Updated: 1/25/2019

Sickle Cell Anemia

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Snapshot
  • A radiograph of a 25-year-old patient of West Indian origin shows bilateral hip deformities with increased density of the bone. Her hemoglobin electrophoresis reveals predominantly Hgb S, slightly increased Hgb F, and no Hgb A.
Introduction

  • An autosomal recessive disorder due to a mutation in hemoglobin β-chain
    • Glu to Val at position 6  
  • Hgb S tetramers polymerize causing sickling of deoxygenated RBCs
    • requires > 90% HbS to sickle in systemic vasculature
      • exception is in the renal papilla where oxygen tension is low enough to induce sickling
  • Homozygotes have systemic / hematologic disease
  • Heterozygotes are usually asymptomatic and have some resistance to malaria, painless hematuria with the correct family history is a sign of the diagnosis. 
  • Blacks are most commonly affected
  • Acute vaso-occlusive sickling episodes are often precipitated by 
    • infection
    • acidosis
    • hypoxia
    • dehydration
  • HbF is protective for first several months of life
Presentation
  • Presents with sickle cell vaso-occlusive crises
    • chest pain
    • bone pain
    • fever
    • stroke
    • priapism
    • abdominal pain
      • autosplenectomy 
      • gallstones
    • dactylitis 
      • painful swelling of the hands and feet
      • up to 50% of children under three will develop
  • Physical exam
    • splenomegaly
    • jaundice
    • pallor
    • bone / joint tenderness
Evaluation
  • Labs
    • normocytic or microcytic anemia
    • ↑ reticulocyte count
      • low in aplastic crises
    • ↓ haptoglobin
  • Histology
    • peripheral blood smear shows sickling, Howell-Jolly bodies
      • no sickling seen in sickle cell trait
    • bone marrow smear is hypercellular
  • Imaging
    • check CXR for chest syndrome
    • hair-on-end/crew cut skull XR
      • due to expansion of marrow as a result of extramedullary hematopoiesis
  • Hemoglobin electrophoresis 
    • sickle cell disease
      • HbS, ↑ HbF, no HbA
    • sickle cell trait
      • HbS, ↓ HbA
  • Metabisulfite screen
    • induces sickling at any HbS concentration
    • positive in sickle cell trait and sickle cell anemia
Treatment
  • Treat acute attacks with
    • hydration
    • oxygen
    • analgesia
  • Medical
    • hydroxyurea 
      • decreases frequency and severity of crises by increasing HbF production
    • gardos channel blockers
      • decreases potassium efflux and therefore RBC dehydration by inhibiting calcium-activated potassium channels (Gardos channels)
    • pneumococcal vaccine 
      • to prevent pneumococcal sepsis
      • be alert for infection by encapsulated organisms due to functional asplenia
Prognosis, Prevention, and Complications
  • Infection
    • Salmonella paratyphi osteomyelitis
    • encapsulated organisms due to functional asplenia 
    • aplastic anemia/crisis with parvovirus B19 infection
      • will have low reticulocyte count
  • Splenic sequestration
    • acute painful enlargement of spleen due to trapping of red blood cells
    • can cause symptoms of hypovolemia if prolonged
  • Acute chest syndrome
    • vaso-occlusion of pulmonary vasculature
    • most common cause of death in SC patients
  • Avascular necrosis of the femoral head
  • MI
  • Gallbladder disease
    • ↑ RBC turnover results in increased bilirubin in the bile
    • favorable environment for stone formation
  • Renal papillary necrosis
  • Retinopathy
 

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Questions (10)
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.4666) A 24-year-old African American male with sickle cell disease has been followed by a hematologist since infancy. Two years ago, he was started on hydroxyurea for frequent pain crises but has not achieved good control. The addition of a Gardos channel blocking agent is being considered. What is the mechanism of action of this class of medications? Review Topic

QID: 107109
1

Prevents RBC dehydration by inhibiting K+ efflux

48%

(11/23)

2

Increases production of hemoglobin F

17%

(4/23)

3

Prevents dehydration of RBCs by inhibiting Ca2+ efflux

4%

(1/23)

4

Encourages alkalinization of the blood by facilitating H+/K+ antiporter activity

17%

(4/23)

5

Increases water diffusion by increasing activity of aquaporin-1 receptors

0%

(0/23)

M1

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PREFERRED RESPONSE 1
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(M1.HE.74) A 5-year-old African American boy presents with extreme abdominal pain. He has a history of several such episodes, as well as acute episodes of extreme bone pain. He has previously presented with the findings illustrated in Figure A. A peripheral blood smear is obtained, and is shown in Figure B. What is the most likely mechanism responsible for this patient's disorder? Review Topic

QID: 106635
FIGURES:
1

Tri-nucleotide repeat amplification

3%

(4/140)

2

Mutation in the gene coding for hemoglobin-alpha

4%

(5/140)

3

Point mutation at the 6th position of the ß-hemoglobin chain

86%

(120/140)

4

Increased levels of hemoglobin-F

2%

(3/140)

5

Reduced levels of folic acid

3%

(4/140)

M1

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PREFERRED RESPONSE 3

(M1.HE.74) A 4-year-old African American boy presents with extreme abdominal pain. He has had similar episodes in the past. A peripheral smear is obtained, and shows the findings illustrated in Figure A. Which of the following is a mechanism which can precipitate this condition? Review Topic

QID: 106614
FIGURES:
1

Elevated cellular pH

17%

(13/78)

2

Elevated 2,3-diphosphoglycerate

62%

(48/78)

3

Elevated arterial oxygen concentration

4%

(3/78)

4

Elevated hemoglobin F levels

8%

(6/78)

5

Travel from high to low elevation geographical area

9%

(7/78)

M1

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PREFERRED RESPONSE 2

(M1.HE.52) A 17-year-old African-American male presents to his family physician after noticing red-tinged urine the week before, when he was suffering from a cold. The patient states that he had experienced that before. His father is with him and says that this happens to him on occasion as well. What is the most likely diagnosis for this patient? Review Topic

QID: 104499
1

Acute cystitis

0%

(0/24)

2

Acute interstitial nephritis

0%

(0/24)

3

Sickle cell trait

54%

(13/24)

4

Acute glomerulonephritis

17%

(4/24)

5

Hemophilia

25%

(6/24)

M1

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PREFERRED RESPONSE 3

(M1.HE.11) Patients with the diagnosis of sickle cell anemia make a specific type of hemoglobin known as HgbS. This mutation results in the sickling of their red blood cells when exposed to inciting factors such as hypoxic conditions. Patients are often treated with hydroxyurea, which has which of the following direct effects on their hemoglobin physiology? Review Topic

QID: 104651
1

Increases oxygen carrying capacity of hemoglobin

9%

(9/103)

2

Decreases oxygen carrying capacity of hemoglobin

4%

(4/103)

3

Increases levels of fetal hemoglobin (HgbF)

83%

(85/103)

4

Decreases levels of HgbS

2%

(2/103)

5

Decreases levels of fetal hemoglobin (HgbF)

2%

(2/103)

M1

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(M1.HE.33) A 7-year-old girl with a history of painful crises and impaired growth presents for evaluation of sickle cell disease. You perform hemoglobin gel electrophoresis, and diagnose her with homozygous sickle cell disease. Which of the gel electrophoresis lanes in the image is hers? Review Topic

QID: 100098
FIGURES:
1

Lane 2

3%

(4/147)

2

Lane 3

2%

(3/147)

3

Lane 4

83%

(122/147)

4

Lane 6

5%

(8/147)

5

Lane 7

5%

(7/147)

M1

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(M1.HE.86) An 8-year-old boy complains of extremity pain and difficulty "catching his breath" while running on the playground. His mother also reports that he complains of intermittent abdominal pain. Physical examination reveals splenomegaly. The patient's blood smear is shown in Figure A. What is the most likely mutation present? Review Topic

QID: 100151
FIGURES:
1

Deleted tryptophan

1%

(2/148)

2

Deleted glycine

1%

(1/148)

3

Glutamic acid to valine

69%

(102/148)

4

Glutamine to valine

24%

(35/148)

5

Inserted lysine

1%

(2/148)

M1

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PREFERRED RESPONSE 3
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