49 Thalassemia Flashcards
Thalassemia was initially called
Cooley anemia
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
- 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
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
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
The most common β-thalassemia mutation in Southeast Asia
HbE (β26 Glu→Lys)
2 major forms of thalassemia
α-thalassemia and β-thalassemia
Rare: γ-thalassemia, δ-thalassemia, and εγδβ-thalassemia
The clinical severity of thalassemia depends largely on the inherited __________.
Genotype
Result from a large deletion in chromosome 11
Involve the β-LCR
εγδβ-thalassemia
Difference between HPHF heterozygotes vs heterozygotes for δβ-thalassemia
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
TRUE OR FALSE
A deficiency of α-globin chain production affects Hb synthesis in both fetal and adult life
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.
α-globin genes are found in chromosome
Chromosome 16
α-globin and the rest of fetal hemoglbin
β-globin gene cluster on the short arm of chromosome _____.
Chromosome 11
α- thalassemia is most commonly caused by __________
Deletions
α2β2
HbA
α2δ2
HbA2
less than 3.5%
less than 2% of fetal Hb or HbF (heterodimer of α-globin and γ-globin, α2γ2
Red cells are initially made in the _______ of the developing embryo and prior to week _____ of intrauterine life
yolk sac
8 weeks
3 embryonic Hbs
Gower 1 (ξ2ε2)
Gower 2 (α2ε2)
Portland (ξ2 γ2)
Adult counterparts:
ξ-globin
ε-globin
ξ-globin : α-globin and β-globin
ε-globin : γ-globin, and δ-globin chains
α2γ2
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
HbF
At birth, the ratio of molecules containing Gγ-globin chains to those containing Aγ-globin chains is approximately______
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.
Toward the ____________, the marrow becomes active in erythropoiesis
End of the second trimester
Hb switching, occurs between ________of age
6 and 12 months
Postnatally, γ-globin chain production (HbF) is replaced by β-globin chain production (HbA), commonly referred to as Hb switching
The physiologic nadir of infancy—at a Hb level of 90–100 g/L—usually occurs by _______
8 weeks
β-Globin synthesis commences early during fetal life, at approximately_______ of gestation
8–10 weeks
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 _______
F cells
Identified as a key repressor of the γ-globin gene and a critical mediator in the switch from fetal to adult Hb expression
BCL11A
Fetal Hb synthesis is higher in this hematologic malignancy
Juvenile myelomonocytic leukemia
The vast majority of mutations causing β-thalassemia are ____________
Nondeletional
β-Thalassemia is rarely caused by deletions.
This condition often is characterized by the presence of inclusion bodies in the red cell precursors, it has been called inclusion-body β-thalassemia
Dominantly Inherited β-Thalassemia
The causative mutation in X-linked thrombocytopenia and β-thalassemia
Amino finger of erythroid-specific GATA-1
Gene mutations seen on patients with trichothiodystrophy and β-thalassemia trait.
Xeroderma pigmentosa (XPD) protein
These disorders consist of a range of disorders characterized by decreased or absent HbA production and a variable compensatory increase in HbF synthesis
δβ-Thalassemia and HPFH
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.
HbLepore
δβ+-Thalassemia
Rare conditions and result from large deletions of the β-globin gene cluster, which involve the β-LCR.
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
The most common forms of α+-thalassemia
Deletion : –α3.7 and –α4.2
Five mutations that affect termination of translation and give rise to elongated α-globin chains have been identified:
HbConstant Spring, HbIcaria, HbKoya Dora, HbSeal Rock, and HbPakse
(Non-deletion)
4 phenotypes of α-Thalassemia
(a) normal
(b) conditions characterized by mild hematologic changes but no clinical abnormality
(c) HbH disease
(d) HbBart’s hydrops fetalis syndrome
HbH occurs most frequently in :
Usually results from the compound heterozygous state for α0-thalassemia and either deletion or nondeletion α+-thalassemia
Southeast Asia (–SEA–/–α3.7) and the Mediterranean region (usually –MED–/–α3.7)
Usually results from the homozygous state for α0-thalassemia
HbBart’s hydrops fetalis syndrome
Most commonly –SEA–/–SEA– or –MED–/–MED–
α-thalassemia associated with mental retardation suggested the lesions involving the α-globin gene locus were acquired in the ________ germ cell
Paternal germ cell
ATR-X
α-thalassemia results from deficiency of a trans-activating factor involved in regulation of the α-globin genes
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
ATR-X
TRUE OR FALSE
Thalassemias, in general, are syndromes of ineffective erythropoiesis.
TRUE
Thalassemias, in general, are syndromes of ineffective erythropoiesis.
α or β-thalassemia
Ineffective erythropoiesis is markedly greater in ___________ and contributes much more to the manifestations of the disease
β-thalassemia
3 major components of ineffective erythropoiesis in β-thalassemia:
- (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
Major cause of anemia in α-thalassemia
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
γ4-homotetramers
HbBart’s
HbBart’s is more stable than HbH and does not form large inclusions.
β4-homotetramers
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
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 .
- (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
In β-thalassemia, excess α-globin chains result in mechanical instability and oxidative damage primarily to ______________
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.
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
HbE β-thalassemia
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
Increased erythroferrone
Reduces hepcidin
- Leads to increased iron absorption and impaired iron sequestration
- These changes are less common in α-thalassemia
A refined method for assessing iron overload
Magnetic resonance imaging (MRI)
Risks for vascular disease in thalassemia is highest among
- Nontransfused patients with severe ineffective erythropoiesis
- Post-Splenectomy
The procoagulant effect of thalassemia cells results from increased expression of ____________ on the red cell surface
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.
Classification of thalassemia based on genotype:
- 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)
The major factor determining the severity of thalassemia
Degree of globin-chain imbalance
Transfusion volumes are usually approximately _____ mL/kg of packed red cells in children
15 mL/kg
Typically, adults usually receive _____ U of packed red cells each time, with intervals of 2, 3, or 4 weeks, depending on body size
2 U
After approximately _____ transfusions, it is predicted that the liver iron concentration will have more than doubled and iron chelation will be initiated
12–15
Radiologic findings in thalassemia
The diploe widens, with a “hair on end” or “sunray” appearance and a lacy trabeculation of the long bones and phalanges.
If iron chelation is not begun appropriately for transfusional iron overload, iron-induced endocrinopathies can develop, usually after approximately ______years of age
10 years of age
If the anemia is not treated, heart failure may develop, resulting in death, usually within the first ______ years of life.
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.
Hemoglobin Bart’s Hydrops Fetalis Syndrome
Embryos with homozygous α0-thalassemia (a thalassemia major) will begin to have manifestations of anemia in the_______trimester
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
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
HbConstant Spring
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 _______________
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
TRUE OR FALSE
A marrow examination is not required for diagnosis OF Homozygous β0-Thalassemia
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.
2 main classes of “normal HbA2 β-thalassemia”
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
The most clinically important associations of β-thalassemia with β structural Hb variants are:
- HbS/β-thalassemia (sickle–β-thalassemia)
- HbC/β-thalassemia, and
- HbE/β-thalassemia
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.
β-thalassemia mutation
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
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
Incubation of the red cells with brilliant cresyl blue results in multiple ragged inclusion bodies in almost all cells resembling golf balls.
Hemoglobin H Disease
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.
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.
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.
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.
The goals of treatment for the thalassemia syndromes are to:
- (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
The only currently available curative therapy for thalassemia
HSC transplantation
Hgb target range supports near-normal activity, growth and development, and suppression of ineffective erythropoiesis
95–105 g/L
Hypertransfusion regimen
Amount of tratransfusion in children and in adults
- 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.
Indications for splenectomy in NTDT
- Massive splenic enlargement with risk of rupture and pain in the left upper quadrant
- Dropping Hb level
Presentation with abdominal pain, diarrhea, and vomiting should always suggest an infection with a member of the ___________ class of bacteria
Yersinia class of bacteria
A noninvasive estimation of myocardial iron
T2* MRI
Initiate chelation in thalassemia patients when the serum ferritin reached _____ mcg/dL
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.
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).
15 transfusions
6–8 mg/g dry weight
Liver MRIs are recommended _______.
Annually
In children treated with iron chelation, cardiac imaging is usually not performed until the child is older than _______ years
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.
First chelating agent of proven long-term value for treatment of iron overload in thalassemia.
Deferoxamine (desferrioxamine)
Must be given by SQ infusion over 8–12 hours, preferably daily, but at least 5–6 times per week
Deferoxamine (desferrioxamine)
Long-term side effects of deferoxamine
- 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
An oral, once-daily iron chelator
Deferasirox
A first-line drug for the management of transfusional iron overload
Deferasirox
Toxicities of Deferasirox
- Nonprogressive elevation of the serum creatinine
- Elevation of liver enzymes
Oral iron chelator with short half-life, must be taken 3 times a day
Deferiprone
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
Deferiprone
The most concerning side effect of Deferiprone
Neutropenia, and occasionally agranulocytosis
Butyrate analogues and hydroxyurea did not show very positive results, except in homozygotes for _________
HbLepore
Therapies that focus on Augmentation of Fetal Hemoglobin Production by Editing the BCL11A Gene
- (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
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
Luspatercept
Prevention can be achieved in 2 ways:
Genetic counseling and prenatal screening
