Pa 16.3 Sickle Cell Anaemia and Thalassaemia

PA 16.
3 SICKLE CELL
ANAEMIA
&
THALASSAEMIA
Dr. Ujwala Maheshwari
Professor
Dept. of Pathology
P.A 16.3 SPECIFIC LEARNING OBJECTIVES
At the end of the lecture the student must know the

following w.r.t. Sickle Cell Anaemia & Thalassaemia-
1. Introduction
2. Etio- pathogenesis
3. Haematologic indices
4. Pathologic features/ Peripheral Blood Smear
HEMOLYTIC ANAEMIAS
BRIEF ABOUT HEMOLYTIC ANAEMIAS
 A group of disorders leading to anemia caused by a reduction in red cell life span .
 Anemia is the result of premature destruction of red cells exceeding the erythropoietic
capacity of the bone marrow.
CLASSIFICATION
Hereditary Hemolytic Anemia Acquired Hemolytic Anemias
Based on Red cell defect of: Based on

1) Membrane 1) Mechanical stress
2) Enzmes 2)Drugs
3) Haemoglobin 3) Infections
4) Others
5
HEREDITARY HEMOLYTIC ANEMIA
A.Defect in red cell membrane: C.Enzyme deficiency of Glycolytic

Hereditary spherocytosis pathway:
Hereditary eliptocytosis Pyruvate kinase deficeincy
Hereditary pyro-poikilocytosis Hexokinase deficiency
Hereditary stomatocytosis
B. Defect in Globin synthesis:

D.Enzyme deficiency of Pentose
THALASEMIA
phosphate pathway:
SICKLE CELL ANEMIA
G6PD Deficeincy
unstable hemoglobin disease
6
SICKLE CELL ANAEMIA
INTRODUCTION
Sickle cell disease is a common hereditary hemoglobinopathy caused by a point

mutation in β-globin that promotes the
Polymerization of deoxygenated hemoglobin,
 Leading to red cell distortion,
 Hemolytic anemia,
 Microvascular obstruction, and
 Ischemic tissue damage.
Sickle cell disease is caused by a missense point mutation in the β-
globin gene that leads to substitution of glutamic acid by valine at sixth
position of β-globin chain. The abnormal physiochemical properties of
the resulting sickle hemoglobin (HbS) is responsible for the disease.
Sickle cell disease is caused by a missense point mutation in the β-
globin gene that leads to substitution of glutamic acid by valine at sixth
position of β-globin chain. The abnormal physiochemical properties of
the resulting sickle hemoglobin (HbS) is responsible for the disease.
People heterozygous for HbS, are largely asymptomatic and are
called as Sickle cell trait. People homozygous for HbS, are largely
symptomatic(affected), almost all the hemoglobin in the red cell is HbS
(α2βs2) and they are said to have Sickle Cell D/S.
 Mode of inheritance is Autosomal Recessive.
 Disease is common in black people of Afro-American origin.
Sickling disorders are very common in Africa, Middle East, Central and southern parts of INDIA. It is thought that
the disease has achieved high frequency due to evolutionary selection for resistance against falciparum
malaria. It has been suggested that G6PD deficiency and thalassemia also protect against malaria.
PATHOGENESIS
The major pathologic manifestations—chronic hemolysis, microvascular occlusions, and tissue
damage—all stem from the tendency of HbS molecules to stack into polymers when
deoxygenated.
Initially, this process converts the red cell cytosol from a freely flowing liquid into a viscous gel.
With continued deoxygenation, HbS molecules assemble into long needle like fibers within red cells,
producing a distorted sickle or holly-leaf shape.
Initially sickling of red cells is reversible. The sickle shape corresponds to the polymerised Hb. With
oxygenation, polymerised HbS (viscous gel state) returns to depolymerised (fluid-liquid state).
When repeated sickling and unsickling of red cells occurs, membrane is damaged and the red cell
shape becomes permanently altered leading to formation of irreversibly sickled cells, now even
with reoxygenation, shape of red cells do not return to normal.
Sickle cell disease (peripheral blood smear).
(A) Low magnification shows irreversibly sickled cells as well as target cells and red
cell anisocytosis and poikilocytosis.
(B) Higher magnification shows an irreversibly sickled cell in the center
CLINICAL FEATURES
Growth and Development Retardation.

Recurrent leg ulcers.
Dactylitis or Hand Foot Syndrome.
Acute infections – Pneumonia ,Meningitis.
Osteomyelitis
Jaundice, Pigmented stones, Acute abdominal
pain
Priapism
Sickle retinopathy- Salmon patches -Intra retinal
haemorrhage and proliferation.
16
CRISIS IN SICKLE CELL DISEASE
Hemolytic crisis- low Hb, reticulocytosis, jaundice

Vaso-occlusive crisis
Aplatic crisis
Splenic sequestration crisis
Hand foot syndrome
Acute chest syndrome (chest pain ,fever ,leukocytosis)
17
SICKLING TEST
18
 D) HPLC
19
SICKLE CELL HOMOZYGOUS (SS)
Sickle Cell Disease

Moderate to severe anemia
with Hb between 4-8gm/dl.
HbS- >50%
HbA2-2-3%
HbF-20%
20
SICKLE CELL HETEROZYGOUS (SA)
Sickle cell Trait
Normal Hb 60%
HbS between 30-40%.
- It has enough normal Hb to

prevent most complications which
develop in homozygous state.
21
MORPHOLOGY OF SPLEEN AND BONE MARROW
In early childhood, the spleen is enlarged (up to 500 g) by red pulp congestion caused by the trapping of sickled red
cells in the cords and sinuses. With time, however, chronic erythrostasis leads to splenic infarction, fibrosis, and
progressive shrinkage, so that by adolescence or early adulthood only a small nubbin of fibrous splenic tissue is left, a
process called autosplenectomy
Marked expansion of the marrow leads to bone resorption and secondary new bone formation, producing
prominent cheekbones and changes in the skull that resemble a “crewcut” on radiographic studies.
Extramedullary hematopoiesis may also appear. The increased breakdown of hemoglobin may cause hyperbilirubinemia
and formation of pigment gallstones
 Fish mouth vertebrae occurs due to vaso-occlusive crisis.
(A) Spleen in sickle cell disease (low power). Red pulp cords
and sinusoids are markedly congested; between the congested areas, pale
areas of fibrosis resulting from ischemic damage are evident.
(B) Under high power, splenic sinusoids are dilated and filled with sickled red
cells
“Autoinfarcted” splenic remnant in sickle cell disease.
CASE 1:
10 year old male child presenting with weakness, fatigue.

Recurrent severe pain of long bones, fever
O/E- Pallor+
CBC- HB-6.8 g/dL, TC-14000, RC-3%
LDH-600
S. Bilirubin-5mg%
PS shows the following:
PERIPHERAL SMEAR:
27
THALASSAEMIA
INTRODUCTION
 It results from inherited defect in the rate of synthesis of globin chains.
 Imbalance of globin chain production leads to:

o Ineffective erythropoiesis,
o Defective Hb production,
o Red cell Hb precipitates,
o Hemolysis and variable degree of anemia.
o About 250 million people carry thalassemia gene.

o Thalassemias considered quantitative hemoglobinopathy since no structural abnormal
hemoglobin is synthesized.
CLASSIFICATION OF THALASSAEMIA
Alpha Thalassemia-
 The alpha gene deleted, loss of one gene or both gene from each chromosome 16 may
occur in association with production of some or no alpha globin chain.
Beta Thalassemia-
 Defective production usually result from disabeling point mutation causing no or
reduced ß chain production.
PATHOPHYSIOLOGY
33
BETA THALASSEMIA MAJOR
Severe Homozygous
Childhood, Growth delay
Severe Anemia, Hepatosplenomegaly
Iron overload-endocrine dysfunction
PS features- Severe Microcytosis, Target cells
Hb electrophoresis: HbF - 90-96 %

HbA2- 3.5 %- 5.5%
HbA - 0
34
CLINICAL FEATURES
β-Thalassemia major. X-ray film of the skull
showing new bone formation on the
outer table, producing perpendicular
radiations resembling a crewcut.
PS features- Severe Microcytosis, Target cells
MECHANISM OF IRON OVERLOAD
BETA THALASSEMIA MINOR
Profound Microcytosis, Target cells, Minimal Anemia

Similar picture of Iron deficiency Anemia
Lab Ix:
MCV & MCH reduced, MCHC near normal
MCV<75, Hct <30-33%
Hb electrophoresis: HbA2-3.5-7.5% (normal

<3%)
HbA-80-95%,
HbF 1-5%
39
PS SHOWS
40
MENTZER’S INDEX
 Mentzer Index = MCV

Red Cell Count
Normal Range= 16.5-18.5
If <13 – Suggestive of Thalassemia trait
If >13 – Suggestive of Iron Deficiency Anemia
41
BETA THALASSEMIA INTERMEDIA
 Clinical spectrum between Thalassemia Major & Minor

 Anemic but not Transfusion dependent
 Less severe than major
 Moderate Anemia, Microcytosis, Hypochromia
 Hb electro - HbF - 20-100%

HbA2 -3.5%-5.5%
HbA – 0-30%
42
HIGH PERFORMANCE LIQUID CHROMATOGRAPHY
High-performance liquid chromatography findings in

(A) b thalassaemia major, and (B) b thalassaemia minor
NESTROF TEST(NAKED EYE SINGLE TUBE RED
CELL OSMOTIC FRAGILITY TEST)
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PA 16.

At the end of the lecture the student must know the

Hereditary Hemolytic Anemia Acquired Hemolytic Anemias

Based on Red cell defect of: Based on

A.Defect in red cell membrane: C.Enzyme deficiency of Glycolytic

B. Defect in Globin synthesis:

Sickle cell disease is a common hereditary hemoglobinopathy caused by a point

Growth and Development Retardation.

Hemolytic crisis- low Hb, reticulocytosis, jaundice

Sickle Cell Disease

Sickle cell Trait

- It has enough normal Hb to

10 year old male child presenting with weakness, fatigue.

 It results from inherited defect in the rate of synthesis of globin chains.

 Imbalance of globin chain production leads to:

o About 250 million people carry thalassemia gene.

Hb electrophoresis: HbF - 90-96 %

Profound Microcytosis, Target cells, Minimal Anemia

Hb electrophoresis: HbA2-3.5-7.5% (normal

 Mentzer Index = MCV

Normal Range= 16.5-18.5

If <13 – Suggestive of Thalassemia trait

If >13 – Suggestive of Iron Deficiency Anemia

 Clinical spectrum between Thalassemia Major & Minor

 Hb electro - HbF - 20-100%

High-performance liquid chromatography findings in

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