Sickle cell disease (SCD) is an inherited hemoglobinopathy with a mutation in the β-globin chain. Low oxygen tension results in sickling of the abnormal hemoglobin within the red blood cells, which presents as ischemia or hemolysis. As a chronic illness, patients depend on pain management. Disease management encompasses acute care, prevention, and screening for complications.

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Image: “Sickle Cell Anemia” Peripheral blood smear by Ed Uthman. License: CC BY 2.0


Epidemiology and Etiology

Epidemiology

  • Most common in people of Sub-Saharan African, Mediterranean, and Middle Eastern heritage
  • 1 in 500 inhabitants of Sub-Saharan Africa
  • Equally present between males and females

Image: “Mode of Inheritance in Sickle Cell Disease” by the National Heart Lung and Blood Insitute (NIH). License: Public Domain

Etiology

  • Autosomal recessive inheritance pattern
  • Mutation in the β-globin gene 
  • HbS gene is a point mutation
  • Chromosome 11, codon 6 – position 15.5 – adenine → thymine (GAG → GTG)
  • Amino acid substitution at position 6; glutamic acid → valine 
  • Homozygous: two HbS genes → sickle cell disease (HbSS)
  • Heterozygous: one HbS gene → sickle cell trait ( HbAS)
  • Compound heterozygous: one HbS gene, one HbC gene (HbSC)
  • HbC is a hemoglobinopathy where glutamic acid → lysine at the sixth position of the β-globin gene
Sickle Cell Disease. Point mutation

Image: “Sickle Cell Disease. Point mutation” By Lecturio.

Video Gallery

Sickle Cell Anemia by Kevin Ahern, PhD
Sickle Cell Anemia: Etiology by Carlo Raj, MD
Pediatric Sickle Cell Disease by Brian Alverson, MD

Pathophysiology

  • HbS is prone to polymerization with other hemoglobin molecules under conditions of low oxygen tension.
  • Polymerization results in a rigid structure that distorts the membrane.
  • Membrane damage results in calcium influx and efflux of potassium and water, which dehydrates the RBC giving it the characteristic sickle shape.
  • Sickling is aggravated by:
    • Infection
    • Dehydration
    • Hypoxia
    • Fever
    • Acidosis
  • The fragile cell leads to hemolysis and vessel occlusion
  • Hemoglobin released from hemolyzed cells readily binds to NO
  • Depletion of NO results in vascular smooth muscle cell contraction and platelet aggregation
  • There is a shortened half-life of the HbS containing RBCs to 12 days (average is 120 days)
  • The sickle-shaped cell and shortened half-life renders immunity to malaria
sickle-cell

Image: “Abnormal Hemoglobin results in Sickling” Figure A shows normal red blood cells flowing freely in a blood vessel. The inset image shows a cross-section of a normal red blood cell with normal hemoglobin. Figure B shows abnormal, sickled red blood cells blocking blood flow in a blood vessel. The inset image shows a cross-section of a sickle cell with abnormal (sickle) hemoglobin forming abnormal strands. By The National Heart, Lung, and Blood Institute. License: Public Domain

Clinical manifestations

Mechanism Symptoms
Chronic hemolysis (intravascular/extravascular)
  • Anemia 
    • SOB
    • Fatigue
    • Tachycardia
    • Growth Retardation
  • Splenomegaly (child)
  • Cholelithiasis
Vaso-occlusive crisis (infarction) Fever plus any of the following:

  • CNS: ischemic stroke
  • Eyes: retinopathy, blindness
  • Lung: cor pulmonale
  • Heart: silent myocardial infarction
  • Spleen: autosplenectomy (adults)
  • Kidney: glomerulonephritis, proteinuria, hematuria, renal papillary necrosis
  • GI: acute abdomen
  • Liver: RUQ syndrome (RUQ pain and jaundice)
  • Penis: painful priapism
  • Bones: osteomyelitis, septic arthritis
  • Skin: ulceration
Acute pain crisis 
  • Splenic sequestration:
    • In children
    • Spleen pools blood  → shock (low Hb)
  • Acute chest syndrome:
  • Infections/bacteremia:
    • Auto-splenectomy → encapsulated organisms
    • Streptococcus pneumoniae 
    • Haemophilus influenzae 
    • Neisseria meningitidis 
    • Osteomyelitis (salmonella, Staph. Aureus)
  • Aplastic crisis:
    • Transient bone marrow suppression secondary to parvovirus B19

Video Gallery

Sickle Cell Anemia: Vaso-occlusive Crisis by Carlo Raj, MD

Diagnostics

  • CBC
    • ↓↓ Hb ( Hb <6)
    • Normal MCV
    • ↑↑ retic
    • ↓ Hct
    • ↓ ESR
    • ↑ WBC
    • ↑ bilirubin
    • ↑ BUN, ↑ creatinine
    • LFT -↑ AST/ALT 
  • Sickle Smear Prep: expose smear to sodium metabisulfite → low oxygen tension
    • Best initial test
    • Sickle cell 
    • Howell-Jolly bodies (patients with autosplenectomy)
    • Cannot differentiate between HbAS and HbSS
  • Hb electrophoresis 
    • Most accurate test
    • No HbA
    • HbS band (90%)
    • HbA2 normal
    • ↑↑ HbF  (8%)
    • In sickle cell trait: HbA is present, HbS is 45%
  • Genetic screening
Diagnostic tests useful in complications
Complication Test Findings
Acute chest syndrome ECG Myocardial infarction (STEMI/NSTEMI changes)
CXR Pneumonia: consolidation
Vaso-occlusive crisis X-ray Avascular necrosis (MRI most accurate)
Septic arthritis Joint aspiration Increased leukocyte

Salmonella-growth

Kidney  Urine-analysis Hematuria

Proteinuria

Casts

CNS CT/MRI Stroke (ischemic)
Cardiac ECHO Pulmonary hypertension

Systolic dysfunction

Video Gallery

Sickle Cell Anemia: Hemoglobin Electrophoresis by Carlo Raj, MD

Image: “Sickle Cell Anemia” Peripheral blood smear by Ed Uthman. License: CC BY 2.0

Treatment

  • Genetic counseling
  • HbAS: no treatment needed
  • HbSS: 
    • Folic acid to compensate for high turn-over and folate deficiency
    • Hydroxyurea: 
      • Enhances differentiation of stem cells to HbF
      • Reduces polymerization
    • Treating vaso-occlusive crisis
    • Screening for complications
    • Prevention of crisis: preventing infection, hypoxia, acidosis
Management of HbSS
Symptom Management
Acute pain crisis
  • Oxygen
  • Hydration
  • Analgesics/opioids
  • Exchange transfusion 
    • Hb <6
    • ACS
    • Aplastic crisis
    • Splenic sequestration
    • Stroke
Acute splenic sequestration
  • Exchange transfusion
  • Splenectomy (delay until the age of 3–5 years)
Infections Prevention:

  • Immunization: pneumococcus, meningococcal, and Hib
  • Prophylactic penicillin for children <5 years
Priapism
  • Hydration
  • Analgesics
Aplastic Anemia
  • IVIG (intravenous immunoglobin)
Screening
  • Stroke: transcranial doppler; annually (age 216 years)
  • Retinopathy: retinal exam; annually (beginning at 10 years)
  • ECHO: pulmonary hypertension (childhood/early adulthood)
  • Urinalysis: annually for proteinuria/casts
Refractory Hematopoietic stem cell transplant (HSCT) for:

  • Refractory to hydroxyurea
  • End organ damage
  • Child (age < 18)

Differential Diagnoses

  • Hemolytic Anemia: encompasses anemia due to a shortened RBC half-life. Sickle cell disease is a form of hemolytic anemia. Other causes of hemolytic anemia must be considered as differential diagnoses.
  • Thalassemia: An inherited deficiency in either the alpha (α) or beta (β) globin chain, resulting in hypochromic anemia. The presentation is mainly due to severe anemia, and the patient is transfusion dependent.
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