Thalessemia

What are thalassemias?

They are a group of inherited disorders caused by genetic mutations that reduce or prevent the synthesis of one or more of the golden chains of the HGB tetramer

What is the cause of thalassemia?

It results from gene mutations that reduce the synthesis of one or more globin chains (either Alpha (α) or Beta (β) hemoglobin chains), leading to impaired hemoglobin production.

What is the cause of thalassemia?

Because Hb A (A2B2) is the major adult HGB, and the imbalance caused by decreased synthesis of one chain leads to severe anemia

What happens when there is reduced or absent synthesis of one globin chain?

It leads to decreased HGB production and an imbalance in the alpha/beta ratio. The unaffected gene continues to produce globin chains at normal levels, which causes an accumulation of unpaired normal chains

How does the accumulation of unpaired globin chains affect red blood cells (RBCs)?

It damages RBC or their precursors, resulting in their premature destruction. This exacerbates anemia in thalassemia

Why does the imbalance between alpha and beta chains worsen anemia in thalassemia?

The imbalance leads to the formation of unstable HGB, which results in ineffective erythropoiesis and increased premature destruction of RBC, worsening anemia

Where is thalassemia most commonly found?

In the Mediterranean through Middle East, India, Southeast Asia, and south to Northern Africa

Which populations are most affected by thalassemia?

Those living near the Mediterranean Sea, including Italians, Greeks, and Syrians.

What is the structure of a normal hemoglobin molecule?

It is a tetramer composed of two alpha-like chains (Alpha/Zeta) and two beta-like chains (Beta, Gamma, Delta, Epsilon)

What are the embryotic HGB

1. Hb Gower-1 (Zeta 2 Epsilon 2)

2. Hb Gower-2 (Alpha 2 Epsilon 2)

3. Hb Portland (Zeta 2 Gamma 2)

What is the fetal HGB

Alpha 2 and Gamma 2

What is the adult HGB

1. Alpha 2 Beta 2

2. Alpha 2 Delta 2

Where are the alpha-like gene clusters located

On chromosome 16 with Alpha and Zeta

Where are the beta-like globin gene clusters located?

On chromosome 11 with Beta, Gamma, Delta, and Epsilon

Into how many types is thalassemia divided?

• β thalassemia

• α thalassemia

Where is α-thalassemia most concentrated?

1. Southeast Asia

2. Malaysia

3. Southern China

Where is β-thalassemia primarily found?

1. Mediterranean Sea

2. Africa

3. Southeast Asia

How does the distribution of thalassemia correlate with the malaria belt?

It follows the malaria belt, as that is where the disease in most common

What causes β-thalassemia?

Point mutations in one or both of the β-globin genes, leading to decreased HGB and hemolysis

How is β-thalassemia categorized?

1. β-Thalassemia Major (Homo)

2. β-Thalassemia (Intermedia)

3. β-Thalassemia Minor (Hetero)

4. Silent Carrier

What is the most common cause of α-thalassemia?

Point deletions that involve the α1- and/or α2-globin genes.

Why are individuals with severe β-thalassemia asymptomatic during fetal life and up to 6 months of age?

Because Hb F (α2γ2) is the predominant circulating HGB, compensating for the reduced β-globin chain production.

When do symptoms typically begin to appear in β-thalassemia?

Between 6-24 months of age, when the switch from gamma to beta is completed and Hb F is reduced

How does the body attempt to compensate for the decreased expression of the β-globin gene in β-thalassemia?

They will increase Hb D or Hb G globin genes. However in β-thalassemia major this increase is insufficent

What is the genotype, zygosity, and severity of Beta Thalassemia Major?

• Genotype: B°B°

• Zygosity: Homozygous

• Severity: Severe

What is the genotype, zygosity, and severity of Beta Thalassemia Major/Intermediate (Double Heterozygous)?

• Genotype: B°B⁺

• Zygosity: Double Heterozygous

• Severity: Severe to Moderate

What is the genotype, zygosity, and severity of Beta Thalassemia Major/Intermediate (Homozygous B⁺)?

• Genotype: B⁺B⁺

• Zygosity: Homozygous

• Severity: Severe to Moderate

What is the genotype, zygosity, and severity of Beta Thalassemia Intermedia/Minor?

• Genotype: B°B

• Zygosity: Heterozygous

• Severity: Moderate to Mild

What is the genotype, zygosity, and severity of Beta Thalassemia Minor/Silent Carrier

• Genotype: B⁺B

• Zygosity: Heterozygous

• Severity: Mild

What is the genotype, zygosity, and severity of Beta Thalassemia/ Minima

• Genotype: BSCB

• Zygosity: Heterozygous

• Severity: Normal

What is the genotype, zygosity, and severity of a normal individual?

• Genotype: BB

• Zygosity: Homozygous

• Severity: Normal

What are clinical manifestations of β-thalassemia Major

1. Sever anemia in infancy (Cooley Anemia)

2. Facial and cranial bone enlargement

3. Splenomegaly

4. Secondary hemochromatosis

5. Transfusion dependent

In β-thalassemia, what is the primary issue with the hemoglobin chains?

Very few beta chain produced leads to increase in alpha and gamma chains making abnormal HGB

What happens to the abnormal hemoglobin in β-thalassemia?

It is unstable and disintegrates, causing RBC destruction and leading to severe anemia

How does the body respond to the effects of β-thalassemia?

Ineffective erythropoiesis and the production of Hb F leading to immature normoblasts and erythroblasts

What is extramedullary hematopoiesis in the context of β-thalassemia?

It refers to the production of blood cells outside the bone marrow, which can be a compensatory mechanism in β-thalassemia.

What is the difference between β0 thalassemia and β+ thalassemia?

In β0 thalassemia, no β chains are produced, whereas in β+ thalassemia, some β chains are produced.

What is a serious complication of iron accumulation in β-thalassemia major?

It leads to progressive organ toxicity

How does the decreased production of α chains manifest in α-thalassemia?

It can manifest in utero because alpha chains are components of both fetal and adult HGB

What happens when there is a decrease in α chain production in the fetus and newborn?

It results in an excess of gamma chains

What forms from the excess γ chains in α-thalassemia?

They form stable tetramers called Hb Bart 4 (Y4), which do not precipitate

What happens to α-thalassemia after 6 months of age when the γ to β switch is completed?

The decrease in alpha chain production results in an excess of Beta chains, which form tetramers called Hb H (B4)

When is β-Thalassemia Major typically diagnosed?

In late infancy

What are the main symptoms of β-Thalassemia Major?

1. Anemia

2. Fever

3. Poor feeding

4. Splenomegaly

What other symptoms are associated with chronic hypoxia in β-Thalassemia Major?

1. Hypoxia

2. Headache

3. Bone pain

4. Listlessness

5. Anorexia

6. Frequent nosebleeds

What cardiovascular-related symptoms might be present in β-Thalassemia Major?

Chest pain and poor exercise tolerance

What growth-related issues are associated with β-Thalassemia Major?

Retarded growth and delayed sexual maturation

What are the complications related to iron overload in β-Thalassemia Major?

hemosiderosis and hemochromatosis.

What type of anemia is seen in β-Thalassemia Major?

Severe microcytic anemia

What is the Hb F level in individuals with β-Thalassemia Major?

Greater than 60% is observed in homozygotes

Which test is used to detect fetal hemoglobin (Hb F) in β-Thalassemia Major?

The Kleihauer-Betke test or Acid Elution test

What is the Hb A2 level in heterozygotes with β-Thalassemia Major?

Greater than 5%

Which procedure is used for quantitative analysis of Hb A2?

Ion exchange chromatography

What is the hemoglobin level in untreated β-Thalassemia Major?

As low as 3-4 g/dL

What is the typical range for MCV in β-Thalassemia Major?

50-70 fL

What abnormalities are observed in the peripheral blood film of a patient with β-Thalassemia Major?

1. Marked microcytosis

2. Hypochromia

3. Anisocytosis

4. Poikilocytosis

5. Target cells

6. Teardrops cells

7. Elliptocytes

8. Polychromasia

9. NRBCs

What inclusions are commonly found in RBCs in β-Thalassemia Major?

1. Basophilic stippling

2. Howell Jolly

3. Pappenheimer

What is the reticulocyte count in β-Thalassemia Major?

Mild to mod elevated

What is the cause of β-Thalassemia Minor?

When one β-globin gene is affected by a mutation that decreases or abolishes it expression, while the other β-globin gene is normal (heterozygous state).

What type of anemia is observed in individuals with β-Thalassemia Minor?

Mild, hypochromic, and microcytic

How does the RBC count present in individuals with one affected gene?

Normal and slightly elevated

What types of RBC abnormalities are seen in individuals with one affected gene?

1. Target cells

2. Elliptocytes

3. Poikilocytosis

4. Basophilic stippling

What is observed in the bone marrow of individuals with one affected gene?

ineffective erythropoiesis and erythroid hyperplasia.

What is the major therapeutic option for those with thalassemia major

Transfusion

What is the Hb A2 level in individuals with one mutated gene for β-thalassemia?

3.5-8.0% measured by ion exchange chromatography

What is the Hb F level in individuals with one mutated gene for β-thalassemia?

1-5%

What is thalassemia intermedia?

It is a type of anemia that is more severe than β-thalassemia minor but does not require regular transfusions to maintain hemoglobin levels and quality of life

What is the HGB levels in thalassemia intermedia?

Greater than 7 g/dL

What is the purpose of the Kleihauer-Betke (Acid Elution) stain?

It detects the presence of increased Hb F

What conditions is the Kleihauer-Betke (Acid Elution) stain used in

β-thalassemia major, Hereditary Persistence of Fetal Hemoglobin (HPFH), and Hemolytic Disease of the Newborn (HDN).

How does the Kleihauer-Betke stain work?

It involves treating the blood with an acidic solution. The acidic solution causes Hb A to leave the cell, but Hb F remains in the RBC, allowing for its detection

What is the typical hemoglobin distribution in thalassemia intermedia?

1. 2-100% Hb F

2. Up to 7% Ab 2

3. 0-80% Hb A

What causes Hemoglobin Lepore Thalassemia?

A structural mutation that results from a fusion of the delta globin gene and the beta globin gene. This fusion occurs during meiosis due to a nonhomologous crossover between the delta globin on one chromosome and the beta globin locus on the other chromosome

What is the treatment for β-Thalassemia Major?

1. Regular hyper transfusion

2. Iron chelation therapy

3. Splenectomy

What treatment options are available for β-Thalassemia Intermedia?

1. Splenectomy

2. Iron chelation therapy

3. Transfusions

4. Antibiotics

How is β-Thalassemia Minor treated?

1. No treatment

2. Maintain good health and nutrition

What are the four clinical syndromes of a-thalassemia?

1. Silent Carrier state

2. a-thalassemia minor

3. Hb H disease

4. Hb Bart hydrops fetalis syndrome

What causes the silent carrier state in a-thalassemia?

The deletion of one a-globin gene leaving three functional a-globin genes (-a/aa)

What causes a-thalassemia minor?

The deletion of two a-globin genes which can be either hetero (- - /aa) or homo (-a/-a)

What is the main cause of Hemoglobin H Disease?

The deletion of three a-globin genes resulting in only one functioning a- globin chain ( - - /-a)

What causes Hb Bart Hydrops Fetalis Syndrome?

Homozygous a0-thalassemia (- -/ - -), which results in the absence of all alpha chain production. This leads to death in utero or shortly after birth

What is the cause of Hb Bart's and Hb H in patients with α-thalassemia?

A decrease in the production of alpha chains

What is Hb Bart's, and when does it occur?

It occurs in newborns and it is the formation of four gamma chains as a result of the lack of alpha chains

What happens to Hb Bart's over time in infants with α-thalassemia?

It is gradually replaced by Hb H during the first month of life and forms 4 beta chains to replace the 4 gamma chains

How do Hb Bart's and Hb H differ from Hb A in electrophoresis?

They both migrate further towards the anode than Hb A

What is the oxygen affinity of Hb H?

It has a high affinity for O2, which impairs it ability to release oxygen to the tissues

What is the stability of Hb H, and what does it lead to?

It is very unstable and can precipitate s toxic Heinz bodies in RBC. These precipitates can cause premature hemolysis

When does the formation of Heinz bodies predominantly occur?

In mature RBC

What causes an increase in Hb H levels?

Oxidative stress, which can lead to hyperhaemolysis in conditions such as an infection or after ingestion of oxidant drugs

What is the genetic cause of Hb H disease?

Compound hetero or homo mutations in HBA1 or HBA2, located on chromosome 16

How does the severity of Hb H disease vary?

It depends on its molecular basis, patients with non deletional Hb H such as constant spring can experience more severe symptoms than those with the common deletional types

What is hydrops fetalis characterized by

An abnormal accumulation of fluid in two or more fetal compartments, including ascites, pleural effusion, pericardial effusion, and skin edema

How is hydrops fetalis usually detected?

With ultrasound exam during the first or second trimester

How is Hb H detected in a blood smear?

When it is stained with brilliant cresyl blue, Hb H precipitates, forming Heinz bodies

What are the typical findings in Hb H disease on electrophoresis

A large band of Hb A and a small band of Hb H which is caused by the inheritance of three deleted alpha chain genes

What is Hemoglobin E/Thalassemia, and where is it commonly found?

A combo of Hb E and β-thalassemia. It is found commonly in Cambodia, Thailand, and parts of India. Clinically, it presents similarly to β-thalassemia major or thalassemia intermedia.

What is Hemoglobin S/Thalassemia, and what are its clinical features?

It is a combination of sickle cell hemoglobin (Hb S) and β-thalassemia. It is found commonly in African and Mediterranean populations. Clinically, it resembles sickle cell anemia, with the additional feature of splenomegaly.

What is Hemoglobin C/Thalassemia, and where is it commonly found?

It is a combo of Hemoglobin C and β-thalassemia it is found commonly in Mediterranean and African populations.

How does Hemoglobin C/β⁰-thalassemia present clinically?

It causes a moderately severe hemolytic anemia and is associated with splenomegaly

How does Hemoglobin C/β⁺-thalassemia differ from Hemoglobin C/β⁰-thalassemia?

It produces a milder form of disease as compared to Hemoglobin C/β⁰-thalassemia.