Thalassemia: Globin Chain Production

• Thalassemias result from the decreased production of one or more globin chains.
• They are classified by the globin chain affected.

Hemoglobin Composition

• Normal hemoglobins are comprised of 2 alpha family genes and 2 beta family genes.
• Hemoglobin A consists of alpha2beta2 (α2β2).
• Hemoglobin A2 consists of alpha2delta2 (α2δ2).
• Hemoglobin F consists of alpha2gamma2 (α2γ2).
• Gower I consists of zeta2epsilon2 (ζ2ε2).
• Gower II consists of alpha2epsilon2 (α2ε2).
• Portland consists of zeta2gamma2 (ζ2γ2).

Genetic Location

• Genes coding Hgb chains are mapped to chromosomes 16 (alpha family) and 11 (beta family).
• The alpha chain, necessary for all adult hemoglobins including Hgb F, has two genes coding for its production.

Beta Thalassemia

• Beta chain production is affected, impacting Hemoglobin A production.
• Patients may produce increased Hgb A2 or Hgb F to compensate.
• The fundamental problem in Beta-Thal is the uncoupling of alpha and beta chain synthesis.
• Normally, these chains are produced in almost equal quantities.

Effects of Decreased Beta Chains

• Total Hgb is reduced as a result of decreased beta chains.
• The body tries to compensate by making more Hgb A2 and F.
• Free alpha chains accumulate, becoming unstable and denaturing into precipitates rapidly, which leads to RBC destruction in the marrow.

Genetic Designations for Beta Thalassemia

• Beta (β) represents a normal gene, inherited from each parent (β/β).
• Beta 0 (βº) represents an abnormal gene where no beta chains are produced.
• Beta + (β+) represents an abnormal gene allowing some, but still abnormal, production of beta chains.
• Beta ++s (β++s) genes produce >50% beta chains and are associated with a silent carrier state.

Silent Carrier (β++s/β)

• A silent carrier involves an abnormal gene inherited from one parent.
• This heterozygous beta mutation results in a small decrease in beta chain production.
• Alpha/beta chain ratios are normal.
• No hematological abnormalities are present.
• Homozygous silent carriers (β++s / β++s) are described in some patients.
• Manifesting as moderate microcytic hypochromic anemia and increased Hgb F and Hgb A2.

Beta-Thalassemia Minor

• Beta-Thalassemia Minor is Heterozygous (β+/β) or (β0/β).
• The effect is one gene affected, one normal.
• Results in mild to moderate anemia, microcytosis/hypochromia, and anisocytosis.
• It may also lead to the presence of target cells, ovalocytes, basophilic stippling, polychromasia (increased reticulocytes).
• Decreased osmotic fragility.
• Elevated levels of bilirubin may be present, potentially resulting in jaundice.
• Bone marrow analysis reveals erythroid hyperplasia.
• Hemoglobin electrophoresis analysis reveals increased Hgb A2 and Hgb F.
• Serum iron studies are typically normal.

Beta-Thalassemia Major

• Beta-Thalassemia Major is Homozygous (β+/β+) or (β+/β0) or (β0/β0).
• Symptoms are similar to Beta-Thalassemia Minor, but are much more severe.
• Results in increased numbers of nucleated red blood cells (nRBCs).
• Marked bone changes are present due to expanded marrow activity
• Hemolysis occurs due to these free alpha chains.
• Schistocytes may be present.
• Extramedullary hematopoiesis occurs.
• Hemoglobin electrophoresis reveals elevated Hgb A2 and Hgb F.
• Serum iron and ferritin levels are increased.
• Pappenheimer bodies may be observed

Beta-Thalassemia Major Management

• Grave prognosis can occur
• Regular transfusions are often needed to prevent anemia and bone changes.
• This can cause iron overload leading to organ toxicity, which is managed with chelating drugs.
• Bone marrow transplant is a potential treatment.
• Drugs that increase gamma gene activity, promoting Hgb F production.
• Possible gene therapy is a consideration.

Beta-Thalassemia Intermedia

• Falls between minor and major forms in severity.
• The condition may be homozygous for a mutation leading to decreased beta-globin production.
  • Or it may be doubly heterozygous for mild mutations.
• Clinical manifestations can vary from mild to severe.

Delta Beta Thalassemia

• Clinically, similar to beta-Thal Intermedia.
• Neither Hgb A nor Hgb A2 can be produced in normal quantities.
• There is more Hgb F, resulting in a mild microcytic/hypochromic anemia.

Hereditary Persistence of Fetal Hemoglobin (HPFH)

• A rare condition that is closely related to Delta Beta Thal.
• Continued production of high levels of Hgb F occurs in adult life.
• The typical clinical and hematological findings of thalassemia are absent.

Gamma Delta Beta Thalassemia

• A very rare condition that include beta chain defects.
• Only heterozygotes have been described.
• It is assumed that the homozygote state is lethal.

Other Beta Chain Family Defects

• Hemoglobin E: Beta chain defect (hemoglobinopathy) with diminished production.
• Hemoglobin Lepore: Delta Beta chain fusion (hemoglobinopathy) with diminished production.

Alpha Thalassemia

• The alpha chain, necessary for the formation of all adult hemoglobins, is coded by two genes.
• Individuals inherit four of these genes, two from each parent.
• Normal genetic designation is αα/αα.

Silent Carrier of Alpha-Thalassemia

• It is designated as (-α/αα).
• One out of four alpha genes is defective.
• Most patients are asymptomatic.

Alpha-Thalassemia Minor

• It is Heterozygous (- -/αα) or (-α/-α).
• Two out of four genes are defective.
• Results in mild microcytic, hypochromic anemia.
• It is very similar clinically and in appearance to the beta-thal minor.

Hemoglobin H Disease

• Three out of four alpha genes are defective, designated as (--/-α)
• Clinically it is similar to beta-thal major, though tends to be milder.
• Alpha chain production is severely depressed, leaving many free Beta family chains.
• These free Beta family chains can form tetramers among themselves.
• Gamma 4 tetramer (γ4), is known as Hgb Barts, and found only in trace amounts in adults.
• Beta 4 tetramer (β4) is known as Hgb H. Hgb H is unstable and forms Hgb H inclusions

Electrophoresis Results

• Both Hgb Barts and Hgb H show up on Hgb Electrophoresis.

Hydrops Fetalis

• All four alpha genes are defective (--/--).
• This condition is incompatible with life.
• The child is born with Hydrops Fetalis.
• There is a very high level of Hgb Barts (γ4).
• Hgb Barts has an extremely high affinity for O2 and will not release it to the fetal tissues.
• Fetal death results from tissue hypoxia.
• The baby is prematurely stillborn or dies shortly after birth.

Alpha Thal Treatment

• Treatment may include regular blood transfusions and iron chelation therapy.
• Surgical removal of the spleen may be needed.
• Patients require daily Folic acid
• Patients should pursue avoidance of certain oxidant drugs in Hgb H disease
• Bone marrow (Stem Cell) transplant has had some success.
• Trials are ongoing for intrauterine stem cell transplant and Gene Therapy.

Hemoglobin Constant Spring

• Involves an alpha chain defect (hemoglobinopathy) with diminished production (thalassemia).

Thalassemia Inheritance

• Thalassemia can be inherited in combination with a Hemoglobinopathy.

Laboratory Findings in Thalassemias

• Decreased osmotic fragility.
• Supravital stain can detect Heinz bodies.
• Hemoglobin Electrophoresis is critical in the diagnosis of beta-Thal.
• Decreased Hgb A and increased Hgb A2 and/or Hgb F can show.
• More difficult to detect an alpha-Thal because all normal Hgbs will be decreased in proportion to each other.
• Abnormal Hgbs such as Hgb H and Hgb Barts can be detected.