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WILLIAM'S HEMATOLOGY > 49 Thalassemia > Flashcards

49 Thalassemia Flashcards

1
Q

Thalassemia was initially called

A

Cooley anemia

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2
Q

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

A

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

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3
Q

The most common β-thalassemia mutation in Southeast Asia

A

HbE (β26 Glu→Lys)

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4
Q

2 major forms of thalassemia

A

α-thalassemia and β-thalassemia

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

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5
Q

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

A

Genotype

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6
Q

Result from a large deletion in chromosome 11

Involve the β-LCR

A

εγδβ-thalassemia

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7
Q

Difference between HPHF heterozygotes vs heterozygotes for δβ-thalassemia

A

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

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8
Q

TRUE OR FALSE

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

A

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.

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9
Q

α-globin genes are found in chromosome

A

Chromosome 16

α-globin and the rest of fetal hemoglbin

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10
Q

α- thalassemia is most commonly caused by __________

A

Deletions

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11
Q

α2β2

A

HbA

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12
Q

α2δ2

A

HbA2

less than 3.5%

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13
Q

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

A

yolk sac
8 weeks

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14
Q

3 embryonic Hbs

A

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

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15
Q

Adult counterparts:
ξ-globin
ε-globin

A

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

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16
Q

α2γ2

A

HbF

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17
Q

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

A

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.

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18
Q

Toward the ______________, the marrow becomes active in erythropoiesis

A

End of the second trimester

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19
Q

Hb switching, occurs between ________of age

A

6 and 12 months

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

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20
Q

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

A

8 weeks

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21
Q

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

A

8–10 weeks

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22
Q

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 _______

A

F cells

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23
Q

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

A

BCL11A

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24
Q

Fetal Hb synthesis is higher in this hematologic malignancy

A

Juvenile myelomonocytic leukemia

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25
Q

The vast majority of mutations causing β-thalassemia are ____________

A

Nondeletional

β-Thalassemia is rarely caused by deletions.

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26
Q

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

A

Dominantly Inherited β-Thalassemia

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27
Q

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

A

Amino finger of erythroid-specific GATA-1

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28
Q

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

A

δβ-Thalassemia and HPFH

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29
Q

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.

A

HbLepore

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30
Q

The most common forms of α+-thalassemia

A

Deletion : –α3.7 and –α4.2

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31
Q

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

A

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

(Non-deletion)

32
Q

4 phenotypes of α-Thalassemia

A

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

33
Q

HbH occurs most frequently in :

A

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

34
Q

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

A

Paternal germ cell

ATR-X

35
Q

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

A

ATR-X

35
Q

TRUE OR FALSE

Thalassemias, in general, are syndromes of ineffective erythropoiesis.

A

TRUE

Thalassemias, in general, are syndromes of ineffective erythropoiesis.

36
Q

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

A

β-thalassemia

37
Q

3 major components of ineffective erythropoiesis in β-thalassemia:

A

(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

38
Q

Major cause of anemia in α-thalassemia

A

Hemolysis and poorly hemoglobinized red cells

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

39
Q

γ4-homotetramers

A

HbBart’s

40
Q

β4-homotetramers

A

HbH

41
Q

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

A

Protein 4.1

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

42
Q

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

A

Increased erythroferrone
Reduces hepcidin

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

43
Q

A refined method for assessing iron overload

A

magnetic resonance imaging (MRI)

44
Q

Risks for vascular disease in thalassemia

A

Nontransfused patients with severe ineffective erythropoiesis
Splenectomy

45
Q

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

A

Anionic phospholipids

46
Q

Classification of thalassemia based on genotype:

A

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)

47
Q

The major factor determining the severity of thalassemia

A

Degree of globin-chain imbalance

48
Q

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

A

15 mL/kg

49
Q

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

A

2 U

50
Q

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

A

12–15

51
Q

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

A

10 years of age

52
Q

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

A

2-5 years

53
Q

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

A

Second trimester

54
Q

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

A

HbConstant Spring

55
Q

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 _______________

A

2000 kb or longer

Tuberous sclerosis and polycystic kidney disease

56
Q

2 main classes of “normal HbA2 β-thalassemia”

A

Type 1 is the “silent” form of β- thalassemia

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

57
Q

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

A

β-thalassemia mutation

58
Q

The only currently available curative therapy for thalassemia

A

HSC transplantation

59
Q

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

A

95–105 g/L

hypertransfusion regimen

60
Q

Indications for splenectomy in NTDT

A

Massive splenic enlargement with risk of rupture and pain in the left upper quadrant

Dropping Hb leve

61
Q

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

A

Yersinia class of bacteria

62
Q

A noninvasive estimation of myocardial iron

A

T2* MRI.

63
Q

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

A

1000 mcg/dL

** a serum ferritin of 1000 mcg/dL is not a reasonable starting point.

64
Q

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).

A

15 transfusions

6–8 mg/g dry weight

65
Q

Liver MRIs are recommended _______.

A

Annually

66
Q

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

A

older than 10 years

67
Q

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

A

Deferoxamine (desferrioxamine)

68
Q

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

A

Deferoxamine (desferrioxamine)

69
Q

Long-term side effects of deferoxamine

A

ototoxicity (high-frequency hearing loss and tinnitus)

ocular toxicity (visual failure, night and color blindness, and field loss)

70
Q

An oral, once-daily iron chelator

A

Deferasirox

71
Q

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

A

Deferasirox

72
Q

Toxicities of Deferasirox

A

Nonprogressive elevation of the serum creatinine

Elevation of liver enzymes

73
Q

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

A

Deferiprone

74
Q

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

A

Deferiprone

75
Q

The most concerning side effect of Deferiprone

A

Neutropenia, and occasionally agranulocytosis

76
Q

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

A

Luspatercept

WILLIAM'S HEMATOLOGY (90 decks)

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