Topic: SICKLE CELL DISEASE IN CHILDREN-3.pdf

Sickle cell in children

1. SICKLE CELL DISEASE
DrJD KABAMBA

2. 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

3. Definition
Sickle Cell Disease (SCD) denotes all genotypes containing at least one sickle gene
in which HbSmakes up at least half the haemoglobin present.
It is an autosomal recessive genetic disorder
Sickle cell anemia is the most common form of cases of SCD in patients of African
ethnicity.
In addition to Sickle Cell Anaemia (HbSS) there are four other compound
heterozygous conditions which can occur :
•Haemoglobin SC
•Haemoglobin S/DPunjab
•Haemoglobin S/ß thalassaemia
•Haemoglobin S/OArab
•The most common severe syndrome is homozygous sickle cell anaemia(HbSS)
•The co-inheritance of α-thalassaemiaor raised HbF production with HbSS results
in a milder clinical course

4. “Sickle Cell Disease is a genetic condition characterized by the
inheritance of 2 abnormal genes coding for haemoglobin with one of
them coding for HbS” C.Chintu

5. 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 mortality rate for children <5 years of age ranges from 50% to 80%
The high burden of the disease is further exacerbated due to lack of access to
comprehensive healthcare in the region
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
Democratic Republic of the 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.

9. Pathophysiology
•SCdis caused by a genetic
abnormality called a point mutation
•It is characterized by a single
nucleotide substitution in the 6
th
codon of the ßglobin gene results in
the substitution of glutamicacid (A)
for valine (T)on the surface of the
variant ß-globin chain.
•This change allows HbSto polymerise
when deoxygenated, the primary
event in all sickle cell pathology
•This mutation alters the haemoglobin
resulting in HbS which is insoluble
and forms crystals when exposed to
low oxygen tension

10. •When deoxygenation (decreased O
2tension) occurs, the Hbmolecule 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.

12. Clinical Features
The disease does not present clinically until 6months
after birth as the HbFwanes and HbSfully 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

13. 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 3months established
by a careful history and complete
physical examination.

14. SCD events
2. Vaso-occlusive crisis
•The cause of vaso-occlusive crisis (VOC) is
believed to be ischemic tissue injury from the
obstruction of blood flow by sickled
erythrocytes. Reduced blood flow causes
hypoxia and acidosisthat eventually leads to
ischemic tissue injury.
•Infection, fever, acidosis, hypoxia,
dehydration, sleep apnea, and exposure to
extremes of heat and cold can precipitate
crises. Often, no cause is identified.
Treat the precipitant if known.
Administer a potent analgesia following the
WHO ladder of pain management and
intravenous fluids.
Indications for transfusing the patient are: if
pain is severe; involves the whole body;
priapism; acute chest syndrome; stroke;
splenic of hepatic sequestration

15. SCD events
3. Hyper-haemolyticcrisis
Significant change in blood picture
characterisedby a rapid fall in the haemoglobin
level associated with jaundice, marked
reticulocytosis, and polychromasiaon the blood
smear, increased unconjugated
hyperbilirubinaemia, and increased
urobilinogen content in urine above the steady
state level for each individual patient.

16. SCD events
4. Splenic sequestration
Caused by RBCs trapped in the splenic
circulation leading to a rapid decrease in Hb
level, reticulocytosis,rapid enlargement of
the spleen and signs of acute circulatory
collapse.
It is a life threatening event and a medical
emergency!
It is common in children younger than 2
years.
Immediate treatment includes :
Shock treatment and blood transfusion as
patient may present in shock with severe
anemia.
Recurrence is about 50% splenectomyis
often needed.

17. SCD events
5. Aplastic crisis
Aplastic crisis occurs when red cell production
is temporarily (7-10 days)reduced while the
ongoing hemolytic process continues,
resulting in severe anaemia.
The total WBC or platelet counts may or may
not be affected. In addition, there is no
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.
Treatment :
Blood transfusion and isolation of the patient.
After 7–10 days, patients develop an antibody
response resulting in viral neutralization and
resumption of “normal” marrow erythroid
activity.

18. ComplicationsCentral Nervous System Urogenital system
Meningitis Urinary tract infection
Stroke Hyposthenuria
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 Cardiovascular system
Heart failure
Cardiomegaly

21. Avascular necrosis of the femoral headDactylitis

22. Diagnosis
Screening of SCD can be done using the following tests:
•Sickling/Solubility test
•Sickle-Scan
Confirmation of SCD and Newborn screening for SCD
can be done using
•Haemoglobin (Hb) electrophoresis
•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
FBC:
The haemoglobin is usually 6–9 g/dL
Sickle cells and target cells occur in the blood
Howell–Jolly bodies (Features of splenic atrophy)
RDW-CV > 15% (11-15%)
Normal or increased MCV (80-100 fl)
Increased reticulocyte count ( > 3%)

23. Sickling Scan Iso-Electric Focusing

24. HbSolubility Test
In the presence of Sodium Dithionite, HbS
precipitates causing turbidity of the reaction
mixture. Under the same conditions, HbA, 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.

25. 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.

26. Haemoglobin Electrophoresis
HbAis the most positively charged among
the normal adult hemoglobin types and
moves the farthest toward the cathode.
HbFhas a slightly lower positive charge
than HbA.
HbA2 is the most negatively charged and
moves only very slightly away from the
anode.

27. SCD Diagnosis
HbElectrophoresis HPLC

28. 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

29. Specific Treatment
•Treat by rest, warmth, rehydrationby oral fluids and/or intravenous normal saline
(3 L in 24 h) and antibioticsif 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 HbS percentage of less
than 30% and, after a stroke, is continued for at least one year with subsequent
hydroxycarbamide.
•For hepatic or splenic sequestration and for aplastic crisis, blood transfusion is
essential and may be life-saving
•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

30. Allogeneic stem cell transplantation
•Allogeneic transplant can cure sickle cell anaemia, with 80% disease
free after the procedure
•The mortality rate is less than 10% if patients are carefully selected
•Transplantation is only indicated in the severest of cases whose
quality of life or life expectancy is substantially impaired

31. Gene therapy
•Clinical trials are in progress using an autologous marrow stem cell
transplant procedure
•Initial trials are aimed at increasing HbF production in harvested stem
cells before they are reinfused
•Patient stem cells are harvested from bone marrow or peripheral
blood, and a lentiviral vector is used to introduce a gene construct in
vitro into these stem cells
•The construct is designed to enhance normal β-globin synthesis, or to
improve fetal haemoglobinsynthesis
•They have produced promising results

33. •References
•Nelson Textbook of paediatrics 17
th
edition-(pgs1624-1628)
•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

34. EXTRA SLIDES

35. 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 thedeviationof the RBC width, not the actual width or size of
individual cells.

36. The RDW test indicates thedifference 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.
Thefollowing types of anemiacan cause a high RDW count:
•macrocytic anemia (Folate and VitB12 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%.

37. Howell-Jolly bodies areremnants 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.

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