Hemoglobinopathies and thalassemia are genetic blood disorders that result in abnormal hemoglobin. Hemoglobinopathies are caused by mutations in the globin chains of hemoglobin molecules, while thalassemias are caused by reduced or absent globin chain production. Sickle cell disease is a hemoglobinopathy caused by a mutation in the beta globin chain that results in sickle-shaped red blood cells. Thalassemias include alpha and beta thalassemia, which are characterized by decreased alpha or beta globin chain production leading to anemia. Management involves blood transfusions, iron chelation therapy, and in some cases stem cell transplantation.

1. Hemoglobinopathies
and
Thalassemia

2. Hemoglobinopathies
HEMOGLOBINOPATHY IS A KIND OF GENETIC DEFECT THAT
RESULTS IN ABNORMAL STRUCTURE OF ONE OF
THE GLOBIN CHAINS OF THE HEMOGLOBIN
MOLECULE. HEMOGLOBINOPATHIES ARE INHERITED SINGLE-GENE
DISORDERS

3. Hb-A Molecule. Hb-A is the major
adult hemoglobin.(97%)

4. Normal Human Haemoglobins
Haemoglobin Structural formula
Adult Hb-A 2 2 97%
Hb-A2 2 2 1.5-3.2%
Fetal Hb-F 2 2 0.5-1%
Hb-Bart’s 4
Embryonic Hb-Gower 1 2 2
Hb-Gower 2 2 2
Hb-Portland 2 2

5. Sickle Cell Disease
(HbS)
 sickle cell anemia is an autosomal recessive
disease that result from the substitution of valin for
glutamic acid at position 6 of beta-globulin chain.
 Patient who are homozygous for the HbS have sickle
cell disease
 Patient who are heterozygous for HbS gene have
sickle cell trait.

6. Sickle-Cell Disease
Pathophysiology
 Deoxygenation of heme moiety of sickle hemoglobin leads to
hydrophobic interaction between adjacent sickle hemoglobin
that aggregate into larger polymers.
 Sickle red blood cell are less deformable and obstruct the
microcirculation, resulting in hypoxia.
 These red blood cell have a life span of only 10-20 days.

7. CLINICAL MANIFESTATIONS
and treatment
 Fever and Bacteremia Fever in a child with sickle cell anemia
is a medical emergency, requiring prompt medical evaluation
and delivery of antibiotics due to the increased risk of bacterial
infection and concomitant high fatality rate with infection
 Treatment antimicrobial therapy by administering a 3rd-
generation cephalosporin.

8. Dactylitis
Dactylitis , often referred to as hand-foot syndrome, is often the
first manifestation of pain in children with sickle cell anemia
occurring in 50% of children by their 2nd year. Dactylitis often
manifests with symmetric or unilateral swelling of the hands and
feet.
Treatment Dactylitis requires pain medications, such as
acetaminophen with codeine, whereas osteomyelitis requires
at least 4-6 week of antibiotics
Splenic Sequestration Acute splenic sequestration is a life-
threatening complication. This is due to sickled cell that block
splenic outflow, leading to pooling of peripheral blood into the
spleen.
Treatment includes early intervention and maintenance of
hemodynamic stability using isotonic fluid or blood transfusions.

9. Pain The cardinal clinical feature of sickle cell anemia is pain,
that can occur in any part of the body but most often occurs in the
chest, abdomen, or extremities.
The exact etiology of pain is unknown, but the pathogenesis is
initiated when blood flow is disrupted in the microvasculature by
sickle cells, resulting in tissue ischemia. Precipitating causes of
painful episodes can include physical stress, infection,
dehydration, hypoxia, local or systemic acidosis, exposure to cold.
 The majority of painful episodes in patients with sickle cell
anemia are managed at home with comfort measures, such as
heating blanket, relaxation techniques, massage, and pain
medication(acetaminophen or a nonsteroidal agent)
Lung Disease Lung disease in children with sickle cell anemia is the
second most common reason for admission to the hospital and a
common cause of death. ACS findings include a new radiodensity on
chest radiograph, fever, respiratory distress, and pain that occurs in the
chest.

10. common pulmonary complications such as bronchiolitis, asthma,
and pneumonia
TREATMENT
Blood transfusion
Supplemental oxygen
Empirical antibiotics (cephalosporin and macrolide)
Bronchodilators and steroids for patients with asthma
Optimum pain control and fluid management.
Other complication includes.
Kidney Disease
Psychological Complications
Neurologic Complications
Priapism
sickle cell retinopathy, delayed onset of puberty, avascular
necrosis of the femoral and humeral heads, and leg ulcers.

11. Laboratory Diagnosis
 In peripheral smear, sickle-shaped red blood cell are found.
 Anemia and thrombocytopenia
 Leukocytosis
 Rise in WBC count more than 20000
with a left shift indicative of infection
 If diagnosis of sickle cell anemia
Has not been made sickling test will
Establish the presence of sickle cell
Anemia.
 Hemoglobin electrophoresis can differentiate between
homozygous(80-90% HbSS) and heterozygous(35-40% HbSS)

12. Preventive care
 All children require prophylaxis with penicillin or amoxicillin up to 5 year of
age
 Immunization with pneumococcal, meningococcal and hemophillus
influenzae B vaccine
 Life long folate supplementation
 Regularly screening for development of gall stone
 Genetic counseling and testing should be offered to family.

13. Thalassemia Syndromes
• Hereditary disorders that can result in moderate to severe anemia
• Basic defect is reduced production of selected globin chains
.

14. There are two basic groups of thalassaemia.
 thalassemia: There are four types categorized according to the
severity of their effects on persons with thalassemia.
ß thalassemia: There are 3 types categorized according to severity
 Thalassemia minor
 Thalassemia intermedia
 Thalassemia major
Types of Thalassemia

15. α-Thalassemia
 An absence or deficiency of α-chain synthesis due to deletion of α-genes.
 Predominant cause of alpha thalassemia is large number of gene deletions in
the α-globin genes on chromosome no. 16
 There are four clinical syndromes present in alpha thalassemia:
 Silent Carrier State
 Alpha Thalassemia Trait (Alpha Thalassemia Minor)
 Hemoglobin H Disease
 Bart's Hydrops Fetalis Syndrome

16. Variants of α-Thalassemia
Silent carrier
Deletion of single α-gene
Genotype α-/αα
Asymptomatic
Absence of RBC abnormality
Can only be detected by DNA studies.
Thalassemia trait
Also called Alpha Thalassemia Minor.
Deletion of 2 α-genes
Genotype --/αα or -/-
Asymptomatic, minimal or no anemia
Minimal RBC abnormalities

17.  Second most severe form alpha thalassemia.
Deletion of 3 α-genes
Genotype --/- α
75% reduction of α-chain
Only 25% α-chain synthesis small amount of HbF, HbA, & HbA2
Fetus can survive
Severe anemia
Severe RBC abnormalities
RBCs are microcytic, hypochromic with marked poikilocytosis
Hemoglobin H Disease

18. Most severe form. Incompatible with life. Have no functioning α chain
genes (- -/- -).
Baby born with hydrops fetalis, which is edema and ascites caused by
accumulation serous fluid in fetal tissues as result of severe anemia. Also
hepatosplenomegaly and cardiomegaly.
Bart’s Hydrops Fetalis Syndrome

19. β Thalassemia
 The molecular defects in β thalassemia result in the absence or
varying reduction (according to the type of mutation) in β chain
production.
 In individuals with beta thalassemia, there is either a complete
absence of β globin production ( β-thalassemia major) or a
partial reduction in β globin production ( β-thalassemia minor).
An absence or deficiency of β-chain synthesis of
adult HbA.

20. Silent carrier state - the mildest form of beta thalassemia.
Beta thalassemia minor - heterozygous disorder resulting in
mild hypochromic, microcytic hemolytic anemia.
Beta thalassemia intermedia - Severity lies between the
minor and major.
Beta thalassemia major - homozygous disorder resulting in
severe transfusion-dependent hemolytic anemia.

21. Beta Thalassemia Minor
 Caused by heterogeneous mutations that affect beta globin synthesis.
 Usually presents as mild, asymptomatic hemolytic anemia unless
patient in under stress such as infection or folic acid deficiency.
 Have one normal beta gene and one mutated beta gene.
 Anemia usually hypochromic and microcytic
 Normally require no treatment

22. Beta Thalassemia Intermedia
 Expression of disorder falls between thalassemia minor and
thalassemia major. May be either heterozygous for mutations
causing mild decrease in beta chain production, or may be
homozygous causing a more serious reduction in beta chain
production.
 Have varying symptoms of anemia, jaundice, splenomegaly and
hepatomegaly.
 Have significant increase in bilirubin levels.
 Anemia usually becomes worse with infections & folic acid
deficiencies.

23. Beta Thalassemia Major
 Characterized by severe microcytic, hypochromic anemia.
 Detected early in childhood:
 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.
 Peripheral blood shows markedly hypochromic, microcytic erythrocytes
with extreme poikilocytosis

24. Laboratory study
 Complete blood count and peripheral blood film exam. Are usually
sufficient to confirm the diagnosis
 Hb level range from 2-8 gm/dL
 MCV and MCH are significantly low
 Reliculocyte count elevated 5-8%
 Leukocytosis
 In PBF marked hypochromasia & microcytosis, polychromatophillic cell,
nucleated red blood cell
 HPCL (high performance liquid chromatography) confirms the diagnosis

25. Complication
 Iron overload: People with thalassemia can get an overload of iron in their
bodies, either from the disease itself or from frequent blood transfusions.
Too much iron can result in damage to the heart, liver and endocrine
system, The damage is characterized by excessive deposits of iron.
Without adequate iron chelation therapy, almost all patients with beta-
thalassemia will accumulate potentially fatal iron levels.
 bone deformities: Thalassemia can make the bone marrow expand, This
can result in abnormal bone structure, especially in the face and skull.
Bone marrow expansion also makes bones thin and brittle, increasing the
risk of broken bones

26. thalassemic facies (maxilla
hyperplasia, flat nasal
bridge, frontal bossing)
Hair on End Appearance
Bone deformities

27. Splenomegaly Thalassemia is often accompanied by the destruction of a large
number of red blood cells and the task of removing these cells causes the spleen
to enlarge. Splenomegaly can make anemia worse, and it can reduce the life of
transfused red blood cells. Severe enlargement of the spleen may reqire its
removal.
•Slowed growth rates: anemia can cause a child's growth to slow. Puberty
also may be delayed in children with thalassemia.
•Heart problems: such as congestive heart failure and arrhythmias may be
associated with severe thalassemia.
• Infection
• Extra-medullary hematopoiesis
• Psychological complication

28. Management
 Hematopoietic stem cell transplantation- it is the only known treatment
for thalassemia, however this option is available only to a relatively small no. of
patient.
 Blood transfusion- blood transfusion should be initiated at an early age
attempt should made to keep Hb lavel to 9-10 g/dL
 Chelation therapy- to overcome iron overload and iron toxicity. The optimal
time for therapy to start is 1-2 year of transfusion when ferratin lavel is about
1000-1500 µg/L
Deferoxime a total dose of 40-60mg/kg/day is infused over 8-12 hrs over night for
5-6 day a week by mechanical pump.

29. Deferiporone 75mg/day may be used as oral chelating agent
Hydroxyurea in dose of 15-20 mg/kg/day used to increase HbF
production and reduce the need of transfusion support

30. Thank you