Updated: 8/11/2018

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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Questions (7)
Lab Values
Blood, Plasma, Serum Reference Range
ALT 8-20 U/L
Amylase, serum 25-125 U/L
AST 8-20 U/L
Bilirubin, serum (adult) Total // Direct 0.1-1.0 mg/dL // 0.0-0.3 mg/dL
Calcium, serum (Ca2+) 8.4-10.2 mg/dL
Cholesterol, serum Rec: < 200 mg/dL
Cortisol, serum 0800 h: 5-23 μg/dL //1600 h:
3-15 μg/dL
2000 h: ≤ 50% of 0800 h
Creatine kinase, serum Male: 25-90 U/L
Female: 10-70 U/L
Creatinine, serum 0.6-1.2 mg/dL
Electrolytes, serum  
Sodium (Na+) 136-145 mEq/L
Chloride (Cl-) 95-105 mEq/L
Potassium (K+) 3.5-5.0 mEq/L
Bicarbonate (HCO3-) 22-28 mEq/L
Magnesium (Mg2+) 1.5-2.0 mEq/L
Estriol, total, serum (in pregnancy)  
24-28 wks // 32-36 wks 30-170 ng/mL // 60-280 ng/mL
28-32 wk // 36-40 wks 40-220 ng/mL // 80-350 ng/mL
Ferritin, serum Male: 15-200 ng/mL
Female: 12-150 ng/mL
Follicle-stimulating hormone, serum/plasma Male: 4-25 mIU/mL
Female: premenopause: 4-30 mIU/mL
midcycle peak: 10-90 mIU/mL
postmenopause: 40-250
pH 7.35-7.45
PCO2 33-45 mmHg
PO2 75-105 mmHg
Glucose, serum Fasting: 70-110 mg/dL
2-h postprandial:<120 mg/dL
Growth hormone - arginine stimulation Fasting: <5 ng/mL
Provocative stimuli: > 7ng/mL
Immunoglobulins, serum  
IgA 76-390 mg/dL
IgE 0-380 IU/mL
IgG 650-1500 mg/dL
IgM 40-345 mg/dL
Iron 50-170 μg/dL
Lactate dehydrogenase, serum 45-90 U/L
Luteinizing hormone, serum/plasma Male: 6-23 mIU/mL
Female: follicular phase: 5-30 mIU/mL
midcycle: 75-150 mIU/mL
postmenopause 30-200 mIU/mL
Osmolality, serum 275-295 mOsmol/kd H2O
Parathyroid hormone, serume, N-terminal 230-630 pg/mL
Phosphatase (alkaline), serum (p-NPP at 30° C) 20-70 U/L
Phosphorus (inorganic), serum 3.0-4.5 mg/dL
Prolactin, serum (hPRL) < 20 ng/mL
Proteins, serum  
Total (recumbent) 6.0-7.8 g/dL
Albumin 3.5-5.5 g/dL
Globulin 2.3-3.5 g/dL
Thyroid-stimulating hormone, serum or plasma .5-5.0 μU/mL
Thyroidal iodine (123I) uptake 8%-30% of administered dose/24h
Thyroxine (T4), serum 5-12 μg/dL
Triglycerides, serum 35-160 mg/dL
Triiodothyronine (T3), serum (RIA) 115-190 ng/dL
Triiodothyronine (T3) resin uptake 25%-35%
Urea nitrogen, serum 7-18 mg/dL
Uric acid, serum 3.0-8.2 mg/dL
Hematologic Reference Range
Bleeding time 2-7 minutes
Erythrocyte count Male: 4.3-5.9 million/mm3
Female: 3.5-5.5 million mm3
Erythrocyte sedimentation rate (Westergren) Male: 0-15 mm/h
Female: 0-20 mm/h
Hematocrit Male: 41%-53%
Female: 36%-46%
Hemoglobin A1c ≤ 6 %
Hemoglobin, blood Male: 13.5-17.5 g/dL
Female: 12.0-16.0 g/dL
Hemoglobin, plasma 1-4 mg/dL
Leukocyte count and differential  
Leukocyte count 4,500-11,000/mm3
Segmented neutrophils 54%-62%
Bands 3%-5%
Eosinophils 1%-3%
Basophils 0%-0.75%
Lymphocytes 25%-33%
Monocytes 3%-7%
Mean corpuscular hemoglobin 25.4-34.6 pg/cell
Mean corpuscular hemoglobin concentration 31%-36% Hb/cell
Mean corpuscular volume 80-100 μm3
Partial thromboplastin time (activated) 25-40 seconds
Platelet count 150,000-400,000/mm3
Prothrombin time 11-15 seconds
Reticulocyte count 0.5%-1.5% of red cells
Thrombin time < 2 seconds deviation from control
Volume  
Plasma Male: 25-43 mL/kg
Female: 28-45 mL/kg
Red cell Male: 20-36 mL/kg
Female: 19-31 mL/kg
Cerebrospinal Fluid Reference Range
Cell count 0-5/mm3
Chloride 118-132 mEq/L
Gamma globulin 3%-12% total proteins
Glucose 40-70 mg/dL
Pressure 70-180 mm H2O
Proteins, total < 40 mg/dL
Sweat Reference Range
Chloride 0-35 mmol/L
Urine  
Calcium 100-300 mg/24 h
Chloride Varies with intake
Creatinine clearance Male: 97-137 mL/min
Female: 88-128 mL/min
Estriol, total (in pregnancy)  
30 wks 6-18 mg/24 h
35 wks 9-28 mg/24 h
40 wks 13-42 mg/24 h
17-Hydroxycorticosteroids Male: 3.0-10.0 mg/24 h
Female: 2.0-8.0 mg/24 h
17-Ketosteroids, total Male: 8-20 mg/24 h
Female: 6-15 mg/24 h
Osmolality 50-1400 mOsmol/kg H2O
Oxalate 8-40 μg/mL
Potassium Varies with diet
Proteins, total < 150 mg/24 h
Sodium Varies with diet
Uric acid Varies with diet
Body Mass Index (BMI) Adult: 19-25 kg/m2
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(M1.HE.48) A 23-year-old Sicilian male 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, 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? Review Topic

QID: 106320
1

Absence of the hemoglobin alpha-chain

5%

(6/117)

2

Absence of the hemoglobin beta-chain

64%

(75/117)

3

Presence of the fetal hemoglobin

4%

(5/117)

4

Mutation resulting in increased iron absorption

20%

(23/117)

5

Mutations resulting in copper accumulation

5%

(6/117)

M1

Select Answer to see Preferred Response

PREFERRED RESPONSE 2

(M1.HE.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? Review Topic

QID: 100085
1

Macrocytic red blood cells

3%

(6/181)

2

Hyperchromic red blood cells

4%

(7/181)

3

Microcytic red blood cells

76%

(138/181)

4

Bite cells

7%

(13/181)

5

Ringed sideroblasts

8%

(15/181)

M1

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PREFERRED RESPONSE 3

(M1.HE.131) A 7-year-old male 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 and normal HbF. Of the following, which is the most appropriate next step in management? Review Topic

QID: 104771
FIGURES:
1

Splenectomy

7%

(11/147)

2

Folic acid supplementation

3%

(5/147)

3

Blood transfusion

20%

(29/147)

4

No treatment is necessary

55%

(81/147)

5

Iron supplementation

12%

(18/147)

M1

Select Answer to see Preferred Response

PREFERRED RESPONSE 4

(M1.HE.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? Review Topic

QID: 101357
1

Sickle cell trait

8%

(12/154)

2

Alpha thalassemia major with Hb Bart's

8%

(13/154)

3

Beta-thalassemia minor

64%

(98/154)

4

Beta-thalassemia major

14%

(22/154)

5

Diabetes mellitus

3%

(4/154)

M1

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PREFERRED RESPONSE 3
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