Sickle Cell Anemia

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 (1/7^th 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
  • 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