Temporal Changes in tPA and PAI-1 after Maximal Exercise

Cooper, Jamie A.; Nagelkirk, Paul R.; Coughlin, Adam M.; Pivarnik, James M.; Womack, Christopher J.

doi:10.1249/01.mss.0000145447.61736.ed

Cited by 26 publications

(11 citation statements)

References 29 publications

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“…Although behavioral or environmental factors such as activity level could also influence PAI-1, our 15-minute mild stress tests likely did not capture the full range of PAI-1 changes that can be induced by behavior. 14,15 This complexity is highlighted by a study that found a blunted PAI-1 rhythm in 2 blind individuals who were not synchronized to the 24-hour light/dark cycle. 16 In animals, lesioning the central circadian pacemaker (suprachiasmatic nucleus) abolished the daily rhythm in PAI-1 17 but also abolished behavioral rhythmicity so it could not be determined if the PAI-1 rhythm is driven directly by the circadian system or indirectly through behavior.…”

Section: Resultsmentioning

confidence: 99%

Human circadian system causes a morning peak in prothrombotic plasminogen activator inhibitor-1 (PAI-1) independent of the sleep/wake cycle

Scheer

Shea

2014

Blood

132

105

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• The human circadian system causes a morning peak in circulating levels of PAI-1, independent of any behavioral or environmental influences.• The circadian system determines to a large extent the PAI-1 rhythm observed during a regular sleep/wake cycle.Serious adverse cardiovascular events peak in the morning, possibly related to increased thrombosis in critical vessels. Plasminogen activator inhibitor-1 (PAI-1), which inhibits fibrinolysis, is a key circulating prothrombotic factor that rises in the morning in humans. We tested whether this morning peak in PAI-1 is caused by the internal circadian system or by behaviors that typically occur in the morning, such as altered posture and physical activity. Twelve healthy adults underwent a 2-week protocol that enabled the distinction of endogenous circadian effects from behavioral and environmental effects. The results demonstrated a robust circadian rhythm in circulating PAI-1 with a peak corresponding to ∼6:30 AM. This rhythm in PAI-1 was 8-times larger than changes in PAI-1 induced by standardized behavioral stressors, including head-up tilt and 15-minute cycle exercise. If this large endogenous morning peak in PAI-1 persists in vulnerable individuals, it could help explain the morning peak in adverse cardiovascular events. (Blood. 2014;123(4):590-593) IntroductionThe ability to clot blood can be life-saving after an injury, but thrombi within vessels can contribute to myocardial infarction, ischemic stroke, and sudden cardiac death. 1-3 Ongoing fibrinolytic activity helps break down thrombi and maintain vessel patency and is largely managed by circulating tissue plasminogen activator, which converts plasminogen to plasmin.1-3 Fibrinolytic activity is significantly reduced in the morning due to an increase in plasminogen activator inhibitor-1 (PAI-1), the primary inhibitor of tissue plasminogen activator.1-3 Thus, increased PAI-1 and decreased fibrinolysis in the morning may increase the risk for development of occlusive thrombi and could help explain the morning peak in adverse cardiovascular events. [1][2][3][4] To begin to understand potential underlying mechanisms in humans, we tested the degree to which the morning increase in PAI-1 is caused by a direct endogenous circadian rhythm in PAI-1 [5][6][7][8] vs influences from the daily behavioral/environmental changes across the night and day (eg, rest/activity, fasting/feeding, dark/light, and ambient-temperature cycles). MethodsWe studied 12 healthy volunteers taking no medications (mean [range], 25.8 [20-42] years; body mass index, 23.6 [19.9-29.6] kg/m 2 ; 6 women). Studies were approved by the Partners Human Research Committee, and participants gave written informed consent in accordance with the Declaration of Helsinki.Participants were assessed throughout a 2-week laboratory protocol designed to desynchronize daily behavioral rhythms from internal circadian rhythms, while maintaining environmental factors constant. Participants had 2 baseline 24-hour days in normal room lighting conditions (;90 lux wak...

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Section: Resultsmentioning

confidence: 99%

Human circadian system causes a morning peak in prothrombotic plasminogen activator inhibitor-1 (PAI-1) independent of the sleep/wake cycle

Scheer

Shea

2014

Blood

132

105

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“…The capacity to thrombolize fibrin clots is influenced by many factors of the fibrinolytic system, but particularly tPA and PAI-1. The increased fibrinolytic potential occurs due to an increase of tPA activity or antigen, which catalizes the conversion of plasminogen into plasmin, and/or a decrease in PAI-1 (Collen et al, 1980;Molz et al, 1993;Rankinen et al, 1995;Weiss et al, 1998;El-Sayed et al, 2000;Huber, 2001;Ivey et al, 2003;Cooper et al, 2004;Womack et al, 2006). Under basal conditions, tPA circulates mainly as a complex with PAI-1 with low levels of free tPA, and PAI-1 inhibits tPA by binding to it and forming an inactive complex.…”

Section: Discussionmentioning

confidence: 99%

Effects of KAATSU training on haemostasis in healthy subjects

Nakajima

Takano

Kurano

et al. 2007

Int. J. KAATSU Ttaining Res.

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Purposes: The KAATSU training is performed under the reduction of muscle blood flow by a speciallydesigned belt (KAATSU belt), which induces blood pooling in capacitance vessels by restricting venous return. However, no prior studies have examined the effects of KAATSU training on haemostasis. The purpose of the present study was to investigate acute effects of KAATSU training on haemostasis including fibrinolytic responses in healthy subjects. Methods: Two protocols have been performed. (1) 6 healthy men (mean age= 48 ± 5 yr) performed KAATSU (160 mmHg) of both thighs for 15 minutes and then KAASTU training combined with low-intensity leg and foot aerobic exercises for ~10 minutes in hypobaric chamber, which mimics 8000 feet in airflight. (2) Another 7 men (mean age=30 ± 4 yr) performed leg press exercises (30 % 1 RM) with and without KAATSU of both thighs 24 h after bed rest. Blood samples were taken at rest, immediately after KAATSU, and exercises with or without KAATSU, and after exercise. For the investigation of blood fibrinolysis, determinations of tissue-type plasminogen activator (tPA) activity or antigen, plasminogen activator inhibitor (PAI)-1 activity or antigen, fibrin degradation product (FDP) and D-dimer were used. Prothrombin time (PT) and platelet counts were also measured. Results: (1) In hypobaric chamber, KAATSU by itself significantly increased tPA activity, while PAI-1 activity was unchanged. Furthermore, immediately after the exercise, tPA activity increased significantly. (2) During the exercises combined with KAATSU 24 h after bed rest, tPA antigen significantly increased, compared with control exercises, but PAI-1 antigen was unchanged. In both cases, KAATSU training did not induce fibrin formation as assessed by fibrin D-dimer and FDP. Conclusions: This study indicates that potentially favorable changes occur in fibrinolytic factors after KAATSU and KAATSU training in healthy subjects.

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“…38 Similar data were reported by Lin et al, who observed a significant increase in t-PA and a significant decrease in PAI-1 values after a standardized cycle ergometer test in active young men, which was followed by a sharp fall 2 hours thereafter. 54 However, increases of t-PA (þ361%) and of PAI-1 (þ235%) were observed by Prisco et al 64 in well-trained, long-distance male runners immediately after a marathon run and by Cooper et al 65 in healthy males after a graded maximal exercise test on a treadmill. Significant increases in fibrinopeptide A (FPA) levels, up to 900% of the pre-exercise values, were observed by Röcker et al after a marathon race, reaching peak values 60 minutes after the run.…”

Section: Influence Of Physical Exercise On Secondary Hemostasismentioning

confidence: 94%

Biological Influence of Physical Exercise on Hemostasis

Lippi

Maffulli²

2009

Semin Thromb Hemost

126

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Some of the benefits of physical activity may result from effects on hemostasis. However, the increased burden of cardiovascular complications and sudden death occurring during and immediately after exercise prompts investigation to elucidate the biological relationship between physical exercise and hemostatic function. Although both the hemostatic and fibrinolytic systems are strongly influenced by physical exercise, the outcomes of available studies to date are biased by several confounding variables, including the subjects investigated, the type, intensity, and duration of the exercise, and the methods used for hemostatic evaluation. Considering these variables and attempting to synthesize the available data, it seems reasonable to conclude that the biological changes induced by physical activity are consistent with a mechanistic model where acute and strenuous exercise is associated with a transient hypercoagulability state, particularly in untrained individuals. This is mostly due to increased thrombin generation, platelet hyperreactivity, and increased activity of several coagulation factors, especially factor VIII and von Willebrand factor. Contextually, increased fibrinolytic activity has been frequently reported after exercise. Such changes, however, seem completely reversible, as trained subjects at rest show a partial exhaustion of platelet function in addition to values of several parameters of both the coagulation and fibrinolytic systems that are globally comparable with or even lower than those observed in the sedentary population. These adaptive changes might be beneficial in the long term, offering some protection against the risk of thrombosis and adverse cardiovascular events in physically active individuals.

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Temporal Changes in tPA and PAI-1 after Maximal Exercise

Abstract: To accurately evaluate the t-PA response to acute exercise, blood samples should be collected within 2 min after the cessation of exercise.

Cited by 26 publications

References 29 publications

Human circadian system causes a morning peak in prothrombotic plasminogen activator inhibitor-1 (PAI-1) independent of the sleep/wake cycle

Human circadian system causes a morning peak in prothrombotic plasminogen activator inhibitor-1 (PAI-1) independent of the sleep/wake cycle

Effects of KAATSU training on haemostasis in healthy subjects

Biological Influence of Physical Exercise on Hemostasis

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