Sickle Cell Disease

Table Of Contents
  1. Overview
  2. Sickle Cell Crises

Overview

Sickle cell disease is a hereditary, autosomal recessive disease caused by a point mutation of the beta-globin gene resulting in the absence of HbA and the production of HbS. Hbs has a preponderance to “sickling” (esp. during hypoxia, dehydration, acidosis). The primary concern for patients with sickle cell disease is vaso-occlusion (causing Cerebrovascular accident (CVA)/TIA, MI, Osteonecrosis, Pulmonary embolism) along with the other “crises”. Patients also present with features of hemolytic anemia, since HbS has a shorter lifespan. Symptoms of complications can and usually manifest by 6 months of life as HbF production drops and HbA increases.

Sickle cell disease can be tested for at birth (by suspicion via history). There is no safe, effective, and curative treatment. The approach to treatment is to prevent sickle cell crises (acute complications) and various long-term complications.

1:700 Africans have sickle cell disease. The carrier rate of HbS is between 2-40% in Africa. In western Kenya the carrier rate is 25%, with a 16% chance of both partners having HbAS. The chance of HbSS birth in western Kenya is 1 in 64. The incidence of stroke is highest between 2 – 9 years of age. 10% of children < 20 years get stroke. 25% get silent strokes.

  • Aetiology of sickle cell anaemia
    • 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 HbS
    • Sickle cell anemia: Homozygous (HbSS). Described in 1910. No HbA.
    • Sickle cell diseases: 2 defective genes. HbSS + HbSC/HbSD/HbSOarab/HbSE. No HbA.
    • Sickle cell trait: HbAS. Generally asymptomatic.
  • Pathophysiology of Sickle cell anemia
    • HbS crystallizes when deoxygenated → deformation (”sickling”) of erythrocytes
      • Events that trigger decreased oxygen tension leading to sickling:
        • Hypoxia (e.g. high altitudes)
        • Infection
        • Dehydration
        • Acidosis
        • Sudden change in temperature
        • Stress
        • Pregnancy
    • Sickled cells lack elasticity and adhere to vascular endothelium
    • Adherence disrupts microcirculation and causes vaso-occlusion and subsequent tissue infarction
    • Anemia results from extravascular and intravascular hemolysis of sickled red cells as well as increased sequestration by the spleen
    • Folate deficiency results from increased demand due to hemolysis and increased turnover of erythrocytes
    • HbF production increases to compensate for low levels of HbA
  • Functional asplenia (auto splenectomy)
    • Occurs by adolescence due infarction of the spleen (following repeated stasis and vaso-occlusion in early childhood)
    • Children need to be immunized since they are susceptible to overwhelming infection by encapsulated bacteria.
Autosplenectomy
Autosplenectomy
  • Signs and symptoms
    • Pallor, Fatigue, and Shortness of breath (due to anaemia)
    • Jaundice
    • Pain
      • Unpredictable Pains affecting any organ or joint
      • Unpredicatble
      • Start with hand/feet in young children
      • Often of long bones, lower back, chest, and/or abdomen
      • Specifically localized or migratory
      • Variable quality (sharp, dull, stabbing, throbbing)
    • Leg ulcers (chronic)
    • Transient Ischemic Attacks and Stroke
      • Infarction (most common): Hemiparesis, Altered speech and vision
      • Hemorrhagic (common in adults): severe headache, vomiting, seizures, altered consciousness
    • Fever and high-risk of infection (as the spleen becomes non-functional)
    • Acute Chest Syndrome
      • Pleuritic chest pain, Tachypnea, and Fever
      • New pulmonary infiltrate
    • Delayed growth and Delayed puberty
  • Investigations
    • Complete blood count
      • Low Hb (5 – 9 g/dL)
    • Peripheral blood film: best initial test
      • Sickle cells (depranocytes)
      • Target cells
      • Howell-Jolly bodies
      • Reticulocytosis
      • Leukocytosis
      • Thrombocytosis
    • Sickle Solubility Test (Sickle test)
      • Positive
    • Haemoglobin electrophoresis: most accurate test
      • HbAS, HBSC, HBSS
    • PCR
      • Detects genetic mutation – genetic counselling
  • Long-term treatment
    • Patient Education
      • Awareness of symptoms of infection, worsening anemia, and attention to pain (which lingers or worsens despite meds)
      • Reassure the patient not to treat any pain trivially
    • Oral pain management
      • NSAIDs or Opioids
      • Over-the-counter pain relievers
      • Hot or cold compresses
    • Hydroxyurea (Hydroxycarbamide) 20mg/kd/d if eGFR is >60mL/min
      • Increases the proportion of HbF (reducing the frequency of sickling, and pain crises. Has proven mortality benefit)
    • Prophylactic penicillin
    • Folate supplementation (boost RBC production)
    • Adhere to immunization schedule (influenza, pneumococcal, meningococcal)
  • Prevention of sickle cell disease
    • Genetic counselling
    • Prenatal testing
    • Parental education (can help prevent 90% of deaths from sequestration crises)
Sickled Cells
Sickled Cells
Hydroxyurea capsules
Hydroxyurea capsules
  • Complications of Sickle Cell Disease
    • Growth defects (chronically ill, bone disease = height defects)
    • Stroke/TIA (because of vaso-occlusion)
    • Blindness (because of vaso-occlusion)
    • Pulmonary hypertension and secondary right ventricular hypertrophy (because of vaso-occlusion in pulmonary vasculature → fibrosis)
    • Osteomyelitis (esp. of the long bones)
    • Septic arthritis
    • Abdominal infarction
    • Cholecystitis/gallstones
    • Nephropathy
    • Priapism
    • Skin ulcers

Sickle Cell Crises

Vaso-occlusive crisis

A vaso-occlusive crisis is an acute occlusion at various points in the circulation of an organ. Symptoms include pain which varies in intensity/ischemic-necrosis to that organ. The most clinically significant vaso-occlusive crisis is acute chest syndrome. Acute chest syndrome is indistinguishable from pneumonia (get sputum or blood culture and jump right to antibiotics)

  • Signs and Symptoms of a vaso-occlusive crisis
    • Severe pain
      • Triggered by cold, dehydration, infection or hypoxia
      • Hands and feet if young (< 3 years – dactilytis)
      • Acute abdomen (Mesenteric ischemia)
    • Seizures, Strokes or Cognitive defects
    • Symptoms of MI
  • Signs and Symptoms of acute chest syndrome
    • Cough (productive or non-productive), wheeze, fever, dyspnea, tachycardia (similar to Pneumonia)
    • Acute chest pain worse with breathing
    • Respiratory distress with clinical signs of consolidation
    • Hypoxia (SpO2 <95% on room air) and/or Cyanosis
  • Treatment of vaso-occlussive crisis
    • Admit
    • Supplemental oxygen (maintain SpO2 >95%)
    • Ample analgesia (lean towards the stronger pain meds)
      • IV Morphine (patient controlled analgesis if possible)
    • Hydration (make sure hydration status is OK)
    • Transfusion (for very severe crisis)
    • Emperic antibioitics if Temp > 38 C or unwell
  • Treatment of Acute chest syndrome
    • Admit
    • Ample analgeisa (lean towards stronger pain meds)
    • Supplemental oxygen (maintain SpO2 >95%)
    • IV antibiotics (Ceftriaxone + Gentamicin) until culture returns
    • Bronchodilation (Salbutamol) if wheezing or obstructive PFTs
    • Gentle hydration (make sure hydration status is OK, avoid overhydration)
    • Transfusion, OR exchange transfusion (if severe ACS)
    • Incentive spirometry

Splenic sequestration crisis

A splenic sequestration crisis is an acute, painful enlargement of the spleen. The biggest concern is addressing circulatory failure (the patient can go into hypovolemia as the spleen traps RBCs). Maintain a VERY high index of suspicion anytime a patient with sickle cell has a fever. DO NOT hesitate to use antibiotics in the presence of fever.

  • Signs and symptoms
    • Hepatosplenomegaly
    • Severe anemia
    • Shock (hypotension, tachycardia, tachypnoea)
  • Treatment
    • Admit
    • Supplemental oxygen
    • Hydration
    • Urgent Transfusion
    • Ample pain meds
    • Antibiotics (third or fourth-gen cephalosporins)

Aplastic crisis

Aplastic crisis is an acute aplastic anemia generally affecting the RBCs. Presents as a “sudden anemia”. Generally triggered by infection with the Parvovirus B19.

  • Symptoms
    • Feeling weak/tired
    • Breathlessness
    • Palpitations
    • Pallor
    • Fatigue
    • Hypotension
    • Tachycardia
  • Treatment Usually self limited (< 2 weeks)
    • Transfusion