14. Thalassemia

Question 1

Thalassemia

Answer 1

• Quantitative disorder
• Inherited disorder caused by gene mutations/deletions that reduce/eliminate the synthesis of one or more globin chains of the hemoglobin tetramer
• Leads to defective hemoglobin production and damage to the RBC
• Named according to the chain that is deficient (ex. alpha thalassemia = deficient in alpha chain)

Question 2

Chromosome 16

Answer 2

• 4 alpha chains

Question 3

Chromosome 11

Answer 3

• 4 Gamma chains
• 2 Delta chains
• 2 Beta chains

Question 4

Geographical Distribution of Thalassemia

Answer 4

• highest frequencies of beta thalassemia occur in the Mediterranean countries (Greece and Italy), the Arabian Peninsula, Turkey, Iran, Africa, India, Southeast Asia, and southern China
• single alpha globin gene deletion(-a/aa): tropical Africa, the Mediterranean region, the Middle East, India, Southeast Asia, and southern China.
• Alpha thalassemia trait in cis presentation (–/aa): ancestry is of Southeast Asian, southern Chinese, or rarely Mediterranean origin.

Question 5

Pathophysiology of Thalassemia

Answer 5

• Imbalance of globin chain synthesis: Lack of hgb — small, hypochromic cells.
• Ineffective erythropoiesis: Excess unpaired hgb chains precipitate in cell causing membrane damage (Cells destroyed in marrow or spleen)

Question 6

Beta- thalassemia minor

Answer 6

Heterozygous (B, B0 or B, B+)

• Mild, asymptomatic, hemolytic anemia
• Hgb: 10 - 13 g/dL
• RBC normal or slightly elevated
• Microcytic, hypochromic
• Mild poikilocytosis, including target cells and elliptocytes, stippled RBCs
• *** Hb A2: 3.5 - 8.0%
• Hb F: 1- 5%

Question 7

Beta- thalassemia major

Answer 7

Homozygous (B0, B0)

• Severe anemia following gamma-to-beta switch
• Diagnosed between 6 months and 2 years
• Bone disfigurations due to extreme erythroid hyperplasia
• Patients are transfusion-dependent causing excessive iron toxicity
• Chelation therapy started as a toddler may prevent cardiac complications and extend the life expectancy to the 4th decade
• Bone marrow transplantation has been approximately 75% successful
• Severely decreased hgb, 3-4 g/dL
• MCV: 50-60 fL
• Marked hypochromia
• Marked poikilocytosis including target cells, teardrop cells, and elliptocytes
• Many nRBC
• Increased reticulocytes unable to compensate for the anemia

Question 8

Beta- thalassemia intermedia

Answer 8

Homozygous B+,B+
or Heterozygous B0, B+

• Lab values are extremely variable
  decrease in beta chains
• Clinical course parallels lab values

Question 9

Kleihauer Betke Fetal Hgb Stain

Answer 9

• Use and elduing solution that washes away all hgb except hgb F
• Hb F is heterogeneously distributed in Beta thalassemia major

Question 10

Hereditary Persistance of Fetal Hgb

Answer 10

• Continued high rate of gamma chain synthesis into adulthood
• Clinically asymptomatic
• Heterozygous form: Hb F - 15-30%
• Homozygous form: Hb F - 100%
• Pancellular Hb F distribution (All cells stain pink in Betke stain)
• HPFH interacts with Hb S or thal
• RBC increased due to increased O2 affinity

Question 11

Hemoglobin Lepore

Answer 11

• Results from a Delta and Beta gene crossover product with a decreased rate of production
• Excess alpha chains precipitate leading to decreased RBC viability

Question 12

Heterozygous Hb Lepore

Answer 12

• Clinically asymptomatic
• Microcytic, hypochromic blood picture
• Hb electrophoresis reveals 10% Hb Lepore, slightly elevated Hb F and normal A2. The remainder is Hb A.

Question 13

Homozygous Hb Lepore

Answer 13

• Variable anemia and clinical course
• Severe anemias may clinically mimic beta-thal major
• Microcytic, hypochomic, anisocytosis, poikilocytosis with target cells and basophilic stippling
• Hb electrophoresis reveals 10-30% Hb Lepore with the remainder Hb F

Question 14

Alpha Thalassemias

Answer 14

• Predominant genetic abnormality is large gene deletions
• Alpha gene loci are duplicated on chromosome 16 and are designated alpha1 and alpha2
• Normal genotype is aa/aa
• Alpha gene deletions result in decreased production of alpha chains
• Causes Tetramers: Hgb Barts = Gamma 4 ; Hgb H = Beta 4

Question 15

Alpha thal - Silent Carrier

Answer 15

• Results for the deletion of one alpha gene
• Genotype: aa/a-
  Alpha chain production = 75%
• No hematologic or clinical abnormalities (normal CBC and blood smear)

Question 16

Alpha thalassemia trait

Answer 16

Results from 2 gene deletions

• Genotype: a -/ a - (Southeast Asia) or aa/- - (african)
• Alpha chain production = 50%
• Mild microcytic, hypochromic anemia
• Newborns may have 5-10% Hb Barts (gamma4)
• Adults demonstrate low normal to low Hb A2

Question 17

Hemoglobin H Disease

Answer 17

• Results from 3 gene deletions
• Genotype = a-/- -
• Alpha chain production = 25%
• Particularly common in SE Asians (because cis config of trait already common)
• Excess beta chains pair to form beta4 tetramers (Hb H) (30 - 50%)
• Newborns have 10 - 40% Hb Barts
• Mild to moderate microcytic, hypochromic anemia
• Marked poikilocytosis, with target cells and irregularly shapes RBCs
• Hb H is unstable and will precipitate to form Heinz bodies
• Hb H Prep: incubation with brilliant cresyl blue (supravital stain) produces fine, evenly distributed RBC inclusions resembling golf balls***

Question 18

Hydrops Fetalis

Answer 18

Results from 4 alpha gene deletions

• Alpha chain production = 0
• Not compatible with life (still born)
• Prenatal diagnosis may be made with DNA testing from chorionic villi or amniotic fluid

Question 19

Hemoglobinopathy - Thalassemia Combos

Answer 19

• Hb S - Beta thal - similar to Hb SS
• Hb S - Alpha thal - similar to Hb AS
• Hb C - Beta thal - similar to Hb CC
• Hb C - Alpha thal - similar to Hb AC

Question 20

Thalassemia vs. Iron Deficiency

Answer 20

Thalassemia Trait:

• Mild erythrocytosis
• Marked microcytosis
• FEP normal (Globin production is effected)
• basophilic stippling***

Iron Deficiency:

• RBC decreased
• Mild to moderate microcytosis
• FEP Increased (because Heme production is effected)

FEP = free erythrocyte protoporphyrin, a by product of Heme production.