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Updated: Sep 26 2022

Sickle Cell Anemia


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Images for anemia - moises d.jpg
  • 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
        • 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
      • decreased haptoglobin
      • dramatically increased hemoglobin S (HbS) ~ 80%
      • elevated fetal hemoglobin as well (HbF) ~ 16%
      • 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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