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Sickle cell disease is the most com-

mon blood disorder in the United
States, affecting 100 000 people. A
genetic mutation creates hemoglobin
S. In the deoxygenated state, hemo-
Sickle Cell
globin S polymerizes, creating sickled
hemoglobin. Sickled hemoglobin
causes a cascade of complex patho-
Disease in the
physiologic events that lead to hemo-
lysis, chronic anemia and endothelial
damage. This results in clinical com-
plications, end organ dysfunction and a
shortened life expectancy. The acute
nature of many sickle cell complica-
tions makes the emergency depart-
ment a common setting where sickle
cell patients present. Common com-
plications (vaso-occlusive episode, fe-
ver, acute chest syndrome, stroke) and
less common complications (splenic
sequestration, priapism, aplastic cri-
and Management
sis, ocular emergencies) will be dis-
cussed. Public health implications will
be discussed briefly.
Christina M. Barriteau, MD, MPH*,
The authors have no conflicts of
interest to disclose. Melissa A. McNaull, MD†
The authors did not receive any

financial assistance for this manu- ickle cell disease (SCD) is the most common blood
script. disorder in the United States, affecting approximately
100 000 people nationwide. 1 Sickle cell disease is a
Keywords: genetic condition. Inheritance of the sickle cell gene
creates an abnormal hemoglobin, hemoglobin S. 2 There are
sickle cell disease; anemia; compli-
various sickle cell genotypes and phenotypes. The most severe
cations; vaso occlusive crisis; vaso
type, hemoglobin SS, is the homozygous form. Other forms of
occlusive episode; acute chest syn- sickle cell disease include hemoglobin S in combination with
drome; stroke; splenic sequestra- other variant hemoglobins such as hemoglobin C or thalassemia.
tion; priapism; aplastic crisis Phenotype varies, even among those with the same genotype, with
some having more severe disease than others. In the deoxygen-
*Division of Hematology and Oncology, ated state, hemoglobin S polymerizes, creating sickled hemoglo-
Department of Pediatrics, Feinberg School bin. Sickled hemoglobin causes a cascade of complex
of Medicine, Northwestern University pathophysiologic events that lead to hemolysis, chronic anemia
Chicago, IL; †Division of Hematology and and endothelial damage. This results in clinical complications,
Oncology, Department of Pediatrics, end organ dysfunction and a shortened life expectancy. Various
University of Mississippi Medical Center sickle cell complications that may present in the emergency
Jackson, MS. department will be discussed.
Reprint requests and correspondence: In 2014, the National Heart, Lung, and Blood Institute (NHLBI)
Christina Barriteau, MD, MPH, 225 East
published updated guidelines, Evidence-Based Management of
Chicago Ave, Box 30, Chicago, IL 60611.
Sickle Cell Disease. 3 One of the more notable guidelines is the
recommendation to offer hydroxyurea to all sickle cell patients


age 9 months and older regardless of disease al. on ED utilization in 8 states. 9 Data on prevalence
severity to reduce complications. Hydroxyurea is of pediatric sickle cell patients with high ED
the only widely available Food and Drug Adminis- utilization showed approximately 5% of patients
tration (FDA) approved disease-modifying medica- under age 20 had 4–10 ED visits in a single year
tion for sickle cell anemia. Hydroxyurea increases andb 1% of patients had N11 visits in a year. 8
fetal hemoglobin, which has anti-sickling properties
and reduces disease complications and mortality. 4,5
The NHLBI guidelines increased hydroxyurea use INTERPRETATION OF COMPLETE BLOOD
among sickle cell patients, therefore emergency AND RETICULOCYTE COUNTS
care providers are likely to encounter patients on
Most sickle cell patients in the ED should have a
hydroxyurea in the emergency department. The
complete blood count (CBC) and reticulocyte count
medication has a favorable side effect profile with
in additional to other labs as indicated. It will be useful
transient myelosuppression being the most common
to know the patient's baseline hemoglobin which can
side effect. 4 Treatment of acute sickle cell compli-
be obtained from the patient, their hematologist or
cations does not need to be tailored to a patient's use
primary provider. Typical ranges for baseline
of hydroxyurea.
hemoglobin are 6-8 g/dl for HbSS, 10-15 g/dl for
Stem cell transplant is currently the only curative
HbSC and 9-12 g/dL for HbSBeta+ thalassemia,
option for sickle cell patients. The field of stem cell
though patients with HbSS on hydroxyurea may
transplantation for sickle cell patients has evolved
achieve a baseline hemoglobin up to 10-11 g/dL. 3
over the last 2 decades. The expansion of stem cell
Reticulocytes are young red blood cells (RBCs).
transplant to include matched unrelated donors and
The reticulocyte count is a useful indicator of how
half-matched (haplo-identical) family members in
well the body makes new RBCs. This is important
addition to matched siblings makes this a viable
in a disease such as sickle cell where chronic
treatment option for more sickle cell patients.
hemolysis and increased turnover of RBCs requires
Matched sibling bone marrow transplantation for
an active production of new RBCs. Typically, sickle
sickle cell anemia achieves high success rates with
cell patients have elevated reticulocyte count at
N90% 5 year overall survival. 6 Matched unrelated
baseline and further elevation during vaso-occlusive
bone marrow transplantation for this group has 79%
pain crisis. Low reticulocyte count can be seen in
overall survival at two years. 6 Newer potentially
conditions such as aplastic crisis, and may be notice
curative options including gene therapy are cur-
for concern.
rently under investigation. Details are outside of the
scope of this article.
The acute nature of many sickle cell complica-
tions makes the emergency department (ED) a Vaso-Occlusive Crisis (Pain Crisis)
common place sickle cell patients present. Programs Chief complaint: sickle cell patient with arm and
such as the Center for Disease Control and leg pain.
Prevention's (CDC) Sickle Cell Data Collection Vaso-occlusive crisis (VOC), also known as vaso-
Program contain ED utilization data. Data is occlussive episode or pain crisis, is the most
primarily available at the state level although there common acute complication of sickle cell disease.
are plans to expand to comprehensive national data A study by Gill et al. observed the natural history of
collection. 7 A recent study by Paulukonis et al. a pediatric sickle cell cohort. 10 Patients had a pain
analyzed ED utilization by pediatric and adult sickle crisis as early as within the first year of life and half
cell patients in California between 2005 and 2014. 8 of HbSS patients experience their first pain crisis by
There were 90 904 ED visits during the study period age 4.9 years. Intravascular sickling and resultant
and 2.1 annual mean visits per person. 8 The tissue and bone infarction cause VOC. 2 Pain
frequency of ED visits varied by age group with typically occurs in the extremities but may occur
young adults having higher ED utilization than in other locations. While some patients have visible
children, 3.0 mean annual visits for patients 18– discomfort during a VOC, others with severe pain
30 years of age, compared to 0.5 mean annual visits may lack the typical physiologic and behavioral
for patients ages 1–9 years and 0.8 mean annual manifestations of pain. This phenomenon is seen in
visits for patients ages 10 to 17 years. This trend is other conditions with recurrent pain. 11 Document-
similar to previously published data by Brousseau et ed autonomic nervous system dysfunction in sickle

cell patients could also explain this phenomenon reticulocyte count, and blood culture drawn and
and therefore heart rate and blood pressure may not given parenteral antibiotics with streptococcus
be reliable indicators of pain severity or control. 12 coverage as soon as possible. Ceftriaxone is a typical
Pain should be treated appropriately. Opioids are antibiotic of choice. For Ceftriaxone allergic pa-
the standard of care for treating acute pain episodes tients, consult your pharmacist about options and
in sickle cell patients. The National Heart, Lung and local antibiotic susceptibility. Judicious search for
Blood Institute recommends patients receive anal- other sources of fever based on history and physical
gesic therapy within 30 minutes of triage. 3 Triaging exam should occur. Admission criteria for sickle cell
sickle cell patients as high priority can help achieve patients with fever varies by institution. Ill appear-
this goal. Incorporating use of intranasal fentanyl ing patients should be admitted. Some hospitals
can decrease time to first analgesic administration. admit all patients with fever younger than a certain
Kavanagh et al. demonstrated that incorporation of age (eg. 12 months) regardless of clinical
intranasal fentanyl reduced time to first dose of appearance.
analgesic from 56 to 23 minutes. 13 If intranasal
fentanyl is used, it should be used in conjunction
Acute Chest Syndrome
with other opioids such as morphine or hydromor-
Chief complaint: sickle cell patient with shortness
phone given its short acting nature. Demerol should
of breath.
be avoided due to high risk of seizures. 14 If pain does
Acute chest is the second most common compli-
not improve with first dose of analgesic, additional
cation of sickle cell disease, after pain, and the
doses and dose titration should occur. Some
leading cause of death in this patient population. 18
patients may benefit from a continuous patient
Sickle cell patients who present with cough,
controlled analgesia (PCA) pump started in the ED
respiratory distress, shortness of breath, tachypnea,
in preparation for hospitalization. Patients whose
chest pain or desaturations should have a chest x-
pain is controlled in the ED may be able to be
ray (CXR) even if they are afebrile. 3 The diagnostic
discharged on scheduled oral opioids and non-
criteria for acute chest syndrome is a new infiltrate
steroidal anti-inflammatory drugs (NSAIDs). All
on chest imaging accompanied by fever, chest pain
states now have patient registries for controlled
or respiratory symptoms (Fig. 1). CXR findings may
substance prescriptions that track the prescriber,
lag behind the clinical course so one should have a
pharmacy, medication, number of pills, and date
high index of suspicion. The inciting event can be fat
filled. Reviewing these systems is mandatory in
embolus, infection (virus, bacteria or atypical
many states and useful in all to determine the
bacteria) or unknown. 18 Treatment should consist
appropriate amount of medication to prescribe. In
of an intravenous (IV) cephalosporin, oral macrolide
general, unless red flags appear in this system, it is
(ie Cefriaxone and Azithromycin) and supplemental
most appropriate to give a prescription for 48–
oxygen and supportive care as indicated. The utility
72 hours of oral medication until the patient can
of simple or exchange transfusion should be
follow up with their primary care provider or
discussed with a hematologist, but evidence sup-
ports a low threshold to transfuse to increase oxygen
carrying capacity. Given the associated high mor-
tality, all patients with acute chest syndrome must
Fever be admitted for further management.
Chief complaint: sickle cell patient with temper-
ature 102 °F.
Fever in sickle cell patients requires prompt Stroke
medical attention. Most sickle cell patients auto Chief complaint: acute neurologic symptoms in a
infarct their spleen by age 5 and are at high risk for sickle cell patient.
infection from encapsulated bacteria such as Strep- Stroke is a serious neurological complication of
tococcus. 15 The use of penicillin prophylaxis and sickle cell disease. Stroke should be ruled out in a
pneumococcal vaccines has reduced incidence and sickle cell patient who presents with any new
mortality from invasive pneumococcal disease. 16,17 neurologic symptoms. Without primary stroke
Sickle cell patients receive daily penicillin prophy- prevention, 10% of sickle cell patients will have a
laxis until age 5. Patients with a history of invasive stroke. 3 Annual transcranial doppler ultrasounds in
pneumococcal infection receive lifelong penicillin children with sickle cell disease identify those at
prophylaxis. After age 5 the risk of overwhelming highest risk for stroke. Patients at risk for stroke
sepsis decreases but is not zero. 15 For this reason, undergo primary prevention with blood transfusions
sickle cell patients with fever should have a CBC, or hydroxyurea. Stroke in children with sickle cell

Fig. 1 Chest X ray demonstrates right upper lobe infiltrate in a 6-

year-old girl with sickle cell disease presenting with fever, cough,
chest pain and hypoxia, consistent with acute chest syndrome. Fig. 2 MRI brain with diffusion weight imaging of a 3-year-old boy
with sickle cell disease and acute hemiparesis shows area of high
signal involving the left cortex at the junction of the left superior
disease is usually ischemic in nature due to stenosis frontal and precentral gyri consistent with acute ischemic stroke.
or occlusion causing infarction. 2 In addition to a
detailed neurological exam, neuro imaging is criti-
cal. Non-contrast head computed tomography (CT) from baseline. 19 The risk for splenic sequestration
should be performed first since it can be obtained varies by age and genotype. It is more common in
quickly. Head CT can rule out hemorrhagic stroke children under age 5 who have an intact spleen that
and may show ischemic stroke. However, CT scan has not yet auto infarcted. Children with hemoglo-
may not detect ischemic stroke within the first bin SC or hemoglobin S Beta thalassemia have some
6 hours. 2 If resources are available, magnetic degree of splenic function throughout life and may
resonance imaging (MRI) of the brain with diffusion get splenic sequestration at an older age. 20 The
weighted imaging is the most sensitive method to classic clinical presentation is abdominal pain and
detect ischemic stroke (Fig. 2). Treatment of stroke splenomegaly but patients may have a nonspecific
requires prompt admission to a facility with presentation including fussiness or generalized
exchange transfusion capabilities. In consultation discomfort; infants and toddlers often have fever
with a hematologist, transfusion should be initiated and/or lethargy without abdominal pain. Patients
prior to MRI if there is high suspicion for stroke, and may present with tachycardia and other signs of
simple transfusion should begin while exchange volume depletion and impending hypovolemic
transfusion is being set up. shock. Associated lab abnormalities include throm-
bocytopenia and leukopenia due to pooling of white
blood cells (WBCs) and platelets in the enlarged
spleen. Mortality can be high and expedient treat-
LESS COMMON COMPLICATIONS ment is warranted. 21 Treatment includes rapid
Fever, pain and acute chest syndrome are the volume resuscitation with a simple blood transfu-
most common complications. Less common but sion. If patients have signs of impending shock,
important complications will be discussed briefly. volume resuscitation with crystalloid should be
performed while awaiting blood products, no matter
how low the hemoglobin level. About 50% of patients
Splenic Sequestration with splenic sequestration have a recurrence. 22
Chief complaint: Abdominal pain in 2-year-old After resolution of the acute episode, consideration
with sickle cell disease. for splenectomy should be discussed with their
Splenic sequestration should be considered in hematologist.
sickle cell patients with abdominal pain and
splenomegaly. Other causes of abdominal pain are Priapism
listed in Table 1. Splenic sequestration is defined as Chief complaint: 10-year-old male with sickle cell
an enlarging spleen and a drop in hemoglobin 2 g/dl disease and an unwanted erection.

B19 the most common. 27 Parvovirus B19 infects red

blood cell precursors in the bone marrow. 28 The
TABLE 1 Causes of abdominal pain in children
baseline chronic hemolysis and increased red blood
with sickle cell disease. cell turnover in sickle cell anemia requires active
Sickle cell related red blood cell production in the bone marrow. In
Vaso-occlusive pain aplastic crisis, impaired red blood cell production
Splenic sequestration causes an acute anemia. Aplastic crisis typically
Cholelithiasis/cholecystitis presents with fatigue, pallor, lethargy or shortness of
Non sickle cell related breath. Viral symptoms may be present. Severe
Constipation cases may have signs of hypovolemic shock. CBC
Gastroesophageal reflux disease and reticulocyte count are key to making the
Irritable bowel syndrome diagnosis. Patients have a significant drop in
Gastroenteritis baseline hemoglobin and marked reticulocytopenia.
Urinary tract infection/pyelonephritis
Spontaneous recovery may occur but severe cases
Pelvic inflammatory disease
require simple red blood cell transfusion. 3

Ocular Emergencies
Priapism is a sustained, unwanted erection lasting Chief complaint: 15-year-old male with sickle cell
N4 hours. Stuttering priapism is multiple self limited disease presents with eye pain.
episodes of priapism lasting b4 hours. 3 Incidence Ocular emergencies are uncommon but should be
varies with Mantadakis et al. showing up to 89% of considered in sickle cell patients who present with
male sickle cell patients experience some form of eye pain or visual disturbances. Acute ocular
priapism by age 20. 23 Priapism can lead to erectile emergencies include hyphema, central retinal ar-
dysfunction. Priapism in sickle cell disease is tery occlusion and orbital wall infarction. Clinical
thought to be caused by nitric oxide pathway history, physical exam, ophthalmologic exam and
dysfunction causing hypoxia, sickling and sludging imaging can aid diagnosis. Ophthalmologists should
of RBCs in the corpora cavernosa. 24 For short be involved in management and treatment deci-
episodes lasting b4 hours, patients can soak in warm sions. Hyphema, blood in the anterior chamber, is
water, perform mild exercise, increase fluid intake, usually caused by trauma. Associated visual abnor-
urinate often and take analgesics. 2 Episodes lasting malities include floaters, blurry vision or light
a few hours should be treated like VOC with IV fluids sensitivity. 3 Ophthalmology should be consulted
and analgesics. Patients with priapism lasting N4 immediately due to risk of visual loss. Treatment
hours should be evaluated by a medical provider, plan may include supportive care, medications or
typically with urology consultation for potential ophthalmology procedure. 29 Central retinal artery
procedural interventions. Transfusion is contrain- occlusion (CRAO) can lead to severe visual distur-
dicated due to ASPEN Syndrome, an odd combina- bances and blindness in sickle cell patients. 3 Sickle
tion of priapism and neurologic complications cell disease is a hypercoagulable state making
brought on by transfusion. 25 The 2017 Cochrane patients at risk for thrombosis. Thrombosis of the
review on treatment of priapism in boys and adults central retinal artery can cause retinal or macular
with sickle cell diseases demonstrates heterogeneity ischemia and infarction. 30 Orbital wall infarction is
in treatment approach. 26 Treatment options in- a vaso occlusive crisis that affects orbital bones. This
clude: alpha agonists, phosphodiesterase type 5 is more common in small children who have
inhibitors (ie sildenafil) or urologic intervention. increased bone marrow space in their orbital
Treatment plan should be made in conjunction with bones. 31 CT or MRI aids in the diagnosis and
urology and hematology. differentiation from orbital cellulitis. 32


Chief complaint: 7-year-old female with sickle cell Public health considerations are relevant for
disease and fever. Baseline hemoglobin is 7 g/dL. sickle cell disease, a disease that disproportionately
Labs show hemoglobin 4 g/dL and reticulocyte affects minorities. Racial bias and disparate treat-
count of 0.5%. ment is well documented in numerous studies
Aplastic crisis is a transient red blood cell aplasia. including the landmark Institute of Medicine report,
It can be caused by viral infection, with Parvovirus Unequal Treatment: Confronting Racial and Ethnic

Disparities in Health Care. 33 In a study by Wakefield et disease: a time-varying model analysis. Physiol Rep 2015;3:
al., 96% of surveyed sickle cell youth age 13–21 1-13.
13. Kavanagh PL, Sprinz PG, Wolfgang TL, et al. Improving the
experienced at least one incidence of racial bias and
management of vaso-occlusive episodes in the pediatric
perceived health-related stigma. 34 14% of partici- emergency department. Pediatrics 2015;136:e1016-25.
pants reported perceived racial bias within medical 14. Ballas SK. Meperidine for acute sickle cell pain in the
settings. 34 Racial bias and stigma can impact pain emergency department: revisited controversy. Ann Emerg
management. Research shows minority children Med 2008;51:217.
receive less adequate pain management than their 15. Navalkele P, Ozgonenel B, McGrath E, et al. Invasive
pneumococcal disease in patients with sickle cell disease. J
Caucasian peers. 35 This is important in sickle cell Pediatr Hematol Oncol 2017;39:341-4.
disease where pain is the most common complica- 16. Gaston MH, Verter JI, Woods G, et al. Prophylaxis with oral
tion. Sickle cell patients note inadequate pain penicillin in children with sickle cell anemia. A randomized
treatment in a variety of medical settings including trial. Med 1986;314:1593-9.
the emergency department and inpatient units. 36 17. Martin OO, Moguist KL, Hennessy JM, et al. Invasive
pneumococcal disease in children with sickle cell disease in
The prevalence of medication addiction in sickle the pneumococcal conjugate vaccine era. Pediatr Blood
cell patients is less than suspected by medical Cancer 2018;65:1-13.
professionals and is uncommon in the pediatric 18. Vichinsky EP, Neumayr LD, Earles AN, et al. Causes and
sickle cell population. 11 The recent public health outcomes of the acute chest syndrome in sickle cell disease.
National Acute Chest Syndrome Study Group. Med 2000;
opioid epidemic and focus on drug addiction may
pose additional barriers for sickle cell patients. 19. Topley JM, Rogers DW, Stevens MC, et al. Acute splenic
Awareness, cultural competency training and im- sequestration and hypersplenism in the first five years in
plicit bias training can help combat the stigma and homozygous sickle cell disease. Arch Dis Child 1981;56:
stereotypes these patients face. 765-9.
20. Brousse V, Buffet P, Rees D. The spleen and sickle cell
disease: the sick(led) spleen. Haematol 2014;166:165-76.
21. Sabarense AP, Lima GO, Silva LM, et al. Characterization of
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