SICKLE CELL DISEASE

DR ALEX MOGERE
CONSULTANT PHYSICIAN
quizz

[Link] of the following is the most common clinical manifestation

of SCD: vaso-occlusive crisis, aplastic crisis,splenic sequestration, acute
chest syndrome
2. Which of the following manifestations of SCD warrants
transfusion?
: parvovirus B19 infection,strep pmneumo, dactylitis, none of the
above
3. Which of the following forms of SCD is least common?:
HbS/b-0 thalassemia, HbS/b+ thalassemia, HbSC disease, HbS/HbE
syndrome
Defn:

• A form of hemoglobinopathy
• Substitution of Glu by Val at position 6 in the beta chain Hb
protein,chromosome 11 ,resulting in HbS variant rather than HbA
• Negatively charged AA replaced by neutral AA
• sickle cell disease occurs when an individual has two HbS genes
(homozygous, HbSS)
• HBSS is an autosomal recessive disorder
Pathophysiology of SCD

• at low pO2, deoxy HbS polymerizes leading to rigid crystal-like rods

that distort membranes “sickles”
• the pO2 level at which sickling occurs is related to the percentage of
HbS present ƒ
• heterozygotes (HbAS); sickling occurs at a pO2 of 40 mmHg ƒ
• homozygotes (HbSS); sickling occurs at a pO2 of 80 mmHg
• sickling aggravated by acidemia, increased CO2, increased 2,3-DPG,
fever, and osmolality
• fragile sickle cells then cause injury in two main ways:
(1) fragile sickle cells hemolyze (nitric oxide depletion)
(2) they also occlude small vessels (ischemia-reperfusion injury)
Pathophysiology of sickle cell crisis
SS SC
CLASSIFICATION OF
HEMOGLOBINOPATHIES
There are 5 major classes of Hemoglobinopathies:
1 structural Hbnopathies:
a). abn Hb polymerization-HBS,hemoglobin sickling
b).altered O2 affinity : high
affinity(polycythemia),low
affinity(cyanosis,psudoanemia)
c). Hemoglobins that oxidize readily
2. Thalassemias:
[Link] hb variants(HbE,Hb constant spring,
Hb Lepore)
[Link]
HEMOGLOBINOPATHIES
[Link] persistence of Fetal Hb(HbF)
[Link] Haemoglobinopathies:
•[Link] due to toxic exposures
•B. Sulfhemoglobin due to toxic exposures
•C. carboxyHb
•D. HbH in erythroleukemia
•E. Elevated HbF in states of erythroid stress & Bone marrow
dysplasia
 What is Sickle Cell Anemia (SCA)?
 First described in Chicago in
1910 by James Herrick as an
inherited condition that results
in a decrease in the ability of
red blood cells to carry
oxygen throughout the body

 Sickle red blood cells become hard and irregularly

shaped (resembling a sickle)
 Become clogged in the small blood vessels and
therefore do not deliver oxygen to the tissues.
 Lack of tissue oxygenation can cause excruciating
pain, damage to body organs and even death.
 Mechanism
 Red blood cells (RBC)
 Contain a special protein called haemoglobin (Hb)
 Hb is the component that carries oxygen from the
lungs to all parts of the body
 Most people have only hemoglobin type – Hb A
within RBC (normal genotype: Hb AA)
 Sickle Cell: HbS
 S similar to A, but one structural change
 Other types: HbC, HbD, and HbE
 Mechanism -HbS

• When sickle haemoglobin (HbS) gives up its oxygen

to the tissues, HbS sticks together
• Forms long rods form inside RBC
• RBC become rigid, inflexible, and sickle-shaped
• Unable to squeeze through small blood vessels, instead
blocks small blood vessels
• Less oxygen to tissues of body
• RBCs containing HbS have a shorter lifespan
• Normally 10-20 days
• Chronic state of anaemia
Genetics
 2 copies of the gene
for Hb (each parent)

 HbS –Recessive
 S=Sickle
 A=Normal
 Sickle Cell Trait

 Sickle haemoglobin (S) + Normal haemoglobin (A) in RBC

 Adequate amount of normal Hb (A) in red blood cells
 RBC remain flexible
 Carrier
 Do Not have the symptoms of the sickle cell
disorders, with 2 exceptions
1. Pain when Less Oxygen than usual (scuba diving,
activities at high altitude (12,000ft), under general
anaesthesia)
2. Minute kidney problems
 3 common types of
Sickle Cell Disorders

1. Sickle Cell Anemia (HbSS)

 Sickle haemoglobin (HbS) + Sickle haemoglobin (HbS)
 Most Severe – No HbA
Other Sickling Disorders

Other types of Hb combine with sickle Hb

2. Hemoglobin S-C disease (HbSC)

• Sickle haemoglobin (HbS) + (HbC)

3. Hemoglobin S-Beta thalassemia

• Beta thalassaemia gene reduces the amount of HbA
that can be made
• Sickle haemoglobin (HbS) + reduced HbA
• Milder form of Sickle Cell Disorder than sickle cell
anemia
 Some Genetic History
 The error in the hemoglobin gene results from a genetic
mutation that occurred many thousands of years ago in people
in parts of Africa, the Mediterranean basin, the Middle
East, and India.

 A deadly form of malaria was very common at that time

 Malaria epidemics caused the death of many
 In areas where malaria was a problem, children who
inherited one sickle hemoglobin gene and who, therefore,
carried the sickle cell trait - had a survival advantage.
 Unlike the children who had normal hemoglobin genes, they
survived the malaria epidemics they grew up, had their own
children, and passed on the gene- for sickle hemoglobin.
Sickle Cell Gene Severe Malaria
 [Link]
 As populations migrated, the sickle cell-mutation
spread to other Mediterranean areas, further into the
Middle East and eventually into the Western
Hemisphere.
 In the United States and other countries where
malaria is not a problem, the sickle hemoglobin gene
no longer provides a survival advantage.
 Instead, it may be a serious threat to the carrier's
children, who may inherit two abnormal sickle
hemoglobin genes and have sickle cell anemia.
 Who is at risk?
 Most common in Africans and African
Americans.
 East Asia, Southern Italy, Saudi Arabia,
India, Egypt, South and Central
American, Cuba, the Caribbean, Greece,
and Iran, and Eastern Jews have also
been found to have a form of this illness.
 Prevalence

 More than 2.5 million Americans have

the trait
 70,000 or more Americans have sickle
cell disease
 About 1,000 babies are born with the
disease each year in America
 In Nigeria, 1/3 population of U.S., 45,000-90,000 babies
with sickle cell disease are born each year
Ct. Prevalence

• In Kenya and most of EA, sickle cell Hb(HbS) is the predominant beta
globin chain Abnormality
• Homozygous sickle cell disease(SCA), is the predominant form of
sickle cell disease( JR Aluoch,1993)
• Survey of sickle cell disease in Kenya(JR Aluoch,1993): >80% of the
patients were Luo or Luhya ethnic origin(Luo 58.4%,Luhya 23.9%)
Among African - Americans
 1 in 12 have Sickle Cell Trait (Hb SA)
 1 in 600 have Sickle Cell Anemia (Hb SS)
 1 in 1500 have Sickle C Disease (Hb SC)
 1 in 350 have Sickle Cell Disease (Hb SS, SC, S-Beta-
Thal)

Among Latinos
 1 in 172 have Sickle Cell Trait (Hb AS)
 1 in 1,000 have Sickle Cell Disease (Hb SS, SC, S-
Beta-Thal)
 Screening
1. Haemoglobin Electrophoresis
 Simple Blood test
 Routine screening in high risk groups
• During pregnancy
• Before anaesthesia

2. Prenatal Testing
 Amniocentesis
 16 and 18 weeks of the pregnancy
 small risk of causing a miscarriage (1 in 100)
 Chorionic villus sampling (CVS)
 9th or 10th week of pregnancy
 very small amount of material from the developing placenta
 slightly higher chance of miscarriage
 Early Symptoms
and Complications
 Typically appear during infant's first year
 1st symptom: dactylitis and fever (6 mo-2 yrs)
 Pain in the chest, abdomen, limbs and joints
 Enlargement of the heart, liver and spleen
nosebleeds
 Frequent upper respiratory infections
 Chronic anemia as children grow older
 Over time Sickle Cell sufferers can experience damage
to organs such as liver, kidney, lungs, heart and spleen
 Can result in death
 Medical Complications

1. pain episodes 9. kidney damage and

loss of body water in urine
2. strokes
10. painful erections in men
3. increased infections
(priapism)
4. leg ulcers
11. blood blockage in the spleen or
5. bone damage liver (sequestration)
6. jaundice 12. eye damage
7. early gallstones 13. low red blood cell counts
(anemia)
8. lung blockage
14. delayed growth
SCD-SS,ACUTE PAIN EPISODE

1) aplastic crises toxins and infections (especially parvovirus B19)

transiently suppress bone marrow
2) splenic sequestration crises usually in children; significant pooling of
blood in spleen resulting in acute Hb drop and shock Šuncommon in
adults due to asplenia from repeated infarction
3) vaso-occlusive crises (infarction) may affect various organs causing
ischemia-reperfusion injury (especially in back, chest, abdomen, and
extremities), fever, and leukocytosis precipitates by infections,
dehydration, rapid change in temperature, pregnancy, menses, and
alcohol
4) acute chest syndrome
Acute chest syndrome

• Acute Chest Syndrome Affects 30% of patients with sickle cell disease
and may be life threatening.
• Presentation includes dyspnea, chest pain, fever, tachypnea,
leukocytosis, and pulmonary infiltrate on CXR.
• Caused by vaso-occlusion, infection, or pulmonary fat embolus from
infarcted marrow.
Tx acute chest syndrome

• A medical emergency
• Vigorous hydration-but care not to cause pulmonary edema
• O2 tx to protect arterial saturation
• Dx /r/o PE,Pneumonia
• Blood transfusions to maintain HCT >30
• Emergency exchange transfusion if arterial saturation drops to <90%
Functional asplenism

increased susceptibility to infection by encapsulated organisms

•S. pneumoniae
•N. meningitides
•H. influenzae
•Salmonella (osteomyelitis
 Serious Complications

 Infectious complications
 Prominent early in life
 Leading cause of morbidity and mortality
 Great improvement in the prognosis related to newborn
screening for sickle cell disease, vaccination for childhood
illnesses, the use of prophylactic antibiotics, and aggressive
diagnosis and treatment of febrile events
 Acute splenic sequestration
 Episodes of rapid increase in splenic size and decrease in
hemoglobin
 Potential source of morbidity and mortality early in life for
children with sickle cell anemia and at any age for those with Hb
SC disease and sickle thalassemia
 Serious Complications

 Strokes
 Up to 15% of children may have overt or silent strokes during
childhood
 Chronic transfusion therapy reduces the recurrence rate of
overt stroke which may approach 75% without intervention

 Bone disease
 Early risk is primarily from osteomyelitis
 Infectious usually painful inflammatory disease of bone often of
bacterial origin and may result in bone tissue death
 Avascular necrosis of the femur and humerus
 Death of bone tissue due to disrupted blood supply
 Marked by severe pain in the affected region and by
weakened bone that may flatten and collapse
 Serious Complications

 Leg ulcers
 Seen in patients older than 10 years of age
 Resistant to therapy and cause significant morbidity

• Ophthalmic complications
• Proliferative retinopathy, vitreous hemorrhage, & retinal detachment

• Priapism
• Distressing complication that occurs at all ages
• Difficult to treat
• Causes a high incidence of impotence

• Chronic Anemia
• Associated with fatigue, irritability, jaundice, pain, delayed puberty, leg sores,
eye problems, gum disease
 Recurrent Pain Episodes or Sickling
Crises

 Occur at any age but appear to be particularly

frequent during late adolescence and early
adult life
 Unpredictable
 Red Blood Cells get stuck in the small veins and
prevent normal blood flow
 Characterized by severe pain in the back, chest,
abdomen, extremities, and head
 Highly disruptive to life
 Most common reasons for individuals to seek health
care
 Danger Signs of a Crisis

1. Fever 7. Any sudden weakness or

2. Chest pain loss of feeling

3. Shortness of Breath 8. Pain that will not go away

with home treatment
4. Increasing tiredness
9. Priapism
5. Abdominal swelling
10. Sudden vision change
6. Unusual headache

SEEK URGENT HOSPITAL TREATMENT IF IN CRISIS

 Crises
 During a crisis
 severe pain in the fingers, toes,
arms, joints,legs, back, abdomen, and bones.

 Decrease in oxygen to the chest and lungs

 May lead to acute chest syndrome
 Damage to the lungs
 Severe pain and fever
 Lungs' airways narrow, further reducing O2
 Leads to an increased risk of potentially
fatal infections
 Triggers of Pain

 Infections
 Thirst and dehydration caused by not drinking
enough even if thirst is not felt
 Over-exertion
 Over-excitement
 Cold weather and cold drinks and swimming
 Bangs, bumps, bruises and strains
 Stress triggers pain in adults, but does not
seem to do so in children.
 Predicting Pain

Children and families can often tell when a

severe sickle pain is coming on by
 Thirst
 Eyes turning yellow (jaundice),
 Sufferer being more irritable or tired than
usual.
Laboratory Findings

• Normocytic anemia- Hgb 5-9 mg/dL

• Peripheral smear
• Target cells
• Poikilocytes
• Sickled cells
• Howell Jolly bodies
• Leukocytosis with neutrophil predominance
• Thrombocytosis
• X-ray- expanded marrow spaces, osteoporosis
 Alleviating Pain
 Warmth: increases blood flow
 Massaging and rubbing
 Heat from hot water bottles and deep heat creams
 Bandaging to support the painful region
 Resting the body
 Cognitive Behavioral Therapy
 Getting the sufferer to relax
 deep breathing exercises
 distracting the attention
 by other psychological methods.
 Pain-killing medicines (analgesics): paracetamol, codeine
non-steroidal anti-inflammatory(ketorolac,ibuprofen),
morphine if necessary
Morphine-0.1-0.15mg/kg every 3-4 hrs
Ketorolac ,30-60mg initial dose,then 15-30 mg every 6-8hrs
Ct. Treatment

• For respiratory distress

• Antibiotic coverage
• Supplemental oxygen
• Partial exchange transfusion
• For splenic sequestration
• Repletion of intravascular volume
• Severe anemia, transfuse
Ct .Treatment

• For suspicion of stroke

• Exchange transfusion
• For priapism
• Analgesia, hydration
• Partial exchange transfusion
Ct .Treatment

• Outpatient
• Vaccinations
• Pneumococcal, meningococcal, influenza vaccines
• Penicillin prophylaxis
• ? Folic acid therapy
• Hydroxyurea for severe symptoms
• Consideration for BMT for severe cases
Tx .vasocclusive crisis

• Oxygen
• Hydration(reduces viscosity)
• Correct acidosis
• Analesics/opiates
• Indication for exchange transfusion: acute chest syndrome, stroke,
multi-organ failure, ICU admission
• Less routinely: antimicrobials for suspected infection (eg cefuroxime,
amoxicillin/clav, ceftriaxone, azithromycin)
 Daily Preventative Measures

1. Taking the folic acid (folate) daily to help make new red
cells
2. Daily penicillin until age six to prevent serious infection
3. Drinking plenty of water daily (8-10 glasses for adults)
4. Avoiding too hot or too cold temperatures
5. Avoiding over exertion and stress
6. Getting plenty of rest
7. Getting regular check-ups from knowledgeable health care
providers
 Psychosocial Issues
 Require regular medical attention
 Especially before and after operations, dental
extraction and during pregnancy.
 Adherence to medical regimen
 Vitamins, antibiotics, fluid intake, activity level
 Schools must be involved
 Family planning
 Suitable types of employment
 Air travel
 Increased fluids, pain killers or oxygen may be
recommended
 Psychosocial Issues
 Child should be encouraged to participate in sports, but not
pushed past their limitations
 If they are in pain or feel tired they should be allowed to
rest and keep warm.
 They should have access to drinks.
 Strenuous exercise, dehydration and cold can induce a
crisis.
 Strenuous outdoor activities should be avoided in cold or
wet weather
 Should only swim if the water is warm and care is taken
to keep warm when leaving the water
 If develops a crisis despite these precautions he or she
should avoid swimming all together
 Psychosocial Issues

 Child Specific Issues: Coping with Pain

 Pain happens more often
 On an average of one third of all days
 Lasts longer
 Generally all day, even if not continuously all day
 Associated with great tiredness about half the time
 Causes them to spend significant time in bed
 On average the time spent wholly or partly in bed
adds up to about a week of every school term.
 Psychosocial Issues

 Variability and Unpredictability

 Some are mildly affected and largely free from pain,
while others have frequent and severe pain
 Most children go through good and bad patches
 Doctors cannot predict who will be severely affected.

 No easily overt detectable signs of sickle pain

 So children known to have sickle cell disorder who say
they are in pain must be trusted
 If they can rely on the adults around them to take them
seriously, they are less likely to take advantage of their
condition to seek attention or avoid distasteful tasks.
 Psychosocial Issues

 To reduce risk of crisis, children are encouraged to drink

much more than normal and more frequently
 May require about 1/4 litre of liquid every 60 - 90
minutes.
 Child will need to go to the toilet more frequently
 May increase risk of Enuresis

 Boys at risk for priapism

 May be too embarrassed to mention to parents
 Severe sickling can lead to impotence
 hydroxyurea
 The first effective drug treatment for adults with
severe sickle cell anemia reported in early 1995
 Daily doses of the anticancer drug, hydroxyurea,
reduced the frequency of painful crises, acute chest
syndrome, needed fewer blood transfusions
 Is cytotoxic and may cause bone marrow suppression
 Dose:10-30mg/kg/day,titrated to maintain white cells
btwn 5k and 8k/ul
 Increases production of fetal hemoglobin in the blood
 Fetal hemoglobin seems to prevent sickling of red
cells
 cells containing fetal hemoglobin tend to survive
longer in the bloodstream
Bone marrow transplantation

 Shown to provide a cure for severely

affected children with sickle cell disease
 Only about 18 percent of children with
sickle cell anemia are likely to have a
matched sibling.
 Justification for BM transplant:
-Repeated crises early in life
-High neutrophil count
-Devt of hand-foot syndrome
 The Ultimate Cure?
Gene Therapy

1. Correcting the “defective gene” and inserting it

into the bone marrow
2. Turning off the defective gene and
simultaneously reactivating another gene that
turns on production of fetal hemoglobin.
No real cure for Sickle Cell Anemia at this time.
“In the past 30 years, the life expectancy of people
with sickle cell anemia has increased. Many
patients with sickle cell anemia now live into
their mid-forties and beyond.”
THANK YOU!