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SICKLE CELL DISEASE

• This is an autosomal recessive disease that results from the substitution of
glutamic acid (hydrophilic) for valine (hydrophobic) at position 6 of the beta-
globin chain.
• The disorder results from a point mutation (GAG changing to GTG) on
chromosome 11p15.5 (chromosome 11 position short arm on position 15.5).
• Patents who are homozygous for HbS gene have sickle cell disease.
• Patients who are heterozygous for HbS gene have sickle trait.
➢ These individuals have both HbA (50-60%), HbS (35-45%) and a small
percentage of HbF.
➢ Patients are usually asymptomatic without anemia unless exposed to severe
hypoxemia.
➢ Some patients have an inability to concentrate urine (isosthenuria) or
hematuria (5%) during adolescence.
➢ Carriers are protected against Plasmodium falciparum.
• Deoxygenation of the heme moiety of sickle hemoglobin leads to hydrophobic
interactions between adjacent sickle hemoglobin (HbS) molecules that aggregate
into larger polymers.
• Sickle red blood cells are less deformable and obstruct the microcirculation,
resulting in tissue hypoxia, which further promotes sickling.
• These red blood cells are rapidly hemolyzed and have a life span of only 10-20
days.
• The usual onset of the disease is 5-6 months of age as HbF (which has 2 alpha
chains and 2 gamma chains) concentration reduces.
• Depending on the type of hemoglobin chain combinations, 3 clinical syndromes
occur:
➢ Homozygous HbSS have the most severe disease.
➢ Combined heterozygosity (HbSC) for HbS and C who suffer intermediate
symptoms.
➢ Heterozygous HbAS (sickle cell trait) have no symptoms.
PATHOGENESIS
• Deoxygenated HbS molecules are insoluble and polymerize. This increases
viscosity.
➢ Polymer formation at concentrations exceeding 30g/dl.
➢ Polymers form a gel-like substance containing Hb crystals called tachoids.
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• Flexibility of the cells is decreased and they become rigid and take up their
characteristic sickle appearance.
• This process is initially reversible but with repeated sickling the cells eventually
lose their membrane flexibility and become irreversibly sickled.
➢ This is due to dehydration, partly caused by potassium leaving the red cells
via calcium activated potassium channels called the Gados channel.
• These irreversibly sickled cells are dehydrated and dense and will not return to
normal when oxygenated.
• Sickling produces:
➢ Shortened red cell survival
➢ Impaired passage of cells through the microcirculation, leading to
obstruction of small vessels and tissue infarction
• Precipitating factors for sickling:
➢ Hypoxia
➢ Dehydration
➢ Cold
➢ Acidosis
➢ Infection and fever
➢ Living at high altitude
• A crisis may occur without the presence of these factors.
• Adhesion proteins on activated endothelial cells (VCAM-1) may play a role
particularly in vaso-occlusion when rigid cells are trapped, facilitating
polymerization.
• HbS releases its oxygen to the tissues more easily than does normal Hb and
patients therefore feel well despite being anemic (except of course during crises
or complications).
CLINICAL FEATURES
• Clinical features are often termed ‘crises’ because they occur suddenly.
• They include:
➢ Sequestration crisis
➢ Hyper-hemolytic crisis
➢ Aplastic crisis
➢ Vaso-occlusive crisis
➢ Mixed
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• Although infection, dehydration, acidosis, cold temperature, exercise, extreme

emotions (all of which favor sickling) can act as triggers, in most cases no
predisposing cause is identifiable.
VASO-OCCLUSIVE CRISIS
• This is the most common crisis.
• This occurs when the microcirculation is obstructed by sickled red blood cells
resulting in ischemic injury.
• The major complaint is pain usually affecting bones such as femur, tibia and
lower vertebrae.
➢ Typically presents as deep, gnawing or throbbing pain lasting 3-7 days.
➢ The pain is recurrent
• Triggers of vaso-occlusive crisis include:
➢ Hypoxemia: may be due to acute chest syndrome or respiratory
complications
➢ Dehydration: acidosis results in a shift of the oxygen dissociation curve
➢ Changes in body temperature
• Vaso-occlusion may present as:
➢ Acute Dactylitis: painful swelling of digits of the hands and feet
o DDx: osteomyelitis
➢ Hand and foot syndrome: painful and swollen hands and/or feet)
➢ Acute abdomen: abdominal pain and distention often caused by sickling
within mesenteric artery.
o DDx: cholecystitis, appendicitis, splenic sequestration
• The spleen may undergo auto-infarction and is often not palpable beyond 6 years
of age (auto-splenectomy).
• Involvement of the kidney results in papillary necrosis leading to inability to
concentrate urine (isosthenuria).
• Other presentations:
➢ Acute chest syndrome
➢ Retinal hemorrhages
➢ Priapism: sustained painful, purposeless erection. Always consider SCD in
any patient presenting with priapism.
➢ Avascular necrosis of the femoral head
➢ Cerebrovascular accidents (Stroke): Dysathria, hemiplegia, may be
asymptomatic.
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ACUTE CHEST SYNDROME

• This is a type of vaso-occlusive crisis that affects the lungs and presents with
chest pain, cough, tachypnea, dyspnea, hypoxemia, fever or a new pulmonary
infiltrate.
• Causes include infection (e.g. viral, Mycoplasma pneumoniae, Chlamydia
pneumoniae, Streptococcus pneumoniae), sickling, atelectasis, fat embolism,
painful bone crises involving the ribs and pulmonary edema from fluid overload.
• Management:
➢ Admission
➢ Hydration: IV fluids
➢ Pain management: analgesics- NSAIDs (diclofenac/ naproxen)
➢ Oxygen support- ventilation (CPAP may be necessary)
➢ Antibiotics (also should cover for mycoplasma and chlamydia, usually
cefuroxime and azithromycin)
➢ Incentive spirometry
➢ Bronchodilators
➢ Steroids
➢ Early use of partial exchange transfusion in a patient who does not improve
rapidly.
SEQUESTRATION CRISIS
• This is due to sickled cells that block splenic outflow, leading to the pooling of
peripheral blood in the engorged spleen resulting in splenic sequestration.
• Less common also occurs in the liver.
• This occurs in patients <6 years of age.
• Presents with abdominal distension, abdominal pain, shortness of breath,
tachycardia, pallor, fatigue, and shock.
• Mortality can be high.
• Labs reveal reticulocytosis.
• There will be severe hemolysis, rapid splenomegaly and a high reticulocyte
count.
• Splenectomy is recommended by some practitioners because recurrence occurs
in up to 50%.
• Children have increased susceptibility to encapsulated organisms (e.g.
Haemophilus influenza, Streptococcus pneumoniae, Neisseria meningitidis)-
thus vaccine should be given
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• They are also at risk of other common infectious organisms such as Salmonella,
Mycoplasma pneumoniae, staphylococcus aureus and Escherichia coli).
APLASTIC CRISIS
• This most commonly occurs following infection with erythrovirus B19
(previously called Parvovirus B19) which invades proliferating erythroid
progenitors.
• There is a rapid fall in hemoglobin with no reticulocytes in the peripheral blood
because of failure of erythropoiesis in the marrow.
• Presents with pallor, fatigue, tachycardia.
• Children with aplastic crisis may present with congestive heart failure due to
severe anemia.
• Usually only supportive care and occasionally packed red blood cells
transfusions are required.
HYPERHEMOLYTIC CRISIS
• Rapid hemolysis.
• Often occurs in patients with other hemolytic diseases (e.g. G6PD deficiency)
• Presents with pallor, fatigue, tachycardia and jaundice.
➢ Remember jaundice also results from turn-over of RBCs with life span of 10-
20 days.
• Usually only supportive care and occasionally packed red blood cells
transfusions are required.
• The hyperhemolytic paradigm proposes that hemolysis in sickle cell disease leads
to increased cell-free plasma Hb which consumes Nitric oxide (NO) leading to a
state of deficiency, endothelial dysfunction and a high prevalence of pulmonary
hypertension.
DIAGNOSIS
• Requires:
➢ Full history: recurrence of symptoms (usually pain- joints, back, abdominal)
➢ Full examination
➢ Investigations
INVESTIGATIONS
• Hb electrophoresis (diagnostic gold standard): can differentiate between
homozygous or heterozygous. (this needs to be checked prior to blood
transfusion)
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• Blood investigations:
➢ FBC: findings include
o Hb: 6-9g/dl
o Hematocrit: 18-27%
o Reticulocyte count: 5-15% (this may be seen as a raised WBC count)
o WBC count: 12 000-20 000 cell/mm3
o Platelet count: increased, often >500, 000 platelet/micro litre
o Increased RDW. (Normal 11-15%)
➢ Peripheral smear
o Shows: Sickle shaped cells, Target cells and Howell-Jolley bodies

Figure 1: Sickle Shaped RBCs with normal shaped RBCs

o Howell jolley bodies indicate that the patient is functionally asplenic.

o Howell jolley bodies are basophilic nuclear remnant (clusters of DNA) in
circulating erythrocytes, during maturation in the bone marrow, late
erythroblasts normally expel their nuclei, but in some cases a small
portion of DNA remains.
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Figure 2: Howell-Jolly Bodies

o Target cells: abnormal form of red blood cell which appears as a dark ring
surrounding a dark central spot. Also known as codoctytes.

Figure 3: Target cells

➢Liver function tests

➢Urea and electrolytes
➢Hemoglobin solubility test
➢Sickling test: if the diagnosis has not been made this is done to establish the
presence of sickle hemoglobin.
➢ Blood culture
➢ Arterial blood gases
• Imaging:
➢ Chest X-ray
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➢ X-ray of skull
o Shows hair on end appearance.

o This is caused by marrow hyperplasia due to chronic hemolysis so the

vertical trabeculae found between the inner and outer tables of the diploe
bones becomes accentuated thus having the hair on end appearance.
o This is also seen on CT scan and can be also illustrated in thalassemia and
other forms of hemolytic anemias.
➢ MRI: for early bone marrow changes
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➢CT
➢Technetium 99 scan to detect early osteonecrosis
➢Transcranial Doppler U/S: to detect risk of stroke in children
➢Abdominal U/S: cholecystitis, cholelithiasis, or ectopic pregnancy and to
measure splenomegaly and hepatomegaly
➢ ECHO for pulmonary hypertension
• Spirometry
COMPLICATIONS
CENTRAL NERVOUS SYSTEM
• Transient ischemic attacks
• Seizures
• Diminished cognition
• Cerebral infarction: most common finding is obstruction of a distal intracranial
internal carotid artery or a proximal middle cerebral artery.
• Cerebral hemorrhage
• Coma
• Stroke
• Eyes:
➢ Ptosis
➢ Retinal hemorrhages
➢ Proliferative retinopathy, retinal detachment.
RESPIRATORY
• Pulmonary emboli
• Fat emboli
• Respiratory distress
• Respiratory failure
• Pulmonary hypertension: NO deficiency by increased free plasma Hb that binds
NO and causes a deficiency.
CARDIOVASCULAR
• Cardiomegaly
• Arrhythmias
• Dilatation of both ventricles and left atrium
• Iron overload cardiomyopathy
• Myocardial infarctions
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• Congestive heart failure

• Cor-pulmonale- from pulmonary hypertension
• Hemochromatosis
GASTROINTESTINAL
• Cholelithiasis- pigment stones occur as a result of chronic hemolysis
• Chronic hepatomegaly
• Liver dysfunction
• Acute Abdomen-Mesenteric artery blockage
• Autosplenectomy
GENITOURINARY
• Chronic tubulointerstitial nephritis
• Isosthenurea: kidneys lose concentration capacity.
• Priapism
• Impotence
DERMATOLOGY
• Leg ulcers over the medial or lateral malleoli.
• Poor wound healing
MUSCULOSKELETAL
• Growth and developmental delay: young children are short but regain their height
by adulthood. They however remain normal weight.
• There is often delayed sexual maturation which may require hormone therapy.
• Bones:
➢ Avascular necrosis of head of femur
➢ Compression of vertebrae
➢ Shortening of bones of hands and feet.
➢ Osteomyelitis due mostly to Staphylococcus aureus and Salmonella.
GYNAE
• Spontaneous abortion: impaired placental blood flow
• Intrauterine growth retardation
• Pre-eclampsia
• Fetal death
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MANAGEMENT AND PROGNOSIS

• Avoid and treat precipitating factors quickly.
• Rehydration
• Pain control: opioids (morphine), NSAIDs
• Oxygen and antibiotics are only given if specifically indicated:
➢ Antibiotics: cefuroxime, amoxicillin/calvulanate, penicillin V, Ceftriaxone,
azithromycin, cefaclor
• Prophylaxis with penicillin 500mg daily and vaccination with polyvalent
pneumococcal and Haemophilus influenza type b vaccine.
• Folic acid is given in all patients with hemolysis.
• Transfusion: for sudden, severe anemia due to acute splenic sequestration,
aplastic crisis or hyper-hemolytic crisis.
• Bone marrow transplantation is the only cure.
• Hydroxyurea has be given to patients with SCD, it increases HbF but has
carcinogenic effect (leukemia) aside this HbF has higher affinity to oxygen so
there is decreased oxygen delivery to tissue (tissue hypoxia).
➢ 15mg/kg/day increased by 2.5mg over 12 weeks depending on response.
• Median life expectancy is in the mid-40s.