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PRESENTED BY
DR. OHIAERI’S UNIT
(TEAM A)
DR. EKE EGHOSASERE PAUL; DR IGBOELI ELOCHUKWU

 Introduction
 Pathogenesis
 Presentation
 Complications
 Diagnosis
 Differential diagnoses
 Investigations
 Management/Treatment
 Conclusion
2/24/2015 2

INTRODUCTION
 Sickle cell disease (SCD) is a potentially devastating
condition that is caused by an autosomal recessive
inherited haemoglobinopathy which results in the
vaso-occlusive phenomena and haemolysis.
 The severity of the complications that occur with this
disorder are widely variable, but overall mortality is
increased and life expectancy decreased when
compared to the general population.
2/24/2015 3

Introduction…
 HbS is a haemoglobin tetramer (α2/βS2) that is poorly
soluble and polymerizes when deoxygenated.
 It is seen worldwide but occurs most frequently in
Africans, and less commonly in those of
Mediterranean and Arab descent. It is also seen in the
Middle East, Southern Europe, some parts of Eastern
Europe and the Indian subcontinent.
2/24/2015 4

Introduction
 1st described in 1910 by Herrick
 SCA denotes the genotype having 2 abnormal Hb both
of which are HbS (i.e. homozygous for HbS)
 SCD denotes all genotypes containing at least one HbS
and another abnormal Hb, in which HbS makes up at
least 50% of the Hb present.
2/24/2015 5

Introduction…
 Inherited as an autosomal recessive (single gene)
disorder
 HbS arises from a mutation substituting thymine for
adenine in the 6th codon of the β-chain gene, GAG to
GTG. This causes coding of valine (fat soluble) instead
of glutamate (water soluble) in position 6 of the Hb β-
chain
2/24/2015 6

Introduction…
 SCD usually manifests early in childhood usually soon
after 6 months of age when HbF levels start to fall
 Epidemiology: In Nigeria, the frequency is 3% of the
general population
 In this centre the total number of patients registered
in the SCA clinic b/w June 2011-January 2013 is 162
patients (age 1-14 yrs)
2/24/2015 7

PATHOGENESIS
 Results from deoxygenation-dependent
polymerization of HbS, with formation of
spindle-shaped liquid crystalline bodies
(tactoids), deforming the RBC , with
increased mechanical fragility and
haemolysis, predominantly at extra-vascular
sites.
2/24/2015 8

Pathogenesis…
 Affected RBCs can undergo repeated cycles
of “sickling and unsickling’’ (when exposed
to low & high O2 levels in the venous &
arterial circulation, respectively)
 Over time some lose the capacity to return
to normal shape →Irreversibly Sickled Cells
(ISC) seen in peripheral blood film
2/24/2015 9

Pathogenesis…
 Factors that promote sickling:
 Often no precipitating cause is found
 Hypoxaemia
 Decreased pH
 Extremes of temperature (fever, cold)
 Advanced cell age
2/24/2015 10

Pathogenesis…
 Increased intracellular HbS
 Dehydration
 Physical Exertion
 Infection
 Hyperleukocytosis
 Low intracellular HbF
 Low 2,3-DPG levels
2/24/2015 11

PRESENTATION
 SCA has a diverse symptomatology
 Any organ or system in the body can be
affected
 Most HbSS patient do not show any sign of
disease in early infancy due to the
predominant presence of HbF
 When HbF levels begin to fall at about age
6mths most patients manifest signs of dx
2/24/2015 13

Presentation…
 6mo to 2yrs
Dactylitis. – due to ischaemic necrosis of
the small bones, believed to be caused by a
choking off of the blood supply as a result of
the rapidly enlarging bone marrow.
Tender,warm,non-pitting swelling of dorsa
of hands and feet.—Hand-foot syndrome.
 Failure to thrive, anaemia, jaundice,
infections, crises.
2/24/2015 14

 Presentation after 2yrs
 Failure to thrive
 Anaemia, jaundice
 Infections
 Crises
 Sickle cell habitus….long, thin limbs,protuberant abd,
gnathopathy, peculiar facies.
2/24/2015 15

Presentation…
 Crises – recurrent episodes of acute illness
experienced by SCA patients
 Steady State – the condition in which the
SCA patient is free of all acute symptoms
and is deemed well
2/24/2015 16

Presentation…
 SCA Crises
 Vaso-occlusive
 Acute anaemic
2/24/2015 17

Presentation…
Vaso-occlusive
 Pain or thrombotic crisis
 Commonest clinical manifestation
 Caused by occlusion of blood vessels
leading to ischaemic injury
 Can affect any part of the body (but
especially the long bones, abdomen,
chest and back)
2/24/2015 18

Presentation…
 About 50% of individuals with SCA
experience VOC
 Frequency of crisis is extremely variable.
Some have up to 6+ episodes/yr. Others may
have episodes only at great intervals or none
at all. But each individual typically has a
consistent pattern for crisis frequency.
 Acute onset and may last several hours to
days and terminate as abruptly as it began.
2/24/2015 19

Presentation…
 Infancy – VOC manifests as hand and foot
syndrome. May present with refusal to walk,
irritability; fever; localized swelling,
tenderness or warmth
 May mimick acute osteomyelitis, septic
arthritis; appendicitis, pancreatitis,
cholecystitis, urinary tract infection, pelvic
inflammatory disease
2/24/2015 20

Presentation…
Acute Anaemic Crises
 Hyperhaemolytic
 Aplastic
 Sequestration
 Megaloblastic
 Iron deficiency
2/24/2015 21

Presentation…
 Hyperhaemolysis – acute exacerbation of the
chronic haemolysis by infectious processes.
Lab shows fall in haematocrit, Hb levels; and
reticulocytosis
 Aplastic – acute failure of erythropoiesis. May
be due to Parvovirus infection; folate
deficiency or severe bone infarction. Lab
shows fall in haemotocrit, Hb; and low or
absent reticulocytes. Usually self-limiting –
bone marrow recovers in 7-10 days
2/24/2015 22

Presentation…
 Sequestration – sudden onset progressive
anaemia, splenomegaly, and signs of
peripheral shock due to trapping of
significant portion of RBC mass in the
spleen.
 Megaloblastic changes – due to higher
folate requirements from the chronic
haemolytic state
2/24/2015 23

Presentation…
Iron deficiency – is uncommon bcos
of increased dietary Fe absorption and
frequent blood transfusions.
May occur as a result of infestations
or poor dietary intake
2/24/2015 24

COMPLICATIONS
 CNS – most severe CNS complication is CVA
(stroke). Others include sensorineural
hearing loss, retinopathy and blindness.
 They may also present with convulsions
 Pulmonary – Acute Chest Syndrome (ACS).
 Is a medical emergency
 Characterized by chest pain, fever, cough,
tachypnoea, prostration, leukocytosis, and
pulmonary infiltrates in the upper lobes.
2/24/2015 25

Complications…
 ACS is usually due to infection. Other
causes: pulmonary infarction, fat
embolism from bone marrow infarction
 Also recurrent sickling episodes in
pulmonary vasculature→formation of
microthrombi→ infarction and damage to
the alveoli. This can result in pulmonary
hypertension
2/24/2015 26

Complications…
 CVS - The heart is affected by the chronic
anemia, and microinfarcts. Haemolysis and
blood transfusion lead to hemosiderin
deposition in the myocardium. Both
ventricles and the left atrium are all dilated
 Liver – 40-80% have hepatomegaly. Usually
due to sinusoidal obstruction (& dilatation)
by sickled RBC, and engorgement of Kupffer
cells ff. phagocytosis of effete RBCs.
 Intrahepatic stasis can result in elevated conj.
bilirubin.
2/24/2015 27

Complications…
 Gallbladder – cholelithiasis; cholecystitis
(Rt upper quadrant pain assoc. with fatty
foods)
 Uncommon in Nigeria due to low fat/high
fibre diet
 Acute cholecystitis may require surgery
 Common bile duct blockage (Rt upper
quadrant pain + elevated conj.
hyperbilirubinaemia)
2/24/2015 28

Complications…
 Spleen
 Splenomegaly in the 1st 2yrs of life due
to extramedullary haemopoiesis,
congestion and sequestration
 Autosplenectomy by 10yrs of age
(especially in temperate regions) as a
result of repeated infarction causing
splenic fibrosis and regression in size
2/24/2015 29

 In Nigeria many SCD children above 10yrs
have splenomegaly probably due to
recurrent malaria infection. However there
is a Functional Asplenia
2/24/2015 30

Complications…
 Immune System
 Impaired immunity & susceptibility to
infections by encapsulated organisms e.g.
H. influenzae, S. pneumoniae. Other
organisms include Salmonella, N.
meningitidis, Mycoplasma, S. aureus, E.
coli and S. pyogenes.
2/24/2015 31

 Underlying factors: Splenic hypofunction,
defective opsonization and abnormal
leukocyte phagocytic action. Recurrent
vaso-occlusion with tissue necrosis, and
elevated serum Fe levels may also be
contributory
2/24/2015 32

Complications…
 Renal:
 Hyposthenuria: inability to concentrate
urine. Presents as polyuria, nocturia and
even enuresis
 Haematuria: from papillary necrosis and
sloughing.
 Nephrotic syndrome has been reported
 CKD is also a common cause of morbidity
& mortality in older patients
2/24/2015 33

Complications…
 UGS:
 Priapism: sustained, painful, and
unwanted erection which may be
spontaneous or follow sexual intercourse
or masturbation.
 Prolonged episodes may lead to impotence
 “Stuttering episodes are managed with oral
stilboestrol while major cases require
sedation and appropriate analgesics
2/24/2015 34

Complications…
 MSS:
 Frontal bossing; gnathopathy (protrusion
of upper teeth; malocclusion)
 Hand/Foot Syndrome (Dactylitis)
 Avascular necrosis of femoral/humeral
head
 Osteomyelitis (frequently Salmonella)
 Leg ulceration (usually affects the
malleolar areas)
2/24/2015 35

Complications…
 Endocrine:
 Delayed physical and sexual development
 Due to chronic anaemia and low
endocrine production
2/24/2015 36

DIAGNOSIS
 Clinical - 80% of cases.
 Screening Tests – indicate presence of HbS
but do not define the Hb genotype e.g.
Solubility test
 4 drops of blood + 2ml of freshly prepared
Na dithionite + K2P04 in a test tube.
 Read against a bright light
 Clear soln…..HbA, CC, DD
 Ppt above, clear soln beneath…….HbSS
 Ppt above, pink soln beneath……HbAS
2/24/2015 37

 Hb Electrophoresis – most common for definitive
diagnosis. Based on differential protein mobility in
an electrical field. Uses cellulose acetate or citrate
agar buffers
2/24/2015 38

 Isoelectric Focusing – also a form of
electrophoresis. Superior to the above.
Method of choice for newborn screening
2/24/2015 39

Diagnosis…
 Prenatal Diagnosis – usually in the first
trimester of pregnancy. Samples are taken
from amniotic cells or chorionic villus and
DNA analysis done by PCR and DNA
sequencing.
2/24/2015 40

LABORATORY FINDINGS
 Full Blood Count
 Increased retic count of 5-15%
 WBC 12-20,000
 Normal MCV
 Hb 5-9g/dl
 Normal or slightly increase platelet count.
 Normal differential or preponderance of
neutrophils
2/24/2015 41

Lab Findings…
 Nucleated RBC indicates severe anaemia
 Target cells, poikilocytosis, anisocytosis,
hypochromic cells, sickled RBC
 Howell-Jolly bodies
 Markedly hyperplastic bone marrow with
erythroid predominance.
2/24/2015 42

DIFFERENTIAL DIAGNOSIS
 1. Leukaemia
 2. Rheumatic fever
 3. Juvenile rheumatoid arthritis
 4. Osteomyelitis
2/24/2015 43

MANAGEMENT
 Early Diagnosis & good follow up
 Determine and record physical,
haematological parameters
 Avoid factors that encourage sickling
 Folic acid supplementation
 Malaria prophylaxis (routine
proguanil)/prevention of other infections
(oral pen V NB-2yrs)
 Immunization: pneumococcal; Hib (@2yrs)
2/24/2015 44

 Health Education & Counselling
2/24/2015 45

Management of Acute Illnesses &
Complications
 Objectives of Mgt
 To relieve pain promptly
 To treat precipitating cause e.g. infection,
dehydration
 To prevent or delay recurrence
 To correct fluid and electrolyte imbalance
 To relieve anxiety
2/24/2015 46

 Management of VOC
Mild to moderate:
 Bed rest at home.
 Liberal oral fluids.
 Analgesics.
 Identify and treat cause.
2/24/2015 47

 Admit
 Administer analgesics commensurate with
degree of pain.
 I.V. fluids are usually given at 1.5x
maintenance
2/24/2015 48

 Management of Hyperhaemolytic crisis
 Admit
 Give O2
 Transfuse in presence of:
1. Anaemic heart failure.
2. PCV below 15%.
3. Significant fall in pcv below steady
state value.
4. Overwhelming infection.
 Diuretics.
2/24/2015 49

 Acute Sequestration Crisis
 Treat shock; elevate foot of bed, give
parenteral steroids (methylpred or
hydroc.)
 Packed cell transfusion, 5-10 ml/kg.
 N.B. Some sequestered cells will return
to the circulation.
 Partial E.B.T.
 Splenectomy
2/24/2015 50

 Aplastic Crisis
 Intermittent oxygen.
 Whole blood transfusions
 Steroid therapy.
 ?Bone marrow transplantation.
2/24/2015 51

 Management of Infections
 Common organisms…….H. infl.,
pneumococcus, salmonella spp., S.
aureus.
 Choice of antibiotics:
 Chloramphenicol + Erythromycin
 Xtalline pen + Chloramphenicol
 Chloramphenicol + Cloxacillin
 Cephalosporins
2/24/2015 52

 Priapism
 Sedatives/anxiolytics.
 Analgesics.
 Intracavernous injection of adrenergic
agonists…e.g. Etilefrine.
 E.B.T
 Surgery, if ICI fails: caverno-spongiosum
anastomosis.
2/24/2015 53

 Haematuria
 Usually stops spontaneously
 Conservative treatment:
 Liberal fluids, to reduce clot formation
 Correct anaemia
 Epsilon amino caproic acid, an
antifibrinolytic agent, is useful in mgt
2/24/2015 54

Other Approaches
 Induction of HbF synthesis
 Hydroxyurea - 15mg/kg/24 hrs. MOA – increases HbF
levels, decreases expression of adhesive molecules on
RBCs and so prevents VOC. Gradually increase to max of
30mg/kg/24hrs. Monitor FBC, LFT and HbF. Increase
in HbF is usually 10-15%
 Recombinant human erythropoietin (rhEPO)
 Resveratrol, a natural dietary polyphenol
 Butyric acid
2/24/2015 55

 Bone Marrow Transplantation
 Has curative potential
 Problems:
1. GVHD
2. Acute effects of total body irradiation
2. Lack of suitable stem cell donors.
3. Limited access to normal HLA
identical
2/24/2015 56

 Stem cell
 Originally, stem cells were procured from
the bone marrow by direct puncture and
aspiration of bone marrow and re-infused
intravenously
 An improvement on bone marrow
transplantation
2/24/2015 57

CONCLUSION
 SCA is a debilitating genetic disease but symptoms can
be alleviated with early diagnosis, and with general
improvement of health status through health
education, regular medical follow up and which can be
prevented with pre-marital counselling.
2/24/2015 58

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SICKLE CELL ANAEMIA

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