The Effects of a Transcontinental Flight on Markers of Coagulation and Fibrinolysis in Healthy Men After Vigorous Physical Activity

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The effects of a transcontinental ﬂight on markers of coagulation and ﬁbrinolysis in healthy men after vigorous physical activity

Article in Chronobiology International · February 2017 DOI: 10.1080/07420528.2016.1247851

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The effects of a transcontinental flight on markers of coagulation and fibrinolysis in healthy men after vigorous physical activity

Brian R. Kupchak, William J. Kraemer, David R. Hooper, Cathy Saenz, Lexie L. Dulkis, Paul J. Secola, Lee E. Brown, Andrew J. Galpin, Jared W. Coburn, William H. DuPont, Lydia K. Caldwell, Jeff S. Volek & Carl M. Maresh

To cite this article: Brian R. Kupchak, William J. Kraemer, David R. Hooper, Cathy Saenz, Lexie L. Dulkis, Paul J. Secola, Lee E. Brown, Andrew J. Galpin, Jared W. Coburn, William H. DuPont, Lydia K. Caldwell, Jeff S. Volek & Carl M. Maresh (2016): The effects of a transcontinental flight on markers of coagulation and fibrinolysis in healthy men after vigorous physical activity, Chronobiology International, DOI: 10.1080/07420528.2016.1247851

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Download by: [Brian Kupchak] Date: 06 November 2016, At: 10:57 CHRONOBIOLOGY INTERNATIONAL http://dx.doi.org/10.1080/07420528.2016.1247851

The effects of a transcontinental flight on markers of coagulation and fibrinolysis in healthy men after vigorous physical activity Brian R. Kupchaka,c, William J. Kraemerb, David R. Hooperd, Cathy Saenzb, Lexie L. Dulkisc, Paul J. Secolac, Lee E. Browne, Andrew J. Galpine, Jared W. Coburne, William H. DuPontb, Lydia K. Caldwellb, Jeff S. Volekb, and Carl M. Mareshb aDepartment of Military and Emergency Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, USA; bDepartment of Human Sciences, The Ohio State University, Columbus, OH, USA; cDepartment of Kinesiology, University of Connecticut, Storrs, CT, USA; dDepartment of Health Sciences, Armstrong State University, Savannah, GA, USA; eDepartment of Kinesiology, California State University- Fullerton, Fullerton, CA, USA

ABSTRACT ARTICLE HISTORY Purpose: Athletes and military service members are known to undergo strenuous exercise and some- Received 6 August 2016 times have to take long haul flights soon afterwards; however, its combined effect on many physiolo- Revised 20 September 2016 gical functions is relatively unknown. Therefore, we examined the combined effects of a full-body Accepted 10 October 2016 muscle-damaging workout and transcontinental flight on coagulation and fibrinolysis in healthy, KEYWORDS resistance trained men. We also determined the efficacy of a full-body compression garment in limiting coagulation; compression their coagulation responses. Materials and Methods: Nineteen healthy, resistance trained men flew from apparel; exercise; fibrinoly- Connecticut (CT) to California (CA), performed a full-body muscle-damaging workout and then flew sis; long-haul flights back to CT. Ten participants wore full-body compression garments (FCG) for the duration of both flights and during all other portions of the study except during workouts and blood draws, when they wore loose clothing. Nine controls wore loose clothing (CON) throughout the study. Blood samples were collected at 16 h and 3 h before the initial flight from CT, immediately after landing in CA, immediately before and immediately after the full-body workout in CA, immediately after landing in CT, and at 29 h after landing in CT. Plasma markers of coagulation included activated partial thromboplastin time (aPTT), prothrombin fragment 1+2 (PTF 1+2) and thrombin ant-thrombin (TAT). Markers of the fibrinolytic system included the tissue plasmigen activator (tPA), plasminogen activator inhibitor-1 (PAI-1) and D-Dimer. Results: Both FCG and CON groups exhibited a faster aPTT after the full-body workout compared to all other time points. Thrombin generation markers, TAT and PTF 1+2, increased significantly after the full-body workout and immediately after landing in CT. Additionally, tPA increased after the full-body workout, while PAI-1 increased before the flight to CA, after the full-body workout, and just after landing in CT. The D-Dimer significantly increased after the full-body workout and at 29 h post-flightinbothgroups.Betweengroups,aPTTwas significantly faster and TAT elevated with the CON group at 29 h post-flight. Also, PAI-1 demonstrated higher concentrations immediately after landing in CT for the CON group. Conclusion:Afull-bodymuscle-damagingworkout in conjunction with a trans- continental flight activated the coagulation and fibrinolytic systems. Additionally, wearing a full-body compression garment may limit coagulation following a workout through the recovery period.

Introduction More than 2 billion passengers fly annually world- et al., 1988). Additionally, the long periods inside wide, with estimated 300 million flights considered an airplane may lead to dehydration and hemo- long-haul flights (> 5 h) (Anning, 2005). The concentration (Moyses, 1988). Long-haul travel combination of long-haul flights and limited thus increases the risk of deep vein thrombosis space available for passengers traveling in econ- (DVT) between 2- and 4-fold (Schwarz et al., omy class forces many travelers into periods of 2003). Nonetheless, previous research regarding prolonged sitting, which in turn reduces venous the effects of long haul flights on coagulation and return from the lower extremities due to compres- fibrinolytic processes has yielded only conflicting sion of popliteal and femoral veins (Cruickshank results on blood parameters, including an increase

CONTACT William J. Kraemer [email protected] Department of Human Sciences, The Ohio State University, A054 PAES Building, 305 Annie & John Glenn Avenue, Columbus, OH 43210, USA. Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/icbi. © 2016 Taylor & Francis 2 B. R. KUPCHAK ET AL. in thrombin generation or fibrinolytic parameters 93% in healthy individuals (Toff et al., 2006). (Schreijer et al., 2006), a decrease (Boccalon et al., In addition, the atmosphere inside commercial air- 2005), or no changes (Schobersberger et al., 2002). liners is typically very dry, usually around 1% Regular endurance exercise, recommended for relative humidity, which can cause increased per- the avoidance of thrombotic events (Sacco et al., spiration rates. The environmental factors inside 2006), may also protect against the formation of the aircraft coupled with reduced access to ad lib. deep vein thrombosis and pulmonary embolism fluid intake can lead to dehydration and hemo- (Gough et al., 1992). Both acute endurance exercise concentration. Yet, although a synergistic effect of (Menzel and Hilberg, 2011) (marathon) and resis- these three risk factors may contribute to the for- tance exercise (Kupchak et al., 2013a) (6 sets of 10 mation of VTE, taken independently they likely do repetitions of squats) can activate the coagulation not explain clot formation during air travel cascade, through stripping away at the endothelium (Schreijer et al., 2008). baselayer through increased blood viscosity, exhib- Traveler-related risk factors can also play a role in ited by a decrease in activated partial thromboplas- the development of VTE. Many of these risk factors, tin time (aPTT) (a measure of the intrinsic and including being overweight or obese (Body Mass common pathways) and increases in markers of Index (BMI) ≥ 25 kg∙m2), having a history of VTE, thrombin formation (prothrombin fragments 1 recent major surgery, or exercise that causes muscle and 2, PTF1+2 and TAT). Such exercises also acti- damage can increase the odds of clot formation dur- vate the fibrinolytic systems, as seen by increases in ing a flight (Landgraf et al., 2002).Themorerisk the tissue plasminogen activator (tPA) (enzyme factors that apply to an individual, the greater his/ that catalyzes the conversion of plasminogen to her chance of developing a thrombosis through flight. plasmin, the major enzyme responsible for clot Despite the increased risk of DVT after long-haul breakdown), plasminogen activator inhibitor flights (Kuipers et al., 2006), anticoagulant therapy (PAI-1) (main inhibitor of tPA) and D-Dimer (a carries its own risks (bleeding). Use of prophylaxic

marker of fibrin degradation). Even with the activa- anticoagulants (Vitamin K antagonists (Coumadin) tion of both systems, however, most healthy indivi- lower levels of factors II, VII, IX and X). The hepar- duals remain in a state of hemostatic balance. ins and fondaparinux work indirectly through Previous studies have shown an increased risk antithrombin. Rivaroxaban and apixaban directly of venous thromboembolism (VTE), an absolute inhibit Factor Xa and several anticoagulants risk of 1 in 4600, for flights over a 4-h duration directly inhibit thrombin), which is therefore not (Kuipers et al., 2007). Additionally, other studies typically justified. Yet, the balance of risk may be have shown association between air travel time different for athletes and military warfighters who and VTE (Collins et al., 1979; Homans, 1954). undergo strenuous exercise soon before they travel Many factors contribute to VTE including both for long distances. Since vigorous exercise can also cabin-related and traveler-related risk factors. affect hemostasis, a long-haul flight coupled with a The three main cabin-related risk factors full body muscle-damaging workout can disrupt known to increase the risk of developing VTE hemostatic balance in favor of coagulation. include extended sitting (long periods of immo- Use of a full-body compression garment allows bility), hypoxia and low humidity. Sitting for an the traveler to avoid many of the risks of pharma- extended time (even < 3 h) is associated with a cologic prophylaxis and requires little instruction reduced velocity of venous blood flow in lower or training. Previous studies have demonstrated extremities (Wright & Osborne, 1952)andan that compression gear such as compression stock- increase in blood viscosity (Landgraf et al., 1994), ings have a positive effect on limiting the forma- a known risk factor for VTE (Dormandy & tion of DVT (Sachdeva et al., 2014). Compression Edelman, 1973). The decreased air pressure and stockings have also been used by runners to hypoxia in the airline cabin can limit fibrinolytic enhance recovery from an athletic performance activity and lead to venous stasis (Maher et al., (Beliard et al., 2015), and there is anecdotal evi- 1976). At the air pressure maintained for transcon- dence that compression gear diminishes their DVT tinental US flights, arterial oxygen saturation is risk (Hadfield, 2013). CHRONOBIOLOGY INTERNATIONAL 3

Another factor in our study is diurnal variation for our findings from this particular study, includ- of both coagulation and fibrinolytic markers: our ing experimental understanding of our systems study takes place over several days, with blood interpretation. sampling performed during different times of the day. Although aPTT, PTF 1+2 and TAT are gen- Subjects erally shown to have low biological variability Healthy males between the ages of 18 and 35 years (<10%), the fibrinolytic parameters (tPA) and completed a medical history and physical activity their inhibitor (PAI-1) have a higher degree of questionnaire and were screened by a physician to variability. tPA is characterized by an early morn- ensure eligibility. All subjects were involved with ing drop and a peak in the afternoon, while PAI-1 progressive heavy resistance training with comple- typically exhibits the opposite time-course mentary endurance training, each performed three (Siahkouhian et al., 2013). Furthermore, studies to four times a week. Resistance training was char- of diurnal variation in D-Dimer concentrations acterized by periodized, multiple sets, whole body, have yielded conflicting results (Iverson et al., large muscle group exercises with targets for mus- 2002; Trifiletti et al., 2000). cle strength and size. Subjects were mostly former The effects of long-haul travel on coagulation high school and college athletes, who participated and fibrinolyctic parameters have been ambiguous in a variety of sports including football, basketball, (Boccalon et al. 2005; Schobersberger et al. 2002; track and field, wrestling, and baseball and some Schreijer et al., 2006). Still less is known about the were former military service members who were hemostatic effects following a trans-continental accustomed with intense weekly physical training flight preceded by a full-body, muscle-damaging routines. Subjects were non-tobacco users and workout such as those typical of athletes and mili- reported no history of cardiovascular disease. tary service members. The purpose of this study is Exclusion criteria included the following to limit therefore to determine the coagulant and fibrinoly- confounding effects on the variables being mea-

tic responses from a full-body, muscle-damaging sured or ability to complete exercise protocol: 1) workout followed by a transcontinental flight in diagnosis of liver, kidney, or gastrointestinal dis- physically active young adults. A secondary aim of ease, or severe metabolic or endocrine disorder; 2) the study is to investigate the utility of wearing a history of blood clotting disorders or venous full-body compression garment in reducing coagu- thromboembolisms; 3) reported use of choles- lation activation. We hypothesized that exercise- terol-lowering, blood pressure, or nonsteroidal induced activation of the coagulation and fibrino- anti-inflammatory medications; 4) reported use lytic systems would be augmented after a trans- of anticoagulant medications (e.g. Coumadin); 5) continental flight and that wearing a full-body com- reported use of hormonal substances including pression garment during travel would limit hemo- testosterone, anabolic steroids, or growth hor- static responses. mones; 6) current musculoskeletal or orthopedic injuries; 7) fear of flying and 8) other conditions or medications considered by the medical monitor to Materials and methods have potential impact on participant safety or the results of the investigation. The Institutional Experimental approach Review Board for use of human subjects in This study was part of a larger investigation of jet- research at the University of Connecticut approved lag and trans-continental flight stress and recovery this study. All subjects provided written informed (Kraemer et al., 2016). In this study, we focused on consent after having the study risks and benefits the effects of long-wear compression garments on carefully explained to them and their questions the coagulation and fibrinolytic systems and their answered. role in recovery. We overlaid our analyses for this study on the basic format of the primary investiga- Experimental design tion. We therefore provide here an overview of The study involved a battery of physiological tests, results from the larger investigation as context a muscle-damaging resistance exercise protocol, 4 B. R. KUPCHAK ET AL.

Figure 1. Experimental timeline. BDL, Bradley International Airport (in Connecticut, CT); LAX, Los Angeles Internal Airport (in California, CA); BL, Baseline, 1300 EDT (Day 1); 1CT, morning before flight from BDL to LAX, 0600 EDT (Day 2 in CT); 2CA, immediately after the flight, 1500 PDT (Day 2 in CA); 3CA, the next day immediately before full-body workout, 1300 PDT (Day 3 in CA); 4CA, immediately post-workout, 1500 PDT (Day 3 in CA); 5CT, immediately post-flight to CT, 0900 EDT (Day 4 in CT); 6CT, 1 day post-flight, 1300 EDT (Day 5 in CT). Syringe represents blood draw. Action figure represents muscle-damaging full-body workout protocol (Day 3, 1400 PDT). and two trans-continental flights over five days min) and utilize lower water temperatures (tem- (Figure 1). Twenty subjects were assigned by perature was not monitored) when bathing or Ponderel Index (Babar, 2016); pairs were then showering after completing the exercise protocol; randomly split into two groups at study enroll- to abstain from any strenuous or moderate physi- ment: the intervention group (FCG) wore a full- cal activity (i.e. lifting, running) other than those

body compression garment throughout the study activities required for tasks of daily living; and to except during workouts and blood draws, when use no pain-relieving modalities including heat, they wore loose-fitting clothes. Controls (CON) ice, or massage. In addition, a registered dietitian wore loose-fitting clothes throughout the entire screened subjects for any unusual (i.e. ketogenic, study. Since one enrolled subject could not make low fat diets) diets or supplements which might the flight, nineteen recreationally-trained men (i.e. have compromised variables measured in the with weight training and endurance training for study and monitored food intake during their par- over 6 months) participated in the study: a ten- ticipation by utilizing dietary logs. Meals were not subject compression group (FCG) and a nine-sub- uniform for the subjects during the study, but each ject control group (Table 1). subject ate approximately the same time. No For the duration of the study, subjects were attempt was made to limit caffeine ingestion, as asked not to ingest any alcohol; to refrain from only water was allowed 4 h prior to testing, and taking any oral pain medications, including only normal caffeine ingestion was observed. NSAIDs; and to abstain from heavy lifting for a period beginning 3 days prior to till the end of the Familiarization study. Subjects were also asked to limit time (<5 Subjects were screened, consented to the study, and had their anthropometrics recorded at the University of Connecticut (UConn) Human Table 1. Subject characteristics. Performance Laboratory (HPL). The body height CON FCG was recorded to the nearest 0.1 cm using a stadi- Age, yr 23.2 ± 2.3 23.1 ± 2.4 Height, cm 177.5 ± 6.3 174.8 ± 5.3 ometer (Seca, Hamburg, Germany) while the sub- Body Mass, kg 84.3 ± 9.0 84.9 ± 10.1 jects were not wearing shoes. Body mass was BMI, kg∙m2–1 26.8 ± 2.8 27.8 ± 3.2 % Body Fat 15.1 ± 6.4 15.3 ± 6.0 measured to the nearest 0.1 kg on a calibrated Values are means and standard deviation; CON, Control group; FCG, digital scale (OHAUS Corp., Florham Park, NJ) Compression Garment group; CO, n = 9; CG, n = 10. with subjects wearing only a t-shirt and shorts. CHRONOBIOLOGY INTERNATIONAL 5

BMI was calculated as body mass (kg)/height (m2). transported to the California State University- The body composition (% body fat) was measured Fullerton (CSUF) HPL by coach bus with a travel by a trained technician via the 3-site Jackson– time of 1 h. At the CSUF HPL, the FCG group Pollock skinfold technique (Jackson & Pollock, removed their compression garments and all subjects 1978). All subjects were measured by the same gave a blood and urine sample (after the flight to CA/ technician using a caliper (Bodycare Harpenden 2CA) at 1500 PDT. FCG subjects put their compres- Caliper, England) at the chest, abdomen and sion garments back on immediately after the blood thigh. Subjects were then familiarized with the draw. All subjects were then transported to a hotel, study’s muscle-damaging protocol. wheretheywereinstructedtorelaxandstaywithin walking distance of the hotel. Participants were also Clothing instructed as to turn in by 2200 PDT to get ready for Subjects were assigned by the Ponderel Index the next day’sevents.FCGsubjectsworetheircom- (Mass/Height3) (measure of leanness, and shown pression garments to sleep. to have a lower false positive rate in athletes) Day 3: Subjects awoke between 0700 to 0800 (Babar, 2016) and then randomized into either the PDT and were then instructed to rest until testing. compression garment (FCG) group or the control At 1300 PDT, subjects were transported to the (CON) group. The compression garment used was CSUF HPL. FCG subjects removed the compres- the UnderArmour Recharge™ garment (75% nylon sion garments and put on loose-fitting clothing for and 25% spandex) [UnderArmour, Baltimore, MD, testing and the full-body, muscle-damaging work- USA], which consisted of a long-sleeved shirt and out. All subjects had their hydration status leggings. These garments have been shown to effec- obtained and a blood sample was taken (before tively improve recovery after high-intensity resis- the full-body workout/3CA). Subjects then per- tance training workouts (Kraemer et al., 2010). formed the muscle-damaging physical testing pro- Compression garments were worn at all times dur- tocol (1400 PDT). The protocol was performed at

ing the study (including sleep) except during the an outdoor grass athletic field on the campus of muscle-damaging workout, during brief showers, California State University – Fullerton. Prior to and blood draws. administration of the exercise protocol, each participant performed a warm-up protocol that con- Timeline sisted of 5 min on a cycle ergometer with light Day 1: Subjects arrived at UConn HPL at 1300 resistance and a constant speed of 60 rpm, fol- EDT and provided a urine sample to determine lowed by a series of standard dynamic stretches hydration status. Hydration status was measured that included forward lunges, lateral lunges, knee using a refractometer. A urine specific gravity of hugs, quad pulls and straight-leg march. The par- <1.020 was used to define adequate hydration. ticipants then completed the exercise protocol, Subjects were then seated for 10 min and provided which consisted of the following exercises selected a blood sample (baseline/BL). to induce muscle damage (Kraemer et al., 2016): 5 Day 2: Subjects arrived at the UConn HPL 0600 sets of 10 repeated countermovement jumps, 5 sets EDT and provided a urine and blood sample (before of 10 plyometric push-ups, 5 sets of 10 Nordic the flight to CA/1CT). Subjects then put on a com- hamstring curls and 5 sets of 10 standard pushups. pression garment or loose-fitting clothing. All exercises were performed with 60 s rest Following testing, at 0600 EDT, participants were between sets. These exercises were followed by a transported by bus for 30 min to Bradley repeated sprint protocol: subjects performed 15–20 International Airport (BDL) in Hartford, CT for a m sprints with a maximum of 10 m deceleration departing flight at 0900 EDT. The flight was direct to distance (thereby producing eccentric damage). Los Angeles International Airport (LAX) flying on a Sprints were performed every minute, with a rest Boeing 737–800 airliner with participants traveling in period between sprints for the time remaining in coach class, randomly ticketed throughout the plane each minute. The exercise protocol was performed with a travel time of approximately 6 h and 20 min by the entire group, led by an exercise leader, and arrived at 1220 PDT. Participants were then while other members of the research team cheered 6 B. R. KUPCHAK ET AL. and encouraged individual performance. Upon centrifuged at 1,500 x g for 15 min. While, sodium completion of the exercise protocol, the partici- citrate vials were centrifuged at 2,000 x g for 30 pants immediately returned to the laboratory at min to extract platelet poor plasma. The serum, 1500 PDT for post-exercise blood and urine sam- sodium citrate plasma, and EDTA-plasma was pling. At the start of the exercise, the tempera- separated into several individual cryovials and ture was 71°F and the humidity was 63%. subsequently flash frozen with liquid nitrogen. Following the exercise protocol, participants The frozen serum and plasma in the cryovials provided a blood and urine sample (immediately were immediately stored and then shipped on after the full-body workout, 4CA), showered, and dry ice to the UConn HPL. On arrival, specimens put back on the prescribed clothing. Later that were stored in a –80°C ultra-low freezer until evening, all participants and research team arrived biochemical analysis was conducted. Participants at the CSFU HPL at 2000 PDT, where they were provided a urine sample and hydration state was then transported by coach bus for 1 h to LAX for confirmed by measuring urine specific gravity the departing flight at 2330 PDT. The flight was (USG) with a handheld urine refractometer direct to BDL with a travel time of approximately (Model Reichert TS400, Reichert, New York). A 5 h and 20 min and arrived at 0750 EDT. Subjects USG < 1.020 indicated euhydration. Subjects were were transported by coach bus for 30 min to the given frequent verbal reminders to stay hydrated, UConn HPL for post-travel testing. and especially to drink 0.5 liters of water at night Day 4: Following arrival at BDL at 0750 EDT, and in the morning. All subjects met this require- subjects were transported by chartered coach to ment. If a participant’s USG was > 1.020 prior to the UConn HPL (30 min travel time), where a any testing session, he was instructed to drink blood and urine sample were obtained at 0900 water until his USG was < 1.020. EDT (after the flight to CT/5CT). Subjects were then released and instructed to not perform any Biochemical assays strenuous or moderate physical activity. Day 5: Subjects were instructed to awake aPTT was measured from sodium citrate platelet- between 0700 to 0800 EDT, and then consume poor plasma using an automated clinical analyzer only water to remain hydrated before testing at (Quest Diagnostics, Willimantic, CT). The serum 1300 EDT. Subjects arrived at UConn HPL at total creatine kinase was measured in duplicate 1300 EDT, and provided a urine sample and from samples utilizing liquid creatine kinase blood sample (after 29 h post-flight/6CT). After reagents (Sekisui Diagnostics, Canton, MI) and testing, all subjects were released and monitored assayed according to manufacturer’s instructions. over the next few days to ensure satisfactory The intra-assay coefficient of variation (CV) was recovery. 3.9%, respectively. PTF 1+2 and TAT were measured in duplicate by ELISA from sodium citrate Blood and urine collection platelet-poor plasma (Enzygnost®; Dade Behring Blood and urine samples were collected at baseline Marberg, Newark, DE). The intra-assay CVs were [BL] (Day 1 – 1300 EDT), before the flight to CA 5.3% and 6.9% and the inter-assay CVs were 9.8% [1CT] (Day 2 – 0600 EDT), after the flight to CA and 8.9%, respectively. D-Dimer, tPA antigen [2CA] (Day 2 – 1500 PDT), immediately before (Ag), and PAI-1 Ag were determined from sodium the full-body workout [3CA] (Day 3 – 1300 PDT), citrate platelet poor plasma (Diagnostica Stago, immediately after the full-body workout [4CA] Inc., Mount Olive, NJ) by ELISA. The intra-assay (Day 3 – 1500 PDT), after the flight to CT [5CT] CVs were 7.0, 4.7 and 6.3% and inter-assay CVs (Day 4 – 0900 EDT) and after 29 h post-flight were 9.2, 5.8 and 10.3%, respectively. Myoglobin [6CT] (Day 5 –1300 EDT). In each case, whole was measured from EDTA-plasma in duplicate by blood was collected from an antecubital vein with- ELISA (CALBiotech, Spring Valley, CA). The out stasis into serum, EDTA, and sodium citrate intra-assay CV was 5.6%, and the inter-assay CV vacutainers, while the subject was in a seated posi- was 7.9%. All ELISAs were performed on a tion. Serum and EDTA vacutainers were Versamax tunable microplate reader (Molecular CHRONOBIOLOGY INTERNATIONAL 7

Devices, Sunnyvale, CA) at the appropriate wave- post-workout compared to BL. Additionally, the length according to the manufacturer’s directions. CON group showed a significantly faster aPTT compared with the FCG group at 29 h post-flight (p = 0.024) (Table 2). TAT significantly rose for Statistical analyses both groups immediately post-workout, after land- Data (means and standard deviation) were ana- ing in CT, and at 29 h post-flight. The FCG group lyzed using SPSS version 20.0. Statistical power showed a significantly lower concentration of TAT was determined to range from 0.83 to 0.96 for at 29 h post-flight (p = 0.049) compared with the the n sizes used in this study (nQuery Advisor; CON group, respectively (Table 2). PTF1+2, Statistical Solutions, Saugus, MA, USA). Reliability another marker of thrombin formation, increased range for the dependent variables intra-class cor- for CON and FCG groups immediately post-work- relation coefficients were R ≥ 0.85. Tests for nor- out, and after landing in CT, respectively mality of distribution (Kolmogorov–Smirnov Chi- (Table 2). However, no significant difference in square test) and homogeneity of variance (Levine’s PTF1+2 levels between the CON and FCG groups test) were for all data sets that were analyzed was exhibited at any time points. where statistical assumptions for linear statistics were met. Any variables that did not meet the Markers of fibrinolysis assumptions were logarithmically (log10) cor- rected and tested again. To compare demographic Both groups exhibited a significant rise in tPA characteristics between the experimental groups, concentrations immediately post-workout, which an independent t-test was utilized, where no sig- returned to baseline levels after landing in CT nificant differences were observed with the match- (Table 3). However, there was no significant differ- ing process. ence in tPA concentrations between groups at any A 2-way analysis of variance with repeated mea- time points. Both groups showed significant

sures for treatment and time was used to statisti- increases in PAI-1 concentrations before the flight cally evaluate the experimental data. When to CA, immediately post-workout, and after land- appropriate, Fisher’s LSD post hoc tests were ing in CT. Between groups, the FCG group had a used to determine pairwise differences. An alpha significantly lower PAI-1 concentration compared level of p ≤ 0.05 was defined as being statistically with the CON group after landing in CT (p = 0.017) significant. (Table 3). D-Dimer concentrations rose significantly in the CON group immediately post-workout, after landing in CT, and at 29 h post-flight, Results while the FCG group concentrations rose signifi- In our study, a trans-continental flight alone did cantly immediately post-workout and at 29 h post- not activate the coagulation and fibrinolytic sys- flight only. D-Dimer levels showed no significant tems. However, a full-body exercise protocol acti- difference between the FCG and CON groups at vated the coagulation system, and the fibrinolytic any time point (Table 3). system. The trans-continental flight following the exercise protocol further maintained a hypercoa- Markers of muscle damage gulable state into recovery. But, the wearing of a full-body compression garment did have a positive Both groups did not show an increase in serum CK − effect on limiting coagulation (decreased clot activity from baseline levels (CON = 110 U·L 1,FCG= − − formation). 123 U·L 1)at1CT(CON=145U·L1,FCG= − − 157 U·L 1), 2CA (CON = 136 U·L 1, FCG = 138 − − U·L 1)and3CA(CON=153U·L1,FCG= Markers of coagulation − 158U·L 1). However, following the muscle damaging aPTT, a marker for activation of the intrinsic and protocol, both groups showed a significant increase − common pathways of coagulation, exhibited a fas- (p < 0.05) from baseline at 4CA (CON = 282 U·L 1, − − ter clotting time for both groups immediately FCG = 245 U·L 1), 5 CT (CON = 686 U·L 1,FCG= 8 B. R. KUPCHAK ET AL.

Table 2. Changes in coagulation markers, aPTT, TAT and PTF 1+2, following a trans-continental flights and a muscle damaging workout. BL 1CT 2CA 3CA 4CA 5CT 6CT aPTT (sec) CON Mean 29.4 29.3 32.0 30.0 27.3abcdf 29.3 28.1cd SD 1.6 1.7 3.4 1.9 1.1 1.9 1.5 FCG Mean 30.4 29.7 32.5 30.3 27.9abcdfg 30.6 29.6# SD 1.2 1.6 1.6 2.2 1.4 2.5 1.5 TAT (μg.mL−1) CON Mean 2.18 2.29 2.73 2.57 5.03abcdg 4.41abcd 3.61abd SD 0.68 0.58 0.85 0.40 0.98 0.93 0.62 FCG Mean 2.32 2.50 2.66 2.69 4.96abcdfg 3.64abcdg 3.03#,abc SD 0.67 0.55 0.34 0.58 0.81 0.71 0.57 PTF 1+2 (pmol.L−1) CON Mean 183 184 245 222 345abcdg 303abcdg 238 SD 53 50 58 52 81 70 63 FCG Mean 184 180 230 210 343abcdfg 322abcdg 253 SD 51 43 52 43 81 86 77 Values are means ± standard deviation; CON, Control group = 9; FCG, Compression Group = 10; aPTT, activated Partial Thromboplastin Time; TAT, Thrombin–Antithrombin Complex; PTF 1+2, Prothrombin Fragment 1+2; BL, Baseline; 1CT, morning before flight to CA; 2CA, immediately after the flight to CA (Day 2 in CA); 3CA, the next day immediately before full-body workout (Day 3 in CA); 4CA, immediately post-workout (Day 3 in CA); 5CT, immediately post-flight to CT (Day 4 in CT); 6CT, 1 day post-flight (Day 5 in CT). Letters represent significantly different for time between each group – a significantly different from BL; b significantly different from 1CT; c significantly different from 2CA; d significantly different from 3CA; E significantly different from 4CA; F significantly different from 5CT; G significantly different from 6CT (p < 0.05). # – FCG significantly different from CON group within same time point (p < 0.05).

Table 3. Changes in fibrinolytic markers, tPA, PAI-1 and D-Dimer, following a trans-continental flights and a muscle damaging workout. BL 1CT 2CA 3CA 4CA 5CT 6CT tPA (ng.mL−1) CON Mean 5.10 5.20 4.61 4.78 9.09abcdfg 5.58 4.70 SD 2.10 2.26 1.78 1.95 3.99 2.96 1.70 FCG Mean 5.75 5.56 5.39 5.22 9.28abcdfg 5.72 5.21 SD 2.44 2.36 2.26 2.14 3.65 2.73 2.17 PAI-1 (ng.mL−1) CON Mean 4.24 8.23acdg 4.42 4.23 13.69abcdg 20.77abcdeg 4.83 SD 2.41 3.05 2.17 1.94 5.13 7.61 1.52 FCG Mean 5.36 9.32acdg 5.31 5.04 12.29acdg 13.48#,abcdg 5.81 SD 3.47 3.23 4.00 2.44 5.06 4.01 3.10 D-Dimer (ng.mL−1) CON Mean 215.0 248.3 236.8 253.7 396.4abcde 292.9a 360.6abcd SD 92.0 102.1 102.0 121.5 198.8 156.5 204.7 FCG Mean 227.3 241.1 235.1 259.9 365.9abcde 280.1 323.8abcd SD 125.6 135.0 149.0 148.4 204.1 149.1 142.9 Values are means ± standard deviation; CON, Control group = 9; FCG, Compression Group = 10; tPA, tissue Plasminogen Activator; PAI-1, Plasminogen Activator Inhibitor; BL, Baseline; 1CT, morning before flight to CA; 2CA, immediately after the flight to CA (Day 2 in CA); 3CA, the next day immediately before full-body workout (Day 3 in CA); 4CA, immediately post-workout (Day 3 in CA); 5CT, immediately post-flight to CT (Day 4 in CT); 6CT, 1 day post-flight (Day 5 in CT). Letters represent significantly different for time between each group – a significantly different from BL; b significantly different from 1CT; c significantly different from 2CA; d significantly different from 3CA; E significantly different from 4CA; F significantly different from 5CT; G significantly different from 6CT, (p < 0.05). # – FCG significantly different from CON group within same time point (p < 0.05). CHRONOBIOLOGY INTERNATIONAL 9

− − 536 U·L 1) and 6CT (CON = 508 U·L 1, FCG = 350 well-hydrated as hydration status were checked − U·L 1). Between groups, the CON group exhibited a immediately before and immediately after each significantly greater CK activity (p <0.05)thanFCG flight. The largest risk to subjects was thus the group at 4CA, 5CT and 6CT. Plasma myoglobin was exercise protocol. also analyzed and showed no increase from baseline The exercise protocol used in the present study − − (CON = 1.7 nmol·L 1,FCG=2.0nmol·L1)at1CT is known to induce muscle damage (Kraemer − − (CON = 2.3 nmol·L 1,FCG=2.3nmol·L1), 2CA et al., 2016). Subjects’ risk for VTE was therefore − − (CON = 1.9 nmol.L 1,FCG=2.2nmol·L1)and increased due to three underlying factors: hyper- − − 3CA (CON = 2.4 nmol.L 1,FCG=2.1nmol·L1) coagulability, stasis, and vein wall damage time points. Plasma myoglobin did significantly (Anning, 2005). In our study, a hypercoagulable increase in both groups after the muscle damaging state existed after the full-body muscle damaging − protocol at 4CA (CON = 10.2 nmol·L 1,FCG=8.0 workout; stasis was introduced by two trans-con- − − nmol·L 1)and5CA(CON=4.3nmol·L 1,FCG=3.6 tinental flights of approximately 5 h in duration − nmol·L 1), but returned to baseline concentrations (35 h apart), with little movement initiated by the − and 6CA (CON = 2.3 nmol·L 1,FCG=1.9 subjects, and vein wall damage was likely intro- − nmol·L 1). Additionally, the CON group exhibited duced from the exercise protocol, as these types of greater concentrations at 4CA compared to the FCG exercise protocols increase blood viscosity (hema- group (p < 0.05) (Kraemer et al., 2016). tocrit) stripping away at the endothelium (Kupchak et al., 2013a). An acute bout of high–intensity exercise acti- Discussion vates the coagulation cascade and produces a Athletes and military service members are known hypercoagulable state (Herren et al., 1992). To to undergo strenuous exercise and sometimes have examine this process, we measured aPTT, a mea- to take long haul flights relatively soon afterwards; sure of the intrinsic and common pathways of

however, its combined effect on many physiologi- coagulation. Our study reaffirmed that intense cal functions are relatively unknown. Thus, this exercise shortens the length of coagulation investigation was designed to examine the effects (Kupchak et al., 2013a; Weiss et al., 1998). of a trans-continental flight preceded by a full- Shortening of aPTT is strongly related to von body muscle-damaging workout on the coagula- Willebrand factor (vWF) an adhesive protein tion and fibrinolytic systems. Additionally, we that is released from endothelium cells during examined whether the use of a full-body compres- exercise (Lekakis et al., 2008), and an increase sion garment can limit the activation of coagula- in Factor VIIIa has been proposed as a cause. tion. The exercise protocol was demanding even Moreover, the diminished liver blood flow along for our resistance-trained subjects, as evidenced by withthemuscledamageimpairingkidneyfunc- an increase in plasma myoglobin concentrations tion during exercise could prolong the clearance (Kraemer et al., 2016). Marked increases in the of blood clotting factors (Cadroy et al., 2002), coagulation and fibrinolytic systems were observed along . post-exercise, and activation of coagulation con- We also utilized aPTT to examine the effects of tinued following the trans-continental flight. coagulation on a trans-continental flight. Schreijer However, wearing a full-body compression gar- et al. (2010) hypothesized that the intrinsic pathway ment limited the degree of coagulation post-exer- may be responsible for air travel-related activation cise and post-flight. of coagulation. In the present study, we demon- Although traveler-related risk factors can pre- strated that aPTT was not decreased following a sent problems for long-haul flights, our subjects transcontinental flight to CA (2CA). This result were deemed low risk, as only a few of them had a was similar to those of previous study (Boccalon BMI above 25 and their body fat % was within the et al., 2005). Nor was aPTT affected on the return normal range. Additionally, hemo-concentration flight to CT (5CT). and dehydration caused by the 1% humidity inside No changes were observed due to diurnal varia- the aircraft was not a problem as subjects were tion (difference between BL and 1CT) in PTF 1+2 10 B. R. KUPCHAK ET AL. and TAT, whose biological variability is consid- which is produced and released from the endothe- ered generally low. Both markers were elevated lium (Kooistra et al., 1994). In our study, tPA after a bout of intense exercise, demonstrating increased only after the full-body workout (4CA), the formation of thrombin. The increase in PTF signifying the effect was attributable to the exercise 1+2 and TAT in response to a bout of intense and not to the travel. This result is consistent with exercise is consistent with previous studies our previous studies, which showed that exercise (Kupchak et al., 2013b; Weiss et al., 1998). This increases concentration of tPA in the blood rise in formation of thrombin is typically transient (Kupchak et al., 2013b). tPA is stimulated through and returns to baseline concentrations fairly multiple mechanisms, including increased shear quickly depending on the type and intensity of stress causing endothelium damage (Levin et al., the exercise. The increase in thrombin markers 1984), generation of thrombin (Levin et al., 1993), are thought to occur mechanistically via a number and catecholamine release (Brommer et al., 1982). of factors, including aerobic metabolism coupled Additionally, other investigators have shown that with lactate formation, platelet activation, lysis of air travel not preceded by exercise had either no red blood cells and tissue damage (Bärtsch et al., effect or a potential decrease on tPA concentra- 1995; Dufaux et al., 1991; Herren et al., 1992; tions (Boccalon et al. 2005; Schobersberger et al., Prisco et al., 1998). Tissue damage is the most 2002)]. Since no change was seen between samples likely cause here, since this exercise protocol has taken in the afternoon (BL) and early morning been shown to cause increases in both myoglobin (1CT), the change we saw in tPA concentrations and CK levels (Kraemer et al., 2016). was not due to diurnal variation Even though tPA Unlike previous studies, we also examined the is known to have a high variability between day effects of a trans-continental flight post-exercise. and night values. Our results are similar to those We observed a significant increase in both PTF 1 of Parker et al. (2011), who demonstrated that tPA +2 and TAT immediately following the second concentrations return to baseline levels 24 h after

trans-continental flight to CT (5CT) and in the completing a marathon and then flying for more follow-up measures the next day (6CT). Previous than 4 h. studies have documented inconsistent results in The main regulatory enzyme of the fibrinolytic thrombin activity after a flight, showing increased system is PAI-1, which functions as the primary (Schreijer et al., 2006), decreased (Boccalon et al., inhibitor of tPA. PAI-1 exhibited an increase 2005), and no changes in formation of thrombin before the flight to CA (1CT) compared to BL, markers (Schobersberger et al., 2002). However, in This result is likely due to the circadian rhythm the present study, the muscle-damaging workout of PAI-1, which peaks in the morning and is the preceding the trans-continental flight back to CT lowest levels in the evening (Siahkouhian et al., (5CT) might be a mitigating factor in the increased 2013). We also demonstrated increased PAI-1 con- concentrations of PTF 1+2 and TAT. Thus, the centrations immediately following the full-body increased levels of thrombin generation markers workout (4CA). Previous studies have found var- immediately after the full-body workout, after ied levels of PAI-1 post-exercise based on the type landing from CA, and at 29 h post-flight may be of exercise performed (Bärtsch et al., 1995; Hilberg attributed to the tissue damage (increased myoglo- et al., 2003; Sumann et al., 2007) and the training bin and CK) incurred from the exercise protocol, status of subjects (Kvernmo & Osterud, 1997). which has been linked to tissue factor mediated Interestingly, in our study PAI-1 remained ele- coagulation activation (Möckel et al., 2001; Prisco vated after landing in CT. This could be for et al., 1993). explained by either of two factors: 1) After landing Additionally, the increases in coagulation levels in CT, blood was drawn at approximately 0900 in the body are commonly balanced by a subse- EDT, when PAI-1 concentrations would be at quent increase in the fibrinolytic system. During their peak, or 2) hypoxia is known to trigger this process, a fibrin clot is broken down to its release of PAI-1 (Li et al., 2005) so could be a soluble form by the enzyme plasmin. Plasmin is risk factor for the increased levels following the activated by tissue plasminogen activator (tPA), trans-continental flight. CHRONOBIOLOGY INTERNATIONAL 11

D-Dimer was examined to measure in vivo acti- compression socks has also shown positive vation of the fibrinolytic system, and is formed results in avoiding travel-related VTE (Clarke after fibrin is degraded. During long-distance et al., 2006). In the literature, full-body compres- flights, Jacobson et al. demonstrated that approxi- sion gear has also shown positive results on mately 8.2% of all passengers had elevated muscle physiology, limiting myoglobin and CK D-Dimer levels. Their result was not limited to levels (Kraemer et al., 2010; Kraemer et al., economy class passengers (Jacobson et al., 2003). 2016). On the other hand, the rises in myoglobin In the present study, we did not see a rise in and CK levels are associated with tissue disrup- D-Dimer immediately after arriving in CA tion and production of thrombin, which lends (2CA). However, we did find an increase in support to the importance of finding non-inva- D-Dimer concentrations immediately after the sive means to attenuate these protein levels full-body workout (4CA), which is consistent (Prisco et al., 1998). with other exercise studies, especially endurance In the present study, compression gear did exhi- exercise (Kupchak et al., 2013b; Röcker et al., bit a positive effect on limiting coagulation, speci- 1990). We did find increased concentrations after fically at 29 h post-flight, when the CON group landing in CT, and at 29 h post-flight. Even showed a significant decreased aPTT compared to though we saw an increase after landing in CT, the FCG group. Additionally, the thrombin gen- this increase was not due circadian variation eration marker, TAT, had a lower concentration in because we found no change between BL (taken the FCG group at 29 h post-flight. This could be at 1300) and 1CT (performed at 0600 the next attributed to the compression garment limiting day). These results are not unprecedented, for muscle damage (Kraemer et al., 2016) in turn Parker et al. (2012) demonstrated elevated levels limiting thrombin generation. A potential explana- of D-Dimers immediately after completing a tion for this observation is the compression gar- marathon, and participants who had traveled >4 ment may holds the limbs in what is known as

h to the race had higher immediate post exercise “dynamic casting,” thereby reducing soft tissue levels than controls who had traveled less than 2 h injury (Kraemer et al., 2001a). This effect is impor- (Parker et al., 2012). However, our data suggest tant because it can limit excessive movement and that performing a muscle-damaging workout fol- vibration of the muscles providing an ideal envir- lowed by a trans-continental flight may place an onment for muscle recovery (Kraemer et al., individual at risk for venous thrombosis, due to 2001b). Kraemer et al. (2010) demonstrated signif- the number of subjects who exhibited D-Dimer icantly lower muscle swelling by ultrasound tech- − values greater than 500 ng∙mL 1 (clinical threshold nology in a group using a compression garment for excluding VTE) immediately after the full- compared to control. This could also explain the body workout (n = 2 for CON; n = 4 for FCG) positive effect of compression garments on PAI-1 and at 29 h post-flight (n = 1 for CON; n =1 concentrations after landing in CT, even though a for FCG). prior study has shown that compression garments In the sports world, there have been a handful do not improve markers of inflammation of case reports of athletes developing cardiovas- (Pruscino et al., 2013), which have been linked to cular events following an athletic event with air PAI-1 levels (Devaraj et al., 2003). Furthermore, travel (Echlin et al., 2004;Harvey,1978;Tao& compression garments may reduce risk of VTE by Davenport, 2010). Therefore, the use of prophy- compressing veins, thereby diminishing venous laxis may be warranted for preventing thrombo- stasis and increasing venous return and arterial tic events after an intense workout and/or flight. blood flow (Kraemer et al., 2000). This is impor- Compression gear is an example of a non-inva- tant since venous stasis has been linked to a sive prophylaxis. Graduated compression stock- decline in intravascular oxygen tension and the ings, used by the medical community for some formation of thrombus in the legs (Yan et al., time, have been shown to be effective in redu- 1999). cing the incidence of DVTs in surgical patients In summary, a trans-continental flight alone did (Sachdeva et al., 2010). Use of graduated not activate the coagulation and fibrinolytic 12 B. R. KUPCHAK ET AL. systems. However, an acute exercise protocol was References able to elicit a response on the blood hemostatic Anning ST. (2005). The historical aspects of venous throm- system, exhibited by the activation of the coagula- bosis. Med Hist. 1:28–37. tion system (aPTT was decreased, while TAT and Annual Review of Civil Aviation (2006). ICAO J. 61:1–44. PTF 1+2 were elevated). In order to balance coa- Babar S. (2016). The use of adiposity indices for wide recei- gulation, the fibrinolytic system (increases in tPA, vers from 2015 NFL combine. Clin J Sports Med. 26:e23. PAI-1 and D-Dimer) was also activated. The trans- Bärtsch P, Welsch B, Albert M, et al. (1995). Balanced activa- continental flight following the exercise protocol tion of coagulation and fibrinolysis after a 2-h triathlon. Med Sci Sports Exerc. 27:1465–70. further maintained a hypercoagulable state as Beliard S, Chauveau M, Moscatiello T, et al. (2015). TAT, PAI-1 and D-Dimers remained elevated Compression garments and exercise: No influence of pres- into recovery. The wearing of a full-body compres- sure applied. J Sports Sci Med. 14:75–83. sion garment did have a positive effect on coagula- Boccalon H, Boneu B, Emmerich J, et al. (2005). Long-haul tion, as individuals showed lower levels of TAT flights do not activate hemostasis in young healthy men. J – and PAI-1 and a slower aPTT in recovery com- Thromb Haemost. 3:1539 41. Brommer EJ, Barrett-Bergshoeff MM, Allen RA, et al. (1982). pared to controls. The results suggest an increased The use of desmopressin acetate (DDAVP) as a test of the susceptibility of clot formation in individuals who fibrinolytic capacity of patients–analysis of responders and travel cross-country via plane to participate in non-responders. Thromb Haemost. 48:156–61. athletic events. Therefore individuals who travel Cadroy Y, Pillard F, Sakariassen KS, et al. (2002). Strenuous but long distances may be at a higher risk for a DVT notmoderateexerciseincreasesthethrombotictendencyin – or PE. However, the use of mechanical prophylaxis healthy sedentary male volunteers. J Appl Physiol. 93:829 33. Clarke M, Hopewell S, Juszczak E, et al. (2006). Compression such as full body compression may be a viable stockings for preventing deep vein thrombosis in airline option, as our research demonstrated that these passengers. Cochrane Database Syst Rev. 19:CD004002. individuals exhibited a slower aPTT and lower Collins RE, Field S, Castleden WM. (1979). Thrombosis of leg levels of TAT and PAI-1 into recovery. arteries after prolonged travel. Br Med J. 2:1478. Cruickshank JM, Gorlin R, Jennett B. (1988). Air travel and

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