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HEMOGLOBINOSIS/HEMOGLOBINOPATHIES – Sickle Cell (SCA)

HEMOGLOBINOSIS/HEMOGLOBINOPATHIES – Sickle Cell (SCA)

  • Mutations in the gene for a globin chain, resulting in synthesis of structurally abnormal Hb
    • Most are β-chain mutations
  • Inherited in an autosomal fashion – mainly AR (homozygotes)
    • Heterozygotes are either asymptomatic or have mild disease
  • Some Hb-pathies can interact – e.g. a person heterozygous for both HbS + HbC has clinical disease
    • Whereas someone who is heterozygous for either one alone is asymptomatic
  • Hb-pathies can also interact with thalassemias – someone who is heterozygous for both B-Thal and HbS will have clinical disease
    • However, inheriting a gene for a-thal tends to decrease severity of HbS
  • Hb-pathies can lead to haemolytic anaemia or ↑/↓ oxygen affinity

Terminology

Genotype – based on the specific globin chains that are present

  • Heterozygous sickle cell (trait) – α2ββs (two normal a chains, one normal b chain, one b chain with sickle mutation)
  • Homozygous sickle cell (anemia) – α2β2S (two normal a chains, two b chains with sickle mutation)
  • Compound heterozygosity for HbS + HbC – α2βSβC

Phenotype – based on the haemoglobin types that are present (Hb in highest conc is written first)

  • Heterozygous sickle cell (trait) – HbAS
  • Homozygous sickle cell (anemia) – HbSS
  • Compound heterozygosity for HbS + HbC – HbSC
  • Patient heterozygous for both HbS and B-Thal – HbSA

Diagnosis of Hb-pathies

  • Electrophoresis – separates Hb based on different size and electrical charges
    • Performed on cellulose acetate
    • Patients should not have been transfused for at least 90 days before ordering electrophoresis test
    • Can be difficult to interpret in neonates due to physiologic elevation of HbF
  • Other tests – sickle solubility test, isopropanol test

Sickle Cell Anemia (HbS)

Epidemiology

  • MC in Africa. Also in areas of Turkey, Mediterranean, India
    • Areas endemic in P.falciparum malaria

Pathophysiology

  • Substitution of valine for glutamic acid at 6th Amino Acid position – β6GLU→VAL
  • Deoxygenated HbS polymerises into long rigid structures which distort the cell into the sickle shape
    • Anything that causes deoxygenation of Hb predisposes to sickling – e.g. hypoxia, acidosis, fever
    • Initial sickling is reversible but repeated cycles of sicking and unsickling damage the cell
      • Eventually RBCs become irreversibly sickled
      • These rigid sickled cells obstruct small blood vessels, causing tissue infarctions (MC in spleen, BM, kidney, mesenteric and pulmonary vessels)
      • They are also ‘sticky’ – adhere to endothelial cells and predispose to thrombosis

Clinical features

  • Heterozygous HbS – Sickle cell trait (HbAS/α2ββS)
    • Asymptomatic, normal Hb and CBC
    • Microscopic hematuria – due to infarction of renal medulla (the hypoxic and acidotic environment causes even heterozygous cells to sickle)
  • Homozygous HbS – Sickle cell anaemia (HbSS/ α2β2S)
    • Children become symptomatic after 3 months of age (before that they are protected by high levels of HbF)
  • Other sickle cell diseases
    • HbSC – less severe than HbSS; retinopathy, pregnancy complications, mild splenomegaly
    • HbSA – mild disease

Complications

  • Vaso-occlusive crises
    • Occlusion of small vessels and infarction of tissues. Pain in abdomen, bones, joints, muscles
  • Sequestration crises
    • MC in 3-4 years of age. Spleen suddenly becomes enlarged and engorged with blood. Can sequester a large portion of total blood volume, can be fatal
  • Aplastic crises
    • Occurs as a complication of infections – MC is parvovirus B19 infection which transiently halts the production of RBCs
    • In patients with SCA, RBC survival is 10-20 days instead of 120 days so Hb drops more quickly
    • Can be fatal without a transfusion
  • Infections – MCC of death in SCD
    • Children are maintained on penicillin prophylaxis against pneumococcal sepsis
  • Acute chest syndrome
    • Causes – infection, fat embolism, PE, vascular occlusions
    • Findings – pulm infiltrates on CXR, chest pain, fever, hypoxemia, tachypnea, cough, dyspnea
  • Splenic infarcts/altered splenic function
  • Renal disease – infarction of medulla (see above)
  • Bilirubin gallstones – due to increased Hb turnover
  • Leg ulcers
  • Retinopathy
  • Pregnancy complications

Diagnosis

  • Sickle cell trait – normal CBC and smear
  • SCA – ↓Hb (5-8g/DL), normocytic, target cells, sickled er (top smear)
    • Howell-Jolly bodies – due to splenic infarction
  • HbSC – rectangular HbC crystals (bottom smear)
  • HbS + B-Thal – target cells and microcytosis
  • Sickle solubility test – deoxygenated HbS has decreased solubility
    • Cant differentiate between trait and SCA
    • Can give false positive in presence of high HbF, so not a reliable test in infants
  • Electrophoresis
    • Performed on cellulose acetate at alkaline pH
    • Useful in infants
    • Can also distinguish between trait and SCA

Treatment

  • Supportive – folate supplements, prophylactic penicillin
    • Children vaccinated against S.pneumoniae, H.influenza, N.meningitidis
  • Painful vaso-occlusive crises – oral hydration and analgesia
  • Transfusions – for cerebrovascular accidents, acute chest syndrome
    • Aim to maintain HbS <30%
    • SE – Fe overload, alloimmunisation, haemolytic reactions, infections
  • Prompt antibiotics for infections
  • Acute chest syn – oxygen, empiric ABs, analgesia, transfusions
  • Hydroxyurea – decreases painful crises, hospitalisations, episodes of ACS, increases HbF
    • SE – myelosuppression
  • BM transplant
  • Genetic counselling

HbC

  • MC in Africa
  • Substitution of lysine for glutamic acid at 6th AA. HbC polymerises into crystals when deoxygenated
  • Both heterozygous HbC (trait) and homozygous HbC (HbCC) are asymptomatic, no treatment required
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