Pediatr Clin N Am 49 (2002) 1193 – 1210

Sickle cell disease

Jason Fixler, MD, Lori Styles, MD*
Children’s Hospital and Research Center at Oakland, Department of Hematology/Oncology,
747 52nd Street, Oakland, CA 94609, USA

Sickle cell disease (SCD) is a serious and life-threatening disease that affects
approximately 1 in 600 African Americans [1,2]. In 1910, Herrick described the
first patient with SCD, and 36 years later, Beet discovered that sickle red blood
cells have an increased resistance to malaria. Protection from malaria helps
maintain the high prevalence of the sickle gene in areas where malaria is
endemic, such as sub-Saharan Africa [3]. Since these initial reports, our
understanding and treatment of this disease has grown tremendously. Because
SCD is common, most pediatricians encounter a child with SCD and should have
a thorough understanding of the disease, its complications, and its treatment.

Genetics and diagnosis

Hemoglobin is composed of four globin chains, two a globin chains, and two b
globin chains. SCD results from either the inheritance of two sickle b globin genes
or the inheritance of one sickle b gene in combination with another b globin chain
defect. The most common form of SCD, hemoglobin SS (sickle cell anemia), is
caused by the inheritance of hemoglobin S from both parents. Hemoglobin SC
disease, hemoglobin S b+ thalassemia, and hemoglobin S b0 thalassemia are the
other three common forms of SCD. Patients with hemoglobin S b+ thalassemia and
S b0 thalassemia have a clinical picture that resembles SCD rather than thalasse-
mia, because with the underproduction of normal b globin, the sickle b globin
predominates. Sickle cell anemia (hemoglobin SS) and sickle b0 thalassemia,
conditions in which there is no normal b globin production, are generally more
severe than hemoglobin SC and hemoglobin S b+ thalassemia. SCD is a clinically
heterogeneous disorder, however, and many sickle cell anemia patients may have a
clinical course that is milder than that of a hemoglobin SC patient [4].

* Corresponding author.
E-mail address: lstyles@mail.cho.org (L. Styles).

0031-3955/02/$ – see front matter D 2002, Elsevier Science (USA). All rights reserved.
PII: S 0 0 3 1 - 3 9 5 5 ( 0 2 ) 0 0 0 8 9 - 5
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In the past, children with SCD were often first diagnosed following an episode
of sepsis or hand-foot syndrome (dactylitis). Today, all 50 states screen all
newborn infants for the presence of SCD. There are a variety of screening
methods in use, with electrophoresis and high performance liquid chromatography
(HPLC) being most commonly used. Pediatricians often learn of a child with SCD
in their clinical practice after being contacted by a state newborn screening
coordinator. It is then the pediatrician’s responsibility to inform the family and to
ensure adequate followup, the initiation of penicillin, and, most likely, the referral
to a comprehensive sickle cell center.
On the first visit to the pediatrician, the results of the newborn screening
testing should be confirmed by retesting the child and both parents, if possible. In
addition to confirmatory testing, pediatricians should begin educating the family
about the importance of initiating and continuing penicillin prophylaxis and
monitoring for signs of infection, including fever. Referral to a pediatric
hematologist often occurs after this first visit, and a close collaboration between
the general pediatrician and the hematologist ensures comprehensive care for the
growing child.

Clinical manifestations
The deleterious effects of SCD can affect nearly every organ system in the
body. The two predominant pathologic features of SCD are hemolytic anemia and
vaso-occlusion [5]. These processes result from the deoxygenation of the
hemoglobin S molecule, which aggregates to form a polymer, which in turn
causes the red cell to sickle [6– 8]. These sickle shaped red cells block the
microvasculature and have increased adherence to the vascular endothelium, both
of which contribute to the pathophysiology of vaso-occlusion [9].

Infection
Infection is the most immediate risk for infants diagnosed with SCD.
Sickling of the red cell results in progressive infarction of the spleen, and with
time, most patients become functionally asplenic [10]. The lack of splenic
function leaves these patients prone to many bacterial infections, especially from
encapsulated organisms such as Streptococcus pneumonia, Salmonella, and
Haemophilus [11,12]. Before the initiation of prophylactic penicillin, there
was substantial morbidity and mortality from sepsis in infants with SCD. The
Prophylactic Penicillin Study (PROPS) demonstrated that prophylactic penicillin
administered twice daily decreases the incidence of pneumococcal bacteremia
by 84% [13]. A subsequent study, PROPS II, was not able to demonstrate a
statistically significant protection for the continuation of penicillin past the age
of 5 years [14]. Although the risk for pneumococcal sepsis decreases after the
age of 5 years, many patients with SCD develop serious pneumococcal in-
fections later in life. This has led many institutions to continue penicillin
prophylaxis throughout childhood. Even with penicillin prophylaxis, children
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with SCD are at high risk for overwhelming sepsis, and fevers should be
evaluated comprehensively. The emerging resistance of S. pneumonia to peni-
cillin and other antibiotics makes a thorough evaluation of the febrile patient
even more important.
Families should be instructed to call their physician immediately if their child
develops a single temperature greater than 38.5 C or two temperatures between
38.0 C and 38.5 C. The child should be seen immediately, and a complete
evaluation should include a physical examination, a complete blood count (CBC)
with a reticulocyte count, blood culture, chest x-ray, urinalysis, and a urine
culture [15]. A broad spectrum antibiotic such as ceftriaxone should be given
immediately while testing is completed. If the child is younger than 1– 2 years of
age, they should be admitted for intravenous antibiotics regardless of the results
of the sepsis workup. Children who are older than 1– 2 years of age with a benign
examination and negative workup can be discharged to home if good followup
can be ensured [16,17]. Children who are discharged after a negative physical
examination and sepsis workup should be seen within 24 hours for further
evaluation and antibiotics if the child remains febrile. All children with a
significantly elevated white count, the presence of an infiltrate on chest x-ray,
a urinalysis suspicious for a urinary tract infection, or who are ill-appearing,
should be admitted for observation and intravenous antibiotics. Children with a
prior history of invasive pneumococcal infection seem to be at even greater risk
than those children without this risk [18].

Vaso-occlusive pain events

Vaso-occlusive pain events (VOE) are the most common manifestation of
SCD. Dactylitis, painful swelling of the hands and feet, is often the first clinical
manifestation of SCD. Dactylitis usually is not seen in older children, because as
the child ages, the sites of hematopoiesis move from peripheral locations such as
the fingers and toes to more central locations such as the arms, legs, and
eventually the chest and ribs. Infants with dactylitis often tolerate these episodes
well and rarely require more than acetaminophen or nonsteroidal anti-inflam-
matory agents (NSAIDs) for these initial episodes. As children age, however, the
severity of these painful episodes often increases dramatically.
Vaso-occlusive pain events are difficult to assess and treat because the patient
with a VOE often has few physical findings to suggest the severity of their
underlying pain. In addition, there are no laboratory tests that are diagnostic or
predictive of acute painful episodes. Leukocytosis, joint inflammation, and fever
are some signs associated with painful crisis, but their absence does not rule out
an acute painful episode [19]. It is important to note that the presence or ab-
sence of sickle cells on the peripheral blood smear and the reticulocyte count
have no diagnostic or predictive value in the severity of painful crisis. A careful
history and physical examination and the use of age appropriate pain evalua-
tions are the best way of assessing and treating the sickle cell patient with an
acute painful episode.
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Instituting adequate pain control for the sickle cell patient with a vaso-occlusive
episode is one of the most challenging and important aspects of care for these
patients. There are many excellent publications on how to approach pain
management in patients with SCD [20,21]. In general, the use of pain medications
follows a stepwise progression. For the patient with mild pain, an NSAID such as
ketorolac or ibuprofen decreases inflammation and is adequate for pain relief with
a minimum of side effects. As the patient’s pain increases in severity, the use of
narcotics either orally or intravenously becomes indicated. The route of admin-
istration of narcotics should be chosen based on the severity of the patient’s pain.
For the patient with mild to moderate pain, acetaminophen or an NSAID in
combination with a narcotic such as codeine can be sufficient for outpatient
management. For moderate to severe pain, parenteral narcotics become the
mainstay of therapy. Morphine is the most commonly used parenteral narcotic
in SCD patients, but other agents such as hydromorphone also are used commonly.
Meperidine (Demerol) use should be discouraged because of the high incidence of
side effects associated with its use, particularly its propensity to induce seizures
[22]. Parenteral narcotics should, in general, be given on an around-the-clock
schedule as opposed to an as-needed dosing. In patients who are older than 7 years
of age, patient-controlled analgesia devices are effective in controlling pain
and reducing the amount of narcotic used [23 – 25]. In addition to narcotics, there
are a variety of other useful adjunctive agents such as antihistamines (eg,
diphenhydramine), benzodiazepines (eg, ativan), and antidepressants (eg, elavil)
[21]. For the hospitalized patient, maintaining adequate hydration is important, as
intracellular dehydration can increase red cell sickling. Pediatricians should be
careful not to over hydrate the patient, however, as this can lead to worsening of
the pulmonary complications of SCD. A target of intravenous plus oral fluids at
1.0 – 1.25  maintenance should be adequate for the patient experiencing a painful
episode. Although commonly used, oxygen therapy is of no proven benefit in the
nonhypoxic patient with a painful event. Finally, nonpharmacologic measures
such as hypnosis, imagery, and distraction can be powerful tools in the treatment
of children with sickle cell pain.

The spleen
Splenic sequestration is a common cause of morbidity in infants and young
children with SCD. Signs of splenic sequestration include the rapid onset of
fatigue, listlessness, and pallor. These symptoms often occur in association with
viral illness, so splenic sequestration can be missed. A CBC reveals a substantial
drop in hemoglobin, and thrombocytopenia and leucopenia also may occur.
Severe splenic sequestration can result in hypovolemia and even shock, as sickle
cells are rapidly removed from circulation by their sequestration within the
spleen. An emergent red cell transfusion and fluid resuscitation removes the child
from immediate danger. Spleen size and hemoglobin level should be monitored
frequently, as a decrease in hemoglobin can be rapid in the child with an evolving
sequestration event. Because of the often rapid onset of this complication, it is
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important that parents be educated on how to palpate for the spleen. Parents often
become adept at detecting enlargements of the spleen, and can alert their
physician to changes. Splenic sequestration can be a recurrent event with
subsequent events being fatal. For this reason, many children with one or two
severe events have their spleen removed to eliminate the risk for further events.
For the infant with a severe sequestration event, a period of chronic transfusion is
often given for the child to reach 2 years of age before removing the spleen.
Children with SCD also may develop chronic splenic hypertrophy. This is
particularly common in patients with hemoglobin SC and the hemoglobin S b
thalassemia syndromes. As hypertrophy develops, it is important to educate
parents about the size and location of splenic enlargement so that this enlarge-
ment is not confused with an acute splenic sequestration, should the child present
for a medical evaluation. Chronic splenic hypertrophy rarely requires the need for
splenectomy; however, some patients can experience significant discomfort from
splenic enlargement and severe thrombocytopenia.

Acute chest syndrome

Acute pulmonary injury is the second most common complication and leading
cause of death in SCD [26 –28]. The term ‘‘acute chest syndrome’’ (ACS) was
coined to describe acute pulmonary injury in recognition that pneumonia in SCD
has many etiologies and is generally more severe than in the general population
[29]. ACS is defined as a new pulmonary infiltrate in combination with fever,
chest pain, or respiratory symptoms [30,31]. The clinical course of ACS can be
variable, from a small, almost asymptomatic infiltrate to fulminant pulmonary
failure and death.
As its name implies, ACS results from many infectious and noninfectious
etiologies. Although it is not possible to determine the etiology of ACS in all
patients, a thorough evaluation is often successful in determining the etiology of
ACS. Vichinsky et al recently reported, from a national study of more than
600 ACS episodes, on the causes and outcome of ACS in SCD [31]. In this study,
an exhaustive evaluation (including bronchoscopy) for infectious and noninfec-
tious causes of ACS was undertaken. Strikingly, this group documented that
nearly half the patients who developed ACS were initially admitted for another
reason, mainly pain. The association of painful events with ACS was especially
common in patients who had evidence of pulmonary fat embolism [31 – 33].
Pulmonary fat embolism has been reported frequently in children and adults with
ACS and is associated with a particularly severe course of ACS [30,31]. It is
believed that pulmonary fat embolism most likely results from bone marrow
necrosis with subsequent intravascular release of necrotic bone marrow fat, which
travels to the lung, initiating the fat embolism syndrome. Infection is a common
etiology of ACS [31]. The atypical bacterial agents Chlamydia pneumoniae and
Mycoplasma pneumoniae were the most commonly identified infectious patho-
gens; however, respiratory syncytial virus, Staphylococcus aureus, Streptococcus
pneumoniae, and parvovirus were also common.
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Because of the morbidity and mortality associated with ACS and its often
rapidly fulminant course, early recognition of ACS is imperative. Unfortunately,
many children initially present with few symptoms or signs on physical exam-
ination. A chest radiograph should be obtained in all febrile children with SCD, as
Morris et al has shown that new pulmonary infiltrates often are missed by
evaluating physicians [15]. All children with a new pulmonary infiltrate should
be admitted to the hospital for appropriate therapy and close observation.
Once the diagnosis of ACS is made, appropriate therapy needs to be started
immediately. All sickle cell patients should receive a broad spectrum antibiotic
such as cefuroxime or cefotaxime in combination with a macrolide such as
erythromycin or azithromycin to cover for atypical bacteria. Adequate hydration
is necessary; however, careful attention to fluid balance is important, as patients
with ACS are particularly susceptible to pulmonary edema. Intravenous plus oral
fluids of 1.0 –1.25  maintenance are generally sufficient to ensure adequate
hydration. Diuretics should be used if the patient becomes fluid overloaded and
this can substantially improve the patient’s oxygenation. In the patient with
worsening clinical status, repeat chest radiograph is indicated, as infiltrates often
progress quickly in these patients. Because hypoxia leads to increased sickling,
patients with ACS should be carefully monitored and oxygen therapy started if
hypoxic. Pulse oximetry is often inaccurate in children with SCD, particularly in
the face of severe anemia [34]. If hypoxemia is suspected, then an arterial blood
gas should be obtained on room air, if at all possible. Oxygen is only helpful in
those patients with hypoxia and offers no clinical benefits in patients with normal
oxygen saturation.
As many patients with ACS also have significant pain, adequate control of this
pain is critical. Inadequate pain control leads to splinting, poor aeration, and
worsening ACS. Overmedication leads to sedation, hypoventilation, and, again,
worsening of pulmonary disease. Incentive spirometry is effective in reducing
atelectasis and hypoventilation and should be used in all sickle cell patients
admitted with pain or ACS [35]. Many patients with ACS suffer from broncho-
constriction and may benefit from the addition of bronchodilators during their
course of ACS [31]. For the hypoxic patient with ACS, transfusion with packed
red blood cells can bring about substantial clinical improvement. Generally, a
straight transfusion of 10 – 15 cc/kg is sufficient to stabilize or improve the
clinical condition of the patient. Patients with severe hypoxemia may require
further transfusion or exchange transfusion. In the event that a straight transfusion
is given, the target hemoglobin should not be greater than 12– 13 g/dL. If the
patient has a high hemoglobin level, then an exchange transfusion is indicated to
prevent over transfusing the patient.
Most patients with SCD eventually suffer from ACS, and many patients go on
to have repeat episodes of ACS. Severe and repeated episodes of ACS can lead to
chronic lung injury with the subsequent development of pulmonary hypertension
and cor pulmonale [36]. In the sickle cell patient who has had severe or repeated
episodes of ACS, regular monitoring of pulmonary function tests and echocar-
diography should be performed to screen for pulmonary hypertension. If detected
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early, transfusions and other therapy can be initiated to halt the progression of
pulmonary hypertension.

Neurologic complications
Neurologic complications such as cerebral infarction and hemorrhage are com-
mon in the child with SCD. Ten to twelve percent of children with sickle cell
anemia suffer a symptomatic stroke in childhood, and an additional 20% have
evidence of asymptomatic cerebral infarction on MRI of the brain [37,38]. In the
child with a symptomatic stroke, the rapid institution of transfusions often can
reverse the motor deficits associated with stroke; however, these children suffer
from pervasive learning deficits that are life-long [39,40]. Children with asymp-
tomatic cerebral infarction on MRI also have been shown to have significant
neuropsychologic deficits.
Most strokes in children are the result of infarction, but intracranial hemor-
rhage also occurs, and increases in frequency in older children [41,42]. The
vessels of the anterior portion of the circle of Willis show progressive narrowing
with eventual occlusion, collateral vessel development, and, often, progression to
moyamoya. It is not known why children with SCD develop these lesions,
particularly so early in life, but the altered rheology of the sickle red cell and
abnormal adherence of the sickle red cell to the endothelium likely contribute to
endothelial injury in these vessels.
In the child who presents with an apparent cerebrovascular accident, exchange
transfusions should be emergently undertaken. Initiation of this therapy should not
be delayed pending obtaining further radiologic studies such as brain MRI.
Exchange transfusion is undertaken to reduce the level of circulating hemoglobin S
to less than 30%. After transfusion, children often have remarkable recovery from
motor deficits; however, these children are prone to developing seizures. Once the
patient has been stabilized, further radiologic confirmation of the nature of the
cerebrovascular accident can be obtained. A CT scan usually is obtained first, as
this is generally more readily available and shows the presence of hemorrhage that
may require immediate attention. Early CT scanning may completely miss the
presence of a cerebral infarction and may appear normal. To detect a cerebral
infarction, an MRI is the definitive test and shows evidence of infarction
immediately. An MRI early in the course may miss the presence of bleeding.
After the diagnosis of a stroke has been made, the child needs to be maintained on a
chronic, monthly transfusion regimen to maintain the hemoglobin S level at less
than 30%. This is to prevent recurrence of stroke, which is seen in 70% – 90% of
patients and may be fatal [43].
In the absence of focal neurologic findings, the pediatrician should be alert to
some of the more subtle signs of an asymptomatic cerebral infarction. Changes in
behavior and school performance can be subtle signs that the patient may have
asymptomatic neurologic injury [38,39]. In these cases, MRI and MRA scanning
should be considered to rule out undetected cerebral infarction. Patients with
asymptomatic cerebral infarction are at a higher risk for developing symptomatic
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strokes, and MRA scanning may detect the stenosis of the circle of Willis vessels
that predisposes them to a clinically apparent stroke [38].
Because of the lifelong morbidity associated with strokes, there have been
many efforts to identify which patients are at high risk for stroke. Natural history
studies have demonstrated that the risk factors associated with stroke are different
from those associated with the other manifestations of SCD, suggesting a
different pathophysiology [44,45]. The risk factors identified to date include a
history of transient ischemic attacks, seizure, a low baseline hemoglobin level, an
elevated white blood cell count, systolic hypertension, and a recent or remote
history of ACS. Adams et al documented that transcranial Doppler (TCD)
ultrasound is a valuable tool in identifying sickle cell anemia patients at high
risk for stroke [46]. Stenosis in the circle of Willis vessels results in an increased
velocity across these vessels that can be detected with the TCD. Although TCD is
a valuable tool for the screening of sickle cell patients, adequate training in the
performance and interpretation of this test is critical before its use clinically.
TCD ultrasound can be used as a screening tool in children as young as 2 years
of age and should be performed yearly. If the results are conditional (170 –200 cm/
sec) then the patient should have examinations every 2 months to ensure that they
do not progress to abnormal. Patients with abnormal velocities ( > 200 cm/sec)
need to have repeat TCD within 2 –8 weeks to confirm the abnormal velocity. In
patients with a confirmed abnormal velocity, the stroke risk is 10% per year for the
first 3– 4 years [46]. The Stroke Prevention in Sickle Cell Anemia Trial (STOP)
documented that in patients with an abnormal TCD, chronic transfusions reduced
the risk for stroke by more than 90% [47]. Because of the success of this study,
many patients with an abnormal velocity on TCD elect to go on a chronic trans-
fusion program. A second study, STOP II, is underway to determine if transfusions
can be safely stopped after a period of time.

Anemia
All patients with SCD have some degree of anemia. Patients with hemoglobin
SS and S b0 thalassemia tend to have more severe anemia than those with hemo-
globin SC and S b+ thalassemia. Anemia is generally well tolerated throughout
childhood and usually only becomes a problem when there is an increase in red
cell destruction or decrease in production of red cells. Splenic sequestration and
aplastic crisis are the two most common reasons for an acute drop in hemoglobin
level. Splenic sequestration (see earlier discussion) usually can be quickly and
effectively treated with a single red cell transfusion.
Aplastic crisis in SCD is generally the result of infection with Parvovirus [48],
which temporarily causes the complete cessation of red cell production. Aplasia
in the course of parvovirus generally occurs before the development of rash or
other symptoms, so patients do not have the usual signs and symptoms associated
with this infection. The period of red cell aplasia associated with parvovirus
infection is limited, and therefore, a single red cell transfusion is sufficient to
raise hemoglobin until the child resumes red cell production. Parvovirus infection
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also can be associated with severe ACS [31,49]. Parvovirus results in bone
marrow necrosis, and severe episodes of parvovirus-associated ACS have
demonstrated that fat embolism often results from infection with this agent
[50,51]. When the child with sickle cell anemia presents with aplastic crisis, the
child is still in the infectious period of their disease, so they need to be isolated
from other patients with hemolytic anemia and from pregnant women.

Renal and genitourinary complications

SCD manifests in a variety of renal and genitourinary problems, including
priapism, hematuria, enuresis, and renal failure. Enuresis is a common complaint
from families with children with SCD. Enuresis in the child with SCD, unlike in
other children, is caused by an increase in urine production from the kidneys’
inability to concentrate urine [52]. Children with SCD lose the ability to
concentrate urine early in life because of red cell sickling within the kidney
from low oxygen tension and an acidic environment. Because enuresis is the
result of a physiologic problem, it can be particularly difficult to treat.
Hematuria found on screening urinalysis is another fairly common finding in
children with SCD [53]. It is usually intermittent but is particularly concerning if
found in association with proteinuria or hypertension. Proteinuria is a common
finding in adults with SCD but can begin in childhood or the teenage years.
Proteinuria is a harbinger of ongoing renal injury and should be aggressively
treated. Angiotensin-converting enzyme inhibitors such as enalapril have been
shown to be effective in reducing proteinuria and should be instituted in any child
with proteinuria [54].
Papillary necrosis also is seen in children with SCD and manifests with the
acute onset of bloody or red-appearing urine. Treatment for papillary necrosis
involves admission with aggressive intravenous hydration and monitoring of
hemoglobin level. Hematuria usually resolves with aggressive hydration, although
bleeding can be prolonged. Frank renal dysfunction, as reflected by elevated
creatinine, is uncommon in children with SCD, but glomerulomegaly and focal
segmental glomerulosclerosis can begin as early as the second decade of life in
patients with SCD.
Priapism is common in patients with SCD and generally manifests in two ways
in children [55 – 57]. Young, prepubertal children often present with ‘‘stuttering’’
priapism, which consists of short-lived episodes of penile erection that is mildly
tender and resolves spontaneously. Adequate hydration and treatment of any
underlying infection are important in the management of these patients, but more
aggressive means are rarely needed as it usually resolves on its own. More
concerning is the severe, painful priapism that develops in pubescent or older
teens. Early recognition and treatment are critical, and priapism should be treated
as a medical emergency. Initial management should consist of aggressive
hydration and adequate pain relief. Priapism can be severe enough to obstruct
the urinary stream, so urinary obstruction and urinary tract infection need to be
quickly ruled out. Pain management usually requires the use of parenteral nar-
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cotics. Although straight transfusion and exchange transfusion have been reported
to be useful in priapism, it has been the author’s experience that in established
priapism, transfusion rarely produces any benefit and may put the patient at risk
for stroke [58,59].
A variety of therapies have been reported to be of benefit in priapism, including
oral alpha agonists, alkalization of the blood, and direct injection of alpha agonists
into the corpora cavernosa [60 – 62]. In our experience, rapid resolution of
priapism can be achieved in most patients with aspiration and injection of alpha
agonists into the corpora cavernosum. When performed appropriately, this is a safe
and rapidly effective procedure, and patients only rarely require repeat aspiration
and injection for the acute event. After resolution of the acute event, oral
pseudoephedrine and antiandrogen therapies have been reported to be effective
in preventing further events [63]. Unfortunately, even with rapid treatment and
resolution, a significant portion of young men with priapism develop fibrosis
and impotence.

Avascular necrosis
Avascular necrosis (AVN) of the femoral and humeral heads is a common
complication of SCD and results in substantial physical disability [64 – 66].
Although AVN of the humeral head is most common, this joint is not weightbear-
ing and so disability is less frequent than with AVN of the hip. Avascular necrosis
of the femoral head develops in more than 50% of patients with SCD by the age of
35 years [64]. AVN of the femoral head can present in many ways, including
reports of pain in the knee, thigh, or hip, or simply painless limitation of
movement or stiffness at the hip. A careful examination of hip flexion/extension
and rotation reveals pain or decreased range of motion, especially with internal
rotation of the hip. AVN of the head is frequently bilateral but severity may vary
between hips.
Therapy for avascular necrosis is largely supportive, with bed rest, NSAIDs,
and limitation of movement during the acute painful episode. Transfusion therapy
does not seem to delay progression of AVN. Core decompression of the affected
hip has been reported to reduce pain and stop progression of the disease [67,68].
In this procedure, avascularized bone is removed to decompress the area with the
hope of subsequent new bone formation. This procedure seems to be beneficial
only in the early stages of AVN and before loss of the integrity of the femoral
head. Avascular necrosis of the hip may have its onset in childhood, so thorough
musculoskeletal examination with concentration on the hips should be performed
at least yearly in children with SCD. This ensures that AVN is detected early
when it is in its most treatable form.
When AVN progresses with collapse of the femoral head and impingement on
the joint space, hip replacement is often necessary. Unfortunately, the results of
hip replacement in SCD have historically not been good, with chronic infections,
frequent reoperation, and replacements being common [69 – 71]. With new
techniques and prostheses, the outlook for hip replacement may improve.
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Cholelithiasis
Acute cholecystitis and cholelithiasis are common in patients with SCD [72].
Because of ongoing hemolysis, patients have chronically elevated bilirubin that
leads to the formation of bilirubin stones and sludge. Stones can develop early in
life, and any child who presents with right upper quadrant pain should be
evaluated for the presence of cholelithiasis. The presence of biliary sludge does
not mandate the removal of the gallbladder, as many patients do not progress
rapidly to stone formation. If gallbladder stones are documented, the patient
should be treated symptomatically with hydration and pain medications until the
symptoms have resolved. Subsequently, the patient can be readmitted for elective
cholecystectomy, as removal of the gallbladder during acute events should be
avoided. After the gallbladder is removed, patients may still form stones that
lodge in the common bile duct. Common bile duct stones induce a backup of bile
into the liver and cause severe right upper quadrant pain and extreme hyper-
bilirubinemia. In the event of a common bile duct stone, more invasive measures
such as endoscopic retrograde cholangiopancreatography (ERCP) generally are
needed to alleviate this problem [73,74].

Ophthalmologic complications
Sickle retinopathy is common in all forms of SCD, but particularly in those
patients with hemoglobin SC disease [75 –78]. Historically, retinopathy resulted
in significant visual impairment; however, with proper screening and new
methods such as laser surgery, most of the complications of retinopathy can be
avoided. Yearly ophthalmologic examinations including inspection of the retina
are indicated for children over the age of 5 years.

Health care maintenance

Routine health maintenance for the child with SCD begins with the first
newborn visit. Prophylactic penicillin should be initiated between 2 and 4 months
of age, as the infant is at high risk for sepsis even in this early period. Infants and
young children with SCD need not only the usual pediatric healthcare mainte-
nance evaluation, but also require additional tests, vaccinations, and education
beyond the general population. While the child is an infant, the risk for infection
and splenic sequestration should be discussed at every visit. Parents need to be
instructed in and to demonstrate the proper use of a thermometer and how to
palpate for the spleen. In addition to confirmatory testing for the diagnosis of
SCD, all children should have a red cell phenotype drawn on the initial visit. This
allows determination of the child’s red cell antigen phenotype before any
transfusion. Infants and children with SCD should receive all the vaccinations
recommended for unaffected children and, in addition, vaccination against
pneumococcus and influenza virus. The newer 7-valent conjugate vaccine series
for pneumococcus should be started at 2 months of age. The older 23-valent
1204 J. Fixler, L. Styles / Pediatr Clin N Am 49 (2002) 1193–1210

pneumococcal vaccine should be given at 2 years. The influenza virus vaccine

should be given yearly when it becomes available each fall [79].
Growth and development is an area that pediatricians need to address when
caring for patients with SCD. Children with SCD can have delayed growth, but
usually reach their projected adult height [80]. The delay in growth as compared
with their peers, however, does result in significant psychosocial adjustment for
school aged children and teenagers. In addition to growth, puberty can be delayed
by as much as 2– 3 years. The patient and family need regular reassurance that
this delay rarely requires medical intervention.

Therapy
Despite all that is known about the genetics and pathophysiology of SCD,
there are few therapies that target red cell sickling directly. As a result, most of
the therapies used in SCD are supportive and aimed at ameliorating the
complications after they have occurred.

Transfusion
As mentioned earlier, the acute and chronic use of transfusion is one of the
mainstays in the treatment of SCD. For the treatment of anemia or moderately
severe episodes of ACS, a single, straight transfusion of 10– 15 cc/kg of packed
red blood cells is indicated [31]. A single, straight transfusion is also indicated
preoperatively for sickle cell anemia (hemoglobin SS) patients who undergo
surgery [81]. Sickle cell patients should receive blood that is leukocyte-depleted,
Sickledex-negative, and phenotypically matched to the patient at the Rh and Kell
antigen level [82]. These measures decrease the incidence of transfusion reactions
and alloimmunization [83 – 85]. In the child with stroke or life-threatening ACS,
an exchange transfusion is necessary. The exchange transfusion can be performed
manually or using automated apheresis equipment. For a manual exchange
transfusion, usually the goal is to exchange a single volume of the patient’s
blood. The patient’s blood volume is calculated, the packed cells are diluted to a
hemoglobin of 10, and the patient’s blood is exchanged cc for cc with the diluted
blood to reach a target hemoglobin level of 10 [86,87].
Although transfusion is effective and indispensable in the care of children with
SCD, it has substantial risks for the patient. The most significant problems that
result from transfusion include iron overload, infection, and alloimmunization.
Iron overload develops in the patient who receives repeated acute transfusions or
who is placed on a chronic transfusion regimen. If the degree of iron overload is
substantial, chelation with desferrioximine may become necessary. Chelation
involves the subcutaneous administration of desferrioximine over 8– 12 hours per
night, five times per week [88,89]. Not surprisingly, compliance with this
regimen is usually poor and the complications of iron overload develop.
Automated exchange transfusions are used increasingly in chronically transfused
 J. Fixler, L. Styles / Pediatr Clin N Am 49 (2002) 1193–1210 1205

patients and have the substantial benefit of minimal or absent iron loading as
transfused blood is exchanged cc for cc for the patient’s blood [90 –92].
With repeated exposure to blood products, the risk for transfusion-associated
infection increases. With the present blood bank screening, however, the risk for
an infection such as HIV is extremely remote. The risk for hepatitis C infection
also has been substantially reduced, but current screening mechanisms do not
completely eliminate this risk.
Because sickle cell patients often receive more than one transfusion over their
life time, alloimmunization is a substantial problem. Alloimmunization develops
because sickle cell patients are predominantly African American and the blood
supply is largely of Caucasian origin [93]. African Americans do not express
many of the minor red cell antigens expressed in the Caucasian population and,
therefore, sickle cell patients are exposed to foreign red cell antigens and form
antibodies to these antigens. Providing sickle cell patients with phenotypically
matched blood can prevent the development of alloimmunization by eliminating
patient exposure to foreign red cell antigens. Screening blood products for all red
cell antigens is a time-consuming and expensive process, and so practically,
patients are generally only matched at the Rh antigen (C and E) and Kell antigen
level because they make up most cases of alloimmunization. All sickle cell
patients should receive at least limited phenotypically matched blood (Rh and
Kell) and should receive completely phenotypically matched blood if they have
an existing red cell antibody [82,83].

Hydroxyurea
Hydroxyurea is an oral chemotherapeutic agent that has been used for decades
in myeloid leukemias. It also has long been known that hydroxyurea results in the
up regulation of fetal hemoglobin. Fetal hemoglobin, within the red cell,
interferes with polymerization of hemoglobin S, and therefore decreases the
propensity of the red cell to sickle [94]. Hydroxyurea also increases red cell
hydration and decreases the expression of red cell adhesion molecules, therefore
providing additional salutary effects on the red cell [95,96]. Numerous studies in
adults and children have documented the beneficial effects of hydroxyurea in
patients with SCD [97 – 103]. The use of hydroxyurea reduces the number of pain
crises, the incidence of ACS, and the need for transfusions in SCD patients.
Hydroxyurea is Federal Drug Administration (FDA) approved for use in adults
with SCD. It has not yet been approved for use in children; however, many
studies have documented equal, if not superior, efficacy and safety in children as
young as 2 years of age. If anticipating the use of hydroxyurea in a child with
SCD, referral to a pediatric hematologist is indicated.

Stem cell transplantation

Currently stem cell transplantation is the only curative therapy for sickle cell
anemia [104]. More than 100 children with sickle cell anemia have been treated
1206 J. Fixler, L. Styles / Pediatr Clin N Am 49 (2002) 1193–1210

in the United States with bone marrow transplantation. Most of these children
were treated because they had experienced a stroke. Results from transplantation
to date include an overall survival rate of 90% – 95%, a cure rate of 85%, and a
graft rejection rate of 10% [105]. Currently only HLA identical siblings are
appropriate for use as stem cell donors for bone marrow transplantation, but other
research protocols using cord blood and nonmyeloablative techniques are under
investigation and may broaden the potential choice of donors [106].

References
[1] Clinical Practice Guideline Number 6: sickle cell disease. Screening, diagnosis, management,
and counseling in newborns and infants. Publication N. 93 – 0562. Silver Springs, Maryland:
Agency for Health Care Policy and Research; 1993.
[2] Motulsky AG. Frequency of sickling disorders in U.S. blacks. N Engl J Med 1973;288:31 – 3.
[3] Roth Jr EF, Friedman M, Ueda Y, et al. Sickling rates of human AS red cells infected in vitro
with Plasmodium falciparum malaria. Science 1978;202:650 – 2.
[4] Serjeant GR. Natural history and determinants of clinical severity of sickle cell disease. Curr
Opin Hematol 1995;2:103 – 8.
[5] Serjeant GR. Sickle-cell disease. Lancet 1997;350:725 – 30.
[6] Embury SH, Hebbel RP, Mohandas N, Steinberg MH. Sickle cell disease: basic principles and
clinical practice. New York: Raven Press; 1994.
[7] Ballas SK, Mohandas N. Pathophysiology of vaso-occlusion. Hematol Oncol Clin N Am
1996;10:1221 – 39.
[8] Bunn HF. Pathogenesis and treatment of sickle cell disease. N Engl J Med 1997;337:762 – 9.
[9] Hebbel RP. Perspectives series: cell adhesion in vascular biology. Adhesive interactions of sickle
erythrocytes with endothelium. Journal of Clinical Investigation 1997;99:2561 – 4.
[10] Pearson HA, Gallagher D, Chilcote R, et al. Developmental pattern of splenic dysfunction in
sickle cell disorders. Pediatrics 1985;76:392 – 7.
[11] Wright J, Thomas P, Serjeant GR. Septicemia caused by Salmonella infection: an overlooked
complication of sickle cell disease. J Pediatr 1997;130:394 – 9.
[12] Gill FM, Sleeper LA, Weiner SJ, et al. Clinical events in the first decade in a cohort of infants
with sickle cell disease. Blood 1995;86:776 – 83.
[13] Gaston MH, Verter JI, Woods G, et al. Prophylaxis with oral penicillin in children with sickle
cell anemia. A randomized trial. N Engl J Med 1986;314:1593 – 9.
[14] Falletta JM, Woods GM, Verter JI, et al. Discontinuing penicillin prophylaxis in children with
sickle cell anemia. Prophylactic Penicillin Study II. J Pediatr 1995;127:685 – 90.
[15] Morris C, Vichinsky E, Styles L. Clinician assessment for acute chest syndrome in febrile
patients with sickle cell disease: is it accurate enough? Ann Emerg Med 1999;34:64 – 9.
[16] Wilimas JA, Flynn PM, Harris S, et al. A randomized study of outpatient treatment with cef-
triaxone for selected febrile children with sickle cell disease. N Engl J Med 1993;329:472 – 6.
[17] Williams LL, Wilimas JA, Harris SC, et al. Outpatient therapy with ceftriaxone and oral cefixime
for selected febrile children with sickle cell disease. J Pediatr Hematol Oncol 1996;18:257 – 61.
[18] Hongeng S, Wilimas JA, Harris S, et al. Recurrent Streptococcus pneumoniae sepsis in children
with sickle cell disease. J Pediatr 1996;130:814 – 6.
[19] Ballas SK, Larner J, Smith ED, et al. Rheologic predictors of the severity of the painful sickle
cell crisis. Blood 1988;72:1216 – 23.
[20] Guidelines for the management of acute and chronic pain in sickle-cell disease. Glenview, :
American Pain Society; 1999.
[21] Ballas SK, Carlos TM, Dampier C, and the Guidelines Committee. Guidelines for standard of
care of acute painful episodes in patients with sickle cell disease. Philadelphia: Cardeza
Foundation; 2000.
 J. Fixler, L. Styles / Pediatr Clin N Am 49 (2002) 1193–1210 1207

[22] Hagmeyer KO, Mauro LS, Mauro VF. Meperidine-related seizures associated with patient-
controlled analgesia pumps. Ann Pharmacother 1993;27:29 – 32.
[23] McPherson E, Perlin E, Finke H, et al. Patient-controlled analgesia in patients with sickle cell
vaso-occlusive crisis. Am J Med Sci 1990;299:10 – 2.
[24] Schechter NL, Berrien FB, Katz SM. The use of patient-controlled analgesia in adolescents
with sickle cell pain crisis: a preliminary report. J Pain Symptom Manage 1988;3:109 – 13.
[25] Shapiro BS, Cohen DE, Howe CJ. Patient-controlled analgesia for sickle-cell-related pain.
J Pain Symptom Manage 1993;8:22 – 8.
[26] Gray A, Anionwu EN, Davies SC, Brozovic M. Patterns of mortality in sickle cell disease in the
United Kingdom. J Clin Pathol. 1991;44:459 – 63.
[27] Platt OS, Brambilla DJ, Rosse WF, et al. Mortality in sickle cell disease. Life expectancy and
risk factors for early death. N Engl J Med 1994;330:1639 – 44.
[28] Vichinsky EP. Comprehensive care in sickle cell disease: its impact on morbidity and mortality.
Semin Hematol 1991;28:220 – 6.
[29] Charache S, Scott JC, Charache P. ‘‘Acute chest syndrome’’ in adults with sickle cell anemia.
Arch Intern Med 1979;139:67 – 9.
[30] Vichinsky EP, Styles LA, Colangelo LH, et al. Acute chest syndrome in sickle cell disease:
clinical presentation and course. Cooperative Study of Sickle Cell Disease. Blood 1997;89:
1787 – 92.
[31] Vichinsky EP, Neumayr LD, Earles AN, et al. Causes and outcomes of the acute chest syn-
drome in sickle cell disease. National Acute Chest Syndrome Study Group. N Engl J Med 2000;
342:1855 – 65.
[32] Johnson K, Stastny JF, Rucknagel DL. Fat embolism syndrome associated with asthma and
sickle cell=b+-thalassemia. Am J Hematol 1994;46:354 – 7.
[33] Vichinsky EP, Williams R, Das M, et al. Pulmonary fat embolism: a distinct cause of severe
acute chest syndrome in sickle cell anemia. Blood 1994;83:3107 – 12.
[34] Blaisdell CJ, Goodman S, Clark K, et al. Pulse oximetry is a poor predictor of hypoxemia in
stable children with sickle cell disease. Arch Pediatr Adolesc Med 2000;154:900 – 3.
[35] Bellet PS, Kalinyak KA, Shukla R, et al. Incentive spirometry to prevent acute pulmonary
complications in sickle cell diseases. N Engl J Med 1995;333:699 – 703.
[36] Powars D, Weidman JA, Odom-Maryon T, et al. Sickle cell chronic lung disease: prior morbid-
ity and the risk of pulmonary failure. Medicine (Baltimore) 1988;67:66 – 76.
[37] Pegelow CH, Macklin EA, Moser FG, et al. Longitudinal changes in brain magnetic resonance
imaging findings in children with sickle cell disease. Blood 2002;99:3014 – 8.
[38] Miller ST, Macklin EA, Pegelow CH, et al. Silent infarction as a risk factor for overt stroke in
children with sickle cell anemia: a report from the Cooperative Study of Sickle Cell Disease.
J Pediatr 2001;139:385 – 90.
[39] Wang W, Riester K, Gallagher D, et al. Progressive neurocognitive deficits occur in school-
age children with sickle cell disease (SCD) in the absence of clinical or MRI evidence of
infarction. 23rd Annual Meeting of the National Sickle Cell Disease Program. San Francisco,
CA, March 5 – 9, 1999.
[40] Armstrong FD, Thompson RJ, Wang W, et al. Cognitive functioning and brain magnetic
resonance imaging in children with sickle cell disease. Pediatrics 1996;97:864 – 70.
[41] Stockman JA, Nigro MA, Mishkin MM, et al. Occlusion of large cerebral vessels in sickle-cell
anemia. N Engl J Med 1972;287:846 – 9.
[42] Merkel KH, Ginsberg P, Parker J, et al. Cerebrovascular disease in sickle cell anemia: a clinical,
pathological and radiological correlation. Stroke 1978;9:45 – 52.
[43] Powars D, Wilson B, Imbus C, et al. The natural history of stroke in sickle cell disease. Am J
Med 1978;65:461 – 71.
[44] Ohene-Frempong K, Weiner SJ, Sleeper LA, et al. Cerebrovascular accidents in sickle cell
disease: rates and risk factors. Blood 1998;91:288 – 94.
[45] Kinney TR, Sleeper LA, Wang WC, et al. Silent cerebral infarcts in sickle cell anemia: a risk
factor analysis. Pediatrics 1999;103:640 – 5.
1208 J. Fixler, L. Styles / Pediatr Clin N Am 49 (2002) 1193–1210

[46] Adams R, McKie V, Nichols F, et al. The use of transcranial ultrasonography to predict stroke
in sickle cell disease. N Engl J Med 1992;326:605 – 10.
[47] Adams RJ, McKie VC, Brambilla D, et al. Stroke prevention trial in sickle cell anemia. Control
Clin Trials 1998;19:110 – 29.
[48] Serjeant GR, Serjeant BE, Thomas PW, et al. Human parvovirus infection in homozygous
sickle cell disease. Lancet 1993;341:1237 – 40.
[49] Lowenthal EA, Wells A, Emanuel PD, et al. Sickle cell acute chest syndrome associated with
parvovirus B19 infection: case series and review. Am J Hematol 1996;51:207 – 13.
[50] Kolquist KA, Vnencak-Jones CL, Swift L, et al. Fatal fat embolism syndrome in a child with
undiagnosed hemoglobin S-beta+ thalassemia: a complication of acute parvovirus B19 infec-
tion. Pediatr Pathol Lab Med 1996;16:71 – 82.
[51] Godeau B, Galacteros F, Schaeffer A, et al. Aplastic crisis due to extensive bone marrow
necrosis and human parvovirus infection in sickle cell disease. Am J Med 1991;91:557 – 8.
[52] Statius van Eps LW, Pinedo-Veels C, de Vries GH, et al. Nature of concentrating defect in
sickle-cell nephropathy. Microradioangiographic studies. Lancet 1970;1:450 – 2.
[53] Lucas WM. Hematuria in sickle cell disease. J Urol 1960;83:733 – 41.
[54] Falk RJ, Scheinman J, Phillips G, et al. Prevalence and pathologic features of sickle cell ne-
phropathy and response to inhibition of angiotensin-converting enzyme. N Engl J Med 1992;326:
910 – 5.
[55] Mantadakis E, Cavender JD, Rogers ZR, et al. Prevalence of priapism in children and adoles-
cents with sickle cell anemia. J Pediatr Hematol Oncol 1999;21:518 – 22.
[56] Hamre MR, Harmon EP, Kirkpatrick DV, et al. Priapism as a complication of sickle cell disease.
J Urol 1991;145:1 – 5.
[57] Powars DR, Johnson CS. Priapism. Hematol Oncol Clin N Am 1996;10:1363 – 72.
[58] Rackoff WR, Ohene-Frempong K, Month S, et al. Neurologic events after partial exchange
transfusion for priapism in sickle cell disease [see comments]. J Pediatr 1992;120:882 – 5.
[59] Seeler RA. Priapism in children with sickle cell anemia. Clin Pediatr 1971;10:418 – 9.
[60] Mantadakis E, Ewalt DH, Cavender JD, et al. Outpatient penile aspiration and epinephrine
irrigation for young patients with sickle cell anemia and prolonged priapism. Blood 2000;95:
78 – 82.
[61] Baruchel S, Rees J, Bernstein ML, Goodyer P. Relief of sickle cell priapism by hydralazine.
Report of a case. Am J Pediatr Hematol Oncol 1993;15:115 – 6.
[62] Virag R, Bachir D, Lee K, Galacteros F. Preventive treatment of priapism in sickle cell dis-
ease with oral and self-administered intracavernous injection of etilefrine. Urology 1996;47:
777 – 81.
[63] Dahm P, Rao DS, Donatucci CF. Antiandrogens in the treatment of priapism. Urology 2002;
59:138.
[64] Milner PF, Kraus AP, Sebes JI, et al. Sickle cell disease as a cause of osteonecrosis of the
femoral head. N Engl J Med 1991;325:1476 – 81.
[65] Onuba O. Bone disorders in sickle-cell disease. Int Orthop 1993;17:397 – 9.
[66] Ware HE, Brooks AP, Toye R, et al. Sickle cell disease and silent avascular necrosis of the hip.
J Bone Joint Surg Br 1991;73:947 – 9.
[67] Styles LA, Vichinsky EP. Core decompression in avascular necrosis of the hip in sickle-cell
disease. Am J Hematol 1996;52:103 – 7.
[68] Stulberg BN, Davis AW, Bauer TW, et al. Osteonecrosis of the femoral head. A prospective ran-
domized treatment protocol. Clin Orthop 1991;268:140 – 51.
[69] Vichinsky EP, Neumayr LD, Haberkern C, et al. The perioperative complication rate of ortho-
pedic surgery in sickle cell disease: report of the National Sickle Cell Surgery Study Group. Am
J Hematol 1999;62:129 – 38.
[70] Garden MS, Grant RE, Jebraili S. Perioperative complications in patients with sickle cell
disease. An orthopedic perspective. Am J Orthop 1996;25:353 – 6.
[71] Acurio MT, Friedman RJ. Hip arthroplasty in patients with sickle-cell haemoglobinopathy.
J Bone Joint Surg Br 1992;74:367 – 71.
 J. Fixler, L. Styles / Pediatr Clin N Am 49 (2002) 1193–1210 1209

[72] Sarnaik S, Slovis TL, Corbett DP, et al. Incidence of cholelithiasis in sickle cell anemia using
the ultrasonic gray-scale technique. J Pediatr 1980;96:1005 – 8.
[73] Ware RE, Schultz WH, Filston HC, et al. Diagnosis and management of common bile duct
stones in patients with sickle hemoglobinopathies. J Pediatr Surg 1992;27:572 – 5.
[74] Duncan ND, Smith AI, McDonald AH, et al. Biliary surgery in sickle cell disease: the Jamaican
experience. J R Coll Surg Edinb 2002;47:414 – 7.
[75] Serjeant BE, Mason KP, Acheson RW, et al. Blood rheology and proliferative retinopathy in
homozygous sickle cell disease. Br J Ophthalmol 1986;70:522 – 5.
[76] Koduri PR, Agbemadzo B, Nathan S. Hemoglobin S-C disease revisited: clinical study of 106
adults. Am J Hematol 2001;68:298 – 300.
[77] Ballas SK. Complications of sickle cell anemia in adults: guidelines for effective management.
Cleve Clin J Med 1999;66:48 – 58.
[78] Charache S. Eye disease in sickling disorders. Hematol Oncol Clin N Am 1996;10:1357 – 62.
[79] Health supervision for children with sickle cell disease. Pediatrics 2002;109:526 – 35.
[80] Platt OS, Rosenstock W, Espeland MA. Influence of sickle hemoglobinopathies on growth and
development. N Engl J Med 1984;311:7 – 12.
[81] Vichinsky EP, Haberkern CM, Neumayr L, et al. A comparison of conservative and aggressive
transfusion regimens in the perioperative management of sickle cell disease. The Preoperative
Transfusion in Sickle Cell Disease Study Group [see comments]. N Engl J Med 1995;333:
206 – 13.
[82] Talano JM, Johnston ST, et al. Partial phenotype matching (RH,KE11) reduces alloimmu-
nization in children with Sickle Cell Disease (SCD). J Pediatr Hematol Oncol 2000;22:
369 – 70.
[83] Vichinsky EP, Luban NL, Wright E, et al. Prospective RBC phenotype matching in a stroke-
prevention trial in sickle cell anemia: a multicenter transfusion trial. Transfusion 2001;41:
1086 – 92.
[84] Vichinsky EP. Current issues with blood transfusions in sickle cell disease. Semin Hematol
2001;38:14 – 22.
[85] Singer ST, Wu V, Mignacca R, et al. Alloimmunization and erythrocyte autoimmunization in
transfusion-dependent thalassemia patients of predominantly Asian descent. Blood 2000;96:
3369 – 73.
[86] Eckman JR. Techniques for blood administration in sickle cell patients. Semin Hematol 2001;
38:23 – 9.
[87] Charache S. The treatment of sickle cell anemia. Arch Intern Med 1974;133:698 – 705.
[88] Olivieri NF, Brittenham GM. Iron-chelating therapy and the treatment of thalassemia. Blood
1997;89:739 – 61.
[89] Kushner JP, Porter JP, Olivieri NF. Secondary iron overload. Hematology (Am Soc Hematol
Educ Prog) 2001:47 – 61.
[90] Adams DM, Schultz WH, Ware RE, et al. Erythrocytapheresis can reduce iron overload and
prevent the need for chelation therapy in chronically transfused pediatric patients. J pediatr
Hematol Oncol 1996;18:46 – 50.
[91] Kim HC, Dugan NP, Silber JH, et al. Erythrocytapheresis therapy to reduce iron overload in
chronically transfused patients with sickle cell disease. Blood 1994;83:1136 – 42.
[92] Singer ST, Quirolo K, Nishi K, et al. Erythrocytapheresis for chronically transfused children
with sickle cell disease: an effective method for maintaining a low hemoglobin S level and
reducing iron overload. J Clin Apheresis 1999;14:122 – 5.
[93] Vichinsky EP, Earles A, Johnson RA, et al. Alloimmunization in sickle cell anemia and trans-
fusion of racially unmatched blood. N Engl J Med 1990;322:1617 – 21.
[94] Charache S, Barton FB, Moore RD, et al. Hydroxyurea and sickle cell anemia. Clinical utility
of a myelosuppressive ‘‘switching’’ agent. The Multicenter Study of Hydroxyurea in Sickle
Cell Anemia. Medicine (Baltimore) 1996;75:300 – 26.
[95] Styles LA, Lubin B, Vichinsky E, et al. Decrease of very late activation antigen-4 and CD36 on
reticulocytes in sickle cell patients treated with hydroxyurea. Blood 1997;89:2554 – 9.
1210 J. Fixler, L. Styles / Pediatr Clin N Am 49 (2002) 1193–1210

[96] Ballas SK, Dover GJ, Charache S. Effect of hydroxyurea on the rheological properties of sickle
erythrocytes in vivo. Am J Hematol 1989;32:104 – 11.
[97] Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on the frequency of painful
crises in sickle cell anemia. N Engl J Med 1995;332:1317 – 22.
[98] Hoppe C, Vichinsky E, Quirolo K, et al. Use of hydroxyurea in children ages 2 to 5 years with
sickle cell disease. J Pediatr Hematol Oncol 2000;22:330 – 4.
[99] Ferster A, Vermylen C, Cornu G, et al. Hydroxyurea for treatment of severe sickle cell anemia:
a pediatric clinical trial. Blood 1996;88:1960 – 4.
[100] Jayabose S, Tugal O, Sandoval C, et al. Clinical and hematologic effects of hydroxyurea in
children with sickle cell anemia. J Pediatr 1996;129:559 – 65.
[101] Kinney TR, Helms RW, O’Branski EE, et al. Safety of hydroxyurea in children with sickle cell
anemia: results of the HUG-KIDS study, a phase I/II trial. Blood 1999;94:1550 – 4.
[102] Scott JP, Hillery CA, Brown ER, et al. Hydroxyurea therapy in children severely affected with
sickle cell disease. J Pediatr 1996;128:820 – 8.
[103] Wang W, Wynn L, Rogers Z, et al. Effects of hydroxyurea in very young children with sickle
cell disease: a pilot trial. 23rd Annual Meeting of the National Sickle Cell Disease Program.
San Francisco, March 6 – 9; 1999. p. 167.
[104] Walters MC, Patience M, Leisenring W, et al. Bone marrow transplantation for sickle cell dis-
ease. N Engl J Med 1996;335:369 – 76.
[105] Walters MC, Patience M, Leisenring W, et al. Collaborative multicenter investigation of marrow
transplantation for sickle cell disease: current results and future directions. Biol Blood Marrow
Transplant 1997;3:310 – 5.
[106] Walters MC. Bone marrow transplantation for sickle cell disease: where do we go from here?
J Pediatr Hematol Oncol 1999;21:467 – 74.