SICKLE CELL

DISEASES
By : Asma Husain
Normal hemoglobin

Hemoglobin is the protein that makes blood red. It is composed of four protein chains,
two alpha chains and two beta chains, each with a ring-like heme group containing an
iron atom. Oxygen binds reversibly to these iron atoms and is transported through
blood. Each of the protein chains is similar in structure to myoglobin, the protein used to
store oxygen in muscles and other tissues
Hb A2(alpha ,beta)
Hb F (alpha , gamma) has high affinity to oxygen
Hb A (alpha ,delta )
Objective

 Definition
 Pathogenesis
 Clinical pictures
 Crisis
 Complications
 Investigations
 Treatment
What is sickle cell
anemia

 Sickle cell anemia, or sickle cell disease (SCD), is a genetic

disease of the red blood cells (RBCs). Normally, RBCs are
shaped like discs, which gives them the flexibility to travel
through even the smallest blood vessels. However, with this
disease, the RBCs have an abnormal crescent shape
resembling a sickle. This makes them sticky and rigid and
prone to getting trapped in small vessels, which blocks
blood from reaching different parts of the body. This can
cause pain and tissue damage.
 Chronic hemolytic characterized by
presence of abnormal “Hb s” in RBCs.
 Autosomal recessive where beta
globin misshapen, causing RBCs to
sickle when deoxygenated.
 The defect is in chromosome 11.
 More common in Asian ,African and
Black Americans.
 Sickle cell anemia- homozygous.
 Sickle cell trait- heterozygous.

-the patient is carrier.

-HbS 30% & HbA.
-A symptomatic, but severe
hypoxia may cause Vaso occlusive crisis.
-Resistance to falciparum
malaria.
 Pathogenesis
 Single amino acid substitution in
number 6 position of beta chains
where valine replacing glutamine
resulting a new HbS. Leads to
marked change in physical
characteristics of Hb.

 Sickling is accentuated by hypoxia,

acidosis, dehydration and high or
low temperature .
 Sickling will prevent RBCs from circulating
in microcirculation, they become
entangled , occlusion of microvasculature,
forming a thrombi that cause infarction.
 Weak cell membrane and premature
destroyed “20 days” , intravascular
hemolysis causing anemia.
Clinical pictures

 Manifestation do not appear in the first 3-4 months of life as HbF protects against
sickling.
 Early manifestation
 By 3 months of age “milde hemolysis” with Hb 7-10.
 Hyposplenism can occur at 5 months old and splenomegaly can detected after 6
months old.
 After age of 6 months old, starting features of anemia, chronic hemolysis and renal
disorders.
Symptoms and signs
 Sickle cell cisis.

 Aplastic Crisis: SC present with sudden pallor and weakness confirmed by rapidly dropping hemoglobin levels that
are accompanied by reticulocytopnia. The usual trigger for aplastic crisis is parvovirus B19 that directly suppresses the
bone marrow affecting RBC production, but it can also be caused by other viral infections. The shortened lifespan of
RBC in SCD results in worsening of the patient's baseline anemia, which can dip to dangerously low levels. The
infection is self-limited, typically lasting 7 to 10 days

 Hemolytic Crisis: An acute drop in hemoglobin level marks this crisis. It is common in patients with coexistent G6PD
deficiency.

 Splenic Sequestration Crisis: Patients with SCD have spleen infarction before the end of childhood. The spleen is
affected due to its narrow vessels and its role as a key player in the lymphoreticular system. Splenic sequestration
crisis causes acute, painful enlargement of the spleen due to intrasplenic trapping of red cells. Patients with splenic
sequestration crisis may have a sudden drop in hemoglobin levels, and one should be vigilant about hypovolemic
shock. If not treated promptly, this can be a life-threatening situation
 Infectious crisis: due to hyposplenism (low immunity), patent usually affected with
encapsulated organisms.
 Meningitis “pneumococci & H. Influenzae”.
 Pneumonia “pneumococci”.
 Osteomyelitis “salmonella”.

 Megaloblastic crisis
Vaso-occlusive Crisis
(VOC)
 “Thrombotic or painful crisis”:
the most frequent crisis results
from occlusion of small blood
vessels, causing distal
ischemia and infarction
according to the site of
occlusion. They may persist as
dactylitis, sever limb, chest, or
abdominal pains, cerebral
stoke, hematuria , and etc.
 Precipitating factors: fever, acidosis, dehydration ,infection
& hypoxia.
 Clinical presentation
 Patients present with moderate to severe pain, which has
variable intensity and frequency. Young children can have
severe pain and swelling of both hands and feet (dactylitis).
 Acute Chest Syndrome (ACS): This complication of SCD
accounts for 25% of deaths and can follow vaso-occlusive crises.
The trigger for ACS is frequently hypoxia due to hypoventilation of
the chest caused by VOC crisis. It could also occur as a result of fat
embolism originating from the distal bone in VOC. . The presenting
symptoms and signs include fever, cough, tachypnea, chest pain,
hypoxia, wheeze, respiratory distress, and even failure. Any
pulmonary infiltrate on chest radiography accompanied
by abnormal lung findings should raise the suspicion of ACS.
Affected patients can rapidly progress to worsening respiratory
failure and death
 Cerebrovascular stroke.
 Pulmonary infarction
“hemoptysis”.
 Renal infarction
“hematuria”
 Priapism “sustained ,
painful purposeless
erection”
 Leg ulcer.
Complications :

 Neurological complications
 Silent stroke.
 Sizures.
 Headache.
 Pulmonary Hypertension
 Renal complications
 Gross hematuria.
 Nephritic syndrome.
 Renal failure.
 For anemia: low Hb
.Investigations
 For chronic hemolysis: low RBCs survival &
increase erthropioesis.
 For the cause:
 Blood film:

—detect sickle cells in peripheral blood. If not

detected, sickling can be enhanced by adding
sodium metabisulfite (sickling test).
—Howell-Jolly bodies (neuclear reminants)
and submembraneous pits in RBCs may be
seen indicating hyposplenism.

 Hemoglobin electrophoresis: show HbS

(90%) & HbF (2-10%)

 Neonatal screening for HbS for adequate

care and longer survival.
 Radiology

-Plain X ray of right (A) and left (B) hands of an

infant showing typical findings of bilateral
sickle cell dactylitis
, seen as soft tissue swellings, metatarsal and pha
langeal expansion and multiple
osteopenic patches.

-Chronic osteomyelitis. Anteroposterior

radiographs of the left tibia and fibula in an
infan.
-Skeletal sickle cell anemia. Expanded
medullary cavity. The diploic space is
markedly widened due to marrow
hyperplasia. Trabeculae are oriented
perpendicular to the inner table, giving a
hair-on-end appearance.
Treatment

Protection against infection

-Prophylactic penicillin up to 6 years.

- immunized against pneumococci & H.influenza.
Chronic transfusion therapy & iron chelation.

-patient with stock, splenic sequestration crisis, and repeated episodes of

acute chest syndrome .
Treatment of crisis:
 Supportive care : ABC & remove precipitating factor.
Vaso oclusive:

-Hydroxyurea be given to increase HbF and decrease the attack’s number and severity.
- Hydration at 1.5-2 maintenance & alklinization.
- Analgesic “paracetamol, ibuprofen, opiates”
- if refractory: partial exchange transfusion.

Sequestration:

-Blood transfusion.
-Exchange transfusion (keep sickle <30%).
-if refractory we do emergency splenectomy.

Aplastic/ Hemolytic

-blood transfusion.

Bone marrow transplantation in sever cases.

Sources
 OTHER
HEMOGLOBINOPAT
HIES
By : Asma Hassan
Objective

1. Thalassemia
 Definition
 Pathophysiology
 Clinical picture
 Investigation
 Treatment
 Complication

1. Hemoglobin c
2. Hemoglobin e
3. Hemoglobin d
THALASSEMIA
 Normal HB

Each peptide
attached to
heme group

• 4 α-globin genes are on

chromosome 16
• 2 β-globin genes on
At the 3 - 6' month . . chromosome 11
normal switch from
gamma to Beta chain .
(HbA)
 Definitions

 Thalassemia it is an Autosomal recessive disease characterized by the deficient synthesis of

one or more of the globin polypeptide chains that result in an imbalance between numbers
of alpha and beta globin chains. 1

 It has tow type

. α-Thalassemia: mutation of one or more of the 4 α-globin genes result an absence or reduction in
α-globin production.
2. β-Thalassemia: mutation of one or more of the 2 β-globin genes result in an absence or reduction
in β-globin production.
 a. thalassemia syndromes

Three genes Four genes

One gene Two gene
deletion deletion
deletion deletion

.Silent carrier a thalassemia trait Haemoglobin H disease Fetal hydrops

a. thalassemia syndromes

1. Silent α-thalassaemia (αα/α−): one α gene deletion.

⁻ Asymptomatic.
⁻ Not identifiable hematologically ( Normal MCV, MCH ).
⁻ Electrophoresis in neonatal period shows <3 % Barts hemoglobin ( 4 γ globin chains).
a. thalassemia syndromes

2. α-thalassemia trait (αα/−−) or (α−/α−): Two α gene deletion.

microcytic hypochromic anemia; commonly mistaken as iron deficiency anemia.

Normal iron indices, good dietary history.
Electrophoresis in neonatal period shows: 3-8 % Barts hemoglobin which disappear by
childhood.
Normal levels of Hb F & Hb A2.
 Diagnosed by exclusion.
 To confirm Dx: DNA analysis.
 a. thalassemia syndromes
⁻ 3. Hb H disease (α−/−−): Three α gene deletion.
⁻ Mild to moderate microcytic hemolytic anemia at birth ( target cells and reticulocytes ).
⁻ Evidence of chronic hemolysis ( hepatosplenomegaly and jaundice or cholelithiasis ).
⁻ Bone deformity
⁻ Hemosiderosis.
⁻ Electrophoresis shows:
⁻ Commonly ˃ 25% Barts hemoglobin in neonatal period.
⁻ Dx: DNA analysis
⁻ Require ongoing monitoring of growth and organ dysfunction.
⁻ Dietary supplementation with folate and multivitamins without iron is indicated.
⁻ Intermittent transfusions for worsening anemia may be needed.
⁻ Splenectomy may be beneficial .
 a. thalassemia syndromes

4. Hb Barts disease ( hydrops fetalis ) - (−−/−−): Four α gene deletion

• Severe intra uterine anemia and anemic heart failure.

• Resulting in intrauterine fetal death, still birth or early neonatal death.
• Intrauterine transfusion can improve fetal survival.
• Electrophoresis shows: dominant Barts hemoglobin with complete absence
of normal fetal and adult hemoglobin.
• If the fetus survives, immediate exchange transfusion is indicated.
• Hematopoietic stem cell transplantation is the only cure.
• Note: the barts and H hemoglobins are nonfunctional hemoglobins and result
in extravascular hemolysis.
β-Thalassemia Syndromes
 Beta thalassemia major [Cooley’s] which is a severe disease presenting in early
infancy [4-6 months] caused by a defects in both copies of the Beta globin gene (β° /
β°)
 Beta thalassemia intermedia is a less severe anemia caused by several genetic
combinations (β+/ β+ and others)
 Beta thalassemia minor, which is a mild, non-transfusion dependent anemia is
caused by a defect in one copy of the Beta gene.
Beta thalassemia trait has one Beta gene defect (β/ β°)
whereas a silent carrier form exists where some functional beta thalassemia gene is
produced (β/ β+).
β- Thalassemia trait/minor

 A. One gene mutation : β thalassemia trait/minor

- Most patients have short RBCs survival without evidence of overt hemolysis.
-Microcytic anemia
- Differentiated from iron deficiency anemia by:
-Normal iron indices.
- Increased RBCs count in contrast to iron deficiency
- Electrophoresis: Hb A2 up to 3-7% in over 90% of cases.(diagnostic)
- HbF up to 1-3% in only 50% of cases.
β- Thalassemia Intermedia

 n patients with beta thalassemia intermedia, anemia is present but individuals are not
transfusion dependent.
 Expression of disorder falls between thalassemia minor and thalassemia major.
 Have varying symptoms of anemia, jaundice, splenomegaly and hepatomegaly.
 Have significant increase in bilirubin levels.
 Anaemia usually becomes worse with infections & folic acid deficiencies
 Thalassemia intermedia therapy is aimed not only at treating the anemia, but also at
addressing iron overload and inhibiting the clinical consequences of ineffective
erythropoiesis
 Splenectomy should be reserved for patients with massive splenomegaly,
β- Thalassemia major

 Caused by defects in both copies of the Beta globin gene

 Characterized by severe microcytic, hypochromic anemia.
 Detected early 3-6 months(Hb F replaced by Hb A):
 Infants fail to thrive.
 Have pallor, variable degree of jaundice, abdominal enlargement, and
hepatosplenomegaly.
 Hemoglobin level between 4 and 8 gm/dL.
 Severe anemia causes marked bone changes due to expansion of marrow space for
increased erythropoiesis.
 β-Thalassemia Syndromes

 B. Two genes mutation : β thalassemia major

 Pathogenesis:
 β- Thalassemia Syndromes

2- Iron overload due to:

 Chronic hemolysis.
 - increase Iron absorption
 - Repeated blood transfusion

Lead to Iron deposition in various organs hemosiderosis.

 clinical picture
 The characteristic hallmark of β-thalassemia is anemia caused by ineffective erythropoiesis
 and hemolysis.2 Classic symptoms of anemia include:
 Pallor
 Fatigue
 Asthenia (weakness)
 Dyspnea
 Dizziness
 Headaches
 clinical picture
 Iron accumulation

Heart (cardiomyopathy)
Skin (bronze skin )
Pancreas (DM)
Pituitary (growth retardation –short
stature)
Liver (cirrhosis )
clinical picture
 Thalassemia facies/Skeletal change (bone marrow expansion)
Depressed nasal bridge
Prominent maxillae
Frontal bossing
Investigations
Target red cells
 CBC:
 ↓ Hb ( < 6g/dL ),↓ MCV, ↓ MCH. RDW
 Reticulocyte count:
 Incrased .
 Peripheral blood smear
 hypochromic
 Vary in size and shape (anisocytosis and poikilocytosis)
 Target red cells.
 Nucleated red cells with basophilic stippling.
 HbH inclusion bodies with supravital stain.
 Investigations
Iron study
Elevated serum ferritin and transferrin saturation
Hemoglobin electrophoresis :
Thalassemia major : increase Hb F (98%), Hb A2(2%) , no Hb A
Thalassemia minor :Increase HbF ,HbA2(3.5%), some HbA
Investigations
DNA analysis:
 used for Early definitive diagnosis & screening.
Biochemistry:
 Raised unconjugated serum bilirubin
 Endocrine abnormalities e.g. (DM, Hypogonadism).
 Elevated serum ferritin and transferrin saturation.
 Prenatal diagnosis is possible by chorionic villous sampling (CVS).
Radiological findings:
 skull ( hair-on- end appearance ).
 Complications
Heart failure may be due to:
 Under transfusion: anemic Heart failure.
 Over transfusion: volume overload.
 Cardiomyopathy: hemosiderosis.
Allergic reactions.
Incompatible blood transfusion.
 Disease transmission (HBV, HCV, AIDS)
Hypersplenism:
osteoporosis
Splenectomy:

Sepsis.
 Treatment
Treatment for patients with thalassemia includes the following:
 Long-term transfusion therapy
 Erythroid maturation agents (eg, luspatercept)
 Iron chelation
 Splenectomy
 Supportive treatment
 Hydroxyurea
 Allogeneic hematopoietic transplantation
Treatment
 Iron chelation therapy

Started when serum ferritin > 1000 ng/ml

To Avoid hemosiderosis
Desferrioxamine

• Dose: 30-60mg/kg/day • IV / s/c infusion pump over 12 hr period 5-6 days /wk
DEFERIPRONE

• Oral chelator - > 2yrs old

Dose: 50- 100mg/kg/day
it reduce cardiac iron overload
 Treatment
Splenectomy:
Indications:
 Hypersplenism suggested by:
 Increasing need for transfusion by 50% than usual for more than 6 months.
 Severe leukopenia and/or thrombocytopenia.
 Huge spleen with pain or pressure symptoms.
 When: Preferably after the 5th year.
 Risk: sepsis (esp. if done< 5 years)
 Precautions:
 Immunize the patient two weeks before splenectomy against:

- Hemophilus influenza - Pneumococci - Meningococcal.

 After splenectomy: oral penicillin 250 mg twice daily till adulthood.
 Treatment
Supportive therapy
 Folic acid
 Hepatitis B vaccination
 Treatment for congestive heart failure
 Endocrine follow up
 Cholecystectomy
 Genetic counseling
 Management of osteoporosis (calcitonin & bisphosphonates)
 HEMOGLOBIN C

The mutation for HbC is at the same site as HbS, with

substitution of lysine instead of valine for glutamine.

Hemoglobin C trait (HbAC) :

 This condition is usually
 Asymptomatic . diagnosed through newborn
screening programs.
 HbC crystallizes, disrupting the
Hemoglobin C disease (HbCC) :
red cell membrane, and HbC
 Mild anemia . crystals may be visible on
peripheral smear .
 Splenomegaly .
 Cholelithiasis
 rare cases of spontaneous splenic rupture have been
reported
HEMOGLOBIN E

 HbE is an abnormal hemoglobin resulting from a qualitative mutation in the β-globin

gene and is the second most common globin mutation worldwide.
 Patients may have asymptomatic hemoglobin E trait (HbAE) or benign homozygous
hemoglobin E disease (HbEE).
HEMOGLOBIN D

 At least 16 variants of HbD exist.

 HbD-Punjab (Los Angeles) is a rare hemoglobin that is seen in 1-3% of
Western Indians and in some Europeans with Asian-Indian ancestry and
produces symptoms of sickle cell disease when present in combination
with HbS.
 Heterozygous HbD or hemoglobin D trait (HbAD) is clinically silent.
 Homozygous HbDD or HbD disease produces a mild to moderate
anemia with splenomegaly.
References

 Nelson Textbook of Pediatrics 20th Edition

 Medscape.
Thank you