Sickle cell

disease
HUDA ASIF
CIMS MULTAN
Case

 16 months old baby girl with

PRESENTING COMPLAINTS

 Pallor
 swelling of body, 3 MONTHS
 Fever on and off
History of presenting
illness
 At the age of 6 months, patient
develop low grade fever on, off,
intermittent, relieved by antipyretics
with pallor, irritability and abdominal
swelling. No history of bleeding from
any other site of body. No history of
petechial hemorrhages, and blood
transfusion.
Past history

 History of recurrent respiratory tract

infections due to which h/o multiple hospital
admissions
Family history

 Parents are first cousins. Both healthy

and alive. 3 siblings all healthy and
alive.
 16
13 yrs 11 yrs 7 yrs
months
examination

 Pallor +
 Jaundice
 Spots, ecchymosis -VE
 LNs
 Liver
 SPLEEN
 Edge of spleen palpable.
Laboratory investigations

 CBC & Peripheral Blood Film

 TLC 20
 Hb 7.4
 MCV 71
 PHs 575×10³/µl
 DLC
 Neutrophils 68
 Lymphocytes 20
 Monocytes 06
 Eosinophil 05
 Myelo -01
 NRBCs/100 WBC
 Showing leukoerythroblastic blood picture
Rbc morphology

 Anisocytosis+++
 Hyp++
 Macrocytosis+
 Target cells+
 Poikilocytosis++
 Microcytosis++
 Polychromasia+
 Pencil cells OCC
 Sickle cells -
 Lipid profile
 LFTs
 RFTs
 Urine RE
 PCR
Shows homozygous Hb-S mutation
 Serum Ferritin 44.5ng/ml
 Hb Studies
 Hb electrophoresis
Bands of Hbs, HbF, HbA2
Hb F quantitation 25.5%
Hb A2 quantitation 2%
Hb S 72.5%
Sickling/ sickle solubility test
 Family screening advised – positive
 Genetic counseling
Parents test

Father (sickle cell trait)

Retics 0.3%
Diamorphia+ WBC 6.1
Micro + Hb 13.6 Hb
Aniso + electrophores
MCV 69.1 is
Poik +
Pit 304 HbA 67.5
Target cell few
P 57 HbS 29.2
Elliptocytes few
Sickle cells-
L 27 HbA2 3.3
ocassional M 07
Tear drops few
 Mother (sickle cell trait)

WBC 11.2 Retics 2.1%

Hb
Hb 12.1 Diamorphia Electrophoresis
+
MCV 70.6 HbA 63.5
Micro +
Pit 349 HbF/ Hb Variant
Aniso + 0.8
P 71
Poik + HbS 32.9
L 23
Tear drops - HbA2 2.8
M7 occasional
Both parents are sickle cell
trait
 Diagnosis
 Sickle cell Disease
 Case
presentation
SICKLE CELL DISEASE

 Sickle cell disease is caused by a point mutation in

the sixth codon of β-globin that leads to the
replacement of a glutamate residue with a valine
residue.
 The abnormal physiochemical properties of the
resulting sickle hemoglobin (HbS) are responsible
for the disease.
 Sickle cell disease causes a moderately severe
hemolytic anemia
 Associated with reticulocytosis, hyperbilirubinemia,
and the presence of irreversibly sickled cells
 Sickle Cell Disease RBCs disorder that causes the
sickling of biconcave shaped RBCs.
 HEREDITARY DISORDER (AUTOSOMAL RECESSIVE)
 RED CELLS CONTAIN Hb S
 TYPES:
 HETEROZYGOUS (SICKLE CELL TRAIT)
 HOMOZYGOUS (SICKLE CELL DISEASE)
 SUBSTITUTION OF VALINE FOR GLUTAMIC
 ACID AT SIXTH POSITION OF BETA CHAIN
SICKLE CELL TRAIT

*A person has one abnormal allele of the hemoglobin beta gene.

 *Those who are heterozygous for the sickle cell allele
produce both normal “HbA” and abnormal hemoglobin “HbS”
(the two alleles are co-dominant).
 *Asymptomatic :Don’t show severe symptoms as in Sickle
cell Anemia.
 * HbA : 60%, HbS: 40% , HbF:<2%
 *They act as carriers and can transmit the disease to their off
springs.
 *People with sickle cell who exercise heavily, such as athletes
and those who are exposed to dehydration or altitude
extremes, may sometimes experience sickle cell anemia
symptoms.
1) Exercise-related rhabdomyolysis (skeletal muscle
breakdown)
 2) Exercise-associated sudden death * Occur in
normal, healthy individuals following strenuous
exercise.
 *Sickle cell trait individuals might be at greater risk for
developing the syndrome than those without this trait.
 * This syndrome can result in renal failure and sudden
death.
 *Sickle cell trait deaths occurred predominantly in
football players.
 *Athletes with the trait experienced noninstantaneous
collapse with gradual but rapid deterioration, ie,
dyspnea, fatigue, weakness, and muscle cramping.
 PATHOGENESIS
 DEOXYGENATION – CELLS
BECOME RIGID AND LOSS OF OXYGEN
DEFORMED
 BLOCKING OF SMALL
BLOOD VESSELS POLYMERS OR RIGID RODS
LEADING TO SICKLED RBCS
 IMPAIRMENT OF BLOOD
FLOW
RBCs STICK TO BLOOD
 ISCHAEMIA AND
VESSELS
INFARCTION
 REPEATED SICKLING
CAUSES HEMOLYSIS STASIS
 BOTH INTRA AND
EXTRAVASCULAR
HEMOLYSIS
HYPOXIA PAIN
diagnosis

 BLOOD COUNTS
 PERIPHERAL BLOOD FILM
 SICKLING TEST
 HEMOGLOBIN SOLUBILITY TEST
 HEMOGLOBIN ELECTROPHORESIS
 HPLC
 Solubility test
 Screening test for newborn
 DNA ANALYSIS
 Types of cells in
RBC MORPHOLOGY smear
 Normochromic  Sickle cells
 Anisocytosis  Target cells
 Poikilocytosis
 Howell jolly bodies
Sickling test
Method:
 1) A sample of venous blood or capillary blood may be collected
for this test. (*Venous blood from the arm.*Capillary blood from
the finger tips or ear lobes and in infants from the heel of the
foot.)
 2) Mixing blood with the reducing agent, sodium metabisulphite,
will induce sickling in susceptible cells.
 3) the results can be viewed under a microscope after 20
minutes.
 Normal RBC Sickled RBC
 *Positive sickling test associated with a normal haemoglobin is
likely to indicate a patient with sickle cell trait.
 Positive Test HbS
 Negative Test HbA
 This test is a qualitative test. It is simple and quick, used to
identify the presence of HbS.
 Sickle Solubility Test (SST)
 Method:
 A rapid and inexpensive technique used to screen for the
presence of sickling hemoglobins, can be used at home.
 A positive result must be confirmed by another method
(HPLC or electrophoresis) to confirm the presence of Hb S
and to distinguish Hb AS (carrier state) from Hb SS (sickle
cell disease).
 •Disadvantage: Other insoluble hemoglobins, such as Hb
C-Harlem, will also give a positive result.
 1) Erythrocytes are lysed by saponin.
 Depend on phosphate solubility
 2) The released hemoglobin is reduced by sodium
hydrosulfite in a phosphate buffer.
 3) Reduced HbS is characterized by its very low solubility
and the formation of neumatic liquid crystals (tactoids).
 The resulting tactoids of HbS causes the solution to remain
turbid.
 The presence of HbA under these same conditions results in
a clear red solution.
Hemoglobin Electrophoresis test

 *Haemoglobin electrophoresis will differentiate

between homozygous and heterozygous
conditions.
 * Hemoglobin types have different electrical
charges and move at different speeds.
 *HbSS: Is less negative by 2 compared to HbA .
Migrates slower than HbA
 *HbAS: Has both HbA and HbS. Shows 2 bands
Newborn screening
 In newborns who carry the sickle cell gene, fetal hemoglobin F
will predominate, but a small amount of hemoglobin S will also
be present.
 It is performed via the most sensitive Hb isoelectric focusing
or HPLC fractionation and identifies the specific types of
hemoglobin present.
 DNA analysis
 • This test is used to investigate alterations and mutations in
the genes that produce hemoglobin components.
 •It may be performed to determine whether someone has one
or two copies of the Hb S mutation or has two different gene
mutations.
 •Genetic testing is most often used for prenatal testing: The
usual tests offered are chorionic villus sampling (CVS) or
amniocentesis “14 to 16 weeks”.
 •There also may be a small amount of hemoglobin A if they
have sickle cell trait.
 Chest radiography
 Bone radiography
 Ultrasonography
 Bone scans
 Head CT or MRI
 SICKLE CELL TRAIT
 ASYMPTOMATIC CARRIER
 CELL DO NOT HAVE SUFFICIENT Hb S
 TO SICKLE
 SICKLING ONLY AT HIGH ALTITUDE
 AND UNPRESSURISED CABINS
 SICKLE CELL DISEASE
 ONE DEFECTIVE GENE FROM EACH PARENT
 CHRONIC HEMOLYTIC ANAEMIA
 ORGAN DAMAGE
 INFARCTIONS
 AUTOSPLENECTOMY
 EPISODES OF PAIN
 VENO OCCLUSIVE CRISIS
 GROWTH RETARDATION
 EPISODES OF INFECTION
 APLASTIC CRISIS
 Normally, humans have Haemoglobin
 A two alpha two beta
 A2 two alpha two delta
 F two alpha two gamma
 Of these, Haemoglobin A makes up around 96-97%
of the normal haemoglobin in humans
 Signs and Symptoms
 • Vaso-occlusive crisis.
 • Aplastic crisis
 • Splenic sequestration crisis.
 • Hemolytic crisis
Vaso-oclusive crisis

 Ischemia, Pain, Necrosis, Often leads to organ

damage
 ACUTE CHEST SYNDROME
 Fever, chest pain, difficulty in breathing, pulmonary
infiltrate on chest pain
 Management
1. Severe: analgesics, Opioid
2. Mild: NSAIDs
3. New treatment involving
 Adenosine A2a receptor agonists. These medicines
may reduce pain-related complications.
Splenic squestration crisis
 Acute, painful enlargements of the spleen, caused by
intrasplenic trapping of red cells
 Caused by intrasplenic trapping of red cells . Die within 1-2
hours due to circulatory failure. Autosplenectomy

 Aplastic crisis
 • Paravirus B19. Divides in RBCs precursors and destroys
them
 Stops erythropoiesis for two or three days. Causes
reticulocytopenia
 Disappears within one week with management and blood
transfusions
 Hemolytic crisis
 • Common in patients with G6PD deficiency
 Trigerred by malaria, septicemia, drugs
Factors affecting severity
 Extent of oxygen loss
 Acidity of the environment
 Concentration of HbS in RBC
 Amount of HbF in RBC
 Infections
 Low oxygen tension
 Concomitant medical conditions (e.g., sarcoidosis, diabetes mellitus, herpes)
 Dehydration*
 Extreme physical exercise
 Physical or psychologic stress
 Alcohol
 Pregnancy
 Cold weather
complications

 *Hand-Foot syndrome Pain, Fever, Swelling.

 *Overwhelming post-splenectomy infection (OPSI)
treated with antibiotics and supportive care.
 RESPIRATORY*Acute chest Syndrome Chest pain,
Shortness of breath, Fever. Pulmonary
hypertension Fatigue, Shortness of breath.
 NEUROLOGICAL*Stroke Learning problems, Long
term disability, Brain damage, Paralysis, Death.
 GIT*cholelithiasis (gall stones) & Cholecytitis
 Nausea, Vomiting, Jaundice,
 Sweating, Clay-coloured stool.
complications

 OCCULAR*Retinopathy Blindness.
 RENAL* Sickle cell nephropathy Chronic renal
failure.
 **In pregnancy spontaneous abortion.
 ORTHOPEDIC*Aseptic bone necrosis.
 GENITOURINARY*Priapism Damge to the Penis
and Impotence.
management

• Blood transfusions:
 – Acute chest crisis
 – Decreases the risk for strokes
 – Defrasirox: iron chelator
 • Folic acid daily intake
 • Penicillin
 • Malaria chemoprophylaxis
 • Hydroxyurea.
– Reactivates fetal Hb production
– Decreases severity of attacks
– Increases life span
– More effective with Erythropoietin.
 • Bone marrow transplant during childhood.
 • 5-HMF. This natural compound binds to red blood cells and increases
their oxygen. This helps prevent the red blood cells from sickling.
prevention

 Genetic screening
 Testing for sickle cells in babies.
 Chronic vill sampling
 Amniotic fluid sampling
 Fetal blood samplin
 Daily penicillin for newborn babies with the
disease.
Sickle cell gene and
malaria

 Heterozygous individuals are tolerant to malaria

 Homozygous individuals are less tolerant to
malaria because of the common functional
asplenia