Thalassemia Flashcards
What are the components of hemoglobin?
How many genes control the porduction of alpha and beta globins and in which chromosome?
The hemoglobin molecule is a heterodimer that contains 2 α-globin chains and another pair of different globin chains, normally β or δ; γ chains are produced by the fetus and newborn.
The major hemoglobin in human red blood cells after 4-6 months of age is hemoglobin A1, which consists of 2 α- and 2 β-globin chains (α2β2). Production of α-globin chains is controlled by 4 genes, 2 on each chromosome 16. Product of other globin chains is controlled by one gene cluster on each chromosome 11, which is depected below. The timing of production of various hemoglobins throughout development and their composition are also shown.
What is thalassemia?
What are the two most common types of thalassemias?
Thalassemia is a condition in which there is underproduction of a hemoglobin chain due to a variety of mutations that result in poor or absent function of the globin gene.
Thalassemias can be classified according to which globin gene is affected. The two most common types of thalassemia are alpha-thalassemia and beta thalassemia.
Thalassemias are also classified by the severity of the clinical phenotype. Patients with thalassemia minor have microcytosis but mild to no anemia. Thalassemia major is characterized by severe anemia and dependence on transfusions of RBCs. Thalassemia intermedia is an intermediate phenotype with more severe anemia and intermittent transfusion requirements
Describe Alpha thalassemia:
it is common in which people?
In α-thalassemia, the α-globin chain is underproduced, most often due to an absence of one or more of the four genes which control production. α-thalassemia is most common in persons of southeast Asian, African and Mediterranean descent. The types and characteristics of α-thalassemia are described in the table below:
What time of alpha-thalassemia predominated in those of asian descent?
What about in those of africa descent?
Which is more prone to producing fatal conditions?
In those of Southeast Asian descent, both genes on the same chromosome are usually missing, which means the person has one normal chromosome (with 2 α genes) and one without any α genes (- - / α α). This person can pass on a chromosome with no functional α genes, and if the other parent contributes a similar chromosome, the offspring will inherit no α genes. The fetus will be unable to make any normal form of hemoglobin, since α chains are necessary for all normal hemoglobin molecules, which leads to death in utero (called “hydrops fetalis”) or at birth. Bone marrow transplantation has been successfully performed in utero to prevent hydrops fetalis in affected pregnancies.
In contrast, for those of African descent, each chromosome usually has one intact α gene and one deleted (- α / - α), so offspring inherit at least one α gene. As long as there is one α gene, the fetus can survive. Thus, persons of African descent with α-thalassemia trait are less likely than those of Asian descent to have a pregnancy with hydrops fetalis.
What is the main cause of B-thalassemia?
What is Hb E? In what population is it most common?
In β-thalassemia, the β-globin chain is underproduced, most often due to point mutations which result in dysfunctional genes.
Hemoglobin E (Hb E) is a structurally abnormal hemoglobin, due to a point mutation in the β-globin gene (β26glu®lys), which is unstable. The amount of Hb E in the RBC is lower due to this instability, causing some of the same RBC changes as in classical thalassesmias. β-thalassemia occurs most commonly in persons of Mediterranean, African and southeast Asian descent;
Hb E is most common in those of southeast Asian descent. The types and characteristics of β-thalassemia and Hb E-related diseases are described:
Pathophysiology of Thalassemias:
What is chronic hemolysis?
•Imbalanced globin chain production leads to excess globin chains that can form unstable tetramers or be oxidized to form hemichromes which generate ROS.
- ROS damage red cell membrane proteins, which leads to decreased red cell deformability.
- -> Also it leads to Increased binding of IgG and C3 to red cell membrane that leads to clearance by splenic macrophages.
Why is there an iron overload in thalassemias?
Due to decreased ↓ hepcidin, which is a negative regulator of the transpotation of Iron to the blood from cells in the gut. Thus, and increase in ↑iron absorption occurs.
Describe innefective erythropoiesis:
It means premature apoptosis and maturation arrest during erythropoiesis. Can result in:
- Expansion of erythroid precursors pool in the bone marrow
- Extramedullary hematopoiesis
Pathophysiology of thalassemias:
Low Concentration of Hemoglobin in RBCs, why does this happen?
What does the excess in RBC membrane lead to?
RBCs in thalassemia and hemoglobin E are smaller (low MCV) and have a low mean corpuscular hemoglobin concentration (MCHC).
Despite the smaller size, there is an excess of RBC membrane, which results in a shape like a Mexican hat. When viewed in cross-section, the cell appears as a “target” cell, a characteristic feature of thalassemias and Hb E diseases.
Pathophysiology of thalassemias:
Imbalance chain production results due to?
What happens to excess globin chains?
Underproduction of one globin chain results in unmatched excess of the other globin chain.
- For example, in β-thalassemia, there is a relative excess of α-globin chains.
- Excessive, unused globin chains can precipitate, undergo denaturation and oxidation, resulting in membrane damage and increased red cell fragility.
This results in increased RBC apoptosis (death) and ineffective erythropoiesis (inability to make enough mature RBCs).
What is Hb Barts, and when is it produced?
How can you identify Hb Barts?
What if Hb H, when does it occur?
How can you detect Hb H?
Some of the excess chains form relatively unstable tetramer hemoglobin molecules.
The main prenatal hemoglobin is Hb F (α2δ2), so in the fetus/newborn with α-thalassemia, there is an excess of γ-globin chains which forms Hb Barts, made up of 4 γ-chains (γ4). This hemoglobin can be identified by hemoglobin electrophoresis.
In the first six months of life (see figure above), there is a shift to the production of hemoglobin A1 (α2β2). As this occurs in a person with alpha-thalassemia, there is an accumulation of β-globin chains, some of which form hemoglobin H, a relatively unstable tetramer of β chains (β4). Hb H can be detected on fresh blood samples using special hemoglobin separation techniques.
Relative increase in other hemoglobins:
In β-thalassemia, there is an underproduction of β-globin chains. However, production of the other globins in the same gene cluster continue, so there is a relative increase in the percentage of Hb A2 (α2δ2) and persistent/increased production of Hb F (α2γ2).
For alpha-thalassemia trait, what are the clinical presentations/lab findings?
What is the RBC count?
The MCH?
The RDW?
The reticulocyte count?
Hemosysis present?
Complete Blood Count
Normal to mildly decreased Hgb
↑RBC count
↓MCV (microcytosis)
↓MCH,
Normal RDW
The reticulocyte count – Normal
What is show in the peripheral Smear ?– Microcytosis, target cells
Hemolysis Evaluation – Normal (no hemolysis)
Why is the electrophoresis of alpha-thalassemia appear normal?
Patients with α-thalassemia underproduce all types of hemoglobin in proportion to each other, so the hemoglobin electrophoresis is normal.
How do you diagnose alpha-thalassemia trait?
What kind of tetramer globin can you observe?
- Microcytosis without evidence of iron deficiency, normal hemoglobin electrophoresis.
- Small amount (3-8%) Hb Barts on newborn screen
In terms of clinical significance, mild microcytic anemia can be confused with what?
How do you rule out iron deficiency?
Mild microcytic anemia can sometimes be confused with iron deficiency anemia, but the patient is not responsive to iron supplementation.
•Reproductive implications–> genetic counseling
What characterises Hemoglobin H disease?
What are the clinical presentations?
How is the reticulocyte count in comparisson to alpha-thalassemia?
What can you observe in the peripheral smear?
What does the hemolysis evaluation shows?
Complete Blood Count –
Moderately decreased Hgb,
↓MCV, ↓MCH (same as alpha-thalassemia trait).
-The Reticulocyte Count is Increased but RPI may be low.
Peripheral Smear – Microcytosis, target cells, **Hgb H inclusions (supravital stain)
•Hemolysis Evaluation – Increased LDH and total bilirubin, reduced haptoglobin
How do you diagnose Hb H disease?
The presence of Hgb H (β4) on hemoglobin electrophoresis.
Also, elevated levels of Hgb Barts (γ4) = 20-40% on newborn screen
What is the clinical significance of Hb H disease?
- May require intermittent transfusions for more severe anemia
- Risk for:
Iron overload (due to transfusions)
Splenomegaly (due to increases RBC destruction and trapping by macrophages in the spleen)
Bilirubin gallstones
Growth issues
What is hydrops fetalis?
How do you diagnose it?
What kind of hemoglobins are increased?
At what level is the treatment provided?
Clinical Presentation
•Not compatible with extrauterine life
•Usually diagnosed via prenatal testing if parents had previously affected fetus
Diagnosis
•Absence of normal fetal hemoglobin on electrophoresis, increased embryonic hemoglobins
-DNA testing
Treatment
**Intrauterine transfusions
***Intrauterine bone marrow transplant
What allows recognition of Beta-thalassemia?
The diagnosis of β-thalassemia is based on the recognition of increased Hb A2 (α2δ2) and Hb F (α2γ2), relative to the underproduced Hb A1 (α2β2). This happens since B-globin chain is not produced.
The tetramer of alpha-globin is not stable and or equivalent to Hb B (B4).
What is the clinical/laboratory presentation of B-thalassemia trait?
Complete Blood Count:
Normal to mildly decreased Hgb
↑RBC count, ↓MCV, ↓MCH, normal RDW (same as alpha-thalassemia trait)
•Reticulocyte Count – Normal
- Peripheral Smear – Microcytosis, target cells
- Hemolysis Evaluation – Normal
What is the clinical significance of B-thalassemia trait?
-Mild microcytic anemia can sometimes be confused with iron deficiency anemia, not responsive to iron supplementation
Reproductive implications –> genetic counseling
Beta-thalassemia intermediate:
What are the clinical/laboratory presentations?
What is haptoglobin?
CBC – Moderately decreased Hgb, ↓MCV, ↓MCH (same as
Reticulocyte Count – Increased but RPI may be low
Peripheral Smear – Microcytosis, target cells
Hemolysis Evaluation – Increased LDH and total bilirubin, reduced haptoglobin
Haptoglobin is an acute phase reactant that combines with Hb to form a complex that is phagocytosed and degraded by macrophages, causing a decrease in serum haptoglobin
How do you diagnose B-thalassemia intermedia?
Whats its its clinical significance?
- Elevated levels of Hgb A2 and Hgb F on electrophoresis
- DNA testing for beta globin mutations
Clinical Significance
•May require intermittent transfusions for more severe anemia
•Risk for iron overload, splenomegaly, bilirubin gallstones, growth issues
Beta Thalassemia Major (Cooley’s Anemia)
Severe hemolytic anemia can be shown.
β-Thal major (Cooley anemia; βo/βo or βo/β+)
(1) Severe hemolytic anemia
(a) RBCs with α-chain inclusions are removed by splenic macrophages
• Marked increase in unconjugated bilirubin (UCB; jaundice)
(b) RBCs with α-chain inclusions undergo apoptosis in the bone marrow (ineffective erythropoiesis).
β-thal major: severe hemolytic anemia; EMH; hair-on-end skull x-ray
(2) EMH and accelerated erythropoiesis
(a) Hepatosplenomegaly from excessive hematopoiesis
(b) Radiographs of the skull show a hair-on-end appearance (see Fig. 12-3).
(3) Increased RDW due to increased size variation (see Fig. 12-12B)
(4) Increase in reticulocytes, teardrop cells, Howell-Jolly bodies (nuclear remnants), and nucleated RBCs (see Fig. 12-12B)
(a) No synthesis of HbA
(b) Corresponding increase in HbA2 and HbF
β-thal major: no HbA; ↑HbA2, HbF, RDW, reticulocytes
(6) Treatment
(a) Blood transfusion
- Danger of iron overload (called hemosiderosis)
- Requires chelation therapy with desferrioxamine
(b) Bone marrow transplantation (only curative approach)
Describe transfusional Iron overload:
What are its clinical consequences?
How to diagnose Iron overload?
Table with differences in microcytic anemias:
