Thalassemia: Red Cell Disorders

Red Cell Disorders:
Thalassemia
Susanto Nugroho
Faculty of Medicine
University of Brawijaya
Clinical Competencies
After this session:
Students can describe:
- the pathophysiology of thalassemia
- the genetic and clinical classification of thalassemia
- the principal management of thalassemia
- the complications of thalassemia
Students can diagnose thalassemia anemia based on
clinical features and laboratory findings
Introduction
Hb abnormalities are result from :
1.Synthesis of an abnormal Hb (Hb S, Hb C, Hb
DPunjab, Hb OArab)
2.Reduced rate of synthesis of normal or -globin
chains thalassemia
Thalassemia is a heterogeneous group of genetic
disorders which result from a reduced rate of the
synthesis one or more of the globin chains ( or ):
- and -thalassemia
Their clinical severity varies widely, ranging from
asymptomatic to severe form or even fatal
entities.
Hemoglobin Synthesis
Figure 1. Hb synthesis in
the developing red cell.
The mitochondria are the
main sites of
protoporphyrin synthesis,
iron (Fe) is supplied from
circulating transferrin;
globin chains are
synthesized on ribosomes.
RBC: 640 million Hb
molecules.
The adult proportion of Hb A, Hb A2 and Hb F are

usually attained by 6 12 months of age
Figure 2. Synthesis of individual globin chains in

prenatal & postnatal life
Normal Hemoglobin in children/adult
Structure
Normal (%)
Thalassemia
Hb A
Hb F
Hb A2
2 2
96-98
2 2
0.5-0.8
2 2
1.5-3.2
N/
Pathophysiology
The -globin gen & -globin gene mutations:
Decreased or absent production of one globin
chain ( or ) and a relative excess of the
other
Imbalance leads to unpaired globin chains
Precipitate and cause premature death
(apoptosis) of the red cell precursors within
the marrow : hemolysis (ineffective
erythropoiesis)
The damaged RBCs: removed by the spleen or
hemolyzed directly in the circulation due to
the Hb precipitants.
Pathophysiology..
Combined RBC destruction in the BM, spleen, and
periphery causes anemia & ultimately, an
escalating cycle of pathology resulting in the
clinical syndrome of severe thalassemia.
Damaged erythrocytes enter the spleen and are
trapped splenomegaly exacerbates the trapping
of cells and worsens the anemia.
Anemia & poor tissue oxygenation increased
kidney erythropoietin production drives BM
erythropoiesis increased ineffective BM activity
& the classic bony deformities.
Figure 3. Pathophysiology of thalassemia
The genes for the globin chains occurs in 2 clusters :

- , and on chromosome 11
- and on chromosome 16
Figure 4. The globin gene clusters on chromosome 11

and 16
Father: trait
+
Mother: trait
25% thalassemia
50% trait
25% normal
Clinical Classification of Thalassemia

Hydrops fetalis
Four genes deletion -thalassemia
Thalassemia minor
0-thalassemia trait
+-thalassemia trait
Thalassaemia major
Hereditary persistence of fetal Hb
Transfusion dependent, homozygous
-thalassemia trait
0-thalassemia or other combinations
0-thalassemia trait
of -thalassemia trait
+-thalassemia trait
Thalassaemia intermedia
Homozygous -thalassemia
Heterozygous -thalassemia
-thalassemia and hereditary
persistence of fetal Hb
Hemoglobin H disease
Clinical Classification of Thalassemia

-thalassaemia
0
+
Deletion ()
Non-deletion (T)
-thalassaemia
0
+
Variants with unusually high level of HbF or A2
Normal HbA2
Silent
Dominant
Unlinked to b-gene cluster
-thalassaemia
()+
()0
(A)0
-thalassaemia
-thalassaemia
0
+
-thalassaemia
Hereditary persistence of fetal Hb
Deletion
()0
Non-deletion
Linked to b-globin-gene cluster
G+
A+
Unlinked to -globin-gene cluster
Diagnosis
Clinical features of -thalassemia major:
Severe anemia with/without jaundice
Enlargement of then spleen and/or liver
Expansion of bones caused by marrow
hyperplasia: thalassemic facies, thinning of
the cortex of many bones (a tendency to
fractures & bossing of the the skull with a
hair-on-end appearance on X-ray)
Iron overload caused by repeated transfusions
Infections
Osteoporosis
ANEMIA
JAUNDICE
THALASSEMIC
FACIES
SPLEEN
ENLARGEMENT
Diagnosis..
Laboratory findings of -thalassemia major:
Blood smear: a severe hypochromic-microcytic
anemia, reticulocytosis with normoblasts,
target cells and basophilic stippling
Hb-electrophoresis: HbA2 normal, HbA
decreased/ absence and HbF increased; an
increased : ratio with reduced or absent chain synthesis
DNA analysis can be used to identify the
defect on each allele
Figure 5. Thalassemia: the blood film shows marked

hypochromic microcytic cells with target cells & poikilocytosis
Figure 6. Hemoglobin electrophoretic patterns
Assessment of Iron Overload

Assessment of iron stores
Serum ferritin
Serum iron & percentage saturation of transferrin (TIBC)
Bone marrow biopsy (Perls stain) for reticuloendothelial stores
DNA test for mutation resulting in Cys282 Tyr in the HFE gene
Liver biopsy (parenchymal & reticuloendothelial stores)
Liver CT scan or MRI
Cardiac MRI
Desferrioxamine iron excretion test (chelatable iron)
Repeated phlebotomy until iron deficiency occurs
Assessment of tissue damage caused by iron overload
Cardiac
: clinical, chest x-ray, ECG, 24-h monitor, echocardiography, radionuclide (MUGA)
scan to check ejection fraction at rest & with stress
Liver
: liver function tests, liver biopsy, CT scan
Endocrine : clinical examination (growth & sexual development), glucose tolerance test, pituitary
gonadotrophin release tests, thyroid, parathyroid, gonadal & adrenal function,
growth hormone assays, radiology for bone age, isotopic bone density study
Management
Regular transfusion
Iron chelation therapy to treat iron overload
Regular folic acid (5 mg daily) if the diet is poor
Vitamin C 200 mg daily: to increase excretion of
iron
Splenectomy to reduce blood requirements
Endocrine therapy
Immunization: hepatitis B and C
Bone marrow or stem cell transplantation
Complications
Transfusion transmitted infections
Bone expansion (hair on end)
Hypopituitarism
Excessive melanin skin pigmentation (bronze
diabetes)
Hypothyroidism
Hypoparathyroidism
Pulmonary hypertention and embolism
Cardiomyopathy
Venous thrombosis
Complications..
Hemosiderosis and cirrhosis of liver
Extramedullary hematopoiesis
Splenomegaly
Diabetes mellitus
Arthropathy
Delayed puberty & delayed secondary sexual
characteristics
Testicular or ovarian failure
Osteoporosis
Short stature
Modul Task
Case:
A 2 year-old boy, body weight 9 kgs
History taking: pale 2 months; no bleed; no
fever; abdomen enlargement and distended
Physical examination: conjunctiva palpebra
anemic; abdomen enlargement and distended;
liver enlargement ( - BH); spleen enlargement
(Suffner II)
Laboratory results: Hb 6.5 g/dl; white blood
cells 5640/mm3; platelet 284,000mm3; MCV, MCH
and MCHC low; SI and TIBC normal; Hbelectrophoresis: HbA 37.4%; HbF 59.2%; HbA2
3.4%
Questions:
1.What is THE MOST PROBABLE DIAGNOSIS of this
patient?
2.Describe in brief THE CLINICAL AND GENETIC
CLASSIFICATION of this disease!
3.How TO DIAGNOSE this disease based on the
clinical features and laboratory findings?
4.What are THE COMPLICATIONS of this disease?
5.How TO ASSESS iron overload in this patient?
6.How TO MANAGE this patient!
Please.discuss this case in your group!!
THANK YOU

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Red Cell Disorders:

The adult proportion of Hb A, Hb A2 and Hb F are

Figure 2. Synthesis of individual globin chains in

Normal Hemoglobin in children/adult

Figure 3. Pathophysiology of thalassemia

The genes for the globin chains occurs in 2 clusters :

Figure 4. The globin gene clusters on chromosome 11

Clinical Classification of Thalassemia

Clinical Classification of Thalassemia

Figure 5. Thalassemia: the blood film shows marked

Figure 6. Hemoglobin electrophoretic patterns

Assessment of Iron Overload

Please.discuss this case in your group!!

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