Sickle cell disease

Hemoglobin S (Hb S) is the result of a single base-pair change, thymine for adenine,
at the sixth codon of the globin gene. This change encodes valine instead of
glutamine in the sixth position in the globin molecule.
Sickle cell anemia, homozygous Hb S, occurs when both globin genes have the
sickle cell mutation. In sickle cell anemia, Hb S is commonly as high as 90% of the
total hemoglobin .
Sickle cell disease refers to not only patients with sickle cell anemia but also to
compound heterozygotes where one globin gene mutation includes the sickle cell
mutation and the second globin allele includes a gene mutation other than the
sickle cell mutation, such as mutations associated with Hb C, Hb S -thalassemia,
Hb D, and Hb O Arab. In sickle cell disease, Hb S is > 50% of all hemoglobin.
CLINICAL MANIFESTATIONS:
1- Fever in a child with sickle cell anemia is a medical emergency.

In the event that Salmonella spp. or Staphylococcus aureus bacteremia occurs,

strong consideration should be given to evaluation of osteomyelitis with a bone
scan.
2- Dactylitis , often referred to as hand-foot syndrome, is often the first
manifestation of pain in children with sickle cell anemia, occurring in 50% of
children by their 2nd year. Dactylitis often manifests with symmetric or
unilateral swelling of the hands and/or feet. Unilateral dactylitis can be
confused with osteomyelitis, and careful evaluation to distinguish between
the two is important, because treatment differs significantly. Dactylitis
requires palliation with pain medications, such as acetaminophen with
codeine, whereas osteomyelitis requires at least 4-6 wk of IV antibiotics.
3- Acute splenic sequestration is a life-threatening complication occurring
primarily in infants and can occur as early as 5 wk of age (Approximately

30%). Clinically, splenic sequestration is associated with engorgement of the

spleen, subsequent increase in spleen size, evidence of hypovolemia, and
decline in hemoglobin of 2 g/dL from the patient s baseline hemoglobin;
reticulocytosis and a decrease in the platelet count may be present. These
events can be accompanied by upper respiratory tract infections, bacteremia,
or viral infection. Treatment includes early intervention and maintenance of
hemodynamic stability using isotonic fluid or blood transfusions. If blood is
required, typically 5 mL/kg of packed red blood cells (RBCs) is given.
4- Pain: The cardinal clinical feature of sickle cell anemia. The only measure for
pain is the patient. Health care providers working with children with sickle cell
anemia should develop a consistent, validated pain scale, such as the WongBaker FACES Scale for determining the magnitude of the pain. Pathogenesis is
initiated when blood fl ow is disrupted in the microvasculature by sickle cells,
resulting in tissue ischemia.
Precipitating causes of painful episodes can include:
physical stress, infection, dehydration,
hypoxia, local or systemic acidosis, exposure to cold, and
swimming for prolonged periods.
Treatment:
-Acetaminophen
-NSAIDS
-Oral Codeine
-I/V morphine bolus or infusion
- Blood transfusion should be reserved for patients with a decrease in
hemoglobin resulting in hemodynamic compromise, respiratory distress, or a
falling hemoglobin concentration, with no expectation that a safe nadir will be
reached, such as when the child has both a falling hemoglobin level and
reticulocyte count with a parvovirus B19 infection.
- Hydroxyurea, a myelosuppressive agent, is the only effective drug proved to
reduce the frequency of painful episodes. The typical starting dose of
hydroxyurea is 15-20 mg/kg given daily, with an incremental dosage increase
every 8 wk. of 2.5-5.0 mg/kg, if no toxicities occur, up to a maximum of 35
mg/kg per dose. Achievement of the therapeutic effect of hydroxyurea can
require several months. Monitoring children on hydroxyurea is labor intensive,
with initial visits every 2 wk to monitor for hematologic toxicity with dose
escalations and then monthly after a therapeutic dose has been identified.
5- Priapism: is defined as an involuntary penile erection lasting for longer than 30
minutes and is a common problem in sickle cell anemia. On examination, the penis
is erect. The ventral portion and the glans of the penis are typically not involved,
and their involvement necessitates urologic consultation. For acute treatment,
supported therapy, such as sitz bath or pain medication, is commonly employed.
Priapism lasting > 4 hr should be treated by aspiration of blood from the corpora
cavernosa followed by irrigation with dilute epinephrine to produce immediate and
sustained detumescence. For the prevention of recurrent priapism, hydroxyurea.
6-Human parvovirus B19 poses a unique threat for patients with sickle cell anemia
because such infections limit the production of reticulocytes. Any child with
reticulocytopenia should be considered to have parvovirus B19 until proved

otherwise. Acute infection with parvovirus B19 is associated with red cell aplasia
(aplastic crisis), fever, pain, splenic sequestration, acute chest syndrome (ACS),
glomerulonephritis, and strokes.

7- Neurologic complications: associated with sickle cell anemia are varied and
complex
-Silent stroke: without focal neurological deficit but MRI changes
-Headaches,
- seizures,
- cerebral venous thrombosis,
- reversible posterior leukoencephalopathy syndrome (RPLS).
For patients presenting with an acute focal neurologic deficit, a prompt pediatric
neurologic evaluation is recommended. In addition, oxygen administration to keep
oxygen saturations > 96% and simple blood transfusion within 1 hr of presentation
with a goal of increasing the hemoglobin to a maximum of 10 g/dL is warranted.
Subsequently, prompt treatment with an exchange transfusion should be
considered, either manually or with erythrocytapheresis, to reduce the Hb S
percentage to at least < 50% and ideally < 30%.
8- Excessive iron stores in children receiving regular blood transfusions.
Evaluation by serum ferritin level
9- Lung disease in children with sickle cell anemia is the second most common
reason for admission to the hospital and a common cause of death. ACS refers to a
constellation of fi ndings that include a new radiodensity on chest radiograph, fever,
respiratory distress, and pain that occurs often in the chest, but it can also include
the back and/or abdomen only.
The radiographic fi ndings in ACS are variable but can include involvement of a
single lobe (predominantly the left lower lobe) or multiple lobes (most often both
lower lobes) and pleural effusions (either unilateral or bilateral).

The most common illness preceding ACS is a painful episode requiring opioids. The
risk of ACS is influenced by the type of opioid (morphine conveys a greater risk than
nalbuphine hydrochloride) and the route of administration of the opioid (oral carries
a greater risk than IV opioid).
In patients with chest pain, regular use of an incentive spirometer at 10-12 breaths
every 2 hr can significantly reduce the frequency of subsequent acute chest pain
episodes.
Fat emboli have also been implicated as a cause of ACS, are believed to arise from
infarcted bone marrow, and can be life threatening if large amounts are released to
the lungs.
As a result of the clinical overlap between pneumonia and ACS, all episodes should
be treated promptly with antimicrobial therapy , including at least a macrolide and a
third-generation cephalosporin to treat the most common pathogens associated
with ACS, namely S treptococcus pneumoniae , Mycoplasma pneumoniae , and
Chlamydia spp. A previous diagnosis of asthma should prompt treatment with
steroids and bronchodilators even when the patient does not have evidence of
wheezing.
10-Renal disease among patients with sickle cell anemia is a major comorbid
condition that can lead to premature death.
Seven sickle cell anemia associated nephropathies have been identified:
- gross hematuria,

- papillary necrosis,
- nephrotic syndrome,
- renal infarction,
- hyposthenuria,
- pyelonephritis, and
-renal medullary carcinoma.
The presentation of these entities is varied but can include hematuria, proteinuria,
renal insuffi ciency, concentrating defects, or hypertension.
The treatment of asymptomatic proteinuria with angiotensin-converting enzyme
(ACE) inhibitors can decrease renal insufficiency.
Suspicion of renal medullary carcinoma, an aggressive malignant epithelial
neoplasm, is important because most patients present with late-stage disseminated
disease that responds poorly to chemotherapy and radiation therapy.

11-Cognitive and Psychological Complications

12-Other Complications:
-sickle cell retinopathy,
-delayed onset of puberty,
-avascular necrosis of the femoral and humeral heads, and
-Leg ulcers
-hemolytic crisis: if associated with G6PD

Diagnosis:
-Newborn screening program: if suspicious then Hgb electrophoresis is done
at 1st clinic visit and at 6 month visit for definitive diagnosis along with
parents for genetic counselling.
In newborn screening programs, the hemoglobin with the greatest quantity is
reported first followed by the other hemoglobins in decreasing quantity.
In newborns with a hemoglobin analysis result of FS, the pattern supports
Hb SS, hereditary persistent fetal hemoglobin, or Hb S -thalassemia zero.
In a newborn with a hemoglobin analysis of FSA, the pattern is supportive of
diagnosis Hb S -thalassemia + . The diagnosis of Hb S -thalassemia + is
confirmed if at least 50% of the hemoglobin is Hb S, HbA is present, and the

amount of Hb A 2 is elevated (typically > 3.5%), although Hb A 2 is not

elevated in the newborn period.
In newborns with a hemoglobin analysis of FSC, the pattern supports a
diagnosis of Hb SC.
In newborns with a hemoglobin analysis of FAS, the pattern supports a
diagnosis of Hb AS (sickle cell trait).
A newborn with a hemoglobin analysis of AFS has been transfused with red
blood cells before obtaining the laboratory test because the amount of Hb A
is greater than the amount of Hb F or there has been an error. The patient
may have either sickle cell disease or sickle cell trait, and should be started
on penicillin prophylaxis until the final diagnosis can be determined.