| HIGH-PERFORMANCE HEMATOLOGY: ELITE ATHLETES AND WEEKEND WARRIORS |

Balancing exercise risk and benefits: lessons learned from

sickle cell trait and sickle cell anemia
Robert I. Liem

Hematology, Oncology and Stem Cell Transplant, Ann & Robert H. Lurie Children’s Hospital of Chicago,
Chicago, IL; and Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL

Development of exercise guidelines for individuals with sickle cell trait (SCT) and sickle cell anemia (SCA) is hampered
by the need to weigh the benefits against risks of exercise in these populations. In SCT, concern for exercise collapse
associated with sickle cell trait has resulted in controversial screening of student athletes for SCT. In SCA, there exists
unsubstantiated concerns that high-intensity exercise may result in pain and other complications. In both, finding the
“right dose” of exercise remains a challenge for patients and their providers. Despite assumptions that factors pre-
disposing to adverse events from high-intensity exercise overlap in SCT and SCA, the issues that frame our un-
derstanding of exercise-related harms in both are distinct. This review will compare issues that affect the risk-benefit
balance of exercise in SCT and SCA through these key questions: (1) What is the evidence that high-intensity exercise is
associated with harm? (2) What are the pathophysiologic mechanisms that could predispose to harm? (3) What are the
preventive strategies that may reduce risk? and (4) Why do we need to consider the benefits of exercise in this debate?
Addressing these knowledge gaps is essential for developing an evidence-based exercise prescription for these patient
populations.

SCT and SCA are both characterized by the presence of sickle

Learning Objectives
• Review the epidemiological and scientific data that underlie
current concerns related to high-intensity exercise in SCT and
SCA
• Review the potential benefits of regular exercise and steps
necessary to develop evidence-based guidelines for exercise in
SCT and SCA
Introduction
The benefits of regular exercise are well described and span the life
cycle from childhood throughout adulthood, ranging from physio-
logical to psychological to social. Growing evidence suggests that
exercise in all forms triggers epigenetic changes in several pathways
that underlie the physiological benefits of exercise.1-3 As a prevention
strategy, exercise prescription in the general healthy population aims to
reduce future cardiovascular risk. There is now growing acceptance
that exercise prescription among individuals with chronic illness is
equally important both for preventing comorbid conditions and, in
some cases, conferring disease-modifying effects. Thus, the adoption
of the mantra that “exercise is medicine” is essential for both healthy
individuals as well as those with chronic medical conditions.
Despite the importance of regular exercise in the general population
and individuals with other chronic conditions, exercise prescription
guidelines do not currently exist for individuals affected by sickle
cell trait (SCT) and sickle cell anemia (SCA) due to concerns about
the adverse effects of high-intensity exercise in these populations.
hemoglobin in erythrocytes, the amount of which is determined by
the inheritance of 1 (heterozygous) vs 2 (homozygous) copies, re-
spectively, of the same mutation caused by a single-nucleotide
substitution (GAG → GTG) at position 6 in the b-globin gene.
Although SCA may also refer to less common sickling syndromes
that result from the inheritance of SCT and another hemoglobin
variant (eg, hemoglobin C or b-thalassemia trait), SCA in this review
will refer to homozygous disease. In SCT, erythrocyte sickling is
minimal at baseline, and potential adverse health effects (eg, in-
creased risk of kidney disease, venous thromboembolism, adverse
pregnancy outcomes) are generally limited to adulthood; in SCA, an
increased risk of erythrocyte sickling and downstream pathophysi-
ological consequences result in the development of disease-related
complications (eg, chronic anemia, vaso-occlusive pain episodes,
infection, acute organ injury, chronic end-organ damage) throughout
the life span. More recently, increasing evidence for exertional
rhabdomyolysis and associated sudden death, now termed exercise
collapse associated with sickle cell trait (ECAST), has raised con-
cerns for high-intensity exercise in SCT.4,5 In SCA, there exists
unsubstantiated or anecdotal concerns for an association between
moderate- to high-intensity exercise and vaso-occlusive complica-
tions such as pain. Thus, finding the right “dose” of exercise in either
condition remains an enigmatic challenge for patients and their
providers.
The goal of this review is to discuss the evidence underlying con-
cerns for adverse events related to high-intensity exercise in SCT and
SCA and the potential pathophysiologic basis for these concerns. To

Conflict-of-interest disclosure: The author declares no competing financial interests.

Off-label drug use: None disclosed.

418 American Society of Hematology

underscore the need to consider both sides of the risk-benefit balance,
the potential negative implications of limiting exercise in these
populations, given growing evidence for the unique benefits that
regular exercise and improved fitness may confer in SCT and SCA,
will also be discussed. This review will be framed in the form of key
questions, comparing the history of existing evidence over the years
and the gaps that remain in both conditions (Figure 1).
What are the epidemiological data that SCT and SCA
impact cardiopulmonary fitness and what is the
evidence that high-intensity exercise is associated
with harm?
Given the prevalence of SCT is estimated at ~8% of the general
population in the United States, with the highest predominance
among persons of African ancestry, the implications for the current
discussion about the impact of SCT on exercise safety and fitness
are tremendous. The current debate about exertion-related adverse
events in SCT goes back several decades and stems from early case
reports and epidemiological data describing high rates of exertional
collapse and sudden death during high-intensity physical training in
athletes and military fighters with SCT.6-8 In an early study of basic
training in the US Armed Forces, rates of unexplained deaths per
100 000 were 32.2 and 0.7 for black recruits with and without SCT,
respectively. The relative risk of sudden unexplained death among
black recruits with SCT in this study was 27.6 (95% confidence
interval, 9-100; P , .001).6 Additional efforts aimed at trying to
understand the prevalence and risk factors associated with this
phenomenon were initially limited. More recent spikes in interest
have been spurred on by high-profile cases in the lay press involving
athletes as well as the National Collegiate Athletic Association
(NCAA) policy (instituted in 2010 for Division I and 2013 for all
Divisions) mandating SCT testing in all student athletes (https://
www.ncaa.org/sites/default/files/SCT%20testing%20brief%202014.
pdf). This policy has led to controversy and ethical debates about the
nonintended consequences of widespread SCT screening for this
Figure 1. Timeline of important milestones related to application of exercise science and medicine in SCT and SCA. 6-MWD, 6-minute walk distance;
ACSM, American College of Sports Medicine; CHAMP, Consortium for Health and Military Performance; NATA, National Athletic Trainers’ Association;
NCAA, National Collegiate Athletic Association.
Hematology 2018
purpose among various organizations and professional societies that
represent stakeholders, including athletic associations, military
personnel, and physician societies like the American Academy of
Pediatrics and the American Society of Hematology.9-13 However,
an important benefit of these debates has been the organization of
concerted efforts to better study and define exertion-related sudden
death in SCT, develop consensus guidelines for mitigating this risk,
and frame a future research agenda. For example, it is recognized
now that exertional rhabdomyolysis underlies the phenomenon of
potential sudden death during high-intensity exercise under extreme
conditions in SCT. In support of this, a 2016 retrospective study of
nearly 48 000 active military, black soldiers demonstrated that
soldiers with SCT had a significantly higher risk of exertional
rhabdomyolysis (hazard ratio, 1.54; 95% confidence interval, 1.12-
2.12), but not death, when compared with those without SCT.14
Among student athletes, Harmon et al found that the relative risk of
exertional death (though not known if always due to rhabdomyol-
ysis) in those students with vs without SCT ranged from 15 to 37,
with the highest reported among Division I football players, in
a retrospective study of NCAA athletes from 2004 to 2008.15 Al-
though the data are sparse, SCT status in and of itself does not appear
to impact fitness levels. Among young black adults followed lon-
gitudinally in the Coronary Artery Risk Development in Young
Adults study, SCT was not associated with baseline or longitudinal
changes in fitness as measured by exercise duration by treadmill
testing (535 vs 540 seconds; P 5 .62).16 Similarly, small prospective
studies using maximal cardiopulmonary exercise testing demonstrate
no differences in direct measurements of maximal oxygen con-
sumption (VO2 max), considered the standard reference for fitness,
or ventilatory responses to exercise testing, in individuals with or
without SCT.17,18 For example, Marlin et al found no significant
difference in VO2 max between subjects with (42.7 6 2.5 mL/kg per
minute) or without (42.5 6 3.4 mL/kg per minute) SCT in their
study.18
419
In contrast to what is known in SCT, less is known about the actual pathophysiologic factors during exercise challenge that could pre-
adverse events associated with high-intensity physical exertion and dispose to ECAST have been limited, small in scope, and con-
exercise in SCA. Formal studies to evaluate adverse events in these founded by variability in exercise testing conditions and protocol (ie,
settings may be lacking due to assumptions that individuals with intensity, duration). The potential pathophysiologic contributors that
SCA do not participate in high-intensity physical activity and ex- have been considered can be divided into factors related to whole-
ercise because of self- or provider-imposed restrictions or that blood viscosity, the proinflammatory response to exercise, oxidative
physical and physiological limitations stemming from disease- stress, and hemorheological properties (Table 2). Blood viscosity
related complications preclude participation. In the absence of di- appears to be higher at baseline and increases during exercise in
rect data, much of the former stems from unsubstantiated concerns individuals with SCT, although increases in viscosity are similar to
that high-intensity physical exertion may increase sickling and that measured in controls and the effect can be blunted or normalized
predispose to complications such as vaso-occlusive pain. Although with hydration.28,29 In SCT carriers participating in a soccer game,
data from sustained high-intensity exercise are not available, safety for example, blood viscosity decreased significantly under hydrated
data from several studies in both adults and children with SCA that conditions but increased 16.3% under dehydrated conditions.28 Sim-
use maximal cardiopulmonary exercise testing to measure fitness ilarly, RBC rigidity has been shown to be greater at baseline in SCT
suggest that exercising with increasing intensity until exhaustion and may increase after high-intensity, supramaximal exercise.30-32
appears to be safe and does not result in adverse events. What we do In a small study of 8 adults with SCT and 8 controls, Connes et al
know is that in contrast to what has been observed in SCT, SCA is showed that 2 measures of RBC rigidity (Tk and k) did not sig-
associated with markedly decreased cardiopulmonary fitness in both nificantly change during a short supramaximal exercise challenge
children and adults using this gold-standard test.19-21 In their study of despite being higher in adults with SCT at every point of exercise.30
60 children with SCA and 30 matched controls, Liem et al found that However, these studies in general have been largely inconclusive re-
peak VO2 was ~30% lower in children with SCA when compared garding their direct causative relationship to ECAST. Other studies
with controls (26.9 6 6.9 mL/kg per minute vs 37.0 6 9.2 mL/kg per generally demonstrate no major or consistent between-group differences
minute; P , .001).19 In another study, 83% of adults with sickle cell in the proinflammatory responses to exercise, coagulation profiles, as
disease (all genotypes) had evidence for decreased maximal exercise well as lactate metabolism or responses during exercise at moderate to
capacity.20 Besides maximal cardiopulmonary exercise testing, other high intensities in individuals with and without SCT.18,33-35 Impor-
approaches have been used to evaluate fitness in SCA patients, including tantly, Sara et al found no significant difference in the occurrence of the
submaximal exercise testing or 6-minute walk distance, which have first and second lactate thresholds during incremental exercise testing in
commonly been used in adults with SCA to measure impact of disease SCT carriers (38% 6 4.7% and 72.9% 6 3.4% of VO2 max) vs controls
and its complications, such as cardiopulmonary disease, on physical without SCT (37.3% 6 3% and 76.8% 6 5.4% of VO2 max).34
functioning.22-24 Despite challenges in comparing data in these studies
due to variability in testing modality, the data in aggregate demonstrate Such factors of concern in SCT have been less well studied in SCA in
a major impact of disease on fitness and physical functioning. Even less part due to hesitation in using submaximal or maximal exercise
data are available to help us understand actual physical activity levels in testing to simulate the conditions under which these factors may be
this population; however, at least 1 study using a Physical Activity examined in individuals with SCA. Limited data from a small study
Questionnaire adapted from the National Health and Nutrition Exam- suggest that although the percentage of dense red blood cells was
ination Survey (NHANES) has suggested that compared with matched increased to a greater degree in adults with SCA (29% vs 12%; P ,
peers, fewer children with SCA reported spending at least 60 minutes per .001) at rest when compared with that seen in controls, no consistent
day in either moderate to vigorous (17% vs 23%; P , .01) or vigorous
intensity (24% vs 43%; P 5 .01) physical activity.25
Table 1. Signs and symptoms of exertional rhabdomyolysis, heat
injury, and heat stroke
What are the pathophysiologic processes that could
predispose to adverse events and what factors impact Exertional Exertional Exertional
fitness in SCT and SCA? Sign or symptom rhabdomyolysis heat injury heat stroke
The potential pathophysiologic mechanisms that trigger concern for Fatigue/weakness • • •
adverse events with high-intensity exercise in SCT and SCA are not Dizziness/lightheadedness • •
well characterized and, importantly, despite some overlap, are not Vision changes • •
necessarily interchangeable between the 2 populations. RBC sickling Headache • •
is minimal among individuals with SCT at baseline or under normal Nausea/vomiting • •
conditions. Early studies, however, have demonstrated that sickling Confusion/altered mental •
status
in individuals with SCT may increase under conditions associated
Muscle weakness •
with extraordinary exercise intensity, including severe dehydration, High core body • •
metabolic acidosis, and hypoxemia.26,27 How these factors converge temperature
to create the “perfect storm” and interact with other considerations Tachycardia •
such as extreme heat or genetic predisposition to result in ECAST in Hypotension •
some individuals and not others is not clear. Moreover, another Dark urine or decreased • • •
challenge to our understanding of the risk conferred by these in- urine output
teractions is that from a pathophysiologic standpoint, ECAST most Seizures •
reflects signs and symptoms of exertional rhabdomyolysis (eg, Hyperkalemia •
muscle weakness or pain, dark urine, renal injury, hyperkalemia, Disseminated intravascular •
coagulation
arrhythmias), yet there is overlap with symptoms of exertional heat
Collapse or cardiac arrest •
injury or heat stroke (Table 1). Studies that have tried to evaluate the

420 American Society of Hematology

Table 2. Potential pathophysiologic mechanisms underlying adverse events during high-intensity exercise in SCT and SCA

Potential factors during exercise SCT SCA

Plasma or whole blood viscosity and
dense sickle RBCs
RBC rigidity and deformability
Oxidative stress markers
Inflammatory response markers
Coagulation markers
Lactate metabolism
IL-6, interleukin 6; RBC, red blood cell; SCT, stem cell transplantation; sE-selectin, soluble E-selectin; sP-selectin, soluble P-selectin.
• Higher at baseline compared with controls
• Increases with exercise but no difference in increase
compared with controls
• Remained elevated at end of recovery compared
with controls
• No effect of a-thalassemia trait on results
• Higher at baseline and during exercise compared
with controls
• Unchanged with exercise
• No difference in baseline levels compared with
controls
• Increased after exercise with postexercise levels
higher compared with controls
• No difference in baseline levels of most cytokines
and adhesion molecules
• Variability in sVCAM and sP-selectin response to
exercise
• No difference in baseline levels of coagulation
profile, fibrinogen, and antithrombin activity
compared with controls
• Unchanged with exercise
• No difference in lactate thresholds or clearance
compared with controls
• Variability in lactate levels throughout exercise and
recovery compared with controls
• Faster RBC uptake of lactate in SCT
• No difference in viscosity at baseline or after exercise
compared with controls
• Increase in dense cells after exercise
• No data in the literature
• No difference in response after acute exercise
compared with controls
• May remain elevated after prolonged exercise
compared with controls
• No difference in response of IL-6 and other
inflammatory markers after exercise compared with
controls
• No difference in sVCAM response to exercise
compared with controls
• No change in sE- or sP-selectin response to exercise
• No data in the literature
• Increases with exercise with lower lactate thresholds
during exercise compared with controls

between-group differences in plasma or blood viscosity were observed.
Moreover, exercise significantly increased plasma viscosity (1.2 6 0.07
mPa per second to 1.28 6 0.1 mPa per second; P , .01) but not whole-
blood viscosity or percentage of dense cells in adults with SCA.36
Recently, there has been greater focus on the potential concern for an
exaggerated inflammatory response to exercise in SCA that might
predispose to adverse events such as vaso-occlusive pain. SCA is
characterized by a proinflammatory state, as evidenced by baseline
elevation in inflammatory markers that worsen during complications
like pain and acute chest syndrome. Acute exercise itself is also as-
sociated with a well-described proinflammatory response in the general
population marked by the immediate and delayed elevation of various
inflammatory biomarkers. Limited data suggest that the inflammatory
response to acute exercise is observed in both adults and children with
SCA. In the only study that compared data to that observed in matched
controls without SCA, the magnitude of the acute inflammatory re-
sponse to maximal exercise testing, defined by change in soluble
vascular cell adhesion molecule (sVCAM) and other biomarkers, was
not any greater in children with SCA.37 In this study, the increase in
sVCAM immediately after exercise was not significantly different in
subjects with SCA vs controls (87 vs 48 ng/mL; P 5 .15). However,
a small study of women with SCA exposed to 3 consecutive days of
exercise suggests that oxidative stress associated with exercise may
remain elevated compared with that observed in controls.38 Acute
exercise is associated in general with other physiologic consequences
that could constitute “danger” signals for precipitating sickling in in-
dividuals with SCA but studies in humans or mouse models are limited.
Small studies in a mouse model of SCA suggest acute exercise can
increase the risk of intramuscular metabolic acidosis and other meta-
bolic derangements.39,40 For example, Chatel et al demonstrated that
reduction in intramuscular pH was greater for SS mice undergoing
electrostimulation simulating exercise when compared with AA mice
(20.28 6 0.06 vs 20.15 6 0.05; P , .01).40 Although these factors
represent the same pathophysiologic mechanisms that drive known
complications of SCA such as vaso-occlusion, whether or not they
directly contribute to potential adverse effects of exercise in SCA is not
clear. Moreover, it is important to note that although these patho-
physiologic consequences of acute exercise might indirectly limit ex-
ercise or physical exertion in SCA, the actual reasons for reduced fitness
in SCA are multifactorial and complex, and studies that have tried to
dissect out the causes are limited. Risk factors may include chronic
anemia, sedentary lifestyle, physical limitations from stroke or avascular
necrosis as well as cardiopulmonary complications such as chronic lung
disease, pulmonary vascular disease, or diastolic dysfunction. The
assessment of breath-by-breath, gas-exchange data obtained during
cardiopulmonary exercise testing has been useful for understanding the
pathophysiology associated with reduced fitness. Such studies in
children and adults with SCA demonstrate derangements in the actual
cardiopulmonary response to exercise, including impaired oxygen
uptake, reduced ventilatory efficiency, and lower oxygen pulse during
exercise.19,20,41,42 These studies also suggest that exercise limitation
cannot adequately be explained by the presence of chronic anemia alone
in this patient population. When compared with that measured in
matched controls without SCA, fitness levels in children with SCA
remained significantly lower even when adjusted for hemoglobin, age,
sex, and body mass index (b 5 5.93; P 5 .005).19

Hematology 2018 421

What is the potential impact of limiting exercise in SCT
and SCA and why do we need to consider the benefits
of exercise in this debate?
Limiting regular exercise in SCT and SCA without a clear under-
standing of the balance of its harms vs benefits may have unintended
consequences and a long-term impact on fitness in populations who
may already be at risk for a sedentary lifestyle and its adverse
outcomes.43 Although the potential risks of high-intensity exercise
cannot be ignored in SCT and SCA, it may be time to change the
current paradigm and shift our attention instead to the benefits of
exercise and physical activity in these populations. Landmark epi-
demiological studies demonstrate that cardiopulmonary fitness re-
mains one of, if not the, most important predictors of all-cause
mortality among individuals who are both healthy or have a chronic
medical condition.44,45 Long-term gains in fitness, physical activity,
and physical functioning are associated with improved cardiovas-
cular outcomes, overall mortality, health-related quality of life and
other patient-centered outcomes in adults. For individuals with SCT,
in whom the development of cardiovascular risk factors is similar to
that observed in the general African American population, reducing
cardiovascular disease risk by increasing physical activity and ex-
ercise remains important.16 This may hold true even more for in-
dividuals affected by chronic conditions such as SCA for whom
finding safe approaches to increasing physical activity and promoting
regular exercise may not represent a priority. For children affected by
SCA, the negative impact of a sedentary lifestyle may be significant
given the known benefits of regular exercise and physical activity
and their contributions to normal growth and development, including
cognitive development, which represent areas negatively affected
by disease. Moreover, parent, physician, or school reluctance to
allow participation in school- or community-based sports or exercise
programs could lead to social isolation and decreased self-esteem
among children with SCA. Uncertainty regarding the benefits vs
risks of regular exercise in specific disease states is not unique to
SCA and has been previously observed in other chronic conditions
such as congestive heart failure, chronic obstructive lung disease,
asthma, rheumatoid arthritis, and cystic fibrosis.46-52 Despite initial
concerns about the inability to tolerate exercise or the harmful effects
of acute exercise in affected individuals, ample data demonstrating
net benefits now support the prescription of regular exercise in these
conditions. SCA in particular may represent an ideal model for
studying the benefits of regular exercise or exercise training due to
the potential for disease-modifying effects that can be extrapolated
from the known physiological benefits ascribed to regular exercise in
the general population. Nearly all known pathophysiologic con-
tributors to sickling and vaso-occlusion, most notably inflammation,
oxidative stress, endothelial/vascular dysfunction, and cell adhesion,
represent mechanisms known potentially to be ameliorated with
exercise training.53-58 In the general population, for example, the
long-term cardiovascular benefits of regular exercise are in part
attributed to the attenuation over time of the acute-phase inflam-
matory response to acute exercise.59
We see signals in the literature that exercise training may in fact have
disease-modifying effects in SCT and SCA. Blood viscosity and
biomarkers of oxidative stress have been found to be lower among
individuals with SCT who are trained vs untrained.60,61 In their
study, for example, Chirico et al found that in response to exercise,
trained subjects with SCA had lower levels of oxidative stress
markers, including advanced oxidation protein products (174 6
121 mM vs 224 6 130 mM; P 5 .012), nitrotyrosine (70.6 6 46.6 nM
422
vs 127 6 29.1 nM; P 5 .003), and protein carbonyl (86.9 6 26.8 nm/mL
vs 114 6 34 nm/mL; P 5 .006), as well as higher levels of some
antioxidant markers, including superoxide dismutase activity (8.5 6
6.2 U/mL vs 4.3 6 2.5 U/mL; P 5 .002) and nitrite and nitrate (28.8 6
11.4 mM/L per minute vs 4.7 6 7 mM/L per minute; P 5 .003), when
compared with that measured in untrained subjects with SCT.60 In
mouse models of SCA, exercise training is associated with a de-
crease in overall inflammation, oxidative stress, and exercise-
related metabolic acidosis.62-64 Investigators have also begun to
examine the role of aerobic exercise training in children and adults
with SCA. A 12-week pilot study of home aerobic conditioning in 10
children with SCA using cycle ergometry with escalating duration and
exercise intensity up to 30 minutes and 100% of ventilatory threshold,
respectively, was safe and feasible.65 Additionally, recent data from 40
adults with SCA undergoing 8 weeks of 3 sessions per week of training
by cycle ergometer resulted in improved lactate thresholds during
exercise as well as increased capillary density on muscle biopsy.66
Given that leg fatigue represents the most common reason for exercise
test termination in studies involving individuals with SCA, adaptive
changes at the muscle level with training could in part explain im-
provements in exercise tolerance in this study.
What are the strategies that have been implemented to
mitigate risks in SCT and SCA and what do we need to
work toward development of guidelines to address
this debate?
Evidence-based guidelines for exercise recommendations currently
do not exist for individuals with SCT and SCA. The implications for
this are tremendous and may affect up to 8% of the black population
that carries SCT and nearly 100 000 individuals living with SCA in
the United States alone. For SCT, consensus statements and rec-
ommendations have been put forth by various groups, including the
US military, the NCAA (https://www.ncaa.org/sites/default/files/
NCAASickleCellTraitforCoaches.pdf), the American College of
Sports Medicine and the National Athletic Trainer’s Association
(https://www.nata.org/sites/default/files/sickle-cell-trait-and-the-athlete.
pdf) for mitigating the risk of ECAST.4,67 Applying these recom-
mendations to individuals with SCT may depend on training in-
tensity, training conditions, and training status but commonalities
include the following general principles: (1) gradual adjustment to
training intensity to facilitate acclimation, especially under extreme
conditions (heat or altitude); (2) reduction of activity or training
intensity after prolonged illness or rest periods; (3) ready access to
fluids at regular intervals; (4) prompt recognition of symptoms
suggestive of ECAST, exertional rhabdomyolysis, or heat-related
illnesses; and (5) rapid termination of training and prompt initiation
of treatment in the event of symptoms. Universal precautions have
been in place since 1982 for military recruits and soldiers in training
and, since their institution, the branches of the US military that have
implemented safeguards as part of training have observed no dif-
ference in rates of sudden deaths, mild heat injury, or heat stroke
in recruits with and without SCT.14,67 Despite their longstanding
adoption for military recruits and soldiers in training, universal
precautions to prevent ECAST have only recently been introduced
for college athletes. However, implementation success and adherence
to these policies as well as their impact on outcomes are not clear for
college athletes.12 Even less guidance for prevention of exercise-
related adverse events exists for individuals with SCA. Anecdotally,
the principles adopted by patients and their providers generally focus
on avoidance of dehydration, extreme temperatures during exercise,
American Society of Hematology
 Figure 2. The balance of short-term potential risks of acute exercise vs long-term benefits of regular exercise in individuals with SCT and SCA.
and prolonged physical exertion at moderate to high intensity without
adequate rest periods.
The development of evidence-based guidelines is critical to imple-
menting safe training and exercise prescription practices among
military personnel, athletes, and all individuals with SCT as well as
those affected by SCA. Essential questions and remaining knowledge
gaps, however, need to be fully addressed before this can be realized,
most important of which is finding the right “dose” of exercise that
children and adults with SCT and SCA at various levels of fitness need
and can tolerate safely. How we strike the right balance between the
risks vs benefits of regular exercise, especially at moderate to high
intensities, for individuals of different training status remains an
important challenge facing these populations (Figure 2). The answer
may be different for SCT, which is characterized primarily by an
increased risk of exertional rhabdomyolysis under extreme conditions,
vs for SCA, which is marked by a proinflammatory state that po-
tentially can be precipitated by the physiologic stress of high-intensity
exercise. As such, the potential areas for further investigation probably
differ for SCT and SCA as well. For SCT, continued efforts should
focus on the following potential areas of impact: (1) mechanisms of
exertional rhabdomyolysis and the unique influence/contribution of
sickling; (2) genetic basis of exertional rhabdomyolysis and ECAST68;
(3) environmental and training factors that increase the risk of ECAST;
(4) susceptibility of “weekend warriors” to ECAST and the influence
of training status on risk of exertional rhabdomyolysis; and (5) de-
velopment and implementation of evidence-based guidelines for
mitigating risk of ECAST. Also worth studying is whether universal
SCT screening for individuals at high or higher risk of ECAST remains
necessary in the setting of implementing universal precautions around
high-intensity exercise and training. For SCA, potential areas of in-
vestigation could instead focus on further understanding the following
broader themes: (1) evaluating the pathophysiologic consequences of
acute exercise, including characterizing the molecular and genetic
basis for the inflammatory response to acute exercise; (2) determining
the relationship among cardiopulmonary fitness, disease severity, and
long-term outcomes, including mortality; (3) exploring the disease-
modulating effects of exercise training on inflammation and endo-
thelial and vascular end points on both a physiologic and molecular
level; and (4) studying the impact of regular exercise and increased
physical activity on pain, quality of life, and other patient-centered
Hematology 2018
outcomes. Systematically addressing these issues has the potential for
better understanding the short- and long-term effects of exercise using
an ideal model for blood disorders such as SCA with potential ap-
plication to other blood disorders, both malignant and nonmalignant.
Summary
In summary, SCT and SCA have in common the presence of sickle
hemoglobin in erythrocytes that predispose to sickling, generally of
minimal consequence in the former but associated with complica-
tions throughout the lifespan in the latter. There has been a renewed
interest in the risks vs benefits of exercise and high-intensity physical
exertion in both SCT and SCA in recent years but for different
reasons. In SCT, the mechanisms underlying the evidence for in-
creased risk of exertional rhabdomyolysis and ECAST are poorly
understood. In SCA, the field is just starting to understand the risks
associated with acute exercise for a disease marked by a baseline
proinflammatory state. For both, however, discovering the right
“dose” of exercise that optimizes the balance between risks and
benefits is key. In working toward the development and imple-
mentation of evidence-based guidelines for exercise prescription,
SCT and SCA also represent ideal models for applying exercise
science and medicine to the field of hematologic disorders.
Correspondence
Robert I. Liem, Ann & Robert H. Lurie Children’s Hospital of
Chicago, 225 East Chicago Ave, Box 30, Chicago, IL 60611; e-mail:
rliem@luriechildrens.org.
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