Sickle Cell Disease

Sickle cell disease is a hereditary, autosomal recessive condition caused by a point mutation in the beta-globin gene found on chromosome 11. This results in the absence of HbA and the production of HbS.

1:700 Africans have sickle cell disease. The carrier rate of HbS is between 2-40% in Africa.

Classification

Hemoglobin pattern

Lifespan of erythrocytes

Hemoglobin levels

Multisystemic features of Sickle Cell Disease

• Risk factors
  • Family history of sickle cell disease
  • Sub-saharan heritage
  • Malaria endemicity – a heterozygote advantage where individuals with sickle cell trait (HbAS) are resistant to Plasmodium falciparum
• Pathophysiology
  • Point mutation in the B-globin gene (chromosome 11) → glutamic acid is replaced with valine → 2 a-globin and 2 mutated B-globin subunits create pathological Hemoglobin S
  • Hemoglobin S is soluble in the RBC as long as the cell is oxygenated
  • Deoxygenation → polymerization and crystallization of HbS → deformation (”sickling”) of erythrocytes → vaso-occlusion and tissue infarction, extravascular hemolysis, and intravascular hemolysis
  • Repeated stasis and vaso-occlusion of the spleen → infarction → functional asplenia (auto-splenectomy) → susceptibility to infection with encapsulated bacteria
  • Anaemia is due to
    • Extravascular hemolysis
    • Intravascular hemolysis
    • Increased RBC sequestration in the spleen
  • Folate deficiency results from increased RBC turnover
• Signs and symptoms
  • Symptoms start manifesting at 6 months of life as HbF production drops and HbA increases.
  • Symptoms of anaemia
  • Jaundice
  • Pain
    • Unpredictable
    • Can affect any organ or joint
    • Often, the long bones, lower back, chest, and abdomen
    • Starts with the hands or feet in young children
    • Localized or migratory
    • Variable quality (sharp, dull, stabbing, or throbbing)
  • Chronic, e.g., ulcers
  • Transient ischemic attacks and stroke
  • Fever and high-risk of infection due to a non-functional spleen
  • Acute Chest Syndrome
    • Pleuritic chest pain
    • Tachypnea
    • Fever
  • New pulmonary infiltrate
  • Delayed growth and delayed puberty
• Investigations
  • Complete blood count
    • Low Hb (5 – 9 g/dL)
    • Leukocytosis (due to reticulocytosis, which is counted as WBCs)
    • Thrombocytosis
  • Peripheral blood film: best initial test
    • Sickle cells (depranocytes)
    • Target cells
    • Howell-Jolly bodies
    • Reticulocytosis
    • Leukocytosis
    • Thrombocytosis
  • Sickle Solubility Test (Sickle test): Screening test to detect sickle cell trait and sickle cell disease
  • Haemoglobin electrophoresis, or High performance liquid chromatography, or Isoelectric focusing for confirmatory testing. It can detect HbAS, HbSC, or HbSS. Hemoglobin electrophoresis is done 2 – 3 months after transfusion
  • Polymerase chain reaction: Detects the genetic mutations
• Treatment
  • Patient Education
    • Awareness of symptoms of infection, worsening anemia, and attention to pain
    • Reassure the patient not to take any pain trivially
  • Treat vaso-occlusive crisis
  • Manage chronic pain syndrome
    • NSAIDs or Opioids
    • Over-the-counter pain relievers
    • Hot or cold compresses
  • Correct chronic hemolytic anemia
    • Folic acid supplementation to support a healthy reticulocyte count
    • Iron supplementation for menstruating women with co-existing iron deficiency
  • Adequate diet
  • Prevent and treat infections
    • Penicillin VK prophylaxis from 2 months up to 5 years or early teens
    • 10-valent Pneumococcal vaccine at 6, 10, and 14 weeks
    • 23-valent or 32-valent Pneumococcal Vaccine at age 2 years with booster every 5 years
    • Adhere to the immunization schedule for influenza, pneumococcal, and meningococcal infection
    • Prompt broad-spectrum antibiotics for infections
  • Manage complications and organ damage syndromes associated with the disease
  • Prevent stroke
  • Detect and treat pulmonary hypertension
  • Hydroxyurea (hydroxycarbamide)
    • Increases the proportion of HbF
    • Reduces the frequency of sickling and pain crises
    • Has a proven mortality benefit
  • Blood transfusion for:
    • Splenic sequestration crisis
    • Aplastic crisis
    • Acute chest syndrome
    • Stroke
    • Stroke prevention in case of abnormal transcranial Doppler
    • Pregnancy
    • General Anaesthesia
  • Bone Marrow Transplant
    • An allogenic bone marrow transplant can cure sickle cell disease. However, it is not 100% safe and is expensive.
    • Cord Blood Stem Cell Transplant is safer than a bone marrow transplant
  • Surgery
    • Skin grafting for chronic leg ulcers
    • Hip replacement or other orthopaedic procedures for avascular necrosis
    • Surgical drainage of the penile corpora for resistant priapism
    • Insertion of a penile prosthesis if impotence occurs
    • Cholecystectomy for gallstones (whether acute cholecystitis is present or not)
    • Surgery for osteomyelitis
• Prevention of sickle cell disease
  • Genetic counselling
  • Prenatal testing
  • Parental education can help prevent 90% of deaths from vaso-occlusive crises
• Complications
  • Transient ischaemic attack
  • Stroke
    • Infarction (most common)
    • Hemorrhagic (common in adults)
    • Peaks at 2 – 9 years of age
    • 10% of children < 20 years old get a stroke
    • 25% of patients get a silent stroke
  • Vision loss
  • Myocardial infarction
  • Osteonecrosis
  • Pulmonary embolism
  • Growth defects
  • Pulmonary hypertension and secondary right ventricular hypertrophy
  • Osteomyelitis
  • Septic arthritis
  • Abdominal infarction
  • Cholecystitis/gallstones
  • Nephropathy
  • Priapism
  • Skin ulcers
  • Complications of repeated transfusion
    • Alloimmunization – increased risk of graft-vs-host reaction when looking for a stem cell donor
    • Iron overload
    • Increased risk of transfusion-transmitted infections
• Factors that predict poor prognosis in children
  • Dactylitis in infants < 12 months
  • Hb level < 7g/dL
  • Leukocytosis in the absence of infection