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  • 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)

  • 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
  • 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
  • Radiographs 
    • indications
      • acute chest syndrome
    • findings 
      • new pulmonary infiltrate of one or more lung segments
  • 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
    • 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
  • ß-thalassemia
    • key distinguishing factors
      • microcytic anemia
      • no sickle cells on peripheral blood smear
  • 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
  • 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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