European Journal of Vascular & Endovascular Surgery
Volume 31, Issue 3 , Pages 266-273, March 2006

A Preliminary Study on the Effects of Exercising to Maximum Walking Distance on Platelet and Endothelial Function in Patients with Intermittent Claudication

  • P. Collins

      Affiliations

    • Department of Vascular Surgery, Aberdeen Royel Infirmary
    • ,
  • I. Ford

      Affiliations

    • Department of Vascular Surgery, Aberdeen Royel Infirmary
    • ,
  • D. Ball

      Affiliations

    • Department of Vascular Surgery, Aberdeen Royel Infirmary
    • ,
  • E. Macaulay

      Affiliations

    • Department of Vascular Surgery, Aberdeen Royel Infirmary
    • ,
  • M. Greaves

      Affiliations

    • Department of Vascular Surgery, Aberdeen Royel Infirmary
    • ,
  • J. Brittenden

      Affiliations

    • Corresponding Author InformationCorresponding author. Dr J. Brittenden, C/O Aberdeen Royal Infirmary, Ward 36, Foresterhill, Aberdeen, Scotland AB25 2ZN, UK.
    • Department of Vascular Surgery, Aberdeen Royel Infirmary

Accepted 5 October 2005. published online 16 December 2005.

Article Outline

Abstract 

Background

Platelet and endothelial activation has been shown to be increased in patients with intermittent claudication (IC). Recent studies have suggested that exercise may induce further platelet activation. The aims of this study were to investigate the effect of exercising to maximum walking distance on platelet and endothelial function in patients with intermittent claudication who were receiving statin and aspirin therapy compared with age matched healthy controls.

Methods

Platelet aggregation through COX-mediated and thrombin receptor activator peptide (TRAP)-stimulated GPIIb/IIIa pathways was measured by the Ultegra point of care system in 20 patients with IC on aspirin and 20 healthy volunteers before, immediately and 1h after exercising to treadmill maximal walking distance (MWD). Soluble P-selectin, vWF and sICAM were measured using an enzyme linked immuno-sorbent assay technique.

Results

Baseline platelet aggregation was significantly reduced in patients with IC compared to volunteers (p<0.05). In patients, exercising to MWD significantly reduced platelet aggregation (COX, median −5% [range −24 to 13%]; p=0.02; GPIIIa/IIb, median −13% [range −72 to 33%]; p=0.02) immediately post-exercise which returned to baseline values at 1h. There was no change in the healthy volunteers following the same median duration of exercise. Baseline sP-selectin levels were higher in the patients with IC compared to the healthy volunteers [Median values (interquartile range), 42.72 (33.28–54.24) versus 29.16 (24.40–34.10), p=0.0003] but there were no differences in vWF levels. Both sP-selectin and vWF levels increased significantly in the control and patient group following exercise (p<0.005). sICAM were higher at baseline in the patients with IC but were unchanged following exercise [Median values (interquartile range),560.9 (405.5–739.4) versus 467.0 (325.7–643.4), p<0.05].

Conclusion

This study is the first to show that platelet aggregation is reduced immediately following treadmill exercise to maximum walking distance in patients with IC despite a rise in sP-selectin and vWF, suggesting endothelial activation. The inhibition of platelet aggregation after exercise in subjects on antiplatelet and statin therapy suggests that exercise is unlikely to exacerbate platelet thrombus formation in patients with IC.

Keywords: Platelet aggregation, Soluble P-selectin, sICAM, von Willebrand factor, exercise, intermittent claudication

 

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1. Introduction 

Supervised exercise therapy has been shown to improve walking distances and improve quality of life in patients with intermittent claudication (IC).1 However, despite these proven benefits of exercise therapy, recent evidence suggests that exercise in patients with IC may induce a systemic inflammatory response.2, 3, 4 There is concern that exercise is associated with an ischaemia-reperfusion type injury with the release of oxygen free radicals, neutrophil activation and the release of pro-inflammatory eicosanoids.2, 3 To date, few studies have investigated the effect of exercise on platelet function in patients with IC Platelets, through their interaction with the vascular endothelium and their role in thrombus formation, have been implicated in the development and progression of atherosclerosis and in the pathogenesis of acute ischaemic events.4 Recent studies have shown that platelet activation is increased in patients with peripheral arterial disease (PAD) despite the use of aspirin.5, 6, 7, 8

The effects of exercise on platelet function have been assessed mainly by measurement of sP-selectin, a marker of platelet activation in four previous studies. Exercising on a treadmill to maximum walking distance (MWD) is associated with either no change or an increase in sP-selectin immediately following exercise.9, 10, 11, 12 P-selectin is a protein found in the alpha granules of resting platelets and the Weibel–Palade bodies of endothelial cells.13 On activation, P-selectin is expressed on the cell surface and then released into the circulation. It is thus a marker of both platelet and endothelial activation.13 More specific and well validated measures of platelet activation include flow cytometry and platelet aggregation.14 To date, two studies have assessed the effect of exercise on platelet function using flow cytometry in patients with intermittent claudication. These have shown an increase in platelet surface markers of activation such as P-selectin and GPIIb/IIIa.15, 16 To the best of our knowledge the effect of exercise on platelet aggregation in patients with IC has not previously been reported. Flow cytometry and aggregation assess different aspects of platelet function and a lack of correlation has been described in patients with intermittent claudication, aortic aneurysms and carotid disease.6

Platelet adhesion to the vascular endothelium is mediated by von Willebrand factor (vWF),17 which also serves as a marker of endothelial function. VWF levels have been shown to be increased in patients with intermittent claudication, but the effect of exercise is unclear with some studies showing an increase.12, 18 and others no change following exercise to maximum walking distance.19, 20 Soluble intercellular adhesion molecules such as sICAM-1, also serve as a marker of endothelial and platelet function and are known to be elevated in patients with IC and those at risk of developing PAD.21 Exercising to maximum walking distance has been shown to increase levels of sICAM-1 in patients with IC.12, 22

We hypothesised, that in patients with IC who were already receiving appropriate secondary prevention including aspirin and a statin that the apparent exercise induced platelet activation would be attenuated. The aims of this study were to investigate the effects of treadmill exercise on platelet and endothelial function in patients with intermittent claudication and healthy controls as assessed by platelet aggregation, soluble plasma P-selectin, von-Willebrand factor (vWF) and sICAM-1.

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2. Patients and Methods 

The study population consisted of 20 patients with intermittent claudication on best medical therapy and 20 healthy controls. The study was approved by the local research ethics committee and written consent was obtained. Patients were required to have a diagnosis of chronic, stable intermittent claudication for at least 6 months and an ankle brachial pressure index (ABPI) of less than or equal to 0.8. All patients were on secondary prevention therapy which included 75mg of aspirin and statin therapy of at least 6 weeks duration. Statin therapy consisted of 40mg of simvastatin or pravastatin and 10mg of atorvastin, depending on individual General practitioners prescribing practice. Patients on clopidogrel, anti-inflamatory therapy, cilostazol or praxilene were excluded as were patients with diabetes. Patients who were judged unable to exercise due to other co-existing morbidities were excluded. The healthy age-matched volunteers were recruited from the surgical out-patient clinics. The presence of cardiovascular disease was excluded by medical questionnaire and physical examination including ABPIs. All volunteers had an ABPI greater than or equal to one. No control subject was taking anti-platelet, statin or non-steroidal therapy for at least 14 days prior to testing. The demographic details for the patient and volunteer group are shown in Table 1.

Table 1. Demographics of patient with IC and volunteer
Volunteers (n=20)Patients with IC (n=20)
Male:Female11:916:4
Mean age (SD)63 (10)68 (8) *
Mean ABPI (SD)1.14 (0.10)0.62 (0.13)
Smokers
Never131
Reformed512
Current27
Aspirin therapy020

Numbers represent means with standard deviations in brackets.

*p=0.072, unpaired t-test.

2.1. Treadmill exercise 

Patients with IC walked on a treadmill (speed 3.5km/h, incline 5 °) to their maximum walking distance. Exercise duration, time to onset and resolution of typical calf pain was recorded for all patients. Healthy controls walked for 3min and 20s which corresponded to the average patient exercise duration and represented a walking distance of 194m.

2.2. Blood sampling and processing 

Patients and volunteers attended for exercise after 9 am fasted for at least 6h having abstained from unaccustomed physical activity for the preceding 24h. All subjects were rested for 30min in a supine position prior to initial blood sampling. An 18 G cannula was inserted into a large vein in the ante-cubital fossa. Patency was maintained by flushing the cannula with 5ml boluses of 0.9% normal saline between sampling. All blood samples were collected using a ‘double syringe’ technique and without the use of a tourniquet. The first 10ml of blood collected was discarded. Citrated blood for platelet aggregation was assayed within 15min of blood drawing. Blood for soluble P-selectin, vWF and sICAM-1were centrifuged (4°C at 2500 G) and the plasma separated, snap-frozen in liquid nitrogen and stored at −80°C for future analysis. Subsequent blood samples were collected immediately after the cessation of exercise and following a period of one hour of rest.

2.2.1. Platelet aggregation 

Platelet aggregation was assessed using the Ultegra Rapid Platelet Function Analyser (Accumetrics, San Diego, CA). This is a well validated, fully automated, point of care, whole blood cartridge based turbidimetric optical detection system which assesses the ability of activated platelets to bind fibrinogen coated micro-beads contained within the cartridge test wells.23, 24 Fibrinogen-coated microparticles agglutinate in whole blood in proportion to the number of available GPIIb/IIIa receptors, causing an increase in light transmittance. It has been shown to correlate well with conventional platelet aggregometry.25 The agonist in the RPFA-TRAP assay is thrombin-receptor activating peptide (TRAP) and in the RPFA-ASA assay consist of a metallic cation and propyl gallate which specifically act on the cyclo-oxygenase (COX) pathway. The analyser measures the change in the optical signal and reports it as platelet aggregation units (PAU) for the RPFA-TRAP assay and aspirin reaction units (ARU) for the RPFA-ASA. Both TRAP-stimulated and COX-mediated platelet aggregation were measured at all three timepoints. All assays were performed by the same individual. Our laboratory inter-assay variation was 5.8% for RPFA-ASA and 5.0% for RPFA-TRAP.

2.2.2. Plasma soluble (s) P-selectin 

sP-selectin was assayed using a commercially available enzyme linked immuno-sorbent assay technique (R&D Systems, Inc., Minneapolis, USA). All samples were assayed in duplicate, the mean value was calculated and all patient samples were analysed on the same run. Intra-assay coefficient of variation in our laboratory was 4.3%.

2.2.3. Plasma vonWillebrand factor (vWF) 

vWF was assayed using an in-house enzyme linked immuno-sorbent assay technique. All samples were assayed in duplicate, the mean value was calculated and all patient samples were analysed on the same run. Intra-assay coefficient of variation in our laboratory was 2.7%.

2.2.4. Soluble cellular adhesion molecule-1 (sICAM) 

S-ICAM was measured by sandwich ELISA (R&D Systems, Inc., Minneapolis, USA). All samples were assayed in duplicate, the mean value was calculated and all patient samples were analysed on the same run. Intra-assay coefficient of variation in our laboratory was 2.7%.

2.3. Statistical analysis 

All statistical analysis was performed using SPSS Version 11.5 for windows. Age data was normally distributed. The remainder of the data was non-parametrically distributed. Initial analysis was via Friedman's test (one-factor within subjects). Between time-point comparisons were performed using the Wilcoxon signed-rank test. Thus, for each patient the post-exercise values were compared to their original baseline values and, therefore, each patient served as their own control. We acknowledge that there are a large number of possible confounding variables, which could influence an individual patients response to exercise. However, it was felt that subgroup analysis of a patient cohort of 20 would be inappropriate. The difference in baseline measurements between groups was tested using the Mann–Whitney U-test. Chi-squared test was used to measure variation in demographic parameters between the groups. Expert statistical advice was sought from the Department of Statistics, University of Aberdeen.

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3. Results 

3.1. Platelet aggregation 

Baseline COX-mediated aggregation was significantly lower in the patients with IC compared to the healthy volunteers [Median values (interquartile range), 514 (341–667) versus 573 (343–751), p=0.002]. Similarly baseline TRAP-stimulated aggregation was significantly lower in the patients with IC compared to the healthy volunteers [Median values (interquartile range), 185 (120–232) versus 215 (111–313), p=0=0.005]. On the treadmill, the mean maximal walking time of the patients was 3min 20s (SD 130s) which corresponded to a mean distance of 194m (SD 12m). Exercise to maximum walking distance in the patients with IC resulted in a significant fall in both COX-mediated and TRAP-stimulated aggregation immediately post exercise (Fig. 1, Fig. 2, p<0.005, one way Friedman's test). Median percentage change was −13% (range −72 to 33% [p=0.02, Wilcoxon rank test]) for TRAP-stimulated and −5% (range −24 to 13% [p=0.005, Wilcoxon rank test]) for COX-mediated aggregation. There was no change in platelet aggregation following exercise in the volunteer group (Fig. 3, Fig. 4). None of the healthy volunteers complained of lower limb pain during the exercise.

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  • Fig. 1. 

    COX-Mediated platelet aggregation following treadmill exercise in patients with IC. Timepoint (A) baseline, (B) immediately post-exercise, (C) after 1h of rest. Data presented as box-plots-line in centre of box represents the median value; the box represents the inter-quartile range and the whiskers represent the range. Friedman test: p=0.026, p<0.005 Wilcoxon signed rank test at time B compared to baseline [0h].

  • View full-size image.
  • Fig. 2. 

    TRAP-Stimulated platelet aggregation following treadmill exercise in patients with IC. Time point (A) baseline, (B) immediately post-exercise, (C) after 1h of rest. Data presented as box-plots-line in centre of box represents the median value; the box represents the inter-quartile range and the whiskers represent the range. Friedman test: p=0.002, p<0.02 Wilcoxon signed rank test at time B compared to baseline [0h].

  • View full-size image.
  • Fig. 3. 

    COX-Mediated platelet aggregation following treadmill exercise in healthy volunteers. Timepoint (A) baseline, (B) immediately post-exercise, (C) after 1h of rest. Data presented as box-plots-line in centre of box represents the median value; the box represents the inter-quartile range and the whiskers represent the range. Friedman's test (One-factor within subjects): p>0.05

  • View full-size image.
  • Fig. 4. 

    TRAP-Stimulated platelet aggregation following treadmill exercise in healthy volunteers. Timepoint (A) baseline, (B) immediately post-exercise, (C) after 1h of rest. Data presented as box-plots-line in centre of box represents the median value; the box represents the inter-quartile range and the whiskers represent the range. Friedman's test (One-factor within subjects): p>0.05

3.2. Plasma sP-selectin 

Baseline sP-selectin levels were higher in the patients with IC compared to the healthy volunteers [Median values (interquartile range), 42.72 (33.28–54.24) versus 29.16 (24.40–34.10), p=0.003]. sP-selectin levels increased significantly in both groups following exercise (Table 2).

Table 2. Plasma soluble P-selectin, von-Willebrand factor and ICAM-1 values
GroupBaseline (A)Post-exercise (B)1h Rest (C)p
Plasma sP-selectin (ng/ml)
Volunteers29.16 (24.40–34.10)32.00 (25.80–35.34)*29.42 (26.45–36.46)<0.001*
Patients with IC42.72 (33.28–54.24)43.87 (35.17–55.47)*42.05 (31.54–54.03)0.048*

Plasma von-Willebrand Factor (IU/dl)
Volunteers135.42 (119.82–175.20)164.21 (115.96–226.18)*153.15 (104.56–208.09)0.025*
Patients with IC169.95 (131.44–192.74)174.43 (140.33–202.65)*162.75 (132.45–193.63)0.040*

sICAM-1 pg/ml
Volunteers467.0 (325.7–643.4)481.4 (370.5–762.5)451.1 (318–744.5)NS
Patients with IC560.9 (405.5–739.4)542.2 (425.0–929.6)544.1 (415.2–695.4)NS

Numbers represent medians with the inter-quartile range in brackets. Baseline (A) compared to immediately post-exercise (B), (C) after 1h of rest. p value is for Wilcoxon-signed rank test.

3.3. Plasma vWF 

There was no difference in baseline vWF levels between patients with IC and volunteers [Median values (interquartile range), 169.95 (131.44–192.74) versus 135.42 (119.82–175.20), p>0.05]. vWF levels increased significantly in both groups following exercise. The magnitude of the change was greatest in the healthy volunteers (Table 2).

3.4. sICAM-1 

Baseline sICAM-1 levels were higher in the patients with IC compared to the healthy volunteers [Median values (interquartile range), 560.9 (405.5–739.4) versus 467.0 (325.7–643.4), p<0.05]. sICAM-1 levels were unchanged following exercise in both groups (Table 2).

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4. Discussion 

To the best of our knowledge, this is the first study to investigate the effect of acute exercise on platelet aggregation in patients with IC. The patients were on secondary prevention therapy, which included a statin and aspirin both of which are known to reduce platelet aggregation.26, 27 This resulted in a lower baseline aggregation in the patients compared to the controls for both GPIIb/IIIa pathway TRAP-stimulated and COX-mediated platelet aggregation. This is reassuring, given the fact that a number of studies have shown that platelet activation as assessed by flow cytometry is increased in patients with IC despite aspirin and statin therapy.5 A previous study had shown a higher rate of spontaneous and collagen induced platelet aggregation in patients with PAD compared to healthy controls despite the use of aspirin.6 This study, however, included a mixture of patients with IC and rest pain and it is unclear if the patients were on statin therapy in addition to aspirin. In this and other studies a large variation has been shown to exist in platelet function in both patients with IC and healthy volunteers.5, 6, 7, 8 A value of less than 550 aspirin reaction units with the ultegra RPFA-ASA has been shown to correlate with platelet dysfunction consistent with aspirin use in patients.28 In this small study, seven out of 20 patients had a baseline ARU greater than 550 despite the use of aspirin therapy. For TRAP stimulated platelet aggregation the normal values expected for patients are in the range of 125–330 platelet aggregation units, which is consistent with the findings in this study.23, 24, 25 However, despite the lower baseline aggregation observed in the patients with IC, exercising to maximum walking distance resulted in a further significant fall in platelet aggregation apparent immediately after exercising. Thus, the inhibition of platelet aggregation after exercise in subjects on antiplatelet and statin therapy suggests that exercise is unlikely to exacerbate platelet thrombus formation in patients with IC.

In healthy volunteers the effect of exercise on platelet function has been shown to vary depending on the intensity of exercise and the subjects' fitness.29 Strenuous physical exercise has been shown to activate platelets in sedentary but not in physically active subjects, yet moderate exercise has an inhibitory effect on platelet aggregation. The lack of a fall in platelet aggregation in the volunteer group following treadmill exercise is likely to reflect the fact that the exercise intensity was minimal. The duration of treadmill exercise in the volunteer group was limited to allow direct comparison with the patients with IC. Thus, the inclusion of healthy controls in this study clearly demonstrates that exercise alone did not affect platelet function, but exercising to the point of muscle pain induced by ischaemia did reduce platelet activation. The observed effects on platelet function in patients with IC may be mediated through a catecholamine and haemodynamic response to exercise. It could be postulated that exercise induced epinephrine release and the effect of shear forces on the endothelium result in an increased vWF levels and nitric oxide production.30, 31, 32, 33 Platelet aggregation is attenuated by nitric oxide which is one possible explanation for the reduced aggregation noted in this study.30 The effect of aspirin and statin on nitric oxide production after exercise is not known. While it would have been desirable to have assessed the effect of exercise on platelet aggregation in patients with IC who are not on these medications this would be difficult to achieve and indeed unethical. It would also not be relevant to current accepted practice of the management of patients with IC.

In the current study we did not assess other measures of platelet activation such as flow cytometry. Two studies to date have used flow cytometry and both have shown exercise induced platelet activation with increased expression of surface markers including P-selectin.15, 16 However, while the results of these two studies may appear at odds with the results of this study, it should be noted that previous studies in patients with PAD have shown a lack of correlation between platelet aggregation and flow cytometry detected platelet activation.6 Pasupathy et al., also demonstrated an increase in platelet-leucocyte interaction and platelet-leucocyte aggregation immediately after exercise in patients with claudication.15 This was attenuated by a warm up phase allowing ischaemic pre-conditioning. This observed increase in platelet-leucocyte interactions could reflect leucocyte stimulation by exercise rather than indicating a role for platelets in exercise-induced inflammation.

It could be postulated that the reduction in platelet aggregation in vitro is due to the platelets becoming activated and degranulated in vivo and thus less responsive to subsequent stimulation.34 However, we have previously shown increased platelet aggregation and reduced sP-selectin levels but increased surface P-selectin expression immediately and 24h after surgery in patients with PAD undergoing lower limb revascularisation which is a much more potent stimulus.35 In the current study, there was also no rise in sICAM-1 levels post exercise. Activated platelets have been shown to increase the expression of ICAM-1on endothelial cells in vitro.36, 37 Thus, if the platelets were activated we might expect to see a rise in ICAM-1 following sequestration from the endothelium into the plasma.

In this and other studies, sP-selectin levels were found to be increased in patients with IC compared to healthy controls.10 Following treadmill exercise there was a further increase in sP-selectin levels in both groups. This was also associated with a rise in vWF, suggesting that this is an endothelial response rather than a shedding from activated platelets. This is supported by the recent study of McBane et al. who found significantly lower levels of alpha-granule P-selectin in platelets from patients with peripheral arterial disease compared to controls.38 Furthermore, P-selectin expression on endothelial cells is known to occur within a minute of activation and is transient, whereas platelet express P-selectin for at least an hour before being shedding it into the circulation.39, 40, 41 The previous studies which have examined the effect of treadmill exercise on sP-selectin levels in patients with IC have either shown no difference or an increase immediately following exercise.9, 10, 11, 12 The discrepancy in results may in part be due to differing exercise regimens, variation in sample timing and the fact that not all subjects were rested prior to baseline blood sampling. We ensured throughout this study that patients and volunteers were rested prior to and following the exercise regimen.42

In summary, this preliminary study is the first to show that platelet aggregation is reduced immediately following treadmill exercise in patients with IC. It has also shown a rise in sP-selectin and vWF, suggesting endothelial activation. Further, studies are required to determine the effect of the medium and long term effects of various exercise regimens including arm exercise on platelet and endothelial function. Exercising to maximum walking distance appears to have a potential beneficial effect on platelet function with a reduction in aggregation in patients with IC who are already receiving secondary prevention therapy. It is unclear at this stage, if exercise in addition to so called ‘best medical therapy’ has the potential to reduce thrombotic events in these patients. However, the inhibition of platelet aggregation after exercise in subjects on antiplatelet and statin therapy suggests that exercise is unlikely to exacerbate platelet thrombus formation in patients with IC.

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PII: S1078-5884(05)00642-8

doi:10.1016/j.ejvs.2005.10.011

European Journal of Vascular & Endovascular Surgery
Volume 31, Issue 3 , Pages 266-273, March 2006

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