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Effects of acute and chronic hematocrit modulations on blood viscosity in

endurance athletes

Article  in  Clinical hemorheology and microcirculation · January 2016

DOI: 10.3233/CH-162050

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 Manuscript CHM 15-40

Effects of acute and chronic hematocrit modulations on

blood viscosity in endurance athletes

Pichon Aurélien 1,2,3, Connes Philippe 4,5,6, Robach Paul 7.

1
Laboratory Mobility, aging & exercise (MOVE) - EA 6314, Faculty of Sport Sciences,
University of Poitiers, Poitiers, France, 86000 Poitiers.
2
Laboratory Hypoxia & Lung - EA 2363, UFR SMBH, University Paris 13, Bobigny, France,
3
Association pour la Recherche en Physiologie de l’Environnement (ARPE), UFR de
Médecine, 74 rue Marcel Cachin, 93017 Bobigny, France.
4
Institut Universitaire de France, Paris, France
5
Laboratoire CRIS EA647 – Section « Vascular biology and red blood cell », University of
Lyon 1, 69100 Villeurbanne
6
Laboratoire d’Excellence GR-Ex, Paris, France.
7
Département Médical, Ecole Nationale des Sports de Montagne, site de l’Ecole Nationale de
Ski et d’Alpinisme, Chamonix, France.

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 Manuscript CHM 15-40

ABSTRACT

The aim of the present study was to investigate the effects of manipulating hematocrit by
different methods (acute exercise, training or isovolumic hemodilution) on blood viscosity in
high-level aerobic endurance athletes. We hypothesized than increasing hematocrit does not
always cause a rise in blood viscosity.

Sixteen endurance athletes underwent maximal exercise before and after 4 weeks of training
with (LHTL; n = 10) or without (placebo; n = 6) Live High-Train Low modalities. Total
hemoglobin mass was measured before and after training by a carbon monoxide rebreathing
technique. After training, subjects performed two maximal exercise bouts separated by
isovolumic hemodilution (phlebotomy and/or plasma volume expander) to readjust red blood
cell volume and plasma volume to baseline values. Blood samples were obtained before and
after exercise to assess hematocrit and blood and plasma viscosity.

Training session (LHTL and placebo) increased hematocrit (Hct) in all subjects but without
any significant change in blood viscosity. The decrease in plasma viscosity in all groups may
explain this result. Isovolumic hemodilution caused a drop of Hct without any significant
change in blood viscosity at rest. Maximal exercise increased Hct, blood and plasma
viscosities in both groups, regardless of isovolumic hemodilution. However, peak
hemorheological values after exercise were lower after isovolumic hemodilution.

In conclusion, while acute increase in Hct during exercise caused an increase of blood
viscosity, the chronic increase of Hct induced by training session did not result in a rise in
blood viscosity. The lowering of plasma viscosity during training may compensate for the
increase of Hct, hence limiting its impact on blood viscosity.

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INTRODUCTION

Exercise training, acute exercise and hypoxic exposure are known to modulate red blood cell
volume (RCV)/hematocrit (Hct) [15], [27, 30]. While acute exercise increases Hct, exercise
training usually decreases it, which may result in large blood viscosity changes[7-8, 12].
Chronic hypoxia may increase blood viscosity due to polycythemia [31]. These
hemorheological modifications could impact largely on the oxygen transport and delivery to
tissue during exercise [41] because they are able to change cardiac output [11, 43] and
vascular resistance [10, 28, 38].

During Live High-Train Low (LHTL) training, athletes train near sea level and spend the
remaining time at an altitude higher than 2500m in order to improve aerobic performance [3-
4, 25, 34-35]. Therefore, these athletes are submitted to both exercise training and hypoxic
constraints, which can interact differently to adapt the oxygen transport system to the changes
in hematocrit level or red blood cell (RBC) features. It has been previously proposed that the
improvement in aerobic performance after a LHTL is caused by the erythropoietic-related
increase in RCV and arterial oxygen content. However, a rise in blood viscosity due to the
increase in RCV may increase vascular resistance, which could in turn, theoretically, limit the
cardiac output and decrease both maximal oxygen uptake and thus performance [38]. Besides,
several studies reported significant associations between blood fluidity and indices of aerobic
physical fitness such as time of endurance until exhaustion, exercise capacity at 170 beats/min
or maximal oxygen consumption (VO2max)[5-6]. Indeed, blood viscosity, and more widely
blood rheology, has been proposed to be a determinant of VO2max [12, 38]. However, the
effects of the interaction between acute exercise, training and hypoxia exposure on Hct and
blood viscosity have never been investigated.

Therefore, we investigated the effects of LHTL training, maximal exercise and isovolumic
hemodilution (IH) on hemorheological and hemodynamics parameters. We hypothesized that
increasing hematocrit does not always cause a rise in blood viscosity.

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METHODS

The present experiment is part of a double-blind, placebo-controlled study on LHTL reported

in detail elsewhere [36, 40]. Sixteen (15 males and 1 female, 29±6 years, 179±8 cm, 69±9 kg)
trained cyclists (n=13) and triathletes (n=3) participated in the study after giving oral and
written informed consent. The study was approved by the Ethics Committee of Zurich (2010-
066/0) and Vaud (215/10) (Switzerland), and conformed to the Declaration of Helsinki.

Study design

All subjects resided at the Centre National de Ski Nordique (1135 m, Prémanon, France)
while all experimental procedures were performed at the neighbouring La Vallée hospital
(1020 m, Le Sentier, Switzerland). During the first 2 weeks (lead-in period), all subjects were
exposed to the normal environment at Prémanon and trained normally. For the following 4
weeks (intervention period), the subjects were assigned in a double-blinded, placebo-
controlled manner to ≥16 h/day of either normobaric normoxia (placebo group, n=6) or
normobaric hypoxia equivalent to 3000 m of altitude (LHTL group, n=10): i.e., training camp.
Two testing sessions were scheduled for the present study, the first one during the lead-in
period (baseline), and the second one during the last 3 days of the LHTL intervention period
(W4). Blood parameters were assessed at rest during baseline measurement and at W4 after
the training camp. The effects of hemodilution and maximal exercise testing on blood
parameters were also tested at W4 by taking blood samples before and after a VO2max
determination test [36] performed in control condition and after isovolumic hemodilution.

Maximal oxygen uptake

VO2max was tested on an electronically braked bicycle ergometer (Monark, Varberg, Sweden),
and the athletes used their own shoes and pedals and a race saddle. The exercise protocol
started with a warm-up period of 5 min at a workload of 150 W, followed by 5 min at 200 W,
except for the female athlete, who warmed up at 100 and 150 W. Thereafter, the workload
was increased by 25 W/min−1 until voluntary exhaustion. During the last minutes of the test,
subjects were vigorously encouraged to reach exhaustion, and achievement of VO2max was
established by standard criteria in all tests [2]. Subjects wore a face mask covering their
mouth and nose for breath collection (Hans Rudolph, Kansas City, MO), and O2 and carbon
dioxide concentration in the expired gas were continuously measured and monitored as
breath-by-breath values (Quark, Cosmed, Rome, Italy). The gas analyzers and the flowmeter
of the applied spirometer were calibrated prior each test.

Cardiac output

HR was measured continuously using electrocardiography. Stroke volume (SV) and cardiac
! c) were continuously measured using a non-invasive impedance cardiograph
output ( Q
device, the PhysioFlow PF-05 (Manatec biomedical, Paris, France). This bioimpedance

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 Manuscript CHM 15-40

method uses changes in thoracic impedance during cardiac ejection to calculate SV. The
PhysioFlow concept and methodology have been validated during a maximal progressive
exercise [33, 39]. Cardiac parameters were averaged over 30-s intervals to determined
maximal SV (SVmax), Q! c (Q
! cmax) and HR (HRmax).

Hbmass measurement

Hbmass was quantified by a modified version [26] of a carbon monoxide (CO)-rebreathing

technique [9]. A detailed description of this procedure is given elsewhere [40]. Hbmass was
determined twice during the lead-in period (baseline) and twice at W4, and averaged values of
each duplicate were used for the analyses. The coefficient of variation for Hbmass, assessed
from duplicate baseline during the lead-in period, and expressed as the percent typical error
(ie, SD of difference scores/√2), was 2.6%.

Isovolumic hemodilution

Maximal exercise was performed before and after isovolumic hemodilution at the end of the
intervention period (W4). The amount of extra red blood cells that was gained after LHTL
was withdrawn by phlebotomy, and this volume was replaced by 6% hydroxyethyl starch
(Voluven 6%, Fresenius Kabi, Bad Homburg, Germany) to achieve similar blood volume and
RCV values to those measured at baseline. For each subject, the volume of blood to be
withdrawn was calculated as ΔHbmass /[Hb]×100, with ΔHbmass being the change in Hbmass
with LHTL intervention and [Hb], resting hemoglobin concentration at W4 (measured by a
Radiometer ABL800 FLEX analyser). Taking into account analytical variability for Hbmass
determination, phlebotomy was conducted only if the volume of blood to be removed
exceeded 190 ml. Within 15 min after completion of the first exercise bout, blood was
withdrawn into a blood bag (MRG6282L or MCG2272L, Macopharma, Mouvaux, France)
positioned on a mixing scale (Docon, Möller Medical, Fulda, Germany), and then stored at
4°C. Hydroxyethyl starch infusion was initiated immediately after phlebotomy. In subjects for
whom plasma volume decreased without a concomitant change in Hbmass, only the starch
infusion was performed. The subjects were in supine position and were blinded towards the
procedure by placing their arm through a screen. In subjects for whom no manipulation was
necessary, blood was withdrawn and re-infused to simulate these procedures. The second
maximal test was initiated 2 h after the end of the first bout of exercise. After completion of
the second exercise test, the subjects were either re-infused with their own blood, or infused
with saline, again by using a blinded design. Blood sampling and infusion were performed via
an 18-G catheter inserted in an arm vein [36].

Hematological and hemorheological measurements

Venous blood was sampled in EDTA at baseline and before and after the VO2max tests in both
control and isovolumic hemodilution conditions to perform hematological and
hemorheological measurements. Hct was measured after blood microcentrifugation (Model
1.14, Sigma). Hemorheological parameters were measured within the four hours after

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sampling and after full re-oxygenation of blood for 10-15 min in line with the recent
international guidelines for hemorheological measurements (Baskurt et al. 2009). Blood
viscosity was measured at native hematocrit and at room temperature (≈ 25°C) with a
cone/plate viscometer (Model DV-II, Brookfield Engineering Laboratories, Middleboro,
Massachusetts, USA), with CPE40 spindle at a shear rate of 225 s-1. Plasma viscosity was also
measured with the same device at 450 s-1.

Statistical analysis

The statistics were performed by considering the two groups of subjects (LHTL vs PLA).
Homogeneity of variances and normality of distribution were verified. First, a two ways
ANOVA was performed to assess the effect of LHTL on blood parameters between baseline
and W4 at rest in the 2 groups of subjects. Then, a MANOVA was performed to assess the
effects of maximal VO2max test (before & after) and of isovolumic hemodilution (control vs
isovolumic hemodilution conditions) on all blood parameters in the 2 groups of subjects
(LHTL vs PLA). When significant effects were obtained with the MANOVA, Newman-Keuls
post-hoc tests were performed. Statistics were carried out with the Statistica software
(Statistica). The values are reported as arithmetic means ± SD. Differences were considered as
significant for p<0.05.

RESULTS

Effects of training camp

! c and systolic and diastolic blood pressures were not affected by

Resting values of HR, SV, Q
the LHTL camp.

Training increased VO2max, expressed in ml.min-1, by an average of 1.0 ± 3.8 % in all subjects
(p = 0.06). However, VO2max remained unaffected by the intervention in the LHTL group and
did not differ between groups at any time point. At W4, VO2max did not changed both in the
placebo (2.0 ± 1.6 %) and LHTL (0.0 ± 2.8 %) groups [36].

Despite a similar significant increase in Hct in the two groups between baseline and W4 at
rest (Table 1), blood viscosity remained unchanged. The plasma viscosity of the LHTL and
PLA groups decreased significantly at W4 compared to baseline.

Effects of exercise test

An increase of HRmax was observed for the two groups at W4 as compared to baseline
! cmax remained unchanged.
whereas SVmax and Q

Maximal exercise tests increased Hct, plasma viscosity (significant in the PLA group only)
and blood viscosities (all subjects) at W4.

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 Manuscript CHM 15-40

Effects of isovolumic hemodilution

Resting HR increased whereas maximal exercise HR values decreased after isovolumic

! c did not change
hemodilution. However, resting and maximal exercise values of SV and Q
significantly after isovolumic hemodilution.

Hbmass expansion and plasma volume contraction were observed at W4 in 5 responders to the
LHTL stimulus (LHTL+): blood withdrawal (280 ± 74 ml) was followed by plasma volume
expander infusion (540 ± 89 ml) to readjust values to baseline characteristics. No change in
Hbmass was observed in the 5 remaining athletes submitted to LHTL (LHTL-) and placebo
subjects: so, plasma volume contraction was compensated by plasma volume expander
injection of 572 ± 299 and 567 ± 169 ml, respectively. In all subjects [Hb] decreased from
15.0 ± 0.8 g/dL to 14.1 ± 0.7 g/dL after manipulations.

Isovolumic hemodilution decreased Hct before exercise and at the end of exercise (in both
groups), compared to the condition where hemoglobin mass and/or Hct were not manipulated.
While resting blood viscosity decreased in the PLA group after isovolumic hemodilution,
there was a very slight and non-significant change in the LHTL group. In contrast, both
groups had a reduction in blood viscosity at the end of exercise after isovolumic hemodilution
as compared to before intervention. Plasma viscosity was unchanged by the isovolumic
hemodilution intervention.

DISCUSSION

Our study demonstrates that Hct increased after 4 weeks of training camp in all subjects but
without any significant change in blood viscosity, mainly because of a concomitant decrease
in plasma viscosity. The normalization of Hct caused by isovolumic hemodilution, as
compared to the pre-experiment, did not induce significant change in blood viscosity at rest.
At maximal exercise, isovolumic hemodilution caused a reduction in Hct and blood viscosity
as compared to the control condition.

In this study we observed that maximal exercise induced a significant increase in hematocrit
and plasma viscosity, which caused a rise of blood viscosity. This is a classical finding, which
has been discussed extensively in the past [10]. Briefly, the increase in hematocrit during an
effort may be due to an efflux of plasma from the vascular space to the interstitial fluids and
muscles [13], the adrenergic stimulation of the spleen which contracts to release a certain
amount of stored red blood cells [22] and/or exercise dehydration. Isovolumic hemodilution
resulted in a decrease in hematocrit at rest in the two groups but the change in blood viscosity
was significant in the PLA group only. In contrast, both hematocrit and blood viscosity at

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maximal exercise were reduced after isovolumic hemodilution compared to before the
exercise test. These findings clearly confirm the already known influence of hematocrit on
blood viscosity. Considering that the training camp induced a plasma volume contraction, we
performed an isovolumic hemodilution to restore the blood volume to the baseline values.
However, the infusion of hydroxylethyl starch after the phlebotomy could be considered as an
acute plasma volume expansion as compared to the post training camp values and could
induce some microcirculatory disorders due to the changes in blood volume and blood flow
[29]. Indeed, the blood flow in the microcirculation and the macrocirculation could increase
after the infusion of 500 ml of hydroxyethyl starch [21].

Surprisingly, we observed an increase of Hct after the 4 weeks training-period whereas some
authors [8] observed a decrease of Hct, which was attributed to the increase in plasma
volume, even if the later phenomenon is not always observed [20]. A possible reason for the
increase in Hct after the training camp could be the confinement imposed to the subject to
induce normobaric hypoxia 16 hours per day. These unusually long periods of relative
inactivity in athletes might have conduced to a loss of plasma volume as it has been
previously observed during bed-rest confinement [19]. However, this increase in Hct after
training did not result in a concomitant increase of blood viscosity. This may be explained by
the parallel decrease of plasma viscosity within the same period. The same finding has been
reported by Esteva et al. [16] in rats exposed to a 22-days program of intermittent hypobaric
hypoxia. The authors proposed that the decrease of plasma viscosity should be interpreted as a
compensatory response to limit the consequences of the rise in hematocrit on blood viscosity.
Aerobic training has been shown to promote the decrease in plasma viscosity [37]. We did not
measure the level of various plasma proteins known to modulate plasma viscosity but one
may speculate that fibrinogen, a strong modulator of plasma viscosity [1], could have
decreased after the training camp [42]. Indeed, in contrast to what happens during acute
exercise, a rise in Hct does not always cause a rise in blood viscosity.

The same kind of finding has been recently reported in patients with the double heterozygous
form of sickle cell disease; i.e. sickle SC disease [23]. In this cohort study, it was clearly
demonstrated that patients characterized by blood hyperviscosity were not always those with
the highest Hct. Another study performed in the homozygous form of sickle cell disease (i.e.,
sickle cell anemia or SS) showed that patients with osteonecrosis had lower hemolytic rate
and higher Hct than patients without, but the two groups had similar blood viscosity [24].
This surprising finding was explained by the fact that red blood deformability was increased
in patients with osteonecrosis, hence limiting the impact of the increased Hct on blood
viscosity. Unfortunately, RBC deformability was not measured in the present study and
further works are needed to test the influence of LHTL on this parameter but the decrease of
plasma viscosity during LHTL has probably partly played this compensatory role.

Plasma volume expander volume infusion associated or not with blood withdrawal induced an
increase in resting HR and a significant decrease in Hct, blood viscosity and HRmax. The
decrease in Hct and blood viscosity shows that hemodilution was effective. The increase in
resting HR could be due to the hyperoncotic properties of the hydroxyethyl starch
administrated in the present study that could increase plasma volume because of a possible

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shift of interstitial fluid into the vasculature [32]. At rest, a small decrease in Hct (3%) was
observed in this study after isovolumic hemodilution. This change, lower than 10%, is
generally followed by a significant increase in the O2 partial pressure in heart and muscles due
to cardiac output and blood flow adaptations [18]. However, VO2max, maximal stroke volume
and maximal cardiac output did not change significantly. The effects of hemodilution on
performance decrement have been already observed in healthy subjects [26, 36]. However, it
was also shown that moderate plasma volume expansion (282 mL; i.e. half of the isovolumic
hemodilution used in our study) could improve exercise performance and delayed fatigue
despite a decrease in Hct probably through an increase in SV and Q ! c [14] suggesting that an
increase in blood volume could improve exercise tolerance. Some reasons could be proposed
to explain the decrease in aerobic performance observed in this experiment [36] after
isovolumic hemodilution. First, the decrease in Hct after isovolumic hemodilution could result
in a decrease of oxygen transport capacity and to a possible decline in local tissue
oxygenation. Indeed, red blood cell count could impact oxygen delivery at the muscle level
and modify exercising muscle blood flow [17]. Moreover, the unchanged Q ! cmax after
isovolumic hemodilution in association with the lower blood viscosity could result in a
decreased wall shear stress causing a lower nitric oxide production by endothelial cells [10].
The resulting decreased vasodilation might in turn reduce tissue oxygenation.

In conclusion, exercise training, while affecting Hct, does not affect blood viscosity because
of the decrement of plasma viscosity. In contrast, acute change in Hct during exercise causes a
rise in blood viscosity, which may be lowered by isovolumic hemodilution. This study
demonstrates that an increase of Hct does not always impact on blood viscosity.

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 Manuscript CHM 15-40

ACKNOWLEDGMENTS

We are grateful to the participants in the study. We thanks Siebenmann Christoph, Rasmussen
Peter, Jacobs Robert A, Diaz Victor, Nadine Crivelli and Lundby Carsten for their work and
their help during this experiments. We also would like to thank the team of Le Sentier hospital
for excellent logistical support throughout the experiment, as well as the CNSN team
(Prémanon) for valuable help during the study. This study was funded through grants obtained
from the Bundes Amt für Sport (BASPO, Switzerland), Team Danmark (Denmark) and
Ministère des Sports/Institut National du Sport, de l’Expertise et de la Performance (France).

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TABLES

Table 1 – Hemorheological parameters at baseline and after 4 weeks of LHTL before and after
maximal oxygen uptake (VO2max) exercise tests with and without isovolumic hemodilution in Live High
– Train Low (LHTL) and placebo (PLA) subjects.

W4 + Isovolumic
W4
Hemodilution
Baseline Maximal Maximal
Groups Rest Rest
exercise exercise

Hematocrit PLA 42.0±1.7 45.8±2.0 £ 49.8±1.5 * 42.1±1.6 # 46.4±1.5 *&
(%) LHTL 41.7±2.9 46.3±3.3 £ 50.9±2.5 *° 43.7±2.1 #° 47.5±2.4 *&°

Blood PLA 5.7±0.7 6.1±0.5 6.7±0.8 * 5.5±0.4# 6.1±0.4 *&
viscosity
LHTL 5.5±0.9 5.8±0.5 7.1±0.7 *° 5.5±0.7 6.3±0.6 *&
225/s (cps)

£
Plasma PLA 2.17±0.17 1.70±0.10 1.87±0.14 * 1.745±0.05 1.92±0.15 *
viscosity £
LHTL 2.04±0.28 1.75±0.16 1.86±0.10 1.74±0.12 1.81±0.14
450/s (cps)

Bold values: Main effect of hemodilution; Vertical line: main effect of time (post-exercise vs rest); £:
vs baseline; *: vs before VO2max in the same condition; #: vs rest in the control condition (W4); &: vs
post VO2max in control condition (W4); °: vs placebo group.

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 Manuscript CHM 15-40

Table 2 – Hemodynamic parameters before and after 4 weeks of LHTL with and without isovolumic
hemodilution in responders (LHTL+), non-responders (LHTL-) and placebo (PLA) subjects.

REST MAXIMAL EXERCI

W4 +
Groups Baseline W4 Isovolumic Baseline W4
Hemodilution

HR PLA 67.2 ± 10.1 75.2 ± 4.9 80.2 ± 12.2 185.6 ± 10.0 192.8 ± 7.1
(bpm) LHTL 66.0 ± 13.4 67.8 ± 7.4 74.6 ± 7.3 189.1 ± 9.2 191.5 ± 6.8

SV PLA 107.5 ± 9.2 78.2 ± 11.14 78.2 ± 11.1 147.5 ± 35.9 156.0 ± 30.7
(mL) LHTL 93.8 ± 22.1 95.1 ± 34.2 95.1 ± 34.2 163.5 ± 20.1 159.3 ± 7.1

Qc PLA 7.17 ± 1.14 6.30 ± 0.78 6.25 ± 0.87 30.23 ± 2.21 31.07 ± 2.04
(L) LHTL 5.94 ± 1.29 6.78 ± 2.05 7.42 ± 2.33 27.21 ± 5.65 29.78 ± 5.61


Bold values: Main effect of hemodilution; Vertical line: main effect of time (before vs after training).

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