Updated: 9/27/2020

Thalassemia Anemia

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Snapshot
  •  A 22-year-old Vietnamese woman presents for a routine gyn exam. Her menstrual cycle is normal, and there is no evidence of other bleeding. Guaiac is negative. Her hemoglobin is at 11 (12-16), RBC is 5.8 (3.5-5.5), and an MCV of 70 (80-100) with a normal RDW of 10. WBC and platelets are normal. Hemoglobin electrophoresis shows an increase in the amount of Hgb A2, and Hgb F.
Introduction

  • Autosomal recessive disease caused by decreased production of hemoglobin
    • may involve mutations in α (α-thalassemia) or β (β-thalassemia) globin gene
  • There are 4 α genes (2 on each chromosome) and 2 β genes that make up three forms of Hgb
    • Hgb A
      • subunits: α,α,β,β
      • 96-98% of adult hemoglobin
    • Hgb A2
      • subunits: α,α,δ,δ
      • present in trace amounts in adults.
    • Hgb F
      • subunits: α,α,γ,γ
      • declines in the first year of life
      • cannot bind 2,3 DPG so has a left-shifted curve
  • α-thalassemia types
    • 1 gene deletion is asymptomatic
    • 2 gene deletion is associated with a mild anemia with RBC hyperplasia
      • called α-thalassemia trait
      • seen in Asians and Africans
        • Asians more commonly have a deletion of two α genes on 1 chromosome (cis deletion)
        • Africans more commonly have a deletion of 1 α gene from each chromosome (trans deletion)
    • 3 gene deletion is associated with severe anemia
    • 4 gene deletion is not compatible with life
      • will cause hydrops fetalis
  • β-thalassemia types
    • 1 gene involvement
      • called β-thalassemia minor 
      • chain may be truncated (β+) or deleted (β0)
      • β/β+ is the most benign form
      • may be caused by mutation in Kozak consensus sequence
    • 2 gene involvement
      • called β-thalassemia major
      • β0/β0 is the most severe form
      • α,α,α,α hemoglobin present
Presentation
  • Symptoms
    • α-thalassemia
      • mild anemia in 2 gene deletion
      • severe anemia in 3 gene deletion
        • symptoms being at birth
    • β-thalassemia 
      • minor form
        • largely asymptomatic 
      • intermedia form
        • hypochromic, microcytic anemia 
      • major form
        • severe anemia
        • symptoms begin after several months of life due to initial presence of HbF
        • chipmunk facies
          • secondary to extramedullary hematopoiesis in the skull
  • Physical exam
    • β-thalassemia
      • major form
        • hepatosplenomegaly due to chronic hemolysis, additionally exacerbated by extramedullary hematopoiesis in these organs
Evaluation
  • Peripheral smear
    • 3 gene deletion α-thalassemia
      • target, hypochromic, microcytic cells, with Heinz bodies from HbH
    • β-thalassemia minor
      • target, hypochromic, microcytic cells
    • β-thalassemia major
      • nucleated RBCs
      • target, hypochromic, microcytic cells
  • Hemoglobin gel-electrophoresis
    • α-thalassemia trait
      • normal
    • 3 gene deletion α-thalassemia
      • HbH (β,β,β,β)
    • 4 gene deletion α-thalassemia
      • Hb Barts (γ,γ,γ,γ)
    • β-thalassemia minor  
      • ↑ HbA2, HbF
      • ↓ HbA
    • β-thalassemia major
      • ↑ HbA2, HbF
      • no HbA
  • Imaging 
    • β-thalassemia major
      • hair-on-end/crew cut appearance of the skull
        • secondary to extramedullary hematopoiesis in the skull
Treatment
  • β-thalassemia major 
    • frequent transfusions required
      • can cause iron overload and hemochromatosis
Prognosis, Prevention, and Complications
  • β-thalassemia major
    • ↑ risk of B19-mediated aplastic crises
  • Thalassemia trait 
    • protects against malaria

 

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(M1.HE.14.131) A 7-year-old boy is brought to his pediatrician for an annual physical. Routine blood work demonstrates hematocrit of 35% and a mean corpuscular volume of 72 fL. Red cell distribution width (RDW) is within normal limits. His peripheral blood smear is shown in Figure A. Electrophoresis demonstrates slightly diminished HbA1, elevated HbA2, and normal HbF. Of the following, which is the most appropriate next step in management?

QID: 104771
FIGURES:
1

Splenectomy

6%

(11/189)

2

Folic acid supplementation

3%

(5/189)

3

Blood transfusion

21%

(40/189)

4

No treatment is necessary

55%

(104/189)

5

Iron supplementation

13%

(24/189)

M 3 D

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(M1.HE.14.48) A 23-year-old Sicilian man presents to his primary care physician complaining of lethargy, joint pain, and urinary frequency. Vitals signs include T 98.7 F, HR 96 bpm, BP 135/71 mm/Hg, RR 18 breaths/minute, O2 99%. Laboratory findings include: random glucose 326 mg/dL, Hemoglobin 7.1, and elevated reticulocyte count and transferrin saturation. The patient is not surprised that his "blood level is low" and suggests that he might need another transfusion. An echocardiogram demonstrates restrictive cardiomyopathy. The disorder with which this patient presents can be characterized by which of the following?

QID: 106320
1

Absence of the hemoglobin alpha-chain

7%

(11/161)

2

Absence of the hemoglobin beta-chain

58%

(93/161)

3

Presence of the fetal hemoglobin

5%

(8/161)

4

Mutation resulting in increased iron absorption

24%

(39/161)

5

Mutations resulting in copper accumulation

4%

(7/161)

M 1 E

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(M1.HE.13.47) A 28-year-old male is found to have 93% HbA, 2% HbF, and 5% HbA2 on hemoglobin electrophoresis. Which of the following is the most likely diagnosis?

QID: 101357
1

Sickle cell trait

8%

(15/193)

2

Alpha thalassemia major with Hb Bart's

8%

(15/193)

3

Beta-thalassemia minor

67%

(130/193)

4

Beta-thalassemia major

12%

(24/193)

5

Diabetes mellitus

2%

(4/193)

M 2 E

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(M1.HE.13.20) The Kozak sequence for the Beta-globin gene has a known mutation which decreases, though does not abolish, translation of the Beta-globin mRNA, leading to a phenotype of thalassemia intermedia. What would the blood smear be expected to show in a patient positive for this mutation?

QID: 100085
1

Macrocytic red blood cells

3%

(6/232)

2

Hyperchromic red blood cells

4%

(9/232)

3

Microcytic red blood cells

78%

(181/232)

4

Bite cells

6%

(14/232)

5

Ringed sideroblasts

8%

(19/232)

M 2 E

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