49 Thalassemia

Question 1

Thalassemia was initially called

Answer 1

Cooley anemia

Question 2

The thalassemia results from mutations in the globin genes and are part of the spectrum of diseases known collectively as the hemoglobinopathies.

What are the 2 types

Answer 2

• Qualitative disorders: structural hemoglobin (Hb) variants are produced, such as sickle cell anemia, unstable Hbs, and methemoglobins
• Quantitative disorders : normal globin production is diminished or absent

Question 3

TRUE OR FALSE

The majority of qualitative mutations (structural hemoglobin (Hb) variants, sickle cell anemia, unstable Hbs, and methemoglobins), cause no significant change in Hb properties or clinical problems

Answer 3

TRUE

The majority of qualitative mutations (structural hemoglobin (Hb) variants, sickle cell anemia, unstable Hbs, and methemoglobins), cause no significant change in Hb properties or clinical problems

However, some mutations lead to a Hb variant that is also produced in reduced amounts, for example, HbE (β26 Glu→Lys), the most common β-thalassemia mutation in Southeast Asia

Question 4

The most common β-thalassemia mutation in Southeast Asia

Answer 4

HbE (β26 Glu→Lys)

Question 5

2 major forms of thalassemia

Answer 5

α-thalassemia and β-thalassemia

Rare: γ-thalassemia, δ-thalassemia, and εγδβ-thalassemia

Question 6

The clinical severity of thalassemia depends largely on the inherited __________.

Answer 6

Genotype

Question 7

Result from a large deletion in chromosome 11

Involve the β-LCR

Answer 7

εγδβ-thalassemia

Question 8

Difference between HPHF heterozygotes vs heterozygotes for δβ-thalassemia

Answer 8

HPFH heterozygotes: normal red cell indices, normal HbA2 levels, and HbF levels of 10% to 35%

δβ-thalassemia heterozygotes: hypochromic microcytic erythrocytes, HbA2 levels are also normal, but the HbF increases are less (5–15%)

The level of compensatory HbF increase is higher in HPFH compared to δβ-thalassemia

Question 9

TRUE OR FALSE

A deficiency of α-globin chain production affects Hb synthesis in both fetal and adult life

Answer 9

TRUE

As α-globin is an essential part of normal fetal (α2γ2) and normal adult (α2β2) Hb, a deficiency of α-globin chain production affects Hb synthesis in both fetal and adult life.

Question 10

α-globin genes are found in chromosome

Answer 10

Chromosome 16

α-globin and the rest of fetal hemoglbin

Question 11

β-globin gene cluster on the short arm of chromosome _____.

Answer 11

Chromosome 11

Question 12

α- thalassemia is most commonly caused by __________

Answer 12

Deletions

Question 13

α2β2

Answer 13

HbA

Question 14

α2δ2

Answer 14

HbA2

less than 3.5%

less than 2% of fetal Hb or HbF (heterodimer of α-globin and γ-globin, α2γ2

Question 15

Red cells are initially made in the _______ of the developing embryo and prior to week _____ of intrauterine life

Answer 15

yolk sac
8 weeks

Question 16

3 embryonic Hbs

Answer 16

Gower 1 (ξ2ε2)
Gower 2 (α2ε2)
Portland (ξ2 γ2)

Question 17

Adult counterparts:
ξ-globin
ε-globin

Answer 17

ξ-globin : α-globin and β-globin
ε-globin : γ-globin, and δ-globin chains

Question 18

α2γ2

Answer 18

HbF

As the embryo develops into the fetus, erythropoiesis moves to the liver and spleen; there is an orderly switch from ξ-globin to α-globin chain and from ε-globin to γ-globin chain production

Question 19

HbF

At birth, the ratio of molecules containing Gγ-globin chains to those containing Aγ-globin chains is approximately______

Answer 19

3:1

The ratio of Gγ-globin chains to Aγ-globin chains in the trace amounts of HbF in normal adults’ switches from a ratio of 3:1 to approximately 1:3.

Question 20

Toward the ____________, the marrow becomes active in erythropoiesis

Answer 20

End of the second trimester

Question 21

Hb switching, occurs between ________of age

Answer 21

6 and 12 months

Postnatally, γ-globin chain production (HbF) is replaced by β-globin chain production (HbA), commonly referred to as Hb switching

Question 22

The physiologic nadir of infancy—at a Hb level of 90–100 g/L—usually occurs by _______

Answer 22

8 weeks

Question 23

β-Globin synthesis commences early during fetal life, at approximately_______ of gestation

Answer 23

8–10 weeks

Question 24

The production of γ-globin chain persists at very low levels in adults, and the small amount of HbF is confined to an erythrocyte population called _______

Answer 24

F cells

Question 25

Identified as a key repressor of the γ-globin gene and a critical mediator in the switch from fetal to adult Hb expression

Answer 25

BCL11A

Question 26

Fetal Hb synthesis is higher in this hematologic malignancy

Answer 26

Juvenile myelomonocytic leukemia

Question 27

The vast majority of mutations causing β-thalassemia are ____________

Answer 27

Nondeletional

β-Thalassemia is rarely caused by deletions.

Question 28

This condition often is characterized by the presence of inclusion bodies in the red cell precursors, it has been called inclusion-body β-thalassemia

Answer 28

Dominantly Inherited β-Thalassemia

Question 29

The causative mutation in X-linked thrombocytopenia and β-thalassemia

Answer 29

Amino finger of erythroid-specific GATA-1

Question 30

Gene mutations seen on patients with trichothiodystrophy and β-thalassemia trait.

Answer 30

Xeroderma pigmentosa (XPD) protein

Question 31

These disorders consist of a range of disorders characterized by decreased or absent HbA production and a variable compensatory increase in HbF synthesis

Answer 31

δβ-Thalassemia and HPFH

Question 32

Contains normal α-globin chains and non–α-globin chains that consist of the first 50–80 amino acid residues of the δ-globin chains and the last 60–90 residues of the normal C-terminal amino acid sequence of the β chains.

Answer 32

HbLepore

δβ+-Thalassemia

Question 33

Rare conditions and result from large deletions of the β-globin gene cluster, which involve the β-LCR.

Answer 33

εγδβ-Thalassemia

• Group I: removes all, or a greater part of the complex, including the β-globin gene and the β-LCR, and
• Group II: removes extensive upstream regions, including the β-LCR but leaving the β-globin gene itself intact

Question 34

The most common forms of α+-thalassemia

Answer 34

Deletion : –α3.7 and –α4.2

Question 35

Five mutations that affect termination of translation and give rise to elongated α-globin chains have been identified:

Answer 35

HbConstant Spring, HbIcaria, HbKoya Dora, HbSeal Rock, and HbPakse

(Non-deletion)

Question 36

4 phenotypes of α-Thalassemia

Answer 36

(a) normal
(b) conditions characterized by mild hematologic changes but no clinical abnormality
(c) HbH disease
(d) HbBart’s hydrops fetalis syndrome

Question 37

HbH occurs most frequently in :

Usually results from the compound heterozygous state for α0-thalassemia and either deletion or nondeletion α+-thalassemia

Answer 37

Southeast Asia (–SEA–/–α3.7) and the Mediterranean region (usually –MED–/–α3.7)

Question 38

Usually results from the homozygous state for α0-thalassemia

Answer 38

HbBart’s hydrops fetalis syndrome

Most commonly –SEA–/–SEA– or –MED–/–MED–

Question 39

α-thalassemia associated with mental retardation suggested the lesions involving the α-globin gene locus were acquired in the ________ germ cell

Answer 39

Paternal germ cell

ATR-X

α-thalassemia results from deficiency of a trans-activating factor involved in regulation of the α-globin genes

Question 40

Mutations involving this gene exlplains hematologic findings of HbH disease or mild α-thalassemia are occasionally observed in elderly patients with primary myelofibrosis or the myelodysplastic syndrome

Answer 40

ATR-X

Question 41

TRUE OR FALSE

Thalassemias, in general, are syndromes of ineffective erythropoiesis.

Answer 41

TRUE

Thalassemias, in general, are syndromes of ineffective erythropoiesis.

Question 42

α or β-thalassemia

Ineffective erythropoiesis is markedly greater in ___________ and contributes much more to the manifestations of the disease

Answer 42

β-thalassemia

Question 43

3 major components of ineffective erythropoiesis in β-thalassemia:

Answer 43

• (a) ineffective erythropoiesis with intramedullary apoptosis of a variable proportion of the developing red cell precursors;
• (b) hemolysis resulting from destruction of mature red cells containing α-globin chain inclusions that have shorter life spans because of the formation of hemichromes and iron-related oxidative damage
• (c) the hypochromic and microcytic red cells that result from the overall reduction in Hb synthesis

Question 44

Major cause of anemia in α-thalassemia

Answer 44

Hemolysis and poorly hemoglobinized red cells

The excess γ-globin and β-globin chains produce soluble homotetramers, HbBart’s and HbH

There is less ineffective erythropoiesis than in β-thalassemia

Question 45

γ4-homotetramers

Answer 45

HbBart’s

HbBart’s is more stable than HbH and does not form large inclusions.

Question 46

β4-homotetramers

Answer 46

HbH

β4 tetramers precipitate as red cells age, with the formation of inclusion bodies, which leads to a shortened survival of red cells mainly taking place in the microvasculature of the spleen

Question 47

α-thalassemia

Deficient fetal oxygenation probably is responsible for the:

Both HbBart’s and HbH show no heme–heme cooperative interaction and have almost hyperbolic oxygen dissociation curves with very high oxygen affinities. Thus, they are not able to effectively release oxygen effectively at physiologic tissue tensions making them very poor oxygen carriers .

Answer 47

• (a) hypertrophied placentas
• (b) the severe erythroblastosis
• (c) the gross hydropic state of the fetus as a result of increased capillary permeability and possibly for
• (d) the associated developmental abnormalities that occur with the severe forms of intrauterine α-thalassemia

Question 48

In β-thalassemia, excess α-globin chains result in mechanical instability and oxidative damage primarily to ______________

Answer 48

Protein 4.1

However, in α-thalassemia, the membranes are hyperstable, and there is no evidence of oxidation or dysfunction of protein 4.1

Furthermore, accumulation of excess β-globin chains in α-thalassemia results in increased hydration of the cells.

Question 49

The extramedullary hematopoiesis and bone lesions are particularly prominent in _________-thalassemia.

Quiescent hematopoietic stem cells (HSCs) in the liver and spleen are activated, resulting in extramedullary hematopoiesis that may result in tumor-like formation in those sites and in other tissue locations, similar to what is seen in primary myelofibrosis

Answer 49

HbE β-thalassemia

Question 50

The iron overload in thalassemia causes ________ erythroferrone, the product of marrow erythroid precursors, _______ hepcidin production through the bone morphogenetic protein/Sma-related and Mad-related protein signaling pathway

Answer 50

Increased erythroferrone
Reduces hepcidin

• Leads to increased iron absorption and impaired iron sequestration
• These changes are less common in α-thalassemia

Question 51

A refined method for assessing iron overload

Answer 51

Magnetic resonance imaging (MRI)

Question 52

Risks for vascular disease in thalassemia is highest among

Answer 52

• Nontransfused patients with severe ineffective erythropoiesis
• Post-Splenectomy

Question 53

The procoagulant effect of thalassemia cells results from increased expression of ____________ on the red cell surface

Answer 53

Anionic phospholipids

• These aminophospholipids are moved to the outer leaflet, thus providing a surface on which coagulation can be activated
• Release of Hb and arginase, resulting in impaired nitric oxide availability and endothelial dysfunction with progressive pulmonary hypertension.

Question 54

Classification of thalassemia based on genotype:

Answer 54

• Thalassemia minor (including 1 or 2 α-globin gene defects and a single β-globin gene defect),
• Thalassemia intermedia (3 α-globin gene defects, HbH disease, other nondeletional forms of α-thalassemia such as HbHConstant Spring, non–β0/β0-thalassemia, including β+/β0, β+/ β+, or HbE/β+-thalassemia, and dominant β-thalassemia)
• Thalassemia major (α0-thalassemia, severe HbHConstant Spring, β0/β0-thalassemia, E/β0-thalassemia)

Question 55

The major factor determining the severity of thalassemia

Answer 55

Degree of globin-chain imbalance

Question 56

Transfusion volumes are usually approximately _____ mL/kg of packed red cells in children

Answer 56

15 mL/kg

Question 57

Typically, adults usually receive _____ U of packed red cells each time, with intervals of 2, 3, or 4 weeks, depending on body size

Answer 57

2 U

Question 58

After approximately _____ transfusions, it is predicted that the liver iron concentration will have more than doubled and iron chelation will be initiated

Answer 58

12–15

Question 59

Radiologic findings in thalassemia

Answer 59

The diploe widens, with a “hair on end” or “sunray” appearance and a lacy trabeculation of the long bones and phalanges.

Question 60

If iron chelation is not begun appropriately for transfusional iron overload, iron-induced endocrinopathies can develop, usually after approximately ______years of age

Answer 60

10 years of age

Question 61

If the anemia is not treated, heart failure may develop, resulting in death, usually within the first ______ years of life.

Answer 61

2-5 years

Toward the end of the second decade, iron-induced cardiac complications arise, and death usually occurs in the second or third decade as a result of intractable heart failure or ventricular arrhythmias from cardiac siderosis.

Question 62

Hemoglobin Bart’s Hydrops Fetalis Syndrome

Embryos with homozygous α0-thalassemia (a thalassemia major) will begin to have manifestations of anemia in the_______trimester

Answer 62

Second trimester

• With worsening anemia, there is heart failure and anasarca, leading to enlargement of the placenta and to a hydropic fetus
• If detected prenatally, intrauterine transfusions may be administered with a good rate of success
• The reason for placental hypertrophy is unknown, although severe intrauterine hypoxia is suspected

Question 63

Forms of α-Thalassemia

The homozygous states for the chain-termination mutant have the characteristic phenotype of thalassemia intermedia with moderate hemolytic anemia with splenomegaly

*non-deletional

Answer 63

HbConstant Spring

Question 64

α-Thalassemia and Mental Retardation

Shorter deletions have α-thalassemia and mental retardation but when the deletion is ________kb or longer, it may involve genes that, when deleted, are responsible for _______and _______________

Answer 64

2000 kb or longer

Tuberous sclerosis and polycystic kidney disease

• When there are mutations of the ATR-X gene, the syndrome is broader and includes skeletal abnormalities, dysmorphic face, neonatal hypotonus, genital abnormalities

Question 65

TRUE OR FALSE

A marrow examination is not required for diagnosis OF Homozygous β0-Thalassemia

Answer 65

TRUE

A marrow examination is not required for diagnosis OF Homozygous β0-Thalassemia

But if performed, shows marked erythroid hyperplasia with a maturation arrest, stippling, and inclusions in the red cell precursors, as well as an increased iron content

High-performance liquid chromatography (HPLC) or Hb electrophoresis shows no HbA in β0 homozygotes, with HbF comprising the majority of the Hb, and a relative increase in HbA2 as a proportion of total Hb.

Question 66

2 main classes of “normal HbA2 β-thalassemia”

Answer 66

Type 1 is the “silent” form of β- thalassemia; no hematologic changes

Type 2 is heterogeneous, compound heterozygous state for β-thalassemia and δ-thalassemia severe transfusion-dependent β-thalassemia

Question 67

The most clinically important associations of β-thalassemia with β structural Hb variants are:

Answer 67

• HbS/β-thalassemia (sickle–β-thalassemia)
• HbC/β-thalassemia, and
• HbE/β-thalassemia

Question 68

Sickle–β-thalassemia

The clinical consequences of carrying 1 gene for HbS and 1 gene for β-thalassemia depend entirely on the type of ___________ mutation.

Answer 68

β-thalassemia mutation

Question 69

Occurs at a high frequency in the eastern half of the Indian subcontinent and throughout Southeast Asia, is one of the most important hemoglobinopathies in the world population

Answer 69

HbE/β-thalassemia

When HbE is inherited with β-thalassemia—and most often this is a β0-thalassemia or severe β+-thalassemia mutation in Southeast Asia and India—a marked deficit of β-globin chain production results, with the clinical picture of severe β-thalassemia

Question 70

Incubation of the red cells with brilliant cresyl blue results in multiple ragged inclusion bodies in almost all cells resembling golf balls.

Answer 70

Hemoglobin H Disease

Question 71

TRUE OR FALSE

The homozygous state for nondeletion forms of α-thalassemia involving the dominant (α2) globin gene causes a more severe deficit of α-globin chains than do the deletion forms of α+-thalassemia.

Answer 71

TRUE

The homozygous state for nondeletion forms of α-thalassemia involving the dominant (α2) globin gene causes a more severe deficit of α-globin chains than do the deletion forms of α+-thalassemia.

In some cases, the homozygous state produces HbH disease.

Question 72

Homozygous State for Nondeletion Types of α-Thalassemia

In the homozygous state for _____________________ , the blood picture shows mild thalassemic changes with normal-size red cells with an associated moderately severe hemolytic anemia.

Answer 72

HbConstant Spring or other chain-termination mutations

• The Hb consists of approximately 5% to 6% HbConstant Spring, normal HbA2 levels, and trace amounts of HbBart’s. The remainder is HbA.

For unclear reasons, no HbH is present but small amounts of HbBart’s may persist into adult life.

The heterozygous state for HbConstant Spring shows no hematologic abnormality.

Question 73

The goals of treatment for the thalassemia syndromes are to:

Answer 73

• (a) maintain optimal levels of Hb for growth and development in children, and appropriate activity at all ages;
• (b) minimize the complications related to ineffective erythropoiesis, by adequately suppressing patient’s own (endogenous) marrow activity;
• (c) prevent complications related to the therapy of the disease; and
• (d) improve longevity while maintaining a good quality of life

Question 74

The only currently available curative therapy for thalassemia

Answer 74

HSC transplantation

Question 75

Hgb target range supports near-normal activity, growth and development, and suppression of ineffective erythropoiesis

Answer 75

95–105 g/L

Hypertransfusion regimen

Question 76

Amount of tratransfusion in children and in adults

Answer 76

• Children: 15 mL/kg to increase to a full unit when the child weighs approximately 15 kg.
• Adults: 2 U of packed red blood cells every 2–4 weeks

Split units are not recommended because they do not afford the benefit of the full amount, and yet expose the recipient to another donor.

Question 77

Indications for splenectomy in NTDT

Answer 77

• Massive splenic enlargement with risk of rupture and pain in the left upper quadrant
• Dropping Hb level

Question 78

Presentation with abdominal pain, diarrhea, and vomiting should always suggest an infection with a member of the ___________ class of bacteria

Answer 78

Yersinia class of bacteria

Question 79

A noninvasive estimation of myocardial iron

Answer 79

T2* MRI

Question 80

Initiate chelation in thalassemia patients when the serum ferritin reached _____ mcg/dL

Answer 80

1000 mcg/dL

Because we can quantify the rate of iron loading, knowing the volume of blood transfused and its iron content, a serum ferritin of 1000 mcg/dL is not a reasonable starting point.

Question 81

Chelation should be initiated after the patient has received approximately _____ transfusions (by which time the liver iron would be estimated to be approximately _____mg/g dry weight).

Answer 81

15 transfusions

6–8 mg/g dry weight

Question 82

Liver MRIs are recommended _______.

Answer 82

Annually

Question 83

In children treated with iron chelation, cardiac imaging is usually not performed until the child is older than _______ years

Answer 83

older than 10 years

In addition, regular monitoring of endocrine functions, including that of the pituitary, endocrine pancreas, thyroid, parathyroid, adrenals and gonads, as these organs also may be severely affected by iron overload, should begin around 10 years of age.

Question 84

First chelating agent of proven long-term value for treatment of iron overload in thalassemia.

Answer 84

Deferoxamine (desferrioxamine)

Question 85

Must be given by SQ infusion over 8–12 hours, preferably daily, but at least 5–6 times per week

Answer 85

Deferoxamine (desferrioxamine)

Question 86

Long-term side effects of deferoxamine

Answer 86

• Ototoxicity (high-frequency hearing loss and tinnitus)
• Ocular toxicity (visual failure, night and color blindness, and field loss)

Can also cause bone changes and growth retardation, and is sometimes associated with bone pain, particularly when used in the absence of significant iron overload

Question 87

An oral, once-daily iron chelator

Answer 87

Deferasirox

Question 88

A first-line drug for the management of transfusional iron overload

Answer 88

Deferasirox

Question 89

Toxicities of Deferasirox

Answer 89

• Nonprogressive elevation of the serum creatinine
• Elevation of liver enzymes

Question 90

Oral iron chelator with short half-life, must be taken 3 times a day

Answer 90

Deferiprone

Question 91

Has good efficacy at purging iron from the myocardium, and is often used in combination with other chelators in patients with lower cardiac T2* values

Answer 91

Deferiprone

Question 92

The most concerning side effect of Deferiprone

Answer 92

Neutropenia, and occasionally agranulocytosis

Question 93

Butyrate analogues and hydroxyurea did not show very positive results, except in homozygotes for _________

Answer 93

HbLepore

Question 94

Therapies that focus on Augmentation of Fetal Hemoglobin Production by Editing the BCL11A Gene

Answer 94

• (a) targeting protein–DNA interactions using either transcription activator-like effector nucleases or zinc finger nucleases, and
• (b) targeting RNA–DNA interactions using CRISPR-Cas-9

Question 95

A recombinant fusion protein containing a modified extracellular domain of ActRIIB, which binds GDF11 and other transforming growth factor-β superfamily ligands, inhibits Smad2/3 signaling, and promotes red cell differentiation/ maturation

Answer 95

Luspatercept

Question 96

Prevention can be achieved in 2 ways:

Answer 96

Genetic counseling and prenatal screening