbreviations APTT = activated partial thromboplastin time; BP = blood pressure; CHD = coronary heart disease; DBP = diastolic blood pressure; FVIII:C = factor VIII clotting activity; Hgb = hemoglobin; Hct = hematocrit; HR = heart rate; PT% = prothrombin time percentage; SBP = systolic blood pressure; TSST = Trier Social Stress Test

Differential association of insulin resistance with cognitive and somatic symptoms of depression

To examine the associations of depressive symptoms with insulin resistance, evaluating somatic and cognitive depressive symptoms separately.

Plasma volume and flight duration effects on post-spaceflight soluble adhesion molecules.

BACKGROUND We examined the effects of plasma volume (PV) changes and flight duration on circulating soluble adhesion markers (sP-selection, sE-selection, and sICAM-1). METHODS Study participants were 22 astronauts (2 women). Missions ranged from 5 to 16 d. Astronauts were split into two groups: those who spent less than 8 d in space and those who spent more than 8 d in space. Soluble adhesion markers and PV were assessed 10 d prelaunch, immediately after landing, and 2-4 d postflight. RESULTS Compared to prelaunch, PV significantly decreased by 4.9% after landing and increased by 9.9% 2-4 d postflight. After landing, sICAM-1 decreased (233.15 vs. 226.78 ng · ml⁻¹) and remained lowered 2-4 d after landing (223.25 ng · ml⁻¹). Adjusting for PV changes, sICAM-1 upon landing was less than prelaunch (218.23 ng · ml⁻¹), but became greater 2-4 d postflight (250.30 ng · ml⁻¹). From prelaunch to landing, sE-selection decreased significantly (30.25 vs. 28.51 ng · ml⁻¹) and returned to prelaunch levels 2-4 d postflight (30.10 ng · ml⁻¹). Adjusting for PV changes, sE-selection was significantly greater 2-4 d postflight (33.48 ng · ml⁻¹) compared to prelaunch. In those who spent less than 8 d in space only, sP-selection increased from prelaunch levels to landing day (31.66 vs. 48.06 ng · ml⁻¹), with and without adjustment for PV changes. Flight duration did not influence PV, sICAM-1, or sE-selection. DISCUSSION Spaceflight leads to an internal environment that decreases PV during flight but rebounds after flight, leading to a dilution of sICAM-1 and sE-selection, but does not appear to affect sP-selection. Flight duration only affected sP-selection.

Comparison of Stress-Hemoconcentration Correction Techniques for Stress-Induced Coagulation

When examining stress effects on coagulation, arithmetic correction is typically used to adjust for concomitant hemoconcentration but may be inappropriate for coagulation activity assays. We examined a new physiologically relevant method of correcting for stress-hemoconcentration. Blood was drawn from healthy men (N = 40) during baseline, mental stress, and recovery, and factor VII activity (FVII:C), factor VIII activity (FVIII:C), activated partial thromboplastin time (APTT), prothrombin time (PT%), fibrinogen, D-dimer, and plasma volume were determined. Three hemoconcentration correction techniques were assessed: arithmetic correction and two reconstitution techniques using baseline plasma or physiological saline. Area-under-the-curve (AUC) was computed for each technique. For FVII:C, uncorrected AUC was significantly greater than AUC corrected arithmetically. For PT%, uncorrected AUC was significantly greater than AUC corrected with saline or arithmetically. For APTT, uncorrected AUC was significantly less than AUC corrected with saline and greater than AUC corrected arithmetically. For fibrinogen, uncorrected AUC was significantly greater than AUC corrected with saline or arithmetically. For D-dimer, uncorrected AUC was significantly greater than AUC corrected arithmetically. No differences in AUC were observed for FVIII:C. Saline reconstitution seems most appropriate when adjusting for hemoconcentration effects on clotting time and activity. Stress-hemoconcentration accounted for the majority of coagulation changes.

Stress-hemoconcentration: plasma volume changes or splenic contraction? A Reply to Engan and Schagatay

In their recent letter regarding our 2011 review article [1], Engan and Schagatay [2] suggest that spleen-induced increases in erythrocyte concentration may be partly responsible for stress-hemoconcentration. They rightly state that, due to a release of erythrocytes into the blood, hemoconcentration occurs as a result of spleen contraction during physiological stressors such as exercise [3] or apneic diving [3, 4]. Moreover, the spleen is sympathetically innervated [3] and catecholamine infusion results in spleen contraction and subsequent release of erythrocytes [5–8]. Although there is much research on this topic in animals, we did not mention animal research in our review because we limited our review to humans. We [9, 10] and others [11] have shown that erythrocytes increase during acute mental stress. After correcting for plasma volume changes, erythrocytes were no longer different from baseline [10] or they even decreased [9]. This suggests that the increase in erythrocytes is a passive by-product of plasma volume shifts as opposed to a result of active release from the spleen. If the release of erythrocytes from the spleen and plasma volume reduction occur simultaneously, it seems unlikely that correcting for plasma volume changes would result in a decrease in erythrocytes. Instead, one would expect that the increase in erythrocytes and the decrease in plasma volume to offset. Moreover, HDL cholesterol, LDL cholesterol [10, 12–14], plasma proteins [13], and immune cells/messengers [15] are affected by hemoconcentration. However, erythrocyte concentration does not change during stress to the same extent that these substances change, suggesting that an increase in erythrocytes is not responsible for these increases. Nevertheless, this does not completely preclude the possibility that the spleen releases erythrocytes during acute mental stress. The next step in this line of research would be to concurrently measure splenic contraction, erythrocyte concentration, and plasma volume before, during, and after stress in order to disentangle how these mechanisms may work together to produce a state of stress-hemoconcentration.

Reply to Letters From Fall and Bailey, and Muldoon

Two letters were recently submitted to the editor regarding our recent publication (1), both of which raised important issues. Fall and Bailey identified discrepancies between their previous work (2) and ours, which deserve consideration. They also used the same correction technique of Dill and Costill (3) after maximal 223 Konstanzer Online-Publikations-System (KOPS)

Positive and Negative Affect Is Related to Experiencing Chest Pain During Exercise-Induced Myocardial Ischemia

Objective Silent myocardial ischemia is thought to be associated with worse cardiovascular outcomes due to a lack of perception of pain cues that initiate treatment seeking. Negative affect (NA) has been associated with increased pain reporting and positive affect (PA) with decreased pain reporting, but these psychological factors have not been examined within the context of myocardial ischemia. This study evaluated the associations between PA, NA, and chest pain reporting in patients with and without ischemia during exercise testing. Methods A total of 246 patients referred for myocardial perfusion single-photon emission computed tomography exercise stress testing completed the positive and negative affect schedule-expanded version, a measure of PA and NA. Presence of chest pain and myocardial ischemia were evaluated using standardized protocols. Results Logistic regression analyses revealed that for every 1-point increase in NA, there was a 13% higher chance for ischemic patients (odds ratio [OR] = 1.13; 95% confidence interval [CI] = 1.02 to 1.26) and an 11% higher chance in nonischemic patients (OR = 1.11; 95% CI = 1.03 to 1.19) to report chest pain. A significant interaction of PA and NA on chest pain reporting (&bgr; = 0.02; 95% CI = 0.002 to 0.031) was also observed; nonischemic patients with high NA and PA reported more chest pain (57%) versus patients with low NA and low PA (13%), with high NA and low PA (17%), and with high PA and low NA (7%). Conclusions Patients who experience higher NA are more likely to report experiencing chest pain. In patients without ischemia, high NA and PA was also associated with a higher likelihood of reporting chest pain. Results suggest that high levels of PA as well as NA may increase the experience and/or reporting of chest pain.

Factors associated with study completion in patients with premature acute coronary syndrome

Background Factors associated with study completion in younger adults are not well understood. This study sought to describe psychosocial, clinical, and demographic features associated with completion of a study of men and women with premature acute coronary syndrome. Methods As part of the GENdEr and Sex determInantS of cardiovascular disease: From bench to beyond-Premature Acute Coronary Syndrome (GENESIS-PRAXY) study, demographic, psychosocial, and clinical variables were assessed in 1213 patients hospitalized for acute coronary syndrome (≤ 55 years; 30% women). Patients were followed for 12 months. Dropouts withdrew from the study or were lost to follow-up after 12 months; completers were still enrolled after 12 months. Results Of 1213 patients initially enrolled, 777 (64.1%) completed 12-month follow-up. Fully adjusted models suggested that being older (OR = 1.04, 95% CI [1.01, 1.06]), higher subjective social status within one’s country (OR = 1.11, 95% CI [1.01, 1.22]), being free of type II diabetes, (OR = 0.66, 95% CI [0.45, 0.97]), non-smoking status (OR = 0.70, 95% CI [0.51, 0.95]) and being free of depression (OR = 1.52, 95% CI [1.11, 2.07]) were independently associated with study completion. Conclusions Recruitment/retention strategies targeting individuals who smoke, are younger, have low subjective social status within one’s country, have diabetes, or have depression may improve participant follow-up in cardiovascular cohort studies.