SICKLE CELL DISEASE

Dr JD KABAMBA
Learning Objectives

At the end of this lecture, the student will be able to:

1. Understand the epidemiology of SCD
2. Define SCD and SCA
3. Determine the cause of SCD
4. Understand the pathophysiology of SCD
5. Elicit clinical manifestations and complications
6. Institute management
Definition
“Sickle Cell Disease is a genetic condition characterized by the inheritance of 2
abnormal genes coding for haemoglobin with one of them coding for Hb S”
C.Chintu
In addition to Sickle Cell Anaemia (HbSS) there are 4 other compound heterozygous
conditions which can occur :
• Haemoglobin SC
• Haemoglobin S/DPunjab
• Haemoglobin S/ß thalassaemia
• Haemoglobin S/OArab
It is an autosomal recessive genetic disorder
Sickle cell anemia is the most common form of cases of SCD in patients of African
ethnicity.
• The most common severe syndrome is homozygous sickle cell anaemia (Hb SS)
• The co-inheritance of α-thalassaemia or raised Hb F production with Hb SS results
in a milder clinical course
Epidemiology
 4.4 million people have sickle cell disease worldwide, whilst about 43 million are
living with sickle cell trait
 About 80% of sickle cell disease cases occur in sub-Saharan Africa
 The incidence of sickle cell trait ranges from 20% to 30% in Cameroon, the
Democratic Republic of the Congo, Gabon, Ghana, and Nigeria.
 90% of the world’s sickle cell disease population lives in Nigeria, India, and the DR
Congo, where the disease affects up to 2% of the population.
 Nigeria has the largest population of persons affected with sickle cell disease
globally.
 In Zambia, the sickle cell trait is carried by 20-25% of the population and 1-2% of
babies born with the disease.
Pathophysiology
• SCd is caused by a genetic
abnormality called a point mutation
• It is characterized by a single
nucleotide substitution in the 6th
codon of the ß globin gene results in
the substitution of glutamic acid (A)
for valine (T)on the surface of the
variant ß-globin chain.
• This change allows HbS to polymerise
when deoxygenated, the primary
event in all sickle cell pathology
• This mutation alters the haemoglobin
resulting in Hb S which is insoluble
and forms crystals when exposed to
low oxygen tension
• When deoxygenation (decreased O2 tension) occurs, the Hb molecule undergoes
rearrangement secondary to the amino acid substitution.
• The RBC becomes elongated, rigid, and curved on the ends, resembling a sickle
shape.
• Abnormalities within the red blood cells include:
- Abnormal hemoglobin (HbS)
- Decreased intracellular potassium ,
- Abnormal phosphorylation in cellular membrane leading to dehydration within
the cell and increased membrane calcium levels, leaving the cell in an irreversible
sickle shape.
The red cells containing this denatured fibrous haemoglobin experience membrane
damage and form sickle shapes, and may block different areas of the
microcirculation or large vessels, causing damage (infarcts) of various organs.
Clinical Features

The disease does not present clinically until 6 months

after birth as the HbF wanes and HbS fully expressing
itself.
Early clinical features are as a result of hyperhemolysis
and increased erythropoesis:
1. Skull bones bossing as a result of extramedullary
illustrated by hair-on-end picture on X-ray.
2. Recurrent jaundice ( usually mild) due to haemolysis
3. Anaemia: 6-8g/dl
4. Splenomegaly ( in infancy)/ Hypersplenism
5. Failure to thrive
SCD events
1. Steady state:
This is defined as that period when
there is no recent drop in the
hemoglobin level and there is absence
of infection, pain, acute complicating
factors or acute clinical symptoms or
crisis for at least 3 months established
by a careful history and complete
physical examination.
SCD events
2. Vaso-occlusive crisis
• The cause of vaso-occlusive crisis (VOC) is  Treat the precipitant if known.
believed to be ischemic tissue injury from the  Administer a potent analgesia following the
obstruction of blood flow by sickled WHO ladder of pain management and
erythrocytes. Reduced blood flow causes intravenous fluids.
hypoxia and acidosis that eventually leads to
ischemic tissue injury.  Indications for transfusing the patient are: if
pain is severe; involves the whole body;
• Infection, fever, acidosis, hypoxia, priapism; acute chest syndrome; stroke;
dehydration, sleep apnea, and exposure to splenic of hepatic sequestration
extremes of heat and cold can precipitate
crises. Often, no cause is identified.
SCD events
3. Hyper-haemolytic crisis
Significant change in blood picture
characterised by a rapid fall in the haemoglobin
level associated with jaundice, marked
reticulocytosis, and polychromasia on the blood
smear, increased unconjugated
hyperbilirubinaemia, and increased
urobilinogen content in urine above the steady
state level for each individual patient.
SCD events
4. Splenic sequestration
 Caused by RBCs trapped in the splenic Immediate treatment includes :
circulation leading to a rapid decrease in Hb
 Shock treatment and blood transfusion as
level, reticulocytosis ,rapid enlargement of
patient may present in shock with severe
the spleen and signs of acute circulatory
anemia.
collapse.
 Recurrence is about 50% splenectomy is
 It is a life threatening event and a medical often needed.
emergency!
 It is common in children younger than 2
years.
SCD events
5. Aplastic crisis
 Aplastic crisis occurs when red cell production Treatment :
is temporarily (7-10 days) reduced while the
 Blood transfusion and isolation of the patient.
ongoing hemolytic process continues,
After 7–10 days, patients develop an antibody
resulting in severe anaemia.
response resulting in viral neutralization and
 The total WBC or platelet counts may or may resumption of “normal” marrow erythroid
not be affected. In addition, there is no activity.
significant increase in the unconjugated
fraction of serum bilirubin.
 The condition is characterized by a rapid fall
in haemoglobin and the reticulocyte from a
direct effect of parvovirus B19 or (rarely)
other infectious agents on erythroid
progenitors in the marrow.
 Complications

Central Nervous System Urogenital system Cardiovascular system

Meningitis Urinary tract infection Heart failure
Stroke Hyposthenuria Cardiomegaly
Delayed sexual maturation
Musculoskeletal system Priapism
Vaso-occlusive crisis
Arthritis Gastroentestinal
Osteomyelitis
Leg non-healing ulcers Acute abdomen
Cholecystitis
Respiratory system Cholelithiasis
Pneumonia Hepatitis
Tuberculosis
Acute chest syndrome
Avascular necrosis of the femoral head Dactylitis
Diagnosis
Screening of SCD can be done using the following tests: FBC:
• Sickling/Solubility test The haemoglobin is usually 6–9 g/dL
• Sickle-Scan Sickle cells and target cells occur in the blood
Howell–Jolly bodies (Features of splenic atrophy)
Confirmation of SCD and Newborn screening for SCD RDW-CV > 15% (11-15%)
can be done using
Normal or increased MCV (80-100 fl)
• Haemoglobin (Hb) electrophoresis
Increased reticulocyte count ( > 3%)
• Iso-electric Focusing (IEF)
• High performance liquid chromatography (HPLC)

Other supporting tests (Which can serve as baseline

tests and follow up tests include)
• Complete/Full blood count [CBD/FBC]
Liver function tests (LFTs)
• Kidney/Renal function tests (RFTs)
• And others on per patient basis
Sickling Scan Iso-Electric Focusing
Hb Solubility Test
In the presence of Sodium Dithionite, Hb S
precipitates causing turbidity of the reaction
mixture. Under the same conditions, Hb A, as
well as most other hemoglobins, are soluble.

Reactive - If any sickling hemoglobin is present,

the solution will be sufficiently turbid to prevent
reading the Line Scale through the test tube.
Nonreactive - If a sickling hemoglobin is not
present, the solution will be clear enough to
allow the Line Scale to be seen through the test
tube.
Electrophoresis is a separation
technique used in clinical and research
laboratories for the purpose of
separating molecules according to their
size and electrical charge in a fluid or gel
under the influence of an electric field.
Haemoglobin Electrophoresis
HbA is the most positively charged among
the normal adult hemoglobin types and
moves the farthest toward the cathode.
HbF has a slightly lower positive charge
than HbA.
HbA2 is the most negatively charged and
moves only very slightly away from the
anode.
SCD Diagnosis
Hb Electrophoresis HPLC
Management

General Treatment
• Prophylactic – avoid those factors known to precipitate crises, especially
dehydration, anoxia (e.g. high altitudes), infections, stasis of the circulation
and cooling of the skin surface
• Folic acid
• Good general nutrition and hygiene
• PCV, Hib and meningococcal vaccination and regular oral penicillin are
effective at reducing the infection rate with these organisms
• Hepatitis B vaccination should also be given, as transfusions may be
needed and
• Malarial prophylaxis is required in countries where malaria is prevalent
Specific Treatment
• Treat by rest, warmth, rehydration by oral fluids and/or intravenous normal saline
and antibiotics if infection is present
• Analgesia at the appropriate level should be given. Suitable drugs are
paracetamol, a non-steroidal anti- inflammatory agent and opiates, depending on
the severity of pain
• Blood transfusion is given if there is very severe anaemia with symptoms or with
impending critical organ complications.
• Exchange transfusion may be needed, particularly if there is neurological damage
or repeated painful crises. This is aimed at achieving an Hb S percentage of less
than 30% and, after a stroke.
• For hepatic or splenic sequestration and for aplastic crisis, blood transfusion is
essential and may be life-saving
• Hydroxyurea triggers HbF induction.
• Crizanlizumab : A monoclonal antibody against P-selectin that is involved in
adhesion of sickle cells to blood vessel walls, has been shown to reduce the time
to resolution of a painful crisis
Hydroxyurea benefits

 Induces HbF
 Reduces marrow production of neutrophils, reticulocytes known to vaso-
occlusion through vascular adhesion
 Reduces number of platelets which is an important mediator of inflammation.
 Increases mean corpuscular volume, despite reduced reticulocytosis.
 Increases mean corpuscular hemoglobin
 Improves RBC hydration leading to less hemolysis and fewer sickled forms.
 Improves overall blood flow
• References
• Nelson Textbook of paediatrics 17th edition- (pgs 1624-1628)
• Guidelines for the Management of the Acute Painful Crisis in Sickle
Cell Disease:
• British Committee for Standards in Haematology: Task Force by the
Sickle Cell Working Party
• The management of Sickle cell Disease. NIH Division of blood diseases
and resources. 2002
EXTRA SLIDES
Red Blood Cell Distribution Width (RDW): Definition

The red cell distribution width (RDW) is a measurement derived from the red blood
cell distribution curves generated on automated hematology analyzers and is an
indicator of variation in RBC size within a blood sample.
The RDW is used along with the indices (MCV, MCH, MCHC) to describe a
population of RBCs.
The RDW measures the deviation of the RBC width, not the actual width or size of
individual cells.
The RDW test indicates the difference in size ( anisocytosis)and shape (
poikilocytosis) between the smallest ( mature; normocytes) and largest red blood
cells ( reticulocytes ) in a sample. The latter are large owing to the fact that they are
nucleated.
The more mature the RBCs are the more concentrated haemoglobin they have. The
uneven distribution of RBCs leads to cells of polychromasia
RDW test results may be higher if more cells are larger or smaller than average.
The following types of anemia can cause a high RDW count:
• macrocytic anemia (Folate and Vit B12 deficiencies)
• microcytic anemia ( Iron deficiency)
• hemolytic anemias ( SCA, Sepsis, Malaria, Myelodysplastic conditions)
A normal range for the RDW-CV is approximately 11.0 - 15.0%.
Howell-Jolly bodies are remnants of RBC nuclei that are normally
removed by the spleen. Thus, they are seen in patients who have
undergone splenectomy (as in this case) or who have functional
asplenia (eg, from sickle cell disease). Target cells (arrows) are another
consequence of splenectomy. RBC: red blood cell.
Copyrights apply
Copyrights apply