Review

Thromboelastographic Study of Psychophysiological Stress: A Review

Clinical and Applied Thrombosis/Hemostasis 2015, Vol. 21(6) 497–512 ª The Author(s) 2013 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1076029613512415 cat.sagepub.com

Henry T. Peng, PhD1 and Shawn G. Rhind, PhD1

Abstract Thromboelastography (TEG) is drawing more attention for clinical and laboratory studies of hemostasis. It has been applied to evaluate the effects of both psychological and physiological stress on whole blood coagulation from the onset of the coagulation cascade through clot formation, to the end with fibrinolysis. We conducted a comprehensive review on the applications of TEG for assessment of different stressors, ranging from physical exercise to emotional situations. The methodology is unique in terms of instrumentation, the methods to activate blood coagulation, the type of blood (citrated vs fresh blood), and study settings (in vitro vs in vivo vs clinical trials). Thromboelastography has most often been used to study the effects of physiological stress. The author’s own work and future directions are discussed as well. The review would facilitate future development of TEG for evaluating hemostasis and potential pathological pathways in response to various forms of stress. Keywords thromboelastography, rotational thromboelastometry, stress, blood coagulation, fibrinolysis

Introduction Physical and psychological stressors exert a broad range of biological effects on the human body. Some effects include cardiovascular changes and diseases1 and induced neuroimmunological functions.2 Moreover, stress is widely recognized as an important risk factor in the etiology of cardiovascular and immune-related diseases.3 Importantly, stress has been shown to affect blood coagulation and fibrinolysis and to alter inflammatory responses.4 For example, acute physical exertion generally increases platelet number and activity and activates coagulation and fibrinolytic processes.5 Although acute exercise may change the hemostatic milieu in favor of increased coagulation,6 its long-term effects on coagulation and fibrinolysis lead to a reduced risk of stress-related disease processes.7 Hence, it is critical to understand and control the effects of psychophysiological stress on blood clotting, fibrinolysis, and thrombolysis. Although well recognized, the true meaning of stress is often difficult to describe and pinpoint. Selye, who began his pioneering work in the early 20th century, defined stress as the ‘‘nonspecific response of the body to any demand’’ and a stressor is an event that threatens or is perceived to threaten homeostasis.8 In general, any external factor affecting our normal bodily function can be considered as a stressor. Stressors can range from life-threatening acute injuries to chronic physical effects or psychological/mental disorders.9 In the context of a military environment, the stressor is often termed as ‘‘operational stressors’’ and can be both physiological and psychological in nature. This review describes those reports without traumatic injuries and focuses on human studies unless human

data are unavailable and in vitro or animal studies are deemed to be highly relevant. Although a number of in vitro tests have been reported for assessing hemostasis under stress, these tests are mainly concerned with isolated components of the coagulation and fibrinolysis system, such as thrombus formation and platelet function, and thus cannot show overall effects and take into account the interactions of the clotting cascade and platelets in whole blood. It is, therefore, difficult to relate isolated findings from such tests to the overall effects in whole blood systems, as occurs in clinical settings. Thromboelastography (TEG), invented by Hartet in 1948,10 provides a ‘‘global’’ picture of hemostasis by quantitatively measuring the viscoelastic changes in whole blood during clotting, from the beginning of coagulation to the end with fibrinolysis. This includes the onset of clot formation, its progress, and maximum clot strength and clot stability, which provides important information about coagulation, fibrinolysis, and platelet function.11-13 It offers additional information compared to standard laboratory tests (eg, prothrombin time [PT], activated partial thromboplastin time [aPTT], and thrombin clotting

1

Defence Research and Development Canada, Toronto Research Centre, Toronto, Ontario, Canada

Corresponding Author: Henry T. Peng, Defence Research and Development Canada, Toronto Research Centre, 1133 Sheppard Avenue West, Toronto, Ontario, Canada M3K 2C9. Email: [email protected]

Downloaded from cat.sagepub.com by guest on November 16, 2015

498

Clinical and Applied Thrombosis/Hemostasis 21(6) type of stressor (eg, exercise), we will describe the typical physiological changes affecting coagulation and fibrinolysis under each stressor, followed by experimental findings and proposed mechanisms for the changes. The hemostatic effects of physical injuries, disease states, and other relevant factors are discussed briefly. The review also describes our efforts to applying the TEG method for evaluation of hyperbaric, physical exertion, and heat stress. The last section is devoted to the discussion of current limitations and possible future development of TEG.

Methodology

Figure 1. Schematic illustration of (A) the TEG mechanisms, (B) the TEG machine, and (C) a representative TEG tracing showing the relationship between the qualitative tracing and the quantitative parameters. TEG indicates hromboelastography.

time).14 Thromboelastography may also identify the relative contributions of clotting factors, such as fibrinogen and platelets, to the overall coagulation process. Specific evaluation of a particular coagulation process can also be illustrated by modified TEG methods using partial blood components, for example, plasma or coagulation factor-deficient blood. Thromboelastography has been widely used in clinical settings for monitoring blood coagulation system during surgical operation to determine the abnormal blood clotting patterns of patients and the requirement for the administration of lifesaving hemostatic agents and blood products to correct defects in hemostasis.15 In addition to clinical utilization, TEG has found applications in the studies of the coagulation effects of pharmacological agents,16 vasoactive agents,17 coagulation factors,18,19 and resuscitation fluids.20 However, its use as a research tool for evaluating effects of psychophysiological stress and for screening thrombogenicity risks has not been widely reported. Hence, a review was conducted to enable further development and application of the TEG technology for studying the effects of psychophysiological stress. This article is structured into 3 major sections to review current usage of TEG for studying the effects of stress in various forms (eg, physical, psychological, emotional, fear) on blood coagulation and fibrinolysis. The first section discusses the existing TEG methodologies and techniques. The second section describes the use of TEG in studies using a variety of stressors. The topic is discussed according to the type and form of stressor, for example, physiological and psychological stressors, such as exercise, temperature extremes, hypobaric or hyperbaric conditions, mental, and emotional stress. These stresses possess both common and distinct biochemical mechanisms for alteration of the hemostatic system. For each

As TEG technology and utilization evolved, 2 types of systems have emerged: one manufactured by Haemoscope Co (Niles, Illinois) and called thromboelastogram and the other represented by Pentapharm GmbH (Munich, Germany) and called rotational thromboelastometry (ROTEM).21 Both record the viscoelastic changes that occur during the whole coagulation process, but the primary hardware difference is that ROTEM has an immobile cup, wherein the pin/wire transduction system slowly oscillates an arc of 4 450 . In addition, each ROTEM system has 4 channels and a built-in computer to operate as opposed to 2 channels in the TEG system that requires a separate computer to operate. It is argued that the ROTEM system uses a ball-bearing system for power transduction, which makes it less susceptible to movement and vibration.22 Figure 1A schematically shows how the TEG instrument works. The machine measures the viscoelastic properties of blood as it clots under a low shear. It has 2 channels; for each channel, a pin suspended by a torsion wire is immersed in whole blood or plasma in a plastic cup. The cup oscillates back and forth constantly at a set speed through an arc of 4 450 . The torque of the cup is transmitted to the pin, via the fibrin strands in the blood clots as coagulation proceeds, and to the torsion wire for conversion by a mechanical-electrical transducer to an electrical signal, which can be monitored by a computer.12 Figure 1B shows the TEG 5000 hemostasis analyzer manufactured by Haemoscope Co used in our laboratory. The measurement is graphically represented as a characteristic shape profile over time (Figure 1C), from which the following parameters can be derived to provide main information about the coagulation and fibrinolysis: (1) reaction time ‘‘R’’ or time to first clot formation, which is related to plasma clotting factors and circulating inhibitory activity; (2) coagulation time (CT) ‘‘K’’ or time to a specific level of clot strength, which is associated with the activity of the intrinsic clotting factors, fibrinogen and platelets; (3) rate of clot polymerization ‘‘a angle’’ or rapidity of fibrin cross-linking, which is a main function of platelets, fibrinogen, and plasma components residing on the platelet surface; (4) maximum amplitude (MA) or maximum clot strength, which is a direct function of the maximum dynamic properties of fibrin and platelet number and function; (5) time to reach MA (TMA); and (6) fibrinolysis at 30 minutes ‘‘LY30’’ or the rate of amplitude reduction 30 minutes after MA, which relates to fibrinolysis.

Downloaded from cat.sagepub.com by guest on November 16, 2015

Peng and Rhind

499

Parameters similar to TEG (eg, CT, clot formation time [CFT], a angle, maximum clot firmness [MCF], clot lysis index CLI30) can be derived from ROTEM which are commonly used in Europe.23 However, a study comparing TEG and ROTEM concluded that the significant differences between the 2 methodologies do not permit their results to be used interchangeably.24 Both types of instrumentation are covered in the review. Unless specified, TEG is used as a general term for the elastic modulus-based assessment of hemostasis in the review. Thromboelastography refers to the system manufactured by Haemoscope Co, while ROTEM indicates the one manufactured by Pentapharm GmbH. A PubMed search was completed for the TEG studies involving psychophysiological stress. The specific stress of interest (eg, exercise, heat stress) was also used as key words in the search. Abstracts were used to determine the relevance and when appropriate further review of the original articles was warranted. Additional publications were selected from the crossreferences listed in the original papers and from the citing articles, and additional search was made through Medline, Scopus, and Institute of Scientific Information databases for those topics with limited findings from PubMed. Table 1 summarizes different stress models and methods in thromboelastographic studies. Results are presented and discussed in the following sections. It shows that a variety of stressors, both physiological and psychological, have been studied using various TEG methods. The physiological stressors include acute exercise,25-28 extreme temperatures,29-36 hyperbaric,37 and hypobaric conditions.38,39 The psychological stressors include emotional stress.40 Thromboelastography was also used in our recent study on multiple stressors. Depending on the duration of stress (acute vs chronic), TEG was conducted in longitudinal or cross-sectional groups before, during, or after stress. Generally, whole blood samples were collected into citrate-anticoagulated vacuum tubes at baseline and different stress levels. Samples were then aliquoted into a TEG cup and measured immediately upon the addition of calcium chloride solution. The TEG was run to obtain the parameters of interest, typically, R, K, a, and MA in TEG and CT, CFT, a, and MCF in ROTEM. Different procedures have been developed at the discretion of the user/manufacturer as exemplified by whole and partial blood components and various activators to accelerate blood coagulation. Citrated whole blood is mostly used in TEG studies although native and processed blood such as fresh whole blood and plasma-rich blood has also been used. Measurement temperature was mostly set at 37 C but can be adjusted which is useful to study coagulation under hyper- and hypothermia.41 In addition, modified TEG methods allow the evaluation of specific coagulation functions using the blood treated with different coagulation activators (eg, celite, kaolin, tissue factor, and thrombin) or anticoagulants (eg, heparin). For TEG, tissue factor and kaolin mixed with phospholipids and buffered stabilizer are supplemented with blood in most applications.42 For ROTEM, the manufacturer recommends citrated blood recalcified with CaCl2 (starTEM) and activation with tissue thromboplastin for extrinsic

pathway (ex-TEM), activation with partial thromboplastinphospholipid for monitoring the intrinsic pathway (in-TEM), addition of a thrombocyte inhibitor (cytochalasin D) for detection of fibrinogen deficiency and fibrin polymerization disorders (fib-TEM), addition of a fibrinolysis inhibitor (aprotinin) for confirmation of hyperfibrinolysis (ap-TEM), and addition of heparinize I for global analysis of coagulation without the influence of heparin (hep-TEM). There are a few studies where partial coagulation systems were used to understand the interactions with a specific blood component. Most TEG applications were focused on blood coagulation system with few involving fibrinolytic system. Compared to the TEG methods, which evaluate blood coagulation and fibrinolysis based on a cell-based model for hemostasis,43,44 there are more recent ROTEM studies involving both intrinsic and extrinsic coagulation pathways.

Physiological Stress A diverse group of stressors are considered under this category, such as exercise, exposure to extreme temperatures, hypobaric and hyperbaric conditions, and their associated changes in blood coagulation and fibrinolysis have been documented. Exercise/Physical Exertion. Exercise or strenuous physical activity induces profound physiological perturbations. Exercise can be acute or chronic. The former can be further defined as light, moderate, or heavy activity as based on heart rate and oxygen uptake measurements.45 Chronic exercise, sometimes referred to as exercise training, has been defined as acute exercise repeated over time (>3 times/week).46 Among the physiological changes associated with acute and chronic exercise,46,47 immediate cardiovascular responses and long-term risk of development/progression of cardiovascular disease (CVD) have been well documented.6,45 Blood hemostasis in exercise and training has been reviewed.5,48 Several thromboelastographic studies were conducted to assess the effects of different acute exercise conditions on coagulation and fibrinolysis. Blood samples were collected before, during, and after exercise, and TEG was conducted according to different procedures. Comparatively little information is available for the effects of training. The seminal TEG study examining the effects of acute exercise on blood coagulation dates back over almost 4 decades and demonstrated enhanced coagulation at a high exercise workload (ie, 200 W) and at exhaustion.25 The procoagulant effects were attributed to the increase in factor VIII via adrenergic stimulation as circulating catecholamine levels were elevated. In addition, fibrinolysis was activated in direct relation to the exercise intensity and release of plasminogen activator from endothelial cells as the results of changes in vascular diameter and activation via epinephrine. On the other hand, recent studies have suggested that the increased concentration of circulating plasminogen activator was mainly due to its decreased hepatic clearance with proportional decreases in liver blood flow during submaximal exercise.49 This is in agreement with

Downloaded from cat.sagepub.com by guest on November 16, 2015

500

Downloaded from cat.sagepub.com by guest on November 16, 2015

Intensity

Samples

TEG Procedures

300, 600. 900, and 1200 kg m/min, each for 5 Citrated whole blood from healthy males aged Thromboelastograph (Hellige, Freiburg im min and 1500 kg m/min until exhaustion 22-37 yrs (n ¼ 10) Breisgau, Germany): no details available. Downhill marathon with 795 m vertical Citrated whole blood from 13 healthy Ex-TEM and in-TEM assays were performed difference participants (12 men, 1 women) 3-4 d, 3-4 h with 300-mL citrated whole blood recalcibefore and 30 min, next morning after fied with 20 mL of 0.2 mol L1 CaCl2 and activated by either tissue thromboplastin or marathon partial thromboplastin-phospholipid using a ROTEM machine (Pentapharm Co, Munich, Germany). Citrated whole blood from 33 healthy Marathon at a local temperature of 25 C NATEM assay was performed with 300-mL individuals (20 male, 13 female, mean age 35 citrated whole blood recalcified by 20 mL of + 8) immediately before and after 0.2 mol L1 CaCl2 within 3 h of blood sampling using a ROTEM machine marathon (Pentapharm Co, Munich, Germany). Marathon, triathlon, and long distance cycling Citrated whole blood from 68 male volunteers In-TEM and fib-TEM assays were performed competitions immediately before and after each with 300-mL citrated whole blood recalcicompetition fied with CaCl2 and activated by either phospholipids, ellagic acid or tissue factor, cytochalasin D using a ROTEM machine (Pentapharm GmbH, Munich, Germany). Native whole blood from a central venous Temperature Whole-body hyperthermia for metastatic Within 2 min of blood taking, TEG catheter of patients undergoing disease to a maximum core temperature of (Haemoscope Co, Niles, Illinois) was chemotherapy 41.8 C performed with 360 mL of native whole blood activated with 1% celite at 37 C and patient’s body temperatures. Citrated whole blood from 7 healthy men (25- Thromboelastography: no details available. Sauna bath with a dry bulb temperature 36 yrs with a mean of 29) before, 5 and 10 between 90 and 110 C for 10 or 15 min min in the bath; and 5 healthy men (26-31 yrs with a mean of 28.6) before, 7 and 15 min in the bath Whole blood from 15 neonates with advanced TEG was performed with 360 mL of native Mild controlled hypothermia at 35.5 C, 34.5 C, and 33.5 C for 48 h in preterm necrotizing enterocolitis whole blood activated by 1% kaolin using a neonates with advanced necrotizing TEG machine model 5000 (Haemoscope enterocolitis with cooling mattress Co, Niles, Illinois) with 1 channel at 37 C and the other channel at infant’s core temperatures. Moderate local hypothermia by immersing the Native whole blood taken from the left-hand TEG was performed with 360 mL of native dorsum vein of 15 healthy volunteers (27whole blood without any activators at 37 C left forearm in an 18 C water bath (skin 55 yrs, 4 men, 11 women) temperature of 30 C and 28 C) within 1 min after blood sampling using a TEG analyzer model 3000 C (Haemoscope Co, Niles, Illinois). Graded hypothermia (36 C-32 C) by surface Citrated whole blood from a radial artery of Immediately after sample collection, TEG cooling with a forced-air cooling system anesthetized patients prior to elective (Haemoscope Co, Niles, Illinois) was and a cooling blanket intracranial surgery (16 patients, 7 men, and performed with 300 mL of citrated whole 9 women 20-55 yrs) blood and 40 mL of 0.645% CaCl2 at 37 C or patient’s body temperatures.

Exercise

Stressors

Table 1. Methods Used in Thromboelastographic Study of Psychophysiological Stress.

29

30

31

32

33

Decreased R at 39 and 41 C, and decreased K, LY30 at 41 C

Significant reduction in R after 15 min in the bath

Increased R, reduced a, and MA with decreasing core temperature

No differences in R, K, a angle, and MA

Prolonged R, K, and reduced a angle at 32 C body temperature, no effects on MA

(continued)

28

27

26

25

References

Increased/activated coagulation as measured by shortened CT and increased MCF.

Hypercoagulable as evidenced by shortened CT and increased MCF

Shortened R after exercise at 1200 kg m/min and in the exhaustion, no change in K Shortened CT, CFT and increased MCF and a angle

Hemostatic Effects

501

Downloaded from cat.sagepub.com by guest on November 16, 2015

Intensity

TEG Procedures

38

22

39

40

Increased CT, CFT, and decreased a angle after acute exposure (1 d), increased MCF after 1-week exposure

Accelerated clot initiation (CT), clot propagation (CFT and a angle) and an increased clot firmness (MCF) during and after the flight

No differences in CT, CFT, a angle, and MCF

Three groups were identified: hypercoagulable as reflected by shortened R and K; hypocoagulable as indicated by prolonged R, K, and reduced MA; no effects

36

Prolonged R, K, and reduced a angle

37

35

Prolonged R, K, and reduced a angle at 33 C body temperature, no effects on MA

Prolonged K and decreased MA

34

References

No significant effects

Hemostatic Effects

Abbreviations: CT, coagulation time; CFT, clot formation time; MCF, maximum clot firmness; ROTEM, rotational thromboelastometry; MA, maximum amplitude; TEG, thromboelastography.

Emotional stress

Hypobaric hypoxia

Hyperbaria

Samples

79 patients undergoing primary median Thromboelastography: no details available. sternotomy Mild hypothermia down to 33 C induced by Citrated whole blood from an arterial cannula TEG was conducted with 300 mL of citrated cardiopulmonary bypass (CPB) of patients (30 patients, 24 men, 6 women, whole blood and 60 mL of 0.645% CaCl2 at 37 C or patient’s body temperatures using 40-85 yrs) before CPB, at the lowest body Thromboelastographs D (Haemoscope Co, core temperature during CPB and after Niles, Illinois). Heparinase TEG cups were CPB used for heparinase modified measurements. Hypothermic patients undergoing orthotopic Native whole blood taken from the patient’s Thromboelastograph D (Haemoscope Co, liver transplantation internal jugular vein catheter (23 men, 22 Niles, Illinois) modified with a temperature women, 20-65 yrs with a mean age of 45.5) controller: no more details available. Rats exposed to hyperbaric oxygen at 2 atm 1 Citrated plasma from rats Thromboelastograms: no details available. h daily for 5 or 10 consecutive days Citrated whole blood from 47 volunteers (32 In-TEM assay was started within 15 min after Exposure to an intermediate altitude (3300 and 5400 m) for approximately 1 d or 1 males and 15 females, age 24-62) in good blood collection using a ROTEM machine week general health and living at 100%) and activated protein C resistance decreased from 0.95 to 0.8. Furthermore, a significant increase in aPTT (38-43 seconds) was paralleled by significant changes in von Willebrand factor activity (102%-62%).90 Kotwal et al found a hypercoagulable state in 38 volunteers of the Indian army, as indicated by significant increases in hemoglobin, platelet count, fibrinogen, plasminogen activator inhibitor-1 and markers for platelet activation (platelet factor 4 and b-thromboglobin), when measured before and after a 3- and 8-month stay at 3500 m.91 Only 1 recent study was found involving thromboelastometry measurements at an intermediate altitude (3300 and 5400 m).38 In comparison with variables of in-TEM assay measured at sea level, CT and CFT were extended, the a angle was reduced, while MCF was not altered after acute exposure to an altitude of 3300 and 5400 m for 1 to 2 days. Interestingly, after prolonged exposure to the altitude of 5400 m for more than a week, the variables reverted to the baseline values with the exception of MCF, which increased significantly above the acute exposure levels. Furthermore, the coagulation parameters were associated with a significant increase in plasma norepinephrine. This study demonstrated the benefit of ROTEM as a field-deployable point-of-care test, which can be to overcome all logistic difficulties in performing a large battery of single coagulation tests within the frame of high altitude expedition. Whether hypoxia can influence the hemostatic system is still the subject of debate.92 Studies simulating the conditions of reduced cabin pressure during commercial air travel have found no changes in hemostatic parameters (eg, international

Downloaded from cat.sagepub.com by guest on November 16, 2015

506

Clinical and Applied Thrombosis/Hemostasis 21(6)

normalized ratio, PT, aPTT, platelet counts functions, prothrombin fragments 1 and 2, thrombin-antithrombin III complexes, a2-antiplasmin, tissue plasminogen activator, D-dimer) under hypobaric hypoxia for 8 hours,93 normobaric hypoxia for 7 minutes94 and 2 hours,95 and isocapnic hypoxia.96 Although others report transient increases in the concentrations of prothrombin fragments 1 and 2 by 2.5-fold, thrombin–antithrombin complex by 8.2-fold, and factor VII activity by 17% after 8 hours of exposure to 76 kPa air pressure in a hypobaric chamber.97 The discrepancies may be due to the differences in the degree and duration of hypoxia, normobaric versus hypobaric conditions, and other potentially confounding factors, such as sedentarism, dehydration, and even mental stress.98 Most hypoxic environments were created for a short duration simulating a low altitude of 2400 m using hypobaric chambers rather than measurements during actual flights. The clinical significance of any laboratory findings for perturbations in coagulation remains to be explored.92 The utility of TEG has been demonstrated in evaluating coagulation changes in an aircraft during and after a round-trip flight (*8 hours each way).22 Both in-TEM and ex-TEM measurements revealed an accelerated clot initiation (CF), clot propagation (CFT, a angle), and increased clot firmness (MCF) values that were within the upper reference limit. These changes peaked immediately after the flight, but MCF remained elevated to a lesser extent 3 days after the flight. In addition, the activation of coagulation and fibrinolysis was confirmed by reduced aPTT and increased activities of certain plasma markers (eg, factor VII and plasminogen activator inhibitor). This is in contrast with another study simulating normobaric hypoxic conditions in a special chamber corresponding to altitudes between 2000 and 2400 m, where patients remained in a sitting position in the aircraft for 10 hours.39 The in-TEM measurements showed no thromboelastographic changes throughout the study, which is supported by either no changes or minor variations in a number of plasma markers (eg, fibrinogen, plasminogen activator, PT). To differentiate the influence of moderate hypoxia from other factors (eg, prolonged sitting), ROTEM was performed with other coagulation tests on the effects of 10-hour bus travel without hypoxic stress.99 All measured parameters were altered, suggesting an accelerated clot initiation (in-TEM CT), clot propagation (in-TEM CFT and a angle), and clot firmness (in-TEM MCF). Similar results were noted for the ex-TEM, with the exception of MCF which was unchanged. The results of this study imply that additional factors other than hypoxia such as postural constraints are involved in actual conditions of a long-haul flight that may play a role in coagulation changes. Furthermore, the thromboelastographic technology has been widely used to monitor changes in coagulation status in clinical settings following acute physical trauma and critical illness, such as thermal/burn injuries,100 multiple trauma,101 cardiac surgeries and liver transplantations,102,103 sepsis, and septic shock,104 all of which affect coagulation and fibrinolysis to various extents. In particular, injury-related hypothermia and acidosis affect the degree of acute coagulopathy of trauma.105

Patients with trauma display different coagulopathies according to TEG; endogenous acute traumatic coagulopathy is associated with shock and hypoperfusion, whereas the exogenous effects of dilution from fluid resuscitation and/or consumption of coagulation factors through bleeding and blood loss further add to trauma-induced coagulopathy.10 Overall, there is evidence to support the use of TEG as a point-of-care test for assessing patients with critical injuries106,107 and potentially as a guide for transfusion practice after trauma.102,108

Psychological Stress Although psychological effects on coagulation and fibrinolysis are known,109 there are limited studies using TEG to assess these changes. Most studies have focused on soluble molecular markers and standard laboratory tests, such as fibrin D-dimer, fibrinogen, factors VII, VIII, XII, and PT, activated partial prothrombin, associated with acute mental stress,110-112 anxiety,113 vital exhaustion,114 depressive symptoms,115 overcommitment116 and posttraumatic stress disorder (PTSD).117 Furthermore, psychological functioning, exhaustion, affectivity, depression, anxiety, worrying, vigor, and social support were assessed for their associations with stress-induced procoagulant reactivity.118 Moreover, psychological stress and mental disorders have long been linked to cardiovascular disorders.119 In general, prothrombotic changes have been detected under stress through alterations in blood rheology and hemostasis with acute stress being extensively reviewed and strongly associated with the pathogenesis of CVD and acute coronary syndromes.4 Importantly, recent clinical studies show a conclusive link between PTSD and the presence and/or severity of coronary atherosclerosis and suggest that PTSD is an independent risk factor for mortality.120 The biological mechanisms underlying the alterations in coagulation markers have been well addressed but are less conclusive for changes in fibrinolysis due to the limited number of studies and the inconsistency of the findings. Nevertheless, there are a few published reports involving TEG (see Table 1 for details). An early thromboelastographic study of psychological stress was made of healthy humans under emotion stress.40 The stress was simulated in a standardized situation involving intellectual activity with an imposed rapid rate of work and simultaneous interaction between 2 persons on the ‘‘Gomeostat’’ apparatus. The effects on blood coagulation were characterized by thromboelastograms recorded on Thromb-1 thromboelastograph. In addition to reaction time R, time to clot formation K, and maximum clot strength MA, maximum elasticity of thrombus, total blood coagulation constant T, and Serradimigni index were determined demonstrating mixed TEG changes among 35 patients before and after the stress. In particular, 9 of 35 volunteers were categorized as functionally hypercoagulable, 15 were hypocoagulable, and no changes were detected in the remaining patients. The opposite results were found using a model situation of emotional stress involving group interactions. Further studies would provide a better understanding of the regulatory role of the cerebral cortex on the hemostasis

Downloaded from cat.sagepub.com by guest on November 16, 2015

Peng and Rhind

507

70

10 Day Day Day Day Day Day

60 40

R, K and LY30

TEG deflection (mm)

8 Day 1 before EHS Day 1 after EHS

20 0 –20

6

*

1 pre-EHS 1 post-EHS 6 pre-EHS 6 post-EHS 9 pre-EHS 9 post-EHS

*

60 50 40 30

4

Alpha and MA

80

20

–40

*

2

10

–60 0

Figure 4. Typical thromboelastography (TEG) tracings of blood from the same healthy volunteer before and after exposure to exertional heat stress (EHS).

system. Yet, the clinical relevance of the changes in TEG remains to be examined in vivo.

Multiple Stress To date, few studies have evaluated the combined effects of multiple physical or mental stressors on coagulation (eg, exercise and hypoxia95 as exemplified by exercise at high altitude during climbing mountains). DeLoughery et al conducted a study where patients exercised both at room air and at 12% oxygen and found that hypoxia may exert an antithrombotic effect by suppressing exercise-induced procoagulant changes and stimulating fibrinolysis,121 as opposed to their synergetic effects since each stress tends to promote blood coagulation. Military operations routinely expose personnel to a multitude of physical and psychological stressors that can cause deterioration in performance and lead to negative health consequences in soldiers.122 The increased frequency and pace of deployments in both active-duty and reserve populations enhances the potential for stress-related coagulation abnormalities and associated cardiovascular risk factors.123 The impact of operational stress on hemostasis was examined in military fighter pilots, showing a hypercoagulable state after a standardized training flight mission, attributed to the psychophysical stress associated with operational jet flight and exposure to G forces,124 but TEG/ROTEM was not performed. An earlier report using TEG showed a relatively low prevalence (*3%) of hemostatic disorders in air force personnel, with no correlation to flight history.125 Taking advantage of the latest advances in the TEG technology, we have recently conducted an extensive thromboelastographic study to evaluate the effects of 9 days of repeated exertional heat stress (EHS) on blood coagulation and fibrinolysis. Briefly, healthy volunteers walked on a treadmill (4.5 kmh1, 2% incline) in a hot–dry environment (40 C, 30%

) m (m

gr ee (d e

M A

) (% Al ph a

LY 30

in )

100

(m

80

Time (min)

K

60

in )

40

(m

20

R

0

)

0 –80

Figure 5. Coagulation changes in healthy participants in response to exertional heat stress (EHS) at different times. Data represent mean + standard error of the mean (SEM; n ¼ 9). *Significant difference from the pre-EHS (P < .05) based on 1-way repeated measures analysis of variance.

relative humidity) to exhaustion or an ethical maximum core body temperature of 40 C. During acute EHS exposures, Canadian military nuclear, biological, and chemical protective clothing was worn producing an uncompensable exerciseheat stress condition.126 Venous blood was collected at baseline (pre-EHS) and exhaustion on days 1, 6, and 9 of the 9-day repeated EHS exposures through an indwelling venous catheter into citrated tubes. Thromboelastographic measurements were carried out using a computerized TEG Hemostasis System 5000 following the same procedure as described in our aforementioned hyperbaric study. Figure 4 presents representative thromboelastograms for citrated whole human blood from the same individual at the baseline and exhaustion to elucidate the effects on blood coagulation on day 1. The TEG tracings show that the EHS increased blood clottability. As far as blood coagulation is concerned, the stress led to the earlier onset of clot formation (ie, R time, as indicated in Figure 4) and the stronger clot (as measured by the maximal amplitude MA). Similar thromboelastographic profiles were noticed on day 6 and 9. The observed effects could not be attributed to hemoconcentration, as there were no significant shifts in plasma volume during the acute EHS exposure. Figure 5 depicts averaged procoagulant effects and fibrinolytic activation for all patients. The differences in most TEG parameters between the pre- and post-EHS exposure were not profound. This may be due in part to the large individual variation. Another possibility is that the stress not only initiates the normal cascade but also its mode of action relies on activation to blood vessel, which cannot be measured in our current TEG method. On the other hand, markedly procoagulant effects of the stress on days 1 and 9 were indicated by an approximately

Downloaded from cat.sagepub.com by guest on November 16, 2015

508

Clinical and Applied Thrombosis/Hemostasis 21(6)

20% reduction in K and 5% increase in MA, confirming significant activation of the coagulation cascade and possible platelet function. In contrast, the effect on MA is less, which is in accordance with the reported effects of the stress on the maximum clot strength in the literature.50 It should be noted that while there is ample evidence that exercise and heat play a crucial role in thrombosis and hemostasis, respectively, as discussed earlier, it is promising for typical use of TEG to characterize overall synergistic effects of combined and/or multiple stressors on the coagulation and fibrinolytic activities. Our findings for the hemostatic impact of the dual stressors is consistent with previous TEG results,25,30 thereby validating the use of TEG as a tool for assessing the potential effects of other unknown stress.

Remarks and Conclusions Since its invention over 60 years ago, TEG has undergone continuous technological refinements to improve its reproducibility, ease of use, and interpretation in clinical and scientific applications. In theory, TEG has many of the properties of an ideal modern coagulation test for direct monitoring of stressrelated hemostatic changes. It provides a comprehensive assessment of the complex hemostatic system in response to both physiological and psychological stress rather than evaluating only discrete portions of the coagulation cascade as with conventional laboratory tests. It is an inexpensive method that can provide immediate results, is simple to perform, easy to interpret, and can account for the effects of body temperature if needed. Yet, very few studies have been devoted solely to the evaluation of TEG in stress research and none has explored its potential to guide rational design for studying the implications of stress on CVD mechanisms. There are several reasons why TEG has not been widely adopted for experimental studies of human stress physiology. One reason is its excessive reliance on operators and manual procedures compared to other automated coagulation testing devices, a source of criticism by laboratorial societies.82,83 A major virtue of TEG is its remarkable versatility. It can be performed with the same instrument using fresh or anticoagulated whole blood or plasma. The application of specific activators, such as kaolin, tissue factor, and celite, provide the opportunity to investigate the role of contact proteins or tissue factor in initiating the clotting process. However, such versatility also results in TEG being done in many different ways, which leads to difficulty in establishing standard reference values and comparing experimental results between studies. In addition, different protocols in terms of sampling tubes and sample storage have been used. For example, the clotting time of citrated blood is strongly affected by the types of tubes used to collect blood (eg, Vacutainer from Becton Dickinson, vs Monovette from Sarstedt, Germany).127 It has also been consistently documented that widely used citrated blood, stored for less than 30 minutes, is not stable.82,83 Collectively, these factors likely have contributed to the current lack of application of TEG in stress research.

The current lack of universal recognition of TEG as a reliable routine laboratory test may be changed due to recent progress in TEG technology128,129 leading to standardization of the method and improvement in reproducibility. For example, the recent development of computerized interfaces has led to a renewed interest in TEG, particularly to guide blood transfusion practices.130 In addition to the use of normal and abnormal biologic controls as currently recommended quality assurance by the manufacturer, the accuracy of the device may be further calibrated with clinically relevant substances with known viscosities.131 As a point-of-care system, TEG measurements have been performed in the field, such as onboard an aircraft.22 In most studies using TEG, other assays (eg, PT, aPTT, platelet activation and adhesion tests) have been used in parallel to fully understand various hematological effects of stress. In addition to the most commonly measured 4 parameters (ie, R, K, a, and MA in TEG or CT, CFT, a, and MCF in ROTEM), additional parameters, such as LY30 which can be analyzed for fibrinolysis, have not been used as often for assessing the fibrinolytic effects of stress. Currently, TEG has been mainly used to measure coagulation properties, but should be further explored for understanding the complex mechanisms underlying stress–blood interactions. Stress may alter hemostasis through its effects on neuroendocrine responses, such as enhanced sympathetic-mediated catecholamine release,30,132 activated hypothalamic–pituitary– adrenal axis-induced cortisol release,133 immunoinflammatory effects on leukocyte activation/mobilization, mechanical or physical stress on hemolysis of red blood cells28 and endothelial cells,134 and hemoconcentration.135 Considerable interindividual differences in the response of the hemostatic system to psychophysiological stress have been observed. This could be ascribed to training status in the case of exercise.27 Although aberrant coagulation has been associated with an increased incidence of CVD, the clinical significance of stress-induced changes in coagulation remains incomplete. It should be noted that most studies were focused on the effects of a single stressor. Moving forward, it would be important to investigate the effects of multiple stressors, similar to those experienced during military operations, from both a physiological and psychological perspective. In conclusion, both qualitative studies based on thromboelastograms in early applications and quantitative studies using many variables in recent applications have been reviewed. Different methodologies have been used that need to be considered when comparing results across the current literature. It is noted that exercise has an impact on a broad range of biological pathways including blood coagulation and fibrinolysis, compared to the other stressors. Although each stressor may modify physiological conditions through a common pathway (eg, activation of the sympathetic nervous system), other mechanisms such as temperature effects on plasma protein properties may exist that are ascribed to different effects and need to be considered when investigating the physiological changes under stressful conditions. In addition, it should be noted that stress which influences the physiology of hemostasis through interactions

Downloaded from cat.sagepub.com by guest on November 16, 2015

Peng and Rhind

509

with the vascular endothelium or effects on endothelial-platelet interactions may be evaluated using TEG methods incorporating adherent endothelial cells.136 One limitation of the TEG method is that once the process has started, it is not possible to manipulate it further. With advances in the instrument, development and standardization of coagulation assays, TEG can be a valuable tool to study hemostasis and potential pathological pathways in response to stress. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by Defence Research and Development Canada.

References 1. Selye H. The evolution of the stress concept: stress and cardiovascular disease. Am J Cardiol. 1970;26(3):289-299. 2. Friedman EM, Lawrence DA. Environmental stress mediates changes in neuroimmunological interactions. Toxicol Sci. 2002; 67(1):4-10. 3. Fleshner M, Maier SF, Lyons DM, Raskind MA. The neurobiology of the stress-resistant brain. Stress. 2011;14(5):498-502. 4. Thrall G, Lane D, Carroll D, Lip GY. A systematic review of the effects of acute psychological stress and physical activity on haemorheology, coagulation, fibrinolysis and platelet reactivity: implications for the pathogenesis of acute coronary syndromes. Thromb Res. 2007;120(6):819-847. 5. Prisco D, Francalanci I, Filippini M, Hagi MI. Physical exercise and hemostasis. Int J Clin Lab Res. 1994;24(3):125-131. ˚ M. Cognitive performance in ¨ sterberg K, Karlson B, Hansen A 6. O patients with burnout, in relation to diurnal salivary cortisol. Stress. 2009;12(1):70-81. 7. Petrac DC, Bedwell JS, Renk K, et al. Orem DM, Sims V. Differential relationship of recent self-reported stress and acute anxiety with divided attention performance. Stress. 2009;12(4):313-319. 8. Selye H. Forty years of stress research: principal remaining problems and misconceptions. Can Med Assoc J. 1976;115(1):53-56. 9. Uchino BN, Smith TW, Holt-Lunstad J, et al. Stress and illness In: Cacioppo JT, Tassinary LG, Berntson GG, eds. Handbook of psychophysiology. New York, NY: Cambridge University Press; 2009:608-632. 10. Theusinger OM, Wanner GA, Emmert MY, et al. Hyperfibrinolysis diagnosed by rotational thromboelastometry (ROTEM1) is associated with higher mortality in patients with severe trauma. Anesth Analg. 2011;113(5):1003-1012. 11. Salooja N, Perry DJ. Thrombelastography. Blood Coagul Fibrinolysis. 2001;12(5):327-337. 12. Vig S, Chitolie A, Bevan DH, Halliday A, Dormandy J. Thromboelastography: a reliable test? Blood Coagul Fibrinolysis. 2001;12(7):555-561.

13. Donahue SM, Otto CM. Thromboelastography: a tool for measuring hypercoagulability, hypocoagulability, and fibrinolysis. J Veterinary Emerg Crit Care. 2005;15(1):9-16. 14. Greaves M. Assessment of haemostasis. Vox Sang. 2004; 87(suppl 1):S47-S50. 15. Carr ME Jr, Martin EJ, Kuhn JG, Ambrose H, Fern S, Bryant PC. Monitoring of hemostatic status in four patients being treated with recombinant factor VIIa. Clin Lab. 2004;50(9-10):529-538. 16. Lang T, Toller W, Gutl M, et al. Different effects of abciximab and cytochalasin D on clot strength in thrombelastography. J Thromb Haemost. 2004;2(1):147-153. 17. Kawasaki J, Katori N, Taketomi T, Terui K, Tanaka KA. The effects of vasoactive agents, platelet agonists and anticoagulation on thrombelastography. Acta Anaesthesiol Scand. 2007;51(9):1237-1244. 18. Kawaguchi C, Takahashi Y, Hanesaka Y, Yoshioka A. The in vitro analysis of the coagulation mechanism of activated factor VII using thrombelastogram. Thromb Haemost. 2002;88(5):768-772. 19. Landskroner KA, Colson NC, Jesmok GJ. Thromboelastography measurements of whole blood from factor VIII-deficient mice supplemented with rFVIII. Haemophilia. 2005;11(4):346-352. 20. Mittermayr M, Streif W, Haas T, et al. Hemostatic changes after crystalloid or colloid fluid administration during major orthopedic surgery: the role of fibrinogen administration. Anesth Analg. 2007;105(4):905-917. 21. Luddington RJ. Thrombelastography/thromboelastometry. Clin Lab Haem. 2005;27(2):81-90. 22. Schobersberger W, Fries D, Mittermayr M, et al. Changes of biochemical markers and functional tests for clot formation during long-haul flights. Thromb Res. 2003;108(1):19-24. 23. Lang T, Bauters A, Braun S, et al. Multi-centre investigation on reference ranges for ROTEM thromboelastometry. Blood Coagul Fibrinolysis. 2005;16(4):301-310. 24. Nielsen V. A comparison of the thrombelastograph and the ROTEM. Blood Coagul Fibrinolysis. 2007;18(3):247-252. 25. Hawkey CM, Britton BJ, Wood WG, Peele M, Irving MH. Changes in blood catecholamine levels and blood coagulation and fibrinolytic activity in response to graded exercise in man. Br J Haematol. 1975;29(3):377-384. 26. Sumann G, Fries D, Griesmacher A, et al. Blood coagulation activation and fibrinolysis during a downhill marathon run. Blood Coagul Fibrinolysis. 2007;18(5):435-440. 27. Sucker C, Zotz RB, Senft B, et al. Exercise-induced hemostatic alterations are detectable by rotation thrombelastography (ROTEM): a marathon study. Clin Appl Thromb Hemost. 2010;16(5):543-548. 28. Hanke AA, Staib A, Go¨rlinger K, Perrey M, Dirkmann D, Kienbaum P. Whole blood coagulation and platelet activation in the athlete: a comparison of marathon, triathlon and long distance cycling. Eur J Med Res. 2010;15(2):59-65. 29. Pivalizza EG, Koch SM, Mehlhorn U, Berry JM, Bull. The effects of intentional hyperthermia on the thrombelastograph and the sonoclot analyser. Int J Hyperthermia. 1999;15(3):217-223. 30. Britton BJ, Hawkey C, Wood WG. Adrenergic, coagulation, and fibrinolytic responses to heat. Br Med J. 1974;4(5937):139-141. 31. Hall NJ, Eaton S, Peters MJ, et al. Mild controlled hypothermia in preterm neonates with advanced necrotizing enterocolitis. Pediatrics. 2010;125 (2):e300-e308.

Downloaded from cat.sagepub.com by guest on November 16, 2015

510

Clinical and Applied Thrombosis/Hemostasis 21(6)

32. Romlin B, Petruson K, Nilsson K. Moderate superficial hypothermia prolongs bleeding time in humans. Acta Anaesthesiol Scand. 2007;51(2):198-201. 33. Kettner SC, Sitzwohl C, Zimpfer M, et al. The effect of graded hypothermia (36 C-32 C) on hemostasis in anesthetized patients without surgical trauma. Anesth Analg. 2003;96(6):1772-1776. 34. Stensrud PE, Nuttall GA, De Castro MA, et al. A prospective, randomized study of cardiopulmonary bypass temperature and blood transfusion. Ann Thorac Surg. 1999;67 (3):711-715. 35. Kettner SC, Kozek SA, Groetzner JP, et al. Effects of hypothermia on thrombelastography in patients undergoing cardiopulmonary bypass. Br J Anaesth. 1998;80(3):313-317. 36. Douning LK, Ramsay MA, Swygert TH, et al. Temperature corrected thrombelastography in hypothermic patients. Anesth Analg. 1995;81(3):608-611. 37. Cerrati A. An investigation, using the thromboelastographic technique, of the effect of hyperbaric oxygen on the blood. Proc Eur Soc Toxicol. 1976;17(376):380-382. 38. Modesti PA, Rapi S, Paniccia R, et al. Index measured at an intermediate altitude to predict impending acute mountain sickness. Med Sci Sports Exerc. 2011;43(10):1811-1818. 39. Schobersberger W, Mittermayr M, Fries D, et al. Changes in blood coagulation of arm and leg veins during a simulated longhaul flight. Thromb Res. 2007;119(3):293-300. 40. Sokolov EI, Volkova VI, Kostenko VP. Reactivity of the blood clotting system in healthy subjects during emotional stress. Hum Physiol. 1978;4(6):843-846. 41. Felfernig M, Kubricht V, Zimpfer M, Kozek S, Hoerauf K, Blaicher AM. Hypothermia and hyperthermia decrease the anticoagulant potency of low molecular weight heparin measured with thrombelastgraphy. Eur Surg. 2006;38(3):213-216. 42. Chavez JJ, Foley DE, Snider CC, et al. A novel thrombelastograph1 tissue factor/kaolin assay of activated clotting times for monitoring heparin anticoagulation during cardiopulmonary bypass. Anesth Analg. 2004;99(5):1290-1294. 43. Hoffman M, Monroe III DM. A cell-based model of hemostasis. Thromb Haemost. 2001;85(6):958-965. 44. Gonzalez E, Pieracci FM, Moore EE, Kashuk JL. Coagulation abnormalities in the trauma patient: the role of point-of-care thromboelastography. Semin Thromb Hemost. 2010;36 (7):723-737. 45. Andersen KL. The cardiovascular system in exercise In: Falls HB, ed. Exercise Physiology. New York and London: Academic Press; 1968:79-128. 46. Persky AM, Eddington ND, Derendorf H. A review of the effects of chronic exercise and physical fitness level on resting pharmacokinetics. Int J Clin Pharmacol Ther. 2003;41(11):504-516. 47. Novosadova´ J. The changes in hematocrit, hemoglobin, plasma volume and proteins during and after different types of exercise. Eur J Appl Physiol. 1977;36(3):223-230. 48. El-Sayed MS, Sale C, Jones PGW, Chester M. Blood hemostasis in exercise and training. Med Sci Sports Exerc. 2000;32(5):918-925. 49. Fras Z, Keber D, Chandler WL. The effect of submaximal exercise on fibrinolysis. Blood Coagul Fibrinolysis. 2004;15(3): 227-234. 50. Poller L, Priest CM, Thomson JM. Platelet aggregation and strenuous exercise. J Physiol (Lond). 1971;213(3):525-531.

51. Ikkala E, Myllyla¨ G, Sarajas HSS. Hæmostatic changes associated with exercise. Nature. 1963;199(4892):459-461. 52. Campeau S, Liberzon I, Morilak D, Ressler K. Stress modulation of cognitive and affective processes. Stress. 2011;14(5):503-519. 53. Oei NYL, Everaerd WTAM, Elzinga BM, van Well S, Bermond B. Psychosocial stress impairs working memory at high loads: an association with cortisol levels and memory retrieval. Stress. 2006;9(3):133-141. 54. Weiss C, Seitel G, Ba¨rtsch P. Coagulation and fibrinolysis after moderate and very heavy exercise in healthy male subjects. Med Sci Sports Exerc. 1998;30(2):246-251. 55. Kratz A, Wood MJ, Siegel AJ, Hiers JR, Van Cott EM. Effects of marathon running on platelet activation markers: direct evidence for in vivo platelet activation. Am J Clin Pathol. 2006;125(2):296-300. 56. Preckel D, Von Ka¨nel R. Regulation of hemostasis by the sympathetic nervous system: any contribution to coronary artery disease? Heart Drug. 2004;4(3):123-130. 57. Strother SV, Bull JMC, Branham SA. Activation of coagulation during therapeutic whole body hyperthermia. Thromb Res. 1986;43(3):353-360. 58. Wolberg AS, Meng ZH, Monroe III DM, Hoffman M. A systematic evaluation of the effect of temperature on coagulation enzyme activity and platelet function. J Trauma. 2004;56(6):1221-1228. 59. Bouchama A, Bridey F, Hammami MM, et al. Activation of coagulation and fibrinolysis in heatstroke. Thromb Haemost. 1996;76 (6):909-915. 60. Al-Mashhadani SA, Gader AGMA, Al Harthi SS, Kangav D, Shaheen FA, Bogus F. The coagulopathy of heat stroke: alterations in coagulation and fibrinolysis in heat stroke patients during the pilgrimage (haj) to makkah. Blood Coagul Fibrinolysis. 1994; 5(5):731-736. 61. Frank SM. Consequences of hypothermia. Curr Anaesth Crit Care. 2001;12(2):79-86. 62. Boldt L-H, Fraszl W, Ro¨cker L, et al. Changes in the haemostatic system after thermoneutral and hyperthermic water immersion. Eur J Appl Physiol. 2008;102(5):547-554. 63. Tamura K, Kubota K, Kurabayashi H, Shirakura T. Effects of hyperthermal stress on the fibrinolytic system. Int J Hyperthermia. 1996;12(1):31-36. 64. Deguci A, Karitani Y, Hamaguchi H, et al. Effects of spa bathing on blood coagulation and fibrinolysis. J Jpn Assoc Phys Med Balneol Climatol. 1989;52(2):73-78. 65. Maruyama Y, Takenaga S, Matsumoto S, Ohkatsu Y, Uchida J, Maruyama I. The effects of hot spring bathing on blood coagulation and fibrinolytic systems. J Jpn Assoc Phys Med Balneol Climatol. 1989;52(2):104-109. 66. Axelrod YK, Diringer MN. Temperature management in acute neurologic disorders. Neurol Clin. 2008;26(2):585-603. 67. Bouchama A, Knochel JP. Heat stroke. N Engl J Med. 2002; 346(25):1978-1988. 68. Cavallini M, Preis FWB, Casati A. Effects of mild hypothermia on blood coagulation in patients undergoing elective plastic surgery. Plast Reconstr Surg. 2005;116(1):316-321. 69. Arpino PA, Greer DM. Practical pharmacologic aspects of therapeutic hypothermia after cardiac arrest. Pharmacotherapy. 2008; 28(1):102-111.

Downloaded from cat.sagepub.com by guest on November 16, 2015

Peng and Rhind

511

70. Rohrer MJ, Natale AM. Effect of hypothermia on the coagulation cascade. Crit Care Med. 1992;20(10):1402-1405. 71. Yeh CJ, Chan P, Pan WH. Values of blood coagulating factors vary with ambient temperature: the cardiovascular disease risk factor two-township study in taiwan. Chin J Physiol. 1996;39(2):111-116. 72. Bromundt V, Ko¨ster M, Georgiev-Kill A, et al. Sleep–wake cycles and cognitive functioning in schizophrenia. Br J Psychiatry. 2011;198(4):269-276. 73. Differding JA, Underwood SJ, Van PY, Khaki RA, Spoerke NJ, Schreiber MA. First place residents’ competition: trauma induces a hypercoagulable state that is resistant to hypothermia as measured by thrombelastogram. Am J Surg. 2011;201(5):585-589. 74. Spiel AO, Kliegel A, Janata A, et al. Hemostasis in cardiac arrest patients treated with mild hypothermia initiated by cold fluids. Resuscitation. 2009;80(7):762-765. 75. Madsen J, Hink J, Hyldegaard O. Diving physiology and pathophysiology. Clin Physiol. 1994;14(6):597-626. 76. Bosco G, Yang Z, Savini F, et al. Environmental stress on divinginduced platelet activation. Undersea Hyperb Med. 2001;28(4): 207-211. 77. Olszan´ski R, Radziwon P, Baj Z, et al. Changes in the extrinsic and intrinsic coagulation pathways in humans after decompression following saturation diving. Blood Coagul Fibrinolysis. 2001;12(4):269-274. 78. Radziwon P, Olszanski R, Tomaszewski R, et al. Decreased levels of PAI-1 and alpha2-antiplasmin contribute to enhanced fibrinolytic activity in divers. Thromb Res. 2007;121(2):235-240. 79. Olszan´ski R, Radziwon P, Galar M, Kłos R, Kłoczko J. Diving up to 60 m depth followed by decompression has no effect on pro-enzyme and total thrombin activatable fibrinolysis inhibitor antigen concentration. Blood Coagul Fibrinolysis. 2003;14(7): 659-661. 80. Olszan´ski R, Radziwon P, Piszcz J, et al.. Activation of platelets and fibrinolysis induced by saturated air dives. Aviat Space Environ Med. 2010;81(6):585-588. 81. Bowbrick VA, Mikhailidis DP, Stansby GM. The use of citrated whole blood in thromboelastography. Anesth Analg. 2000;90(5): 1086-1088. 82. Zambruni A, Thalheimer U, Leandro G, Perry D, Burroughs AK. Thromboelastography with citrated blood: comparability with native blood, stability of citrate storage and effect of repeated sampling. Blood Coagul Fibrinolysis. 2004;15(1):103-107. 83. Camenzind V, Bombeli T, Seifert B, et al. Citrate storage affects thrombelastography analysis. Anesthesiology. 2000; 92(5):1242-1249. 84. Van Veen JJ, Makris M. Altitude and coagulation activation: does going high provoke thrombosis? Acta Haematol. 2008;119(3): 156-157. 85. Smallman DP, McBratney CM, Olsen CH, Slogic KM, Henderson CJ. Quantification of the 5-year incidence of thromboembolic events in U.S. Air force academy cadets in comparison to the U. S. Naval and military academies. Mil Med. 2011;176(2):209-213. 86. Ritschel W, Paulos C, Arancibia A, Agrawal MA, Wetzelsberger KM, Lu¨cker PW. Pharmacokinetics of acetazolamide in healthy volunteers after short- and long-term exposure to high altitude. J Clin Pharmacol. 1998;38(6):533-539.

87. Heistad D, Wheeler R, Aoki V. Reflex cardiovascular responses after 36 hr of hypoxia. Am J Physiol. 1971;220(6):1673-1676. 88. Doyle JT, Wilson JS, Warren JV. The pulmonary vascular responses to short term hypoxia in human subjects. Circulations. 1952;5(2):263-270. 89. Mannucci PM, Gringeri A, Peyvandi F, Di Paolantonio T, Mariani G. Short-term exposure to high altitude causes coagulation activation and inhibits fibrinolysis. Thromb Haemost. 2002;87(2):342-343. 90. Hefti JP, Risch L, Hefti U, et al. Changes of coagulation parameters during high altitude expedition. Swiss Medical Weekly. 2010;140(7-8):111-117. 91. Kotwal J, Apte CV, Kotwal A, Mukherjee B, Jayaram J. High altitude: a hypercoagulable state: results of a prospective cohort study. Thromb Res. 2007;120(3):391-397. 92. Ba¨rtsch P. How thrombogenic is hypoxia? JAMA. 2006;295(19): 2297-2299. 93. Toff WD, Jones CI, Ford I, et al. Effect of hypobaric hypoxia, simulating conditions during long-haul air travel, on coagulation, fibrinolysis, platelet function, and endothelial activation. JAMA. 2006;295(19):2251-2261. 94. Ma¨ntysaari M, Joutsi-Korhonen L, Siimes MA, et al. Unaltered blood coagulation and platelet function in healthy subjects exposed to acute hypoxia. Aviat Space Environ Med. 2011;82(7):699-703. 95. Schiffer T, Stru¨der HK, Predel HG, Hollmann W. Effects of mild leg exercise in a seated position on haemostatic parameters under normobaric hypoxic conditions. Can J Appl Physiol. 2005;30(6):708-722. 96. Crosby A, Talbot NP, Harrison P, Keeling D, Robbins PA. Relation between acute hypoxia and activation of coagulation in human beings. Lancet. 2003;361(9376):2207-2208. 97. Bendz B, Rostrup M, Sevre K, Andersen TO, Sandset PM. Association between acute hypobaric hypoxia and activation of coagulation in human beings. Lancet. 2000;356(9242): 1657-1658. 98. Schobersberger W, Schobersberger B, Mittermayr M, Fries D, Streif W. Air travel, hypobaric hypoxia, and prothrombotic changes. JAMA. 2006;296(19):2313-2314. 99. Schobersberger W, Mittermayr M, Innerhofer P, et al. Coagulation changes and edema formation during long-distance bus travel. Blood Coagul Fibrinolysis. 2004;15(5):419-425. 100. Park MS, Martini WZ, Dubick MA, et al. Thromboelastography as a better indicator of hypercoagulable state after injury than prothrombin time or activated partial thromboplastin time. J Trauma. 2009;67(2):266-275. 101. Kashuk JL, Moore EE. The emerging role of rapid thromboelastography in trauma care. J Trauma. 2009;67(2):417-418. 102. Wikkelsoe AJ, Afshari A, Wetterslev J, Brok J, Moeller AM. Monitoring patients at risk of massive transfusion with thrombelastography or thromboelastometry: a systematic review. Acta Anaesthesiol Scand. 2011;55(10):1174-1189. 103. Kahlon A, Grabell J, Tuttle A, et al. Quantitation of changes in vwf and fviii following elective orthopedic surgery in normal individuals. Blood. 2009;114(22):531-532. 104. Daudel F, Kessler U, Folly H, Lienert JS, Takala J, Jakob SM. Thromboelastometry for the assessment of coagulation

Downloaded from cat.sagepub.com by guest on November 16, 2015

512

105.

106. 107.

108.

109.

110.

111.

112.

113.

114.

115.

116.

117.

118.

119.

Clinical and Applied Thrombosis/Hemostasis 21(6) abnormalities in early and established adult sepsis: a prospective cohort study. Critical Care. 2009;13(2):R42. Martini WZ, Pusateri AE, Uscilowicz JM, Delgado AV, Holcomb JB. Independent contributions of hypothermia and acidosis to coagulopathy in swine. J Trauma Acute Care Surg. 2005;58(5):1002-1010. Haas T. Point of care diagnostic: thromboelastometry (ROTEM1). Wien Klin Wochenschr. 2010;122 (suppl 5):S19-S20. Leemann H, Lustenberger T, Talving P, et al. The role of rotation thromboelastometry in early prediction of massive transfusion. J Trauma. 2010;69(6):1403-1409. Go¨rlinger K, Dirkmann D, Hanke AA, et al. First-line therapy with coagulation factor concentrates combined with point-of-care coagulation testing is associated with decreased allogeneic blood transfusion in cardiovascular surgery: a retrospective, singlecenter cohort study. Anesthesiology. 2011;115(6):1179-1191. von Ka¨nel R, Mills PJ, Fainman C, Dimsdale JE. Effects of psychological stress and psychiatric disorders on blood coagulation and fibrinolysis: a biobehavioral pathway to coronary artery disease? Psychosom Med. 2001;63(4):531-544. Zgraggen L, Fischer JE, Mischler K, Preckel D, Kudielka BM, von Ka¨nel R. Relationship between hemoconcentration and blood coagulation responses to acute mental stress. Thromb Res. 2005;115(3):175-183. Wirtz PH, Ehlert U, Emini L, et al. Anticipatory cognitive stress appraisal and the acute procoagulant stress response in men Psychosom Med. 2006;68(6):851-858. von Ka¨nel R, Kudielka BM, Haeberli A, Stutz M, Fischer JE, Patterson SM. Prothrombotic changes with acute psychological stress: combined effect of hemoconcentration and genuine coagulation activation. Thromb Res. 2009;123(4):622-630. Geiser F, Meier C, Wegener I, et al. Association between anxiety and factors of coagulation and fibrinolysis. Psychother Psychosom. 2008;77(6):377-383. von Ka¨nel R, Bellingrath S, Kudielka BM. Association of vital exhaustion and depressive symptoms with changes in fibrin Ddimer to acute psychosocial stress. J Psychosom Res. 2009; 67(1):93-101. von Ka¨nel R, Bellingrath S, Kudielka BM. Association between longitudinal changes in depressive symptoms and plasma fibrinogen levels in school teachers. Psychophysiology. 2009;46(3): 473-480. von Ka¨nel R, Bellingrath S, Kudielka BM. Overcommitment but not effort-reward imbalance relates to stress-induced coagulation changes in teachers. Ann Behav Med. 2009;37(1):20-28. von Ka¨nel R, Hepp U, Buddeberg C, et al. Altered blood coagulation in patients with posttraumatic stress disorder. Psychosom Med. 2006;68(4):598-604. Von Ka¨nel R, Kudielka BM, Preckel D, et al. Opposite effect of negative and positive affect on stress procoagulant reactivity. Physiol Behav. 2005;86(1-2):61-68. Cohen BE, Marmar C, Ren L, Bertenthal D, Seal KH. Association of cardiovascular risk factors with mental health diagnoses

120.

121.

122.

123.

124.

125.

126.

127.

128.

129.

130.

131.

132. 133.

134.

135.

136.

in Iraq and Afghanistan war veterans using VA health care. JAMA. 2009;302(5):489-492. Ahmadi N, Hajsadeghi F, Mirshkarlo HB, Budoff M, Yehuda R, Ebrahimi R. Post-traumatic stress disorder, coronary atherosclerosis, and mortality. Am J Cardiol. 2011;108(1):29-33. DeLoughery TG, Robertson DG, Smith CA, Sauer D. Moderate hypoxia suppresses exercise-induced procoagulant changes. Br J Haematol. 2004;125(3):369-372. McNulty PAF. Reported stressors and health care needs of active duty navy personnel during three phases of deployment in support of the war in Iraq. Mil Med. 2005;170(6):530-535. Quan SF, Shaw PJ, Naidoo N, Haeggstro¨m E, Krueger JM, Church GM. Panel discussion: can there be a biomarker for sleepiness? J Clin Sleep Med. 2011;7(5 suppl):S45-S48. Biondi G, Farrace S, Mameli G, Marongiu F. Is there a hypercoagulable state in military fighter pilots? Aviat Space Environ Med. 1996;67(6):568-571. Blundo G, Paolucci G, Rota P. Ascertainment of hemostasis disorders in air force personnel. Riv Med Aeronaut Spaz. 1975; 38(4):427-432. Wright HE, Selkirk GA, Rhind SG, et al. Peripheral markers of central fatigue in trained and untrained during uncompensable heat stress. Eur J Appl Physiol. 2012;112(3):1047-1057. Ramstrom S. Clotting time analysis of citrated blood samples is strongly affected by the tube used for blood sampling. Blood Coagul Fibrinolysis. 2005;16(6):447-452. Samama C, Ozier Y. Near-patient testing of haemostasis in the operating theatre: an approach to appropriate use of blood in surgery. Vox Sang. 2003;84:251-255. Srinivasa V, Gilbertson L, Bhavani-Shankar K. Thromboelastography: where is it and where is it heading? Int Anesthesiol Clin. 2001;39(1):35-49. Sorensen B, Johansen P, Christiansen K, Woelke M, Ingerslev J. Whole blood coagulation thrombelastographic profiles employing minimal tissue factor activation. J Thromb Haemost. 2003; 1(3):551-558. McNulty SE, Maguire DP, Arai LD. An alternate method for calibrating the thrombelastograph. J Cardiothorac Vasc Anesth. 1998;12(6):639-641. Grant PJ. Hormonal regulation of the acute haemostatic response to stress. Blood Coagul Fibrinolysis. 1990;1(3):299-306. Toukh M, Gordon SP, Othman M. Construction noise induces hypercoagulability and elevated plasma corticosteroids in rats. Clin Appl Thromb Hemost. 2014;20(7):710-715. El-Sayed MS. Effects of exercise on blood coagulation, fibrinolysis and platelet aggregation. Sports Med. 1996;22(5): 282-298. Austin AW, Patterson SM, von Ka¨nel R. Hemoconcentration and hemostasis during acute stress: interacting and independent effects. Ann Behav Med. 2011;42(2):153-173. Zipperle J, Schlimp CJ, Holnthoner W, et al. A novel coagulation assay incorporating adherent endothelial cells in thromboelastometry. Thromb Haemost. 2007;97(6):988-997.

Downloaded from cat.sagepub.com by guest on November 16, 2015