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Caffeine Augments the Prothrombotic but Not the Fibrinolytic Response to Exercise

NAGELKIRK, PAUL R.1; SACKETT, JAMES R.1; AIELLO, JOSEPH J.2; FITZGERALD, LIAM F.1; SAUNDERS, MICHAEL J.2; HARGENS, TRENT A.2; WOMACK, CHRISTOPHER J.2

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Medicine & Science in Sports & Exercise: March 2019 - Volume 51 - Issue 3 - p 421-425
doi: 10.1249/MSS.0000000000001815
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Abstract

Blood coagulation represents a significant clinical risk as most adverse cardiovascular events, including myocardial infarctions and cerebrovascular accidents, occur due to an occlusive blood clot (1). Measures of coagulation and fibrinolysis, the ability to dissolve clots, are independently associated with cardiovascular diseases and their associated sequelae (2). Prospective investigations suggest that a hypercoagulable state, as characterized by elevated coagulation and low fibrinolytic activity, may lead to subsequent cardiovascular events, such as myocardial infarction or cerebrovascular accident (3,4).

The hemostatic and fibrinolytic responses to acute exercise are of particular clinical significance as a greater percentage of exercise-induced ischemic events result from occlusive thrombi than events occurring in a resting state (5). Exercise is reported to be responsible for approximately 6% to 17% of all sudden deaths (6), and exertion has been noted as a trigger of myocardial infarction in approximately one third of patients able to identify a trigger (7). Acute exercise stimulates clot formation (8), shortens clotting times (9), and increases plasma concentration of biomarkers of coagulation activity such as coagulation factor VIII (10) and fibrinogen (11). Likewise, fibrinolytic potential is augmented by exertion, largely as a result of increased plasma concentrations of tissue plasminogen activator (tPA), the primary catalyst of fibrinolysis, and decreased levels of plasminogen activator inhibitor-1 (PAI-1), the main circulating inhibitor of tPA (5).

Caffeine, considered the most commonly used mood-altering drug, is consumed by approximately 85% of the US population (12). It is also frequently used by competitive and recreational athletes as an ergogenic aid and has been shown to improve endurance (13) as well as high-intensity anaerobic performance (14). Though the mechanisms underlying caffeine’s ergogenic effects are not clearly defined, the physiologic responses to acute caffeine ingestion have been well studied, and some of these responses are theorized to influence coagulation and fibrinolysis. Caffeine increases sympathetic nervous system activity, which augments a number of indices of hemostatic activity (15), and increases systolic and diastolic blood pressures, likely due to vasoconstriction (16). Vasoconstriction elevates shear stress on vascular endothelial cells, which promotes coagulation activity (17). A single dose of caffeine may also augment endothelial activity (18), potentially leading to altered endothelial synthesis and release of tPA and PAI-1 (19). Caffeine consumption may also increase body temperature (20), which is associated with increased blood coagulability (21). Finally, caffeine intake increases arterial stiffness (22), which is associated with coagulation and fibrinolytic potential (23). Thus, caffeine ingestion may influence coagulation and/or fibrinolytic activity, but this hypothesis has not been tested. Moreover, the influence of caffeine on the hemostatic and fibrinolytic response to acute exercise is unknown.

Thus, the purpose of this study was to assess the impact of caffeine on coagulation and fibrinolytic activity at rest and after an acute bout of exercise. It was hypothesized that, compared with placebo, caffeine would increase resting coagulation and fibrinolytic potential and promote a greater increase in coagulation and fibrinolytic activity during high-intensity exercise.

METHODS

The present study was a collaborative effort between Ball State University and James Madison University. All study procedures were approved by institutional review boards of both institutions, and each participant provided written informed consent before enrollment in the study. Forty-eight apparently healthy men (23 ± 3 yr, 180.9 ± 7.1 cm, 79.9 ± 10.0 kg) completed the study. Subjects were nontobacco users, free from any known cardiovascular or metabolic disease and were taking no medications that may influence the hemostatic parameters under investigation. Participants had no known physical limitations that would prevent them from doing strenuous aerobic exercise. Subjects were moderate caffeine users, defined as consuming an average of 50 to 320 mg (equivalent of one serving of soda, energy drink, coffee, or tea) per day for the past 6 wk.

Experimental procedures

To control for diurnal influences on the variables under examination, all testing was done before 10:00 am. Subjects reported to the laboratory at the same time of day on two occasions, separated by 7 d. Subjects abstained from caffeine and alcohol consumption for 24 h before each visit to the lab, and had no food or drink other than water for 12 h before their visit. In addition, subjects were required to refrain from exercise for 24 h before each visit to the laboratory. Lastly, subjects were excluded from participation if they had any flu or fever symptoms 1 wk before either of their exercise tests.

Supplementation protocol

Before each testing session the subject drank 200 mL of either a noncaloric, flavored placebo beverage or caffeine preparation, determined in random order. Subjects were blinded to which beverage they received. The caffeine preparation consisted of 6 mg of USP grade caffeine per kilogram of the individual’s body weight dissolved into 200 mL of the placebo solution. The subject then rested in a seated position for 1 h, after which a baseline blood sample was obtained.

Exercise testing

The subject was then seated on an electronically braked cycle ergometer and allowed a few minutes to habituate to the equipment. After this brief warm-up period, the exercise test commenced. Subjects were instructed to maintain a constant pedal rate of approximately 60 rpm. Intensity began at 25 W for 1 min, and increased 25 W·min−1 until volitional exhaustion or a point at which the subject could no longer maintain the prescribed pedal rate. A metabolic measurement system (TrueOne® 2400; Parvo Medics, Sandy, UT) was used to collect expired gases during exercise for the determination of maximal oxygen consumption (V˙O2max). A second blood sample was obtained within 3 min after the cessation of exercise.

Blood sampling, assays

At each timepoint, 10 mL of blood was drawn from an antecubital vein using clean venipuncture with minimal stasis. 5 mL were collected into an acidified citrate solution (Stabilyte), whereas the other 5 mL were collected into a regular citrate solution. Blood samples were immediately centrifuged for 20 min at 1500g and 4°C to obtain platelet-poor plasma. Plasma aliquots were frozen and stored at −80°C until assayed. Clotting time measures (prothrombin time, activated partial thromboplastin time) and plasma concentrations of fibrinogen were assessed by coagulometer (Start4®; Diagnostica Stago, Parsippany NJ) according to manufacturer specifications. Commercially available ELISA kits were used to determine plasma concentrations of coagulation factor VIII antigen (VisuLize®, Ontario, Canada), active tPA (Eagle Bioscience, Inc, Nashua, NH), tPA antigen (Eagle Bioscience, Inc), and active PAI-1(Eagle Bioscience, Inc).

Statistical analysis

All statistical analyses were conducted using SPSS for Windows (version 24; SPSS, Chicago, IL). Distribution normality of all variables was assessed using a Shapiro–Wilk test. The following variables deviated significantly from normality and were log transformed before statistical analysis: baseline systolic blood pressure and heart rate, peak RPE, peak heart rate, fibrinogen, tPA activity, tPA antigen, and PAI-1 activity. Subject characteristics are presented using descriptive statistics (mean ± standard deviation). Paired-samples t-tests were used to compare subject characteristics, resting heart rate, blood pressure, test time, heart rate at peak exercise and peak power output between the two exercise tests. Differences in plasma concentrations of each hemostatic variable were assessed with a two-factor ANOVA, using testing condition (caffeine, placebo) and time (preexercise, postexercise) as within-subjects factors. Post hoc pairwise comparisons were made using the Bonferroni method. Statistical significance for all analyses was set at an alpha of 0.05.

RESULTS

Resting heart rate and blood pressure data are available for 27 participants. At baseline, caffeine induced a significantly higher systolic blood pressure (126 ± 11 mm Hg) compared with placebo (119 ± 11 mm Hg). Baseline diastolic pressure (78 ± 11 bpm caffeine, 77 ± 11 bpm placebo) and heart rate (63 ± 9 bpm caffeine, 61 ± 7 bpm placebo) were not different between trials (P > 0.05). Maximal exercise variables are depicted in Table 1. Peak heart rate was significantly higher during the caffeine trial compared to placebo (P < 0.05), but no other differences in peak exercise performance were observed between conditions.

TABLE 1
TABLE 1:
Peak exercise variables.

Significant main effects of time were observed for all fibrinolytic variables, but there were no effects of condition and no time–condition interactions. Plasma concentration of active tPA increased from 0.34 ± 0.20 IU·mL−1 to 9.20 ± 4.32 IU·mL−1 in the caffeine trial, and from 0.30 ± 0.19 IU·mL−1 to 7.49 ± 3.34 IU·mL−1 with placebo. tPA antigen also increased during the caffeine trial from 2.80 ± 4.22 ng·mL−1 to 4.8 ± 5.8 ng·mL−1, and from 2.61 ± 3.58 ng·mL−1 to 4.64 ± 5.38 ng·mL−1 with placebo. PAI-1 activity significantly decreased during both the caffeine trial (12.35 ± 20.0 IU·mL−1 to 8.90 ± 14.80 IU·mL−1) and during the placebo trial (12.21 ± 18.95 IU·mL to 7.73 ± 8.99 IU·mL−1).

The fibrinogen response to exercise is presented in Figure 1. Fibrinogen concentrations significantly increased during both the caffeine as well as the placebo trials. No main effect of condition and no significant time–condition interaction was observed. Plasma concentration of Factor VIII antigen increased significantly during exercise, and there was a main effect of condition in which factor VIII was overall higher during the caffeine trial as compared with placebo. A significant time–condition interaction indicated that caffeine induced a more pronounced increase in factor VIII than placebo (see Fig. 2).

FIGURE 1
FIGURE 1:
Fibrinogen response to exercise. *Significant effect of time (P < 0.05). CAFF, caffeine; PLAC, placebo. Values shown are means ± SE.
FIGURE 2
FIGURE 2:
Factor VIII response to exercise. *Significant effect of time; **Significant effect of condition; †Significant time–condition interaction (P < 0.05). Values shown are means ± SE.

DISCUSSION

The present study explored the effect of caffeine on the coagulative and fibrinolytic responses to a single bout of high-intensity exercise. The primary findings indicate that caffeine augmented the increase in coagulation Factor VIII observed during exercise, but did not influence the increase in fibrinolytic activity. Furthermore, caffeine did not modulate the increase in fibrinogen concentration during exercise.

The observed exercise-induced increase in plasma tPA and decrease in PAI-1 reflect what is commonly reported in the literature (5), but caffeine ingestion did not augment fibrinolytic activity in the present study as hypothesized. The literature shows few examples of studies that specifically assess fibrinolytic activity during acute caffeine consumption. Early studies of fibrinolysis indicate consumption of coffee decreases PAI-1 concentration, increases tPA activity (24), and enhances fibrinolytic potential as measured by prolonged clot lysis time (25). In these investigations, it is difficult to distinguish the effect of caffeine on fibrinolytic potential from the influence of other components of the coffee drinks, because these beverages often contain other chemicals, such as polyphenols and diterpenes, which may contribute to the biochemical responses otherwise attributed to caffeine (26). Although investigations of the effect of caffeine, apart from coffee, on fibrinolysis are scarce, some recent investigations indicate caffeine influences endothelial function, which is directly related to fibrinolytic activity. Buscemi et al. (27) isolated the influence of caffeine from the other components of coffee by comparing the impact of decaffeinated and caffeinated coffee on endothelial function. Brachial artery flow-mediated dilation was not affected by decaffeinated coffee, but decreased significantly after consumption of the caffeinated drink. These findings are contradicted by a subsequent study that indicated 200-mg caffeine, delivered via capsule, led to significant increases in brachial artery flow-mediated dilation in individuals with and without coronary artery disease (18). Because the endothelium is a principal site of tPA and PAI-1 synthesis and release (19), one might expect the caffeine consumed in the present study to lead to measureable differences in plasma tPA and PAI-1 compared with placebo. However, the data from the present study would not suggest that any changes in endothelial function were sufficient to affect plasma tPA or PAI-1.

Fibrinogen levels increased during exercise in the present study, but were not influenced by caffeine. Fibrinogen is a complex molecule that has a well-established role in the coagulation cascade. It is also increasingly recognized as an acute phase reactant that plays a key role in inflammation (28). Fibrinogen synthesis in the liver is stimulated primarily by the inflammatory cytokine IL-6 via a mechanism that is unclear in humans. Numerous studies have demonstrated that IL-6 increases substantially during exercise in a duration- and intensity-dependent manner (29,30). Furthermore, compared with placebo, caffeine consumption induces greater IL-6 increases in response to acute bouts of both strength and endurance exercise (31,32). These observations support a hypothesized influence of caffeine on fibrinogen’s response to exercise, at least indirectly. However, we did not observe any such effect. The complex interplay among caffeine, exercise, inflammation, and lipid metabolism is yet to be elucidated and merits further study.

Unlike the other primary outcome variables, factor VIII was affected by caffeine consumption. The mechanism responsible for this response is not clear. One potential explanation for this finding is the combined effect of exercise and caffeine on hepatic blood flow. The liver is a principal site of factor VIII synthesis (33). Hepatic blood flow decreases progressively with increased exercise intensity (34) and is reduced by a moderate dose of caffeine in healthy adults (35). It is therefore plausible to expect caffeine consumption further reduced liver blood flow during exercise, which may have impacted factor VIII synthesis and release from the liver. Another explanation for these findings is related to nitric oxide (NO) or the β-adrenergic system, which are theorized to modulate the factor VIII response to exercise (36,37) and are modulated by a single dose of caffeine (38,39). Thus, acute consumption of caffeine could augment NO and/or catecholamine levels during exercise, which then stimulates factor VIII production through a yet to be identified mechanism. Finally, the time courses of exercise-induced changes of individual plasma markers of hemostatic activity are varied (40). Caffeine may influence the time course of the factor VIII response to exercise in a way that is unique compared to other markers of coagulation and fibrinolysis. The current study, which included a limited number of hemostatic parameters and a single postexercise measurement, is unable to explore this possibility. Future research is warranted to elucidate these putative mechanisms underlying caffeine’s impact on the coagulative and fibrinolytic responses to exercise.

The present study is limited to young, apparently healthy men, and these findings may not apply to other populations, particularly women or older adults. Although participants in this study were aerobically fit, with V˙O2max values that place them in the 75th percentile for their age, we have no measures of their physical activity level, which may influence the hemostatic response to exercise. We cannot exclude the possibility of activity level influencing the results of the study. The dose of caffeine utilized in the present study, though within normal limits for use as an ergogenic aid, is substantially higher than the caffeine content found in many popular energy drinks, a common cup of coffee, and other products. Future research might explore the effects of varying dosages and/or delivery methods of caffeine on markers of hemostasis. Finally, the incremental exercise test used in the present study is a commonly used laboratory technique, but does not replicate a typical exercise stimulus. The literature consistently shows that maximal-intensity exercise provokes significant hemostatic responses, and the decision to use this particular exercise stressor was intended to maximize our ability to discern a potential effect of caffeine on those responses. It is recommended that future research explore the influence of caffeine on the hemostatic and fibrinolytic responses to acute bouts of constant-intensity exercise that closely resembles the exercise stimulus commonly utilized during recreational exercise, or experienced by athletes in training and competition.

In conclusion, this study explored the influence of a single dose of caffeine on various hemostatic and fibrinolytic responses to acute, high-intensity exercise. Caffeine did not modulate the increase in fibrinolytic capacity observed during exercise, nor did it affect fibrinogen concentrations. However, consumption of caffeine led to a significantly augmented increase in coagulation factor VIII. In summary, these results suggest caffeine consumption before exercise causes increased coagulation potential without a similar increase in fibrinolysis. These findings may indicate caffeine elevates risk of a thrombotic event during exercise.

This study was funded, in part, by a Ball State University ASPiRE grant (P.N., L.F.) The authors declare that no competing interests influenced any aspect of the study. The results of the present study do not constitute endorsement by ACSM. Results of the study are presented clearly, honestly, and without fabrication, or inappropriate data manipulation.

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Keywords:

HEMOSTASIS; COAGULATION; PLASMINOGEN; FIBRINOLYSIS

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