See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/51979005

Exercise limitation, exercise testing and exercise recommendations in sickle

cell anemia

Article in Clinical hemorheology and microcirculation · January 2011

DOI: 10.3233/CH-2011-1465 · Source: PubMed

CITATIONS READS

61 5,802

4 authors, including:

Philippe Connes Roberto F Machado

Institut Universitaire de France - Claude Bernard University Lyon 1 Indiana University School of Medicine
287 PUBLICATIONS 4,558 CITATIONS 303 PUBLICATIONS 8,478 CITATIONS

SEE PROFILE SEE PROFILE

Olivier Hue
Université des Antilles
236 PUBLICATIONS 3,966 CITATIONS

SEE PROFILE

Some of the authors of this publication are also working on these related projects:

Sickle Cell Disease View project

Pulmonary Arterial Hypertension View project

All content following this page was uploaded by Olivier Hue on 01 June 2014.

The user has requested enhancement of the downloaded file.

Clinical Hemorheology and Microcirculation 49 (2011) 151–163 151
DOI 10.3233/CH-2011-1465
IOS Press

Exercise limitation, exercise testing and

exercise recommendations in sickle cell
anemia
Philippe Connesa,b,∗ , Roberto Machadoc , Olivier Huea and Harvey Reidd
a
Laboratory ACTES, Department of Physiology, University of the French West Indies, Pointe a Pitre,
Guadeloupe, French West Indies
b
Inserm, Pointe-à-Pitre, Guadeloupe, Université des Antilles et de la Guyane, Pointe-à-Pitre, France
c
Section of Pulmonary, Critical Care Medicine, Sleep and Allergy, University of Illinois Chicago, Chicago,
USA
d
Department of Basic Medical Sciences (Physiology Section), Faculty of Medical Sciences, University
of the West Indies, Mona Campus, Kingston, Jamaica, West Indies

Abstract. Sickle cell anemia (SCA or SS homozygous sickle cell disease) is an inherited blood disorder caused by single
nucleotide substitution in the ␤-globin gene that renders their hemoglobin (HbS) much less soluble than normal hemoglobin
(HbA) when deoxygenated. The polymerization of HbS upon deoxygenation is the basic pathophysiologic event leading to
RBC sickling, hemolysis, vasoocclusion and ultimately to chronic organ damage. The metabolic changes imposed by exercise
may initiate sickling and vaso-occlusive episodes. Further, in patients with SCA, exercise limitation may be related to anemia
or chronic complications such as pulmonary vascular disease, congestive heart failure and chronic parenchymal lung disease.
Few studies have investigated the cardiorespiratory responses of patients with SCA during either symptom-limited maximal
exercise test on cyclo-ergometer or during a six minute walk test. Therefore, patients are advised to start exercise slowly and
progressively, to maintain adequate hydration during and after exercise, to avoid cold exposure or sudden change in temperature,
and to avoid sports associated with mechanical trauma. There are, however, lack of evidence to allow practitioners to prescribe
an exercise program for patients with SCA, and individuals are usually encouraged to exercise on a symptom-limited basis.
Finally, this review will also highlight the basic principles that are often used for exercise practice and could be used for exercise
prescription and rehabilitation in patients with sickle cell anemia.

Keywords: Sickle cell disease, exercise rehabilitation, exercise testing, clinical complications, physical fitness

1. Sickle cell anemia and pathophysiologic mechanisms

African traditional medicine knew sickle cell anemia (SCA) for centuries. During the cold season,
a part of the African population experienced chronic rheumatisms. In 1910, James Herrick was the
first scientist to describe sickle red blood cells [50] and the mutation causing HbS was described in
1977 by Marotta et al. [67-68]. The gene defect is a mutation of a single nucleotide (A −→ T) on the
∗
Corresponding author: Philippe Connes, Laboratory ACTES (EA 3596), Department of Physiology, University of the French
West Indies, 97159 Pointe a Pitre, Guadeloupe, French West Indies. Tel.: 590 690 36 76 28; Fax: 590 590 83 05 13; E-mail:
pconnes@yahoo.fr.

1386-0291/11/$27.50 © 2011 – IOS Press and the authors. All rights reserved
152 P. Connes et al. / Sickle cell disease and exercise

␤-globin chain, which results in the substitution of valine for glutamic acid in the sixth position of the
beta chain of the hemoglobin S (HbS). The hydrophobic residues of valine at position 6 of the beta chain
in hemoglobin are able to associate with the hydrophobic patch, causing HbS molecules to aggregate and
form fibrous precipitates under deoxygenated condition. Such a phenomenon is called “polymerisation
of HbS” [81, 88] and is usually reversible on reoxygenation. However, after many repeated cycles of
deoxygenation/reoxygenation, RBCs become and remain irreversibly sickled [16, 59, 61].
The term, sickle cell disease (SCD), refers to the homozygous state (HbSS) or SCA, and also to
compound heterozygous states in which other hemoglobin disorders are inherited together with HbS,
such as sickle-hemoglobin C disease (SC), sickle-␤+ thalassemia and sickle-␤0 thalassemia. More than
50 million of persons are affected by this disease worldwide [8].
When red cells from patients with SCA become deoxygenated in the capillaries, the HbS polymerizes
inducing the sickling process, which decreases the deformability of the red blood cells (RBC). Rigid cells
fail to move through the small blood vessels, hence blocking local blood flow in the microvasculature
[54, 66]. The abnormal rheology of the sickled red cells contributes to tissue hypoxia, vaso-occlusive
crisis and ultimately organ damage. Moreover, these rigid RBCs are more fragile than normal RBCs,
hence promoting hemolytic episodes and often severe anemia [39]. It is known that the percentages of
HbS and HbF determine the polymerization tendency and thus can modulate the severity of SCA [83].
However, the pathophysiology of HbS polymerization is insufficient to explain the extreme variable
phenotypic expression of SCA and its multiple complications such as vaso-occlusive painful crisis,
acute chest syndrome, pulmonary hypertension and stroke. Although SCA is a monogenic disorder, the
pathophysiologic mechanisms involved are complex.
Recent data have elucidated some of the mechanisms and events associated with the vasooclusive crisis.
For example, the following has been observed:
– abnormal rheologic properties of RBCs [5, 13, 16, 20, 29, 94]
– predilection of sickle red cells for adherence to the vascular endothelium [48, 56]
– existence of a pro-inflammatory vascular environment with circulating activated endothelial cells,
neutrophils and monocytes [38, 41, 55, 88, 90]
– marked endothelial dysfunction related to decreased nitric oxide (NO) bio-availability [55, 60]
– imbalance between hemostasic/fibrinolytic activities [43]
– alterations in the autonomic nervous system activity [5, 30, 51, 76, 86].
Hence, the morbidity and severity of SCA are modulated by several factors, such as inflammation,
cellular activation mechanisms and adhesion processes, endothelial dysfunction, and abnormal blood
rheology [16, 56, 88].

2. Risks of exercise

Health care providers are often questioned whether patients with SCA should participate in sports or
strenuous physical activity. The major question faced by health care professionals and exercise physiolo-
gists involved in SCA management is the safe level of physical activity they should recommend for their
patients. Exercise and physical activity are known to induce marked metabolic changes, such as lactic
acid production by active muscles. The presence of anemia is responsible for a faster transition from aer-
obic to anaerobic metabolism during exercise, which may stimulate the polymerization of HbS and lead
RBCs to sickle and promote microvascular occlusions [73]. An added consideration is the dehydration
 P. Connes et al. / Sickle cell disease and exercise 153

occurring during exercise together with the acute episodes of tissue hypoxia, which may also contribute
to the sickling of RBCs. Exposure to moderate temperature changes during exercise may also trigger
vaso-occlusive crisis. Furthermore, although regular exercise may improve immune function, acute bouts
of exercise may cause a temporary immune dysfunction with transient increase in several circulating
cytokines [45, 85] which may also trigger vaso-occlusive crisis through an activation of several adhesion
molecules and circulating blood cells [65] which may reduce blood flow in the microcirculation. The
genesis of reactive oxygen species during intense exercise could also promote endothelial dysfunction
and RBCs alterations.
It is often thought that prolonged endurance exercise is more stressful than short periods of exercise
in patients with SCA, however greater efforts should also be paid to the effects of short intense exercise.
For example, intense exercise, such as that which involves repeated jumping, may increase the risks for
muscle and joint injuries [49]. Contact sports, including American football, hockey, and similar events,
should be avoided, particularly by patients with splenomegaly, given the high risk of splenic rupture [52].
All these considerations stimulate fear from physicians about exercise recommendations in SCA
patients. However, as developed later in this article, recent evidences suggest that SCA patients may
practice physical activities even if specific recommendations about exercise duration and intensity is
needed.

3. Physical fitness

3.1. Physical activity/daily practice

SCA is often associated with poor nutritional status and delayed growth in adolescents [84]. These
conditions have been shown to be associated with a 10–20% greater resting energy expenditure (REE)
than is seen in healthy subjects, resulting from higher protein turnover and higher cardiac output [18,
19, 22, 87]. Indeed, to maintain their daily total energy expenditure at the same level as that of healthy
adolescents, SCA adolescents decrease their physical activity energy expenditure (PAEE) [23]. The reason
for lower physical activity in SCA patients compared with normal subjects may be attributable to the
chronic anemia [23].
Millis et al. [72] investigated the differences in performance of routine physical activities between
SCA children and children with normal hemoglobin. Each subject swam 20-yd then 40-yd followed
by a 100-yd “potato” foot-racing event. The results showed significantly reduced performance in SCA
children compared with the control group. Another study investigated the ability to perform simple
physical exercise by children with SCA and compared with children either having the sickle cell trait or
normal hemoglobin genotype (HbA) [73]. The exercises undertaken were a vertical jump to determine
the anaerobic power of leg muscles, a grip, back and leg strength, and a treadmill running test of 5 min
duration at 5 km/h. The different strengths studied and the anaerobic power were decreased in SCA
children as compared with the two other groups. The heart rate measured during the treadmill exercise
was significantly higher in SCA children than in the other children and blood lactate levels at the beginning
and at the end of exercise were greater in SCA children. The greater heart rate found in SCA children
may be interpreted as physiologic adaptation to compensate for the decreased blood oxygen transport
capacity related to anemia and microcirculatory impairment. However, results from Moheeb et al. [73]
also indicated a greater energetic cost and a greater anaerobic contribution in SCA children than in
healthy children for a low intensity exercise. These data are in accordance with the recent findings of
154 P. Connes et al. / Sickle cell disease and exercise

Balayssac-Syransy et al. [14] where a group of SCA patients and a control group performed a cycling
exercise test of 20 min duration at 50 Watts in supine position. Although the exercise intensity proposed
was moderate, SCA patients exhibited a greater cardiorespiratory stress than control subjects with heart
rate and ventilation being higher in the former group. The higher ventilation, as well as the lack of
steady-state ventilation, during the submaximal exercise was probably related to the greater lactic acid
production by exercising muscles in the SCA group [14]. All these information must be considered by
physicians when they recommend physical activity to SCA patients.

3.2. Exercise as a tool for functional and physical fitness assessment

Several studies have examined the mechanisms responsible for the exercise intolerance in SCA patients.
Multiple factors could contribute to this intolerance and they include:
– reduced oxygen carrying capacity related to low Hb level,
– functional and structural cardiac adaptations resulting from chronic anemia [6, 21],
– pulmonary parenchymal dysfunction caused by repeated episodes of acute chest syndrome [27],
– pulmonary vascular disease [24, 37] and
– peripheral vascular impairments due to frequent and repeated microvascular occlusion [24].
Callahan et al. [24] investigated whether one or more of these factors could be involved in the reduced
exercise capacity of 17 SCA patients in the steady-state condition. An important observation was that
all the patients were able to complete the symptom-limited cardiopulmonary exercise testing (CPET)
on ergocycle with intensity being incremental every 2 min, without any complications. Nevertheless, all
the patients showed abnormal exercise responses (VO2 ) responses, i.e. with at least one of the following
abnormalities: peak VO2 less than 80% predicted, anaerobic threshold (AT) less than predicted, low
oxygen (O2 ) pulse (i.e. the ratio of VO2 to heart rate which mimics the stroke volume) or low VO2 -work
rate ratio. The low AT suggested that transition from aerobic to anaerobic exercise was faster in SCA
patients than in the healthy subjects. All the patients from the study of Callahan et al. [24] had high
ventilatory reserve indicating the absence of mechanical ventilation impairment. All the gas exchange
and cardiac responses were carefully analysed by the authors and 3 main mechanisms for the exercise
limitation in SCA were proposed:
a. Anemia which can cause low peak VO2 , low AT, low O2 pulse, elevated heart rate for level of work and
increased respiratory equivalent in carbon dioxide (i.e. elevated VE/VCO2 with VE corresponding
to ventilation) [98]. The authors observed that exercise limitation could be fully explained by the
anemia in only 3 patients.
b. Pulmonary vascular disease was also involved in exercise limitation in about two third of patients.
These patients showed gas exchange abnormalities such as: alveolar-arterial oxygen tension dif-
ference [P(A-a)O2 ] >30 mmHg, abnormal dead-space to tidal volume ratio (VD/VT) in association
with a widening of the arterial-end-tidal carbon dioxide difference suggesting ventilation-perfusion
mismatch, and very high values of VE/VCO2 ) [24]. These gas exchange abnormalities were not
related to anemia and could be due to the presence of pulmonary vascular disease.
c. Peripheral vascular disease and/or myopathy. In 3 patients, the reduced exercise responses were
not fully explained by anemia or impairment in gas exchange. In addition to low VO2 response and
high ventilatory reserve, these patients had a high heart rate reserve, which is not the case in patients
with anemia alone [24]. The authors suggested that micro-vascular occlusion in skeletal muscles
 P. Connes et al. / Sickle cell disease and exercise 155

and repeated ischemia-reperfusion in those organs might have contributed to the development of
peripheral vascular disease/myopathy.

4. Exercise as a clinical tool for identifying clinical complications and for clinical survey

Although SCA patients have impaired aerobic fitness, exercise testing may provide important infor-
mation about medical problems, which may not be apparent in resting conditions but may be uncovered
by exercise. Table 1 summarizes the most frequently used cardiorespiratory parameters that have been
used for screening for SCA’ associated diseases. It has been shown that exercise testing could be useful
in the following cases.

4.1. Screening for pulmonary or peripheral vascular disease

The study of cardiorespiratory parameters and blood gas homeostasis during a symptom limited CPET
with steps increment individualized is a powerful tool to objectively determine the presence or absence of
pulmonary/peripheral vascular disease [24, 82]. Although less rich in information, the study of exercise
response during a 6-min walk test (speed and distance covered) in association with the measurement
of dyspnea [3, 40] and pulmonary function tests (notably spirometry and diffusion capacity of carbon

Table 1
Interpretation of CPET and 6-min walking test data [10, 24, 36, 69]

Classification Criteria Abnormal

Limited exercise capacity Low peak VO2 <80% predicted peak VO2
Low anaerobic threshold <predicted
Low maximum O2 pulse <80% predicted
Low VO2 -work rate ratio <9.5 ml/min/W
Low distance covered during a 6-min <predicted 6-min walking test
walking test distance = 218 + (5.14 × heightcm –
5.32× age) – (1.80 × weightkg
+ 51.31× gender)**
Abnormal gas exchange Abnormal lung function studies (at rest —
and after exercise)*
Increased P(A-a)O2 >30 mmHg
Increased VE/VCO2 >34 (at AT)
Abnormal VD/VT Peak exercise VD/VT<resting VD/VT
Presence of dyspnea —
Ventilatory limitation Low breathing reserve <15 L
Peripheral vascular limitation High heart rate reserve >30 beats/min
Cardiac abnormalities (ischemia) ST segment depression —
Elevated double product —

VO2 = oxygen consumption, O2 pulse = VO2 divided by heart rate, AT = anaerobic threshold, P(A-a)O2 = alveolar-arterial oxygen
tension difference, VD = dead space volume, VT = tidal volume.
∗
Includes spirometry, lung volumes and DLco determination.
∗∗
Gender is factored into the equation by: male = 1, female = 0 [97].
156 P. Connes et al. / Sickle cell disease and exercise

monoxide or DLco) may also give indication about the presence or absence of pulmonary vascular disease
[3, 37]. The 6-min walking test distance, alone, does not aid the clinician in differentiating the nature of a
patient’s exercise limitation. However, factors such as stride length, body weight, and walking skills may
be more important determinants of the 6-min walk test distance than aerobic capacity. Nevertheless, since
the 6-min walk test is less stressful than a symptom-limited CPET and closer from ecologic situations,
it should be preferred in patients with severe SCA (i.e. with frequently recurring crisis and/or severe
anemia). An alternative approach would be to perform CPET but not exceeding the AT.

4.2. Screening for pulmonary hypertension

Pulmonary hypertension (PHT) is an increasingly recognized complication in patients with SCA. The
prevalence of PHT is reported to be about 30% for both children and adults [2, 26, 44, 77, 79, 89]. The
screening for PHT in these patients is important since the high risk of sudden death associated with SCA
might be linked to the presence of PHT [28, 44, 62]. Recent studies have provided evidence that the
etiology of PHT in SCA patients is multi-factorial.
Exercise testing has been used in SCA patients with PHT [10, 62]. Anthi et al. [10] compared the
exercise responses during a symptom limited CPET on ergocycle and a 6-min walk test between SCA
patients with and without PHT. SCA patients with PHT had lower VO2max and lower distance covered
during the 6-min walk test than the control group, indicating exercise limitation in the PHT group. It
is important to note that more than 80% of patients from both groups were able to accomplish the
symptom limited CPET without any further complications. Patients with PHT were found to have lower
ventilatory reserve and higher VE/VCO2 values both at the AT and VO2max levels than control group.
These abnormal ventilatory responses appeared to be related to both pulmonary vascular disease and
pulmonary restrictive condition. Interestingly, the authors reported a negative relationship between the
6-min-walk distance and the tricuspid regurgitant jet velocity suggesting that this exercise protocol may
also be used as a noninvasive test to assess the severity of PHT. Although symptom limited CPET may
give extended useful information, both on physical ability and cardiopulmonary function, the 6-min walk
test may also be considered as a good indicator of PHT and cardiopulmonary function in SCA [10, 63].
Moreover, based on the risks encountered by SCA patients with PHT when subjected to symptom limited
CPET [62], it would be safer and practical to promote the 6-min walking test in this sub-population of
SCA patients. CPET may provide additional information in cases where the cause of exercise limitation
is not determined by other studies.

4.3. Screening for heart disease

Both exercise testing with electrocardiographic (ECG) activity assessment and echocardiographic stud-
ies allow the identification of silent heart disease in SCA patients. Alpert et al. [7] investigated the ECG
responses in children with SCA during an incremental exercise test performed on ergocycle. They found
that half of the patients tested had ischemic responses (15% had definitively ischemic and 34% had
equivocally ischemic responses). However, studies conducted at rest [42] did not support the existence
of an ischemic sickle cell cardiomyopathy. McConnell et al. [69] demonstrated that those patients who
had ischemic responses at exercise, as evidenced by ST-segment depression, had also elevated double
product (systolic blood pressure × heart rate) suggesting increased myocardial oxygen demand during
exercise in this population. In another experiment, Covitz et al. [35] reported that left ventricular end-
diastolic volume decreased most markedly with exercise in patients exhibiting ischemic ECG, suggesting
 P. Connes et al. / Sickle cell disease and exercise 157

an abnormal ejection fraction response [15], wall motion abnormalities and incomplete left ventricular
filling.
Although SCA patients showed limited exercise capacity, it seems that a walking test may not be
intense enough to highlight silent cardiac diseases [1] and we therefore recommend SCA patients to
undergo more intense exercise, such as the classic ramp CPET, if the aim of exercise testing is to screen
non-apparent cardiac disease.

4.4. Screening for bronchial hyperreactivity

Recent studies have provided evidence that asthma and bronchial hyperreactivity (BHR) might be more
common in children with SCA than in the general population [57]. This is particularly important since
the presence of asthma and BHR may predispose children to develop recurrent episodes of acute chest
syndrome [91]. Among challenges used to assess pulmonary function in children, aged 5–10 years old,
Knight-Madden et al. [57] used exercise testing. For this purpose, the SCA children performed ramp
test on a treadmill with speed and inclination being increased every minute. Spirometric assessment of
lung function was performed before exercise and at 1, 5, 10, 15 and 20 min of recovery. The study of
Sylvester et al. [91] recently highlighted the use of exercise to diagnose BHR in SCA patients. The authors
compared two protocols: cold air exposure and exercise testing. Some children responded only to a cold
air challenge and others only to an exercise challenge. That suggested that both exercise and cold air
challenges may be required to diagnose BHR in children with SCA. In adult patients, lung function can
be assessed before and after a symptom limited CPET performed on an ergocyle. However, the 6-min
walking test should be avoided for this purpose because the “ventilatory/respiratory stress” is probably
too low to really exclude the presence of BHR.

4.5. Exercise for clinical survey

Few studies have incorporated exercise testing in the clinical survey strategy of SCA. Some data support
the fact that exercise testing may be a useful tool for the assessment of the beneficial functional effects
of a given therapeutic strategy in different conditions:

4.5.1. Pulmonary hypertension

Sildenafil, an inhibitor of phosphodiesterase 5, is known to improve pulmonary hemodynamics and
functional capacity in different subsets of PHT through its effect on NO-mediated pulmonary vasodilation.
The efficacy of sildenafil therapy has been recently examined in SCA patients with PHT [63]. The authors
reported a decrease in pulmonary artery pressure after treatment, as well as a 20% increased in distance
covered during a 6-min walking test. The plasma levels of the N-terminal pro-brain natriuretic peptide in
these patients were decreased by 80% after therapy. In summary, theses results suggested that sildenafil
therapy led to an improvement in exercise capacity, which was most likely related to improvements in
pulmonary pressure and right ventricular function. Therefore, the 6-min walking test can be considered
as a useful tool to monitor the physiological and functional consequences of therapy in SCA patients
with PHT.

4.5.2. Exchange transfusion

Exchange transfusion or erythrocytopheresis removes sickle RBCs from the circulation and replaces
them with normal RBCs, leading to a reduction of the percentage of HbS cells [53] and an improvement
158 P. Connes et al. / Sickle cell disease and exercise

in the blood rheological profile [92]. Miller et al. [71] tested the effects of partial exchange transfusion on
hematologic and exercise parameters in 10 SCA adults. Their transfusion protocol resulted in an increase
of the percentage of HbA and a small increase of Hb concentration by 1.44 g/dL. These hematological
improvements led to improvements in exercise tolerance and an increase in the anaerobic threshold after
transfusion. Exercise testing in SCA has great potential as a mean to monitor therapy and to assess
the benefits of exchange transfusion [71]. Recently, Das et al. [36] tested the feasibility and safety
of a symptom limited CPET in 16 SCA children, adolescents and young adults (age ranging from 9
to 20 years old), who were subjected to long term erythrocytapheresis. The results from this study
suggested that symptom-limited CPET can be used safely in SCA children and young adults with long
term erythrocytapheresis and lower HbS level after therapy.

4.5.3. Effect of hydroxyurea

Hydroxyurea (HU) is the only approved drug for treatment of SCA [58]. Although HU is primarily
given to increase the percentage of foetal hemoglobin (HbF) into RBCs from SCA patients [64], several
pleiotropic effects of HU have been reported such as improvement in RBC deformability [11, 47] and
changes in the vascular endothelium biology [25, 78]. Hackney et al. [46] investigated the effects of HU
on exercise capacity in SCA patients and compared the response to exercise capacity of SCA patients
receiving a placebo. Surprisingly, the authors tested the anaerobic exercise capacity with a Wingate
protocol, which is known to be a hard exercise with a steep rise of lactic acid produced in a short
time. The authors also used a steady state submaximal exercise test of 10 min cycling to assess aerobic
capacity. Both groups had improvement of anaerobic performance but HU treated patients had a two-fold
increase of maximal anaerobic power in comparison with the placebo group. Aerobic performance was
also increased in the HU-treated group with the heart rate response being decreased after treatment for a
given submaximal exercise intensity. It was concluded that HU treatment improved both anaerobic and
aerobic exercise capacity [46].

5. Exercise prescription and practice

Although exercise testing seems to provide useful information for medical screening and in clinical
survey, exercise and physical activity may induce metabolic changes that can, if too large, potentially
precipitate vaso-occluisve crisis. Consequently, clinicians are reluctant to recommend physical activity
management for patients with SCA, and when they do, the recommendations are often imprecise because
of the lack of strong information in the scientific litterature.
Few studies have investigated the effects of exercise therapy in SCA patients and reported beneficial
effects. Alcorn et al. [4] demonstrated that exercise therapy may contribute to a reduction in the length
of hospitalization in SCA children with painful vaso-occlusive crisis. The exercise therapy consisted of
performing moderate strength and endurance exercise for 10–30 min duration and included recreational
gymnastics, stationary bicycle riding and games. Additionally, the authors emphasized that their program
was widely accepted by both patients and persons involved in the management of the disease. More
recently, Tinti et al. [93] reported the case of a patient with sickle cell anemia submitted to kinesiology
and aquatic rehabilitation twice a week and for 5 weeks. The treatment included warm water exercise
stretching, aerobic exercise and relaxation. The patient experienced a significant decrease in pain, a
significant increase in respiratory muscles strength and improved quality of life. However, no study has
been conducted in larger SCA population to evaluate the benefits of accurate exercise program in SCA.
 P. Connes et al. / Sickle cell disease and exercise 159

But, before the establishment of accurate exercise programs in SCA can be possible, there is a need to
test the exercise type that SCA patients could be able to sustain without any risks of vaso-occlusive and
medical complication. Whereas many studies have been conducted in sickle cell trait carriers to follow
the responses of hemorheological, inflammatory and oxidative stress markers during exercise [12, 31–34,
74, 95, 96], very few studies have been performed in SCA patients [14, 17].
Clinicians should advise patients to start their exercise gradually, to avoid intense exercise and to stop
exercising at the first sign of fatigue. SCA patients should not practice during illness. Prolonged exercise
for more than 20 min without resting should be avoided: a resting period every 20 min of exercise is
recommended to avoid dehydration and lactic acid accumulation. Balayssac-Syransy et al. [14] demon-
strated that a moderate exercise (50% of maximal aerobic power) of 20 min duration did not cause marked
hemorheological alterations in a group of SCA patients suggesting the safety and the feasibility of this
kind of effort in this population. In addition, to prevent dehydration, SCA patients should drink water
during and after exercising. Hydration is particularly important in patients with hemoglobinopathies since
even in the asymptomatic sickle cell trait carriers it may normalize the hemorheological profile of subjects
[96]. For outdoor sports, care should be taken to prevent cold or heat stress. SCA patients, particularly
those with enlargement of the spleen, should also avoid contact sports. However, most of these guidelines
suggest that each patient should be able to independently manage his or her physical efforts, a task that
may not be easy to perform if a person is not familiar with regular physical activity. Overall, the present
data support the safety and potential benefits of involvement of SCA in physical activities, provided that
the intensity is not excessive. Work from Barbeau et al. [17] clearly demonstrates that regular exercise at
moderate intensity could decrease the risk of inflammatory reaction related to exercise and could increase
vasodilatory reserve. Increased vasodilatory reserve may decrease the risks for vaso-occlusive crisis. The
exercise intensity used in the study of Barbeau et al. [17] was between 60–75% of predicted maximum.
And although this intensity may be considered moderate, it may be too high for some patients. The AT
of SCA patients range between 35–60% VO2max [10, 24] and its occurrence during a symptom-limited
CPET represents a transition from aerobic to anaerobic metabolism, which may increase the risks of
sickling. Therefore, one may recommend that exercise intensity for subjects should be equal or less than
the intensity corresponding to AT. No study has been performed to test the effects of a training program,
performed at such an intensity, on SCA patients, but it is widely recognized that AT may be a suitable
intensity for exercise rehabilitation program in many chronic diseases, such as cardiovascular and pul-
monary diseases [70, 75, 80], because it does not induce wide metabolic changes, specifically targets the
aerobic metabolism and improves the clinical condition of patients. Recent results from our group (Waltz
et al, unpublished results) support that an acute exercise bout performed at the AT level could be safe in
SCA patients, from a clinical and hemorheological point of view; and could improve the red blood cell
aggregation properties of patients. Further studies are clearly needed now to test the effects of a training
program performed at such an exercise intensity on the clinical and biological condition of SCA patients.
The paper was written in accordance with the ethical guidelines of the journal Clinical Hemorhology
and Microciculation [9].

References

[1] R.A. Adebayo, M.O. Balogun, N.O. Akinola and A.O. Akintomide, The clinical, electrocardiographic and self-paced
walking exercise features of Nigerians with sickle cell anaemia presenting at OAUTHC, Ile-Ife Niger J Med 11 (2002),
170–176.
160 P. Connes et al. / Sickle cell disease and exercise

[2] M.O. Adedeji, J. Cespedes, K. Allen, C. Subramony and M.D. Hughson, Pulmonary thrombotic arteriopathy in patients
with sickle cell disease, Arch Pathol Lab Med 125 (2001), 1436–1441.
[3] H.F. Alameri, A. Aleem, W. Kardas, A. Jehangir, M. Owais and A. Al-Momen, Dyspnea, pulmonary function and exercise
capacity in adult Saudi patients with sickle cell disease, Saudi Med J 29 (2008), 707–713.
[4] R. Alcorn, B. Bowser, E.J. Henley and V. Holloway, Fluidotherapy and exercise in the management of sickle cell anemia.
A clinical report, Phys Ther 64 (1984), 1520–1522.
[5] T. Alexy, S. Sangkatumvong, P. Connes, E. Pais, J. Tripette, J.C. Barthelemy, T.C. Fisher, H.J. Meiselman, M.C. Khoo and
T.D. Coates, Sickle cell disease: Selected aspects of pathophysiology, autonomic nervous system function and rheological
considerations in transfusion therapy, Clin Hemorheol Microcirc 44 (2010), 155–166.
[6] B.S. Alpert, E.V. Dover, W.B. Strong and W. Covitz, Longitudinal exercise hemodynamics in children with sickle cell
anemia, Am J Dis Child 138 (1984), 1021–1024.
[7] B.S. Alpert, P.A. Gilman, W.B. Strong, M.F. Ellison, M.D. Miller, J. McFarlane and T. Hayashidera, Hemodynamic and
ECG responses to exercise in children with sickle cell anemia, Am J Dis Child 135 (1981), 362–366.
[8] M. Angastiniotis, B. Modell, P. Englezos and V. Boulyjenkov, Prevention and control of haemoglobinopathies, Bull World
Health Organ 73 (1995), 375–386.
[9] Anonymous, Ethical guidelines for publication in clinical hemorheology and microcirculation, Clin Hemorheol Microcirc
44 (2010), 1–2.
[10] A. Anthi, R.F. Machado, M.L. Jison, A.M. Taveira-Dasilva, L.J. Rubin, L. Hunter, C.J. Hunter, W. Coles, J. Nichols, N.A.
Avila, V. Sachdev, C.C. Chen and M.T. Gladwin, Hemodynamic and functional assessment of patients with sickle cell
disease and pulmonary hypertension, Am J Respir Crit Care Med 175 (2007), 1272–1279.
[11] G. Athanassiou, A. Moutzouri, A. Kourakli and N. Zoumbos, Effect of hydroxyurea on the deformability of the red blood
cell membrane in patients with sickle cell anemia, Clin Hemorheol Microcirc 35 (2006), 291–295.
[12] E. Aufradet, G. Monchanin, S. Oyonno-Engelle, L. Feasson, L. Messonnier, A. Francina, L. Bezin, L.D. Serpero, D. Gozal,
M. Dodogba, D. Wouassi, V. Banimbeck, B. Djoda, P. Thiriet and C. Martin, Habitual physical activity and endothelial
activation in sickle cell trait carriers, Med Sci Sports Exerc 42 (2010), 1987–1994.
[13] O.A. Awodu, A.A. Famodu, O.I. Ajayi, M.E. Enosolease, O.Y. Olufemi and E. Olayemi, Using serial haemorheological
parameters to assess clinical status in sickle cell anaemia patients in vaso-occlussive crisis, Clin Hemorheol Microcirc 41
(2009), 143–148.
[14] E.A. Balayssac-Siransy, P. Connes, N. Tuo, C. Danho, M. Diaw, I. Sanogo, M.D. Hardy-Dessources, A. Samb, S.K. Ballas
and P. Bogui, Mild hemorheological changes induced by a moderate endurance exercise in patients with sickle cell anemia,
Br J Haematol 154 (2011), 398–407.
[15] I.C. Balfour, W. Covitz, F.W. Arensman, C. Eubig, M. Garrido and C. Jones, Left ventricular filling in sickle cell anemia,
Am J Cardiol 61 (1988), 395–399.
[16] S.K. Ballas and N. Mohandas, Sickle red cell microrheology and sickle blood rheology, Microcirculation 11 (2004),
209–225.
[17] P. Barbeau, K.F. Woods, L.T. Ramsey, M.S. Litaker, D.M. Pollock, J.S. Pollock, L.A. Callahan, A. Kutlar, G.A. Mensah
and B. Gutin, Exercise in sickle cell anemia: Effect on inflammatory and vasoactive mediators, Endothelium 8 (2001),
147–155.
[18] E.M. Barden, B.S. Zemel, D.A. Kawchak, M.I. Goran, K. Ohene-Frempong and V.A. Stallings, Total and resting energy
expenditure in children with sickle cell disease, J Pediatr 136 (2000), 73–79.
[19] M.J. Borel, M.S. Buchowski, E.A. Turner, B.B. Peeler, R.E. Goldstein and P.J. Flakoll, Alterations in basal nutrient
metabolism increase resting energy expenditure in sickle cell disease, Am J Physiol 274 (1998), E357–E364.
[20] A.S. Bowers, D.J. Pepple and H.L. Reid, Optimal haematocrit in subjects with normal haemoglobin genotype
(HbAA), sickle cell trait (HbAS), and homozygous sickle cell disease (HbSS), Clin Hemorheol Microcirc 47 (2011),
253–260.
[21] D.S. Braden, W. Covitz and P.F. Milner, Cardiovascular function during rest and exercise in patients with sickle-cell anemia
and coexisting alpha thalassemia-2, Am J Hematol 52 (1996), 96–102.
[22] M.S. Buchowski, L.A. Simmons, K.Y. Chen, P.J. Flakoll, B.G. Mellen and E.A. Turner, Plasma leptin association with
body composition and energy expenditure in sickle cell disease, J Am Coll Nutr 19 (2000), 228–236.
[23] M.S. Buchowski, K.M. Townsend, R. Williams and K.Y. Chen, Patterns and energy expenditure of free-living physical
activity in adolescents with sickle cell anemia, J Pediatr 140 (2002), 86–92.
[24] L.A. Callahan, K.F. Woods, G.A. Mensah, L.T. Ramsey, P. Barbeau and B. Gutin, Cardiopulmonary responses to exercise
in women with sickle cell anemia, Am J Respir Crit Care Med 165 (2002), 1309–1316.
 P. Connes et al. / Sickle cell disease and exercise 161

[25] J.P. Cartron and J. Elion, Erythroid adhesion molecules in sickle cell disease: Effect of hydroxyurea, Transfus Clin Biol 15
(2008), 39–50.
[26] O. Castro, Systemic fat embolism and pulmonary hypertension in sickle cell disease, Hematol Oncol Clin North Am 10
(1996), 1289–1303.
[27] O. Castro, D.J. Brambilla, B. Thorington, C.A. Reindorf, R.B. Scott, P. Gillette, J.C. Vera and P.S. Levy, The acute chest
syndrome in sickle cell disease: Incidence and risk factors. The cooperative study of sickle cell disease, Blood 84 (1994),
643–649.
[28] O. Castro, M. Hoque and B.D. Brown, Pulmonary hypertension in sickle cell disease: Cardiac catheterization results and
survival, Blood 101 (2003), 1257–1261.
[29] S. Chien, S. Usami and J.F. Bertles, Abnormal rheology of oxygenated blood in sickle cell anemia, J Clin Invest 49 (1970),
623–634.
[30] P. Connes, Altered autonomic nervous system function in sickle cell disease, Am J Resp Crit Care Med 184 (2011),
398–400.
[31] P. Connes, S. Frank, C. Martin, S. Shin, E. Aufradet, S. Sunoo, B. Klara, E. Raynaud de Mauverger, M. Romana, L.
Messonnier, J. Kang, E. Varlet-Marie, L. Feasson, M.D. Hardy-Dessources, B. Wilhelm and J.F. Brun, New fundamental
and applied mechanisms in exercise hemorheology, Clin Hemorheol Microcirc 45 (2010), 131–141.
[32] P. Connes, O. Hue, J. Tripette and M.D. Hardy-Dessources, Blood rheology abnormalities and vascular cell adhesion
mechanisms in sickle cell trait carriers during exercise, Clin Hemorheol Microcirc 39 (2008), 179–184.
[33] P. Connes, H. Reid, M.D. Hardy-Dessources, E. Morrison and O. Hue, Physiological responses of sickle cell trait carriers
during exercise, Sports Med 38 (2008), 931–946.
[34] P. Connes, J. Tripette, T. Chalabi, E. Beltan, M. Etienne-Julan, R. Chout, O. Hue and M.D. Hardy-Dessources, Effects
of strenuous exercise on blood coagulation activity in sickle cell trait carriers, Clin Hemorheol Microcirc 38 (2008),
13–21.
[35] W. Covitz, C. Eubig, I.C. Balfour, R. Jerath, B.S. Alpert, W.B. Strong and R.H. DuRant, Exercise-induced cardiac
dysfunction in sickle cell anemia. A radionuclide study, Am J Cardiol 51 (1983), 570–575.
[36] B.B. Das, W. Sobczyk, S. Bertolone and A. Raj, Cardiopulmonary stress testing in children with sickle cell disease who
are on long-term erythrocytapheresis, J Pediatr Hematol Oncol 30 (2008), 373–377.
[37] C. Delclaux, F. Zerah-Lancner, D. Bachir, A. Habibi, J.L. Monin, B. Godeau and F. Galacteros, Factors associated with
dyspnea in adult patients with sickle cell disease, Chest 128 (2005), 3336–3344.
[38] A.J. Duits, J.B. Schnog, L.R. Lard, A.W. Saleh and R.A. Rojer, Elevated IL-8 levels during sickle cell crisis, Eur J Haematol
61 (1998), 302–305.
[39] S.H. Embury, The clinical pathophysiology of sickle cell disease, Annu Rev Med 37 (1986), 361–376.
[40] P.L. Enright, The six-minute walk test, Respir Care 48 (2003), 783–785.
[41] M. Etienne-Julan, M.S. Belloy, M. Decastel, S. Dougaparsad, S. Ravion and M.D. Hardy-Dessources, Childhood sickle
cell crises: Clinical severity, inflammatory markers and the role of interleukin-8, Haematologica 89 (2004), 863–864.
[42] J.L. Gerry, B.H. Bulkley and G.M. Hutchins, Clinicopathologic analysis of cardiac dysfunction in 52 patients with sickle
cell anemia, Am J Cardiol 42 (1978), 211–216.
[43] M.T. Gladwin and G.J. Kato, Hemolysis-associated hypercoagulability in sickle cell disease: The plot (and blood) thick-
ens&excl, Haematologica 93 (2008), 1–3.
[44] M.T. Gladwin, V. Sachdev, M.L. Jison, Y. Shizukuda, J.F. Plehn, K. Minter, B. Brown, W.A. Coles, J.S. Nichols, I. Ernst,
L.A. Hunter, W.C. Blackwelder, A.N. Schechter, G.P. Rodgers, O. Castro and F.P. Ognibene, Pulmonary hypertension as
a risk factor for death in patients with sickle cell disease, N Engl J Med 350 (2004), 886–895.
[45] M. Gleeson, Immune function in sport and exercise, J Appl Physiol 103 (2007), 693–699.
[46] A.C. Hackney, W. Hezier, T.P. Gulledge, S. Jones, D. Strayhorn, M. Busby, E. Hoffman and E.P. Orringer, Effects of
hydroxyurea administration on the body weight, body composition and exercise performance of patients with sickle-cell
anaemia, Clin Sci (Lond) 92 (1997), 481–486.
[47] M.R. Hardeman and C. Ince, Clinical potential of in vitro measured red cell deformability, a myth? Clin Hemorheol
Microcirc 21 (1999), 277–284.
[48] R.P. Hebbel, Adhesive interactions of sickle erythrocytes with endothelium, J Clin Invest 100 (1997), S83–S86.
[49] P. Hernigou, F. Galacteros, D. Bachir and D. Goutallier, Deformities of the hip in adults who have sickle-cell disease and
had avascular necrosis in childhood. A natural history of fifty-two patients, J Bone Joint Surg Am 73 (1991), 81–92.
[50] J.B. Herrick, Peculiar elongated and sickle-shaped red blood corpuscles in a case of severe anemia, Arch Intern Med
6 (1910), 517–521.
162 P. Connes et al. / Sickle cell disease and exercise

[51] J. Inamo, P. Connes, J.C. Barthelemy, V. Dan, T. Coates and G. Loko, Pulmonary hypertension does not affect the autonomic
nervous system dysfunction of sickle cell disease, Am J Hematol 84 (2009), 311–312.
[52] A.H. Jama, A.H. Salem and I.A. Dabbous, Massive splenic infarction in Saudi patients with sickle cell anemia: A unique
manifestation, Am J Hematol 69 (2002), 205–209.
[53] S.L. Janes, M. Pocock, E. Bishop and D.H. Bevan, Automated red cell exchange in sickle cell disease, Br J Haematol 97
(1997), 256–258.
[54] F. Jung, From hemorheology to microcirculation and regenerative medicine: Fahraeus Lecture 2009, Clin Hemorheol
Microcirc 45 (2010), 79–99.
[55] G.J. Kato, S. Martyr, W.C. Blackwelder, J.S. Nichols, W.A. Coles, L.A. Hunter, M.L. Brennan, S.L. Hazen and M.T.
Gladwin, Levels of soluble endothelium-derived adhesion molecules in patients with sickle cell disease are associated with
pulmonary hypertension, organ dysfunction, and mortality, Br J Haematol 130 (2005), 943–953.
[56] D.K. Kaul and R.L. Nagel, Sickle cell vasoocclusion: Many issues and some answers, Experientia 49 (1993), 5–15.
[57] J.M. Knight-Madden, T.S. Forrester, N.A. Lewis and A. Greenough, Asthma in children with sickle cell disease and its
association with acute chest syndrome, Thorax 60 (2005), 206–210.
[58] S. Lanzkron, J.J. Strouse, R. Wilson, M.C. Beach, C. Haywood, H. Park, C. Witkop, E.B. Bass and J.B. Segal, Systematic
review: Hydroxyurea for the treatment of adults with sickle cell disease, Ann Intern Med 148 (2008), 939–955.
[59] V.L. Lew and R.M. Bookchin, Ion transport pathology in the mechanism of sickle cell dehydration, Physiol Rev 85 (2005),
179–200.
[60] E.E. Lin, G.P. Rodgers and M.T. Gladwin, Hemolytic anemia-associated pulmonary hypertension in sickle cell disease,
Curr Hematol Rep 4 (2005), 117–125.
[61] S.E. Lux, K.M. John and M.J. Karnovsky, Irreversible deformation of the spectrin-actin lattice in irreversibly sickled cells,
J Clin Invest 58 (1976), 955–963.
[62] R.F. Machado, A.K. Mack, S. Martyr, C. Barnett, P. Macarthur, V. Sachdev, I. Ernst, L.A. Hunter, W.A. Coles, J.P. Nichols,
G.J. Kato and M.T. Gladwin, Severity of pulmonary hypertension during vaso-occlusive pain crisis and exercise in patients
with sickle cell disease, Br J Haematol 136 (2007), 319–325.
[63] R.F. Machado, S. Martyr, G.J. Kato, R.J. Barst, A. Anthi, M.R. Robinson, L. Hunter, W. Coles, J. Nichols, C. Hunter, V.
Sachdev, O. Castro and M.T. Gladwin, Sildenafil therapy in patients with sickle cell disease and pulmonary hypertension,
Br J Haematol 130 (2005), 445–453.
[64] M. Maier-Redelsperger, D. Labie and J. Elion, Long-term hydroxyurea treatment in young sickle cell patients, Curr Opin
Hematol 6 (1999), 115–120.
[65] A.C. Makis, E.C. Hatzimichael and K.L. Bourantas, The role of cytokines in sickle cell disease, Ann Hematol 79 (2000),
407–413.
[66] A. Marossy, P. Svorc, I. Kron and S. Gresova, Hemorheology and circulation, Clin Hemorheol Microcirc 42 (2009),
239–258.
[67] C.A. Marotta, B.G. Forget, M. Cohne-Solal, J.T. Wilson and S.M. Weissman, Human beta-globin messenger RNA. I.
Nucleotide sequences derived from complementary RNA, J Biol Chem 252 (1977), 5019–5031.
[68] C.A. Marotta, J.T. Wilson, B.G. Forget and S.M. Weissman, Human beta-globin messenger RNA. III. Nucleotide sequences
derived from complementary DNA, J Biol Chem 252 (1977), 5040–5053.
[69] M.E. McConnell, S.R. Daniels, J. Lobel, F.W. James and S. Kaplan, Hemodynamic response to exercise in patients with
sickle cell anemia, Pediatr Cardiol 10 (1989), 141–144.
[70] T. Meyer, A. Lucia, C.P. Earnest and W. Kindermann, A conceptual framework for performance diagnosis and training
prescription from submaximal gas exchange parameters–theory and application, Int J Sports Med 26(Suppl 1) (2005),
S38–S48.
[71] D.M. Miller, R.M. Winslow, H.G. Klein, K.C. Wilson, F.L. Brown and N.J. Statham, Improved exercise performance after
exchange transfusion in subjects with sickle cell anemia, Blood 56 (1980), 1127–1131.
[72] R.M. Millis, F.W. Baker, L. Ertugrul, R.M. Douglas and L. Sexcius, Physical performance decrements in children with
sickle cell anemia, J Natl Med Assoc 86 (1994), 113–116.
[73] H. Moheeb, Y.A. Wali and M.S. El-Sayed, Physical fitness indices and anthropometrics profiles in schoolchildren with
sickle cell trait/disease, Am J Hematol 82 (2007), 91–97.
[74] G. Monchanin, D. Serpero Laura, P. Connes, J. Tripette, D. Wouassi, A. Francina, R. Massarelli, D. Gozal, P. Thiriet and
C. Martin, Plasma levels of adhesion molecules ICAM-1 and VCAM-1 in athletes with sickle cell trait with or without
alpha-thalassemia during endurance exercise and recovery, Clin Hemorheol Microcirc 40 (2008), 89–97.
 P. Connes et al. / Sickle cell disease and exercise 163

[75] J. Myers, Applications of cardiopulmonary exercise testing in the management of cardiovascular and pulmonary disease,
Int J Sports Med 26(Suppl 1) (2005), S49–S55.
[76] D. Nebor, A. Bowers, M.D. Hardy-Dessources, J. Knight-Madden, M. Romana, H. Reid, J.C. Barthelemy, V. Cumming,
O. Hue, J. Elion, M. Reid and P. Connes, Frequency of painful crisis in sickle cell anemia and its relationships with the
sympatho-vagal balance, blood rheology and inflammation, Haematologica (In press).
[77] S.C. Nelson, B.B. Adade, E.A. McDonough, K.L. Moquist and J.M. Hennessy, High prevalence of pulmonary hypertension
in children with sickle cell disease, J Pediatr Hematol Oncol 29 (2007), 334–337.
[78] M.H. Odievre, C. Lapoumeroulie and J. Elion, (Effect of hydroxyurea on adhesion proteins in sickle cell anemia), Arch
Pediatr 16 (2009), 95–98.
[79] O.C. Onyekwere, A. Campbell, M. Teshome, S. Onyeagoro, C. Sylvan, A. Akintilo, S. Hutchinson, G. Ensing, P. Gaskin,
G. Kato, S. Rana, J. Kwagyan, V. Gordeuk, J. Williams and O. Castro, Pulmonary hypertension in children and adolescents
with sickle cell disease, Pediatr Cardiol 29 (2008), 309–312.
[80] P. Palange, S.A. Ward, K.H. Carlsen, R. Casaburi, C.G. Gallagher, R. Gosselink, D.E. O’Donnell, L. Puente-Maestu, A.M.
Schols, S. Singh and B.J. Whipp, Recommendations on the use of exercise testing in clinical practice, Eur Respir J 29
(2007), 185–209.
[81] M.F. Perutz and J.M. Mitchison, State of haemoglobin in sickle-cell anaemia, Nature 166 (1950), 677–679.
[82] P. Pianosi, S.J. D’Souza, D.W. Esseltine, T.D. Charge and A.L. Coates, Ventilation and gas exchange during exercise in
sickle cell anemia, Am Rev Respir Dis 143 (1991), 226–230.
[83] O.S. Platt, D.J. Brambilla, W.F. Rosse, P.F. Milner, O. Castro, M.H. Steinberg and P.P. Klug, Mortality in sickle cell disease.
Life expectancy and risk factors for early death, N Engl J Med 330 (1994), 1639–1644.
[84] O.S. Platt, W. Rosenstock and M.A. Espeland, Influence of sickle hemoglobinopathies on growth and development, N Engl
J Med 311 (1984), 7–12.
[85] D.B. Pyne, Exercise-induced muscle damage and inflammation: A review, Aust J Sci Med Sport 26 (1994), 49–58.
[86] S. Sangkatumvong, M.C. Khoo, R. Kato, J.A. Detterich, A. Bush, T.G. Keens, H.J. Meiselman, J.C. Wood and T.D. Coates,
Peripheral vasoconstriction and abnormal parasympathetic response to sighs and transient hypoxia in sickle cell disease,
Am J Respir Crit Care Med 184 (2011), 474–481.
[87] A. Singhal, P. Davies, K.J. Wierenga, P. Thomas and G. Serjeant, Is there an energy deficiency in homozygous sickle cell
disease? Am J Clin Nutr 66 (1997), 386–390.
[88] M.J. Stuart and R.L. Nagel, Sickle-cell disease, Lancet 364 (2004), 1343–1360.
[89] L.L. Sutton, O. Castro, D.J. Cross, J.E. Spencer and J.F. Lewis, Pulmonary hypertension in sickle cell disease, Am J Cardiol
74 (1994), 626–628.
[90] R.A. Swerlick, J.R. Eckman, A. Kumar, M. Jeitler and T.M. Wick, Alpha 4 beta 1-integrin expression on sickle reticulocytes:
Vascular cell adhesion molecule-1-dependent binding to endothelium, Blood 82 (1993), 1891–1899.
[91] K.P. Sylvester, R.A. Patey, G.F. Rafferty, D. Rees, S.L. Thein and A. Greenough, Airway hyperresponsiveness and acute
chest syndrome in children with sickle cell anemia, Pediatr Pulmonol 42 (2007), 272–276.
[92] G.B. Thurston, N.M. Henderson and M. Jeng, Effects of erythrocytapheresis transfusion on the viscoelasticity of sickle
cell blood, Clin Hemorheol Microcirc 30 (2004), 61–75.
[93] G. Tinti, R. Somera Jr, F.M. Valente and C.R. Domingos, Benefits of kinesiotherapy and aquatic rehabilitation on sickle
cell anemia. A case report, Genet Mol Res 9 (2010), 360–364.
[94] J. Tripette, T. Alexy, M.D. Hardy-Dessources, D. Mougenel, E. Beltan, T. Chalabi, R. Chout, M. Etienne-Julan, O. Hue,
H.J. Meiselman and P. Connes, Red blood cell aggregation, aggregate strength and oxygen transport potential of blood are
abnormal in both homozygous sickle cell anemia and sickle-hemoglobin C disease, Haematologica 94 (2009), 1060–1065.
[95] J. Tripette, P. Connes, E. Beltan, T. Chalabi, L. Marlin, R. Chout, O.K. Baskurt, O. Hue and M.D. Hardy-Dessources, Red
blood cell deformability and aggregation, cell adhesion molecules, oxidative stress and nitric oxide markers after a short
term, submaximal, exercise in sickle cell trait carriers, Clin Hemorheol Microcirc 45 (2010), 39–52.
[96] J. Tripette, G. Loko, A. Samb, B.D. Gogh, E. Sewade, D. Seck, O. Hue, M. Romana, S. Diop, M. Diaw, K. Brudey, P.
Bogui, F. Cisse, M.D. Hardy-Dessources and P. Connes, Effects of hydration and dehydration on blood rheology in sickle
cell trait carriers during exercise, Am J Physiol Heart Circ Physiol 299 (2010), H908–H914.
[97] T. Troosters, R. Gosselink and M. Decramer, Six minute walking distance in healthy elderly subjects, Eur Respir J 14
(1999), 270–274.
[98] R.D. Woodson, R.E. Wills and C. Lenfant, Effect of acute and established anemia on O2 transport at rest, submaximal and
maximal work, J Appl Physiol 44 (1978), 36–43.

View publication stats