Updated: 7/21/2020

Sickle Cell Anemia

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Snapshot
  • A 4-year-old African American boy presents to the emergency room for sudden onset severe abdominal pain. He has a history of sickle cell anemia. On physical exam, he is pale, and he has a left upper quadrant palpable mass. Complete blood count is significant for hemoglobin of 7.3 g/dL. Serum unconjugated bilirubin and reticulocyte count are elevated. (Acute splenic sequestration)
Introduction

  • Overview
    • sickle cell anemia is an autosomal recessive disease that results in abnormal hemoglobin characterized by hemoglobin S (HbS), resulting in hemolytic anemia and vaso-occlusion 
    • sickle cell disease is an overarching term including sickle cell anemia, as well as patients with a sickle mutation (HbS) and a different mutation in the ß-globin gene (e.g., ß-thalassemia or hemoglobin C disease)
      • homozygosity (HbSS)
        • sickle cell anemia
      • heterozygotes (HbSA)
        • sickle cell trait, usually asymptomatic and may confer some resistance to malaria 
        • may have painless hematuria as a result of renal papillary necrosis
      • hemoglobin SC disease (HbSC)
        • HbS and HbC
          • hemoglobin C disease (HbC)
            • point mutation in ß-globin gene where glutamic acid is replaced with lysine
  • Epidemiology
    • demographics
      • blacks are most commonly affected
    • risk factors
      • family history
  • Pathogenesis
    • pathophysiology
      • recall that hemoglobin (Hb) is a soluble tetramer composed of 2 α-globins and 2 ß-globins
      • HbS results from point mutation of ß-globin gene that substitutes valine for glutamic acid
        • due to hydrophobic interactions from valine, hemoglobin can polymerize in red blood cells 
        • this makes the hemoglobin tetramer poorly soluble and results in distortion of red blood cells (RBCs) into a sickle shape
        • this form causes vaso-occlusion
      • clinical severity is determined by presence of other Hb mutations
      • elevated 2,3-diphosphoglycerate
      • sickled RBCs undergoes hemolysis every 17 days (1/7th that of normal RBC lifespan)
        • hemolysis generates reactive oxygen species
  • Genetics
    • inheritance pattern
      • autosomal recessive
    • mutations
      • chromosome 11
      • ß-globin gene
  • Prognosis
    • overall survival is reduced
    • prognosis is better with comprehensive care and clinical monitoring
Presentation
  • Clinical presentation 
    • acute events
      • anemia
      • vaso-occlusive events 
        • acute painful episodes
          • previously called “sickle cell crises”
          • may occur on top of chronic pain
          • triggers include cold temperature, stress, alcohol, and menses
          • dactylitis 
            • acute pain in hands and feet particularly common in children
        • acute chest syndrome
        • cerebrovascular accidents 
        • myocardial infarction
        • priapism
        • renal infarction
        • splenic infarction 
          • by 2-4 years of age, patients have functional asplenia
        • venous thromboembolism
    • chronic events
      • pain
      • hemolytic anemia 
        • contributing factors include low erythropoietin concentration (can be due to renal disease) and folate deficiency
      • neurologic deficits
      • stunted growth and development
      • renal disease
        • painless hematuria due to papillary infarcts
        • medication toxicities
        • urinary concentrating defect
  • Physical exam
    • splenomegaly
    • jaundice
    • pallor
    • bone/joint tenderness
Imaging
  • Radiographs 
    • indications
      • acute chest syndrome
    • findings 
      • new pulmonary infiltrate of one or more lung segments
Studies
  • Prenatal testing currently not routinely used
  • Newborn screening
    • methodology varies by state but can be detected via high performance liquid chromatography (preferred), tandem mass spectrometry, DNA testing, or isoelectric focusing (gel electrophoresis)
  • Serum labs
    • decreased hemoglobin and hematocrit
    • increased reticulocyte count
    • mildly elevated fetal hemoglobin (HbF)
    • normocytic anemia
  • Peripheral blood smear
    • Howell-Jolly bodies
      • nuclear remnants of RBCs that have not been phagocytosed due to functional asplenia
    • sickled cells
Differential
  • ß-thalassemia
    • key distinguishing factors
      • microcytic anemia
      • no sickle cells on peripheral blood smear
Treatment
  • Lifestyle
    • prophylactic treatments 
      • modalities 
        • daily folic acid 
        • penicillin until 5 years of age 
        • pneumococcal vaccine 
          • prevents pneumococcal sepsis
  • Medical
    • supportive care 
      • indications 
        • acute attacks 
      • modalities 
        • hydration
        • oxygen
        • analgesia 
    • exchange transfusion 
      • indications
        • acute vaso-occlusive events 
    • hydroxyurea
      • indications
        • decreases frequency and severity of attacks 
        • increases production of fetal hemoglobin, which has a higher affinity for oxygen
        • may consider addition of Gardos channel blocking agent
          • prevents RBC dehydration by inhibiting K+ efflux
  • Surgical
    • hematopoietic cell transplantation
      • indications the only curative treatment
Complications
  • Functional asplenia by an early age 
    • at increased risk for encapsulated bacterial infection (e.g., Streptococcus and Salmonella)
    • may result in splenic sequestration of RBCs and extravascular hemolysis
  • Aplastic crisis associated with parvovirus B19 infection or splenic sequestration crisis
    • low reticulocyte count 
    • supplement with daily folic acid
  • Chronic lung disease and pulmonary hypertention
    • secondary to acute chest syndrome
  • Renal disease 
    • can present as inability to concentrate urine, resulting in frequent urination
  • Retinopathy
    • secondary to retinal artery occlusion
  • Cardiomyopathy
    • left-sided diastolic dysfunction with or without pulmonary hypertension
    • due to pulmonary hypertension, chronic anemia and hypoxemia with increased cardiac output, transfusion overload, and hypertension
  • Cholelithiasis
    • secondary to chronic hemolysis
 

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(M1.HE.15.4666) 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? Tested Concept

QID: 107109
1

Prevents RBC dehydration by inhibiting K+ efflux

40%

(17/42)

2

Increases production of hemoglobin F

17%

(7/42)

3

Prevents dehydration of RBCs by inhibiting Ca2+ efflux

14%

(6/42)

4

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

19%

(8/42)

5

Increases water diffusion by increasing activity of aquaporin-1 receptors

0%

(0/42)

M 3 D

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(M1.HE.15.74) 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? Tested Concept

QID: 106635
FIGURES:
1

Tri-nucleotide repeat amplification

3%

(5/195)

2

Mutation in the gene coding for hemoglobin-alpha

5%

(9/195)

3

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

86%

(168/195)

4

Increased levels of hemoglobin-F

2%

(4/195)

5

Reduced levels of folic acid

2%

(4/195)

M 1 B

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(M1.HE.15.74) 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? Tested Concept

QID: 106614
FIGURES:
1

Elevated cellular pH

15%

(14/96)

2

Elevated 2,3-diphosphoglycerate

64%

(61/96)

3

Elevated arterial oxygen concentration

4%

(4/96)

4

Elevated hemoglobin F levels

7%

(7/96)

5

Travel from high to low elevation geographical area

9%

(9/96)

M 1 D

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(M1.HE.14.52) 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? Tested Concept

QID: 104499
1

Acute cystitis

0%

(0/48)

2

Acute interstitial nephritis

2%

(1/48)

3

Sickle cell trait

69%

(33/48)

4

Acute glomerulonephritis

12%

(6/48)

5

Hemophilia

15%

(7/48)

M 2 D

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(M1.HE.14.11) 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? Tested Concept

QID: 104651
1

Increases oxygen carrying capacity of hemoglobin

9%

(11/123)

2

Decreases oxygen carrying capacity of hemoglobin

4%

(5/123)

3

Increases levels of fetal hemoglobin (HgbF)

82%

(101/123)

4

Decreases levels of HgbS

2%

(3/123)

5

Decreases levels of fetal hemoglobin (HgbF)

2%

(2/123)

M 1 D

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(M1.HE.13.33) 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 Figure A is hers (Lanes 1 and 5 contain the reference marker samples including Hemoglobin variants A, F, S, C)? Tested Concept

QID: 100098
FIGURES:
1

Lane 2

3%

(6/177)

2

Lane 3

3%

(5/177)

3

Lane 4

81%

(144/177)

4

Lane 6

5%

(9/177)

5

Lane 7

6%

(10/177)

M 2 E

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(M1.HE.13.86) 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? Tested Concept

QID: 100151
FIGURES:
1

Deleted tryptophan

2%

(3/198)

2

Deleted glycine

2%

(3/198)

3

Glutamic acid to valine

69%

(137/198)

4

Glutamine to valine

21%

(42/198)

5

Inserted lysine

1%

(2/198)

M 2 D

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