Hematology 425 Thalassemias

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Hematology 425 Thalassemias

• Russ Morrison
• November 17, 2006

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Thalassemias

• Thalassemias are a diverse group of inherited
  disorders caused by gene mutations
• These gene mutations reduce or completely
  eliminate the synthesis of one or more of the
  globin chains of the Hgb tetramer
• The homozygous state for the abnormal autosomal
  gene for beta-globin chain synthesis (Cooleys
  anemia) has become known as thalassemia major

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Thalassemias

• The heterozygous state for the abnormal gene for
  beta-globin chain synthesis is called thalassemia
  minor
• The heterozygous, milder forms of thalassemia are
  the most frequent genetic defect in humans
• The homozygous, more sever forms are capable of
  causing significant morbidity and mortality

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Thalassemias

• Thalassemia is a group of disorders defined as a
  condition in which a reduction in the rate of
  production of one or more of the globin chains
  leads to
• Imbalanced globin chain production
• Defective Hgb production
• Damage to the RBCs or their precursors by the
  buildup of the globin chain that is produced in
  excess

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Thalassemias

• Usually it is the synthesis of either the alpha
  or beta chains of hemoglobin A (HbA a2ß2) that
  is impaired
• Thalassemias are named according to the chain
  with reduced or absent globin synthesis

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Thalassemias Genetic Control of Hgb Synthesis

• The normal Hgb molecule is a tetramer (double
  dimer) of two alpha-like chains (either a or ?)
  with two beta-like chains (either ß, ?, d or e)
• Combinations of these chains produce six normal
  hemoglobins
• Three of the normal Hgbs are embryonic
• Gower-1 (?2e2)
• Gower-2 (a2e2)
• Portland (?2?2)

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Thalassemias Genetic Control of Hgb Synthesis

• The other three normal Hgbs are
• Fetal (a2?2)
• A (a2 ß2)
• A2 (a2 d 2)
• By the 10th week of gestation, zeta and epsilon
  chain production ceases and gamma chain synthesis
  begins
• The gamma chains combine with alpha chains to
  make HbF, which predominates during fetal life

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Thalassemias Genetic Control of Hgb Synthesis

• After birth, gamma chain production decreases and
  beta chains are the predominant chains produced
• The transition from gamma chain to beta chain
  globin production is called the gamma-to-beta
  switch
• HbA is 95-97 of normal adult Hgb, HbA2 is 2-3
  and HbF is 2

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Thalassemias Genetic Control of Hgb Synthesis

• The alpha and zeta genes are located on the short
  arm of chromosome 16
• The cluster of beta-like genes is distributed on
  the short arm of chromosome 11
• The alpha gene loci are duplicated on each
  chromosome 16 and named a1 and a2
• With this duplication of alpha genes a normal
  genotype would be aa/aa

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Thalassemias Genetic Control of Hgb Synthesis

• An individual inherits one each of the five
  functional genes (ß, G?, A?, d or e) on both
  chromosomes 11
• The genotype for normal beta chain synthesis
  would be designated as ß/ß

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Categories of Thalassemia

• Thalassemias are divided into ß thalassemias,
  which include all of the disorders of reduced
  globin chains affecting the cluster of genes on
  C11 and
• a thalassemias, which involve the a1 and a2
  loci on C16
• The ß-thalassemias affect mainly the beta chain
  production, but may also involve delta, gamma
  (both types) and epsilon chains

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Categories of Thalassemia

• Included in the ß-thalassemia group is ß0-
  thalassemia, in which no beta chains are produced
  from the beta gene locus on one C11
• Additional designations for the main group of
  thalassemias are included in table 25-2 of the
  text

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Thalassemia Geographic Distribution

• Thalassemias are found world-wide, but some
  geographic regions demonstrate higher
  concentrations
• Beta-thalassemia is more common in Mediterranean
  regions (southern Italy and Greece) while
  alpha-thalassemia is more common in Thailand,
  China, the Philippines and other Asian countries

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Thalassemia Geographic Distribution

• It has been suggested that the frequency of
  thalassemia may be associated with selective
  advantage of protection from malaria
• It is theorized that malarial parasites can not
  acquire sufficient nutrients from digestion of
  Hgb in thalassemic cells
• Alpha- and beta-thalassemic RBCs may bind greater
  levels of anti-malarial antibodies than other
  cells leading to greater removal of parasitized
  RBCs

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Thalassemia-Pathophysiology

• Pathophysiology of the thalassemias is due to the
  imbalance of globin chain synthesis
• In B-thalassemia, imbalanced production of globin
  chains results in a lack of hemoglobin produced
  in the erythroid precursors
• This, in turn, results in hypochromic, microcytic
  RBCs
• It also results in excess unpaired globin chains,
  which precipitate in the developing RBCs, causing
  surface membrane damage in both developing and
  mature cells

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Thalassemia-Pathophysiology

• This causes ineffective erythropoiesis (cells
  being destroyed in the marrow) or premature
  hemolysis of peripheral RBCs through removal by
  macrophages
• Persons are asymptomatic during fetal life and up
  to 4-6 months of age because they are protected
  by HbF (a2?2)
• They begin to demonstrate symptoms after the
  gamma-to-beta switch

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Thalassemia-Pathophysiology

• In a-thalassemia, non-alpha-chain production has
  different consequences
• Because alpha chains are shared by both fetal and
  adult hemoglobins, all stages of life (fetus
  through adult) are impacted
• In the fetus there is excess gamma-chain
  production, which produces ?4 tetramers
• These tetramers do not precipitate in the BM, but
  do precipitate in the PB

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Thalassemia-Pathophysiology

• In the PB, the precipitates form RBC inclusion
  bodies followed by removal of the cells from the
  circulation by the spleen
• A hemolytic process develops with RBCs that are
  microcytic and hypochromic due to decreased
  hemoglobin synthesis and incorporation into the
  RBCs

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Thalassemia-Genetic Defects

• Research has shown that there are many different
  types of defects at the molecular level that lead
  to thalassemia
• Genetic defects that cause a decrease or lack of
  production of a particular globin chain are
• Single nucleotide (or point) mutation that
  interferes with one of the critical steps in
  messenger mRNA production, causing the amount of
  mRNA to be decreased

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Thalassemia-Genetic Defects

• Base substitutions that alter promoter function
  RNA processing, or mRNA translation or modify a
  codon into a nonsense codon that leads to
  premature termination of translation or to the
  substitution of an incorrect amino acid
• Insertion or deletion mutations within the coding
  region of the mRNA creating frameshifts that
  prevent the synthesis of a complete, normal
  globin polypeptide

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Thalassemia-Genetic Defects

• large deletion within the alpha- or beta-globin
  clusters that removes one or more genes or alters
  the regulation of the remaining genes in the
  cluster
• All of these varied genetic defects or mutations
  cause a decrease in or lack of synthesis of one
  globin chain, resulting in a thalassemia syndrome

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Clinical Syndromes of ß-Thalassemia

• ß-thalassemia is divided into three clinical
  syndromes
• ?-thalassemia minor (heterozygous), a mild
  microcytic, hyochromic hemolytic anemia
• ?-thalassemia major (homozygous), a severe
  transfusion-dependent anemia
• ?-thalassemia intermedia, with symptoms of
  severity between the first two

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Clinical Syndromes of ß-Thalassemia

• A fourth syndrome designated as a silent carrier
  has also been described
• Many of the mutations cause the beta gene to not
  be expressed at all (ß0 gene)
• Others cause a variable decrease in production of
  beta chain (ß gene)
• ß genes produce from 10 to 50 of normal
  beta-chain synthesis

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Clinical Syndromes of ß-Thalassemia

• The silent carrier state results in almost
  normal beta-chain production and was recognized
  through family studies
• If a patient is homozygous for this carrier
  state, serious hemolytic anemia will develop
• Other thalassemias may be caused by alterations
  of the beta cluster genes

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Thalassemia Major
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Thalassemia Minor
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ß-Thalassemia - Prognosis

• Individuals with thalassemia minor (thalassemia
  trait) usually have asymptomatic mild anemia.
  This state does not result in mortality or
  significant morbidity.
• The prognosis of patients with thalassemia major
  is highly dependent on the patient's adherence to
  long-term treatment programs, namely the
  hypertransfusion program and life-long iron
  chelation. Allogeneic bone marrow transplantation
  may be curative.

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a-Thalassemias

• In contrast to the beta-globin cluster, in which
  point mutations are the most common cause of
  thalassemia, large deletions in the alpha-globin
  genes are the predominant cause of a-thalassemia
• The degree of decreased production of the alpha
  chain depends on
• The specific mutation
• The number of alpha genes affected
• Whether an a2 or a1 gene is affected

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a-Thalassemias

• The a2 gene is thought to produce approximately
  75 of the alpha-globin chains in normal RBCs
• Notation for the normal alpha gene haplotype is
  aa, signifying there are two normal genes (a2 and
  a1) on one C16
• The normal genotype is aa/aa

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a-Thalassemias

• a-thalassemias may also be divided into
  a-thalassemia which have decreased production
  from the alpha-chain complex and a0-thalassemia
  in which no alpha-globin is produced
• The most common deletions generate one chromosome
  bearing a single alpha gene and another with two
  alpha-globin genes

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a-Thalassemias

• Clinical syndromes of a-thalassemia are listed in
  table 25-5 of the text
• Homozygous a-thalassemia (--/--) is incompatible
  with life and results in the absence of all alpha
  chain synthesis
• The infant is born with hydrops fetalis, which is
  edema caused by accumulation of serous fluid in
  the fetal tissues as a result of severe anemia
• Infants with this genotype deliver prematurely
  and are stillborn or die shortly after birth

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Thalassemias

• As discussed in chapter 24, a variant hemoglobin
  may be inherited along with a thalassemia, as
  seen in HbC-thalassemia
• Diagnosis of thalassemia is made from the RBC
  morphology, Hgb electrophoresis, Heinz body test
  and HbA2 and HbF quantitation
• Thalassemia must be differentiated from other
  microcytic, hypochromic anemias, especially iron
  deficiency anemia and iron studies are an
  important part of this differentiation