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Sickle Cell Anemia : Overview, Pathogenesis, Symptoms, Morphology, Lab investigation & Treatment

Sickle Cell Anemia : Overview, Pathogenesis, Symptoms, Morphology, Lab investigation & Treatment

Definition

  • Sickle cell anemia is the prototypical (and most prevalent) hemoglobinopathy, stems from a mutation(Point mutation) in the β-globin gene that creates sickle hemoglobin (HbS) by the substitution of one amino acid out of 146 i.e. valine for glutamic acid at the sixth amino acid residue of β-globin.
  • It is inherited as an autosomal recessive trait
  • The hemoglobinopathies are a group of hereditary disorders caused by inherited mutations that lead to structural abnormalities in hemoglobin.
  • Normal hemoglobins are tetramers composed of two pairs of similar chains. On average, the normal adult red cell contains 96% HbA (α2β2), 3% HbA2 (α2δ2), and 1% fetal Hb (HbF, α2γ2).
  • In homozygotes, all HbA is replaced by HbS, whereas in heterozygotes, only about half is replaced.
  • Sickle cell anemia is the most common familial hemolytic anemia in the world.

Pathogenesis 

Following abnormalities are observed :-
1. Basic molecular lesion:

  • Sickle cell anemia stems from a mutation (Point mutation) in the β-globin gene that creates sickle hemoglobin (HbS) by the substitution of one amino acid out of 146 i.e. valine for glutamic acid at the sixth amino acid residue of β-globin.
  • Sickle cell anemia is charactrised by Hb α2β2S.

2. Mechanism of sickling:

  • This process termed sickling occurs both within the intact red cells and in vitro in free solution.
  • On deoxygenation, HbS molecules form long rod like polymers by means of intermolecular contacts that involve the abnormal valine residue at position 6. These polymers distort the red cell, which assumes an elongated crescentic, or sickle, shape.
  • The sickling of red cells initially is reversible upon reoxygenation. However, the distortion of the membrane that is produced by each sickling episode leads to an influx of calcium, which causes the loss of potassium and water and also damages the membrane skeleton. Over time, this cumulative damage creates irreversibly sickled cells, which are rapidly hemolyzed.
  • Many variables influence the sickling of red cells in vivo.

3. Factors determining rate of sickling:

  • The presence of hemoglobins other than HbS
  • The intracellular concentration of HbS
  • The transit time for red cells through the microvasculature
  • Total haemoglobin concentration
  • Extent of deoxygenation
  • Acidosis and dehydration
  • Increased concentration of 2, 3-BPG in the red cells.

Consequences

Two major consequences arise from the sickling of red cells :
1. Chronic hemolytic anemia

  • The red cell membrane damage and dehydration caused by repeated episodes of sickling produce a chronic hemolytic anemia.

2. Microvascular obstructions / Vaso-occlusion

  • The mean life span of red cells in sickle cell anemia is only 20 days (one sixth of normal). Second, red cell sickling produces widespread microvascular obstructions, which result in ischemic tissue damage and pain crises.
  • Vaso-occlusion does not correlate with the number of irreversibly sickled cells and therefore appears to result from factors such as infection, inflammation, dehydration, and acidosis that enhance the sickling of reversibly sickled cells.
  • Vaso-obstruction affecting different organs and tissues results in infarcts which may be of 2 types:
    – Microinfarcts affecting particularly the abdomen, chest, back and joints and are the cause of recurrent painful crises in SS.
    – Macroinfarcts involving most commonly the spleen (splenic sequestration, autosplenectomy), bone marrow (pains), bones (aseptic necrosis, osteomyelitis), lungs (pulmonary infections), kidneys (renal cortical necrosis), CNS (stroke), retina (damage) and skin (ulcers), and result in anatomic and functional damage to these organs.

Morphology

  • The anatomic alterations in sickle cell anemia stem from
    – The severe chronic hemolytic anemia
    – The increased breakdown of heme to bilirubin
    – Microvascular obstructions, which provoke tissue ischemia and infarction.
  • In peripheral smears, elongated, spindled, or boat-shaped irreversibly sickled red cells are evident.
  • Both the anemia and the vascular stasis lead to hypoxia-induced fatty changes in the heart, liver, and renal tubules.
  • There is a compensatory hyperplasia of erythroid progenitors in the marrow. The cellular proliferation in the marrow often causes bone resorption and secondary new bone formation, resulting in prominent cheekbones and changes in the skull resembling a “crewcut” in radiographs. Extramedullary hematopoiesis may appear in the liver and spleen.
  • In children there is moderate splenomegaly (splenic weight up to 500 g) due to red pulp congestion caused by entrapment of sickled red cells. However, the chronic splenic erythrostasis produces hypoxic damage and infarcts, which over time reduce the spleen to a useless nubbin of fibrous tissue. This process, referred to as autosplenectomy, is complete by adulthood. Vascular congestion, thrombosis, and infarction can affect any organ, including the bones, liver, kidney, retina, brain, lung, and skin. The bone marrow is particularly prone to ischemia because of its sluggish blood flow and high rate of metabolism. Priapism, another frequent problem, can lead to penile fibrosis and erectile dysfunction. As with the other hemolytic anemias, hemosiderosis and gallstones are common.

Laboratory findings & Investigations

The laboratory findings in these cases are as under:
1. Moderate to severe anaemia (haemoglobin concentration 6-9 g/dl).
2. The blood film shows sickle cells and target cells and features of splenic atrophy such as presence of Howell- Jolly bodies.
3. A positive sickling test .

  • The presence of HbS can be demonstrated by exposing red cells to a reducing agent such as sodium dithionite, sodium metabisulfite
  • HbA gives a clear solution, whereas HbS polymerises to produce a turbid solution.
  • This forms the basis of emergency screening tests before surgery in appropriate ethnic groups but cannot distinguish between sickle-cell trait and disease.

4. Haemoglobin Electrophoresis

  • The definitive diagnosis requires Haemoglobin Electrophoresis
  • Haemoglobin electrophoresis shows no normal HbA but shows predominance of HbS and 2-20% HbF.

Clinical symptoms

  • Homozygous sickle cell disease usually is asymptomatic until 6 months of age when the shift from HbF to HbS is complete.
  • Sickling is precipitated by hypoxia, acidosis, dehydration and infection.
  • Irreversibly sickled cells have a shortened survival and plug vessels in the microcirculation. This results in a number of acute syndromes, termed ‘crises’, and chronic organ damage :
    – Painful vaso-occlusive crisis
    – Sickle chest syndrome
    – Sequestration crisis
    – Aplastic crisis

Management

  • All patients with sickle-cell disease should receive prophylaxis with daily folic acid, and penicillin V to protect against pneumococcal infection, which may be lethal in the presence of hyposplenism. These patients should be vaccinated against pneumococcus, meningococcus, Haemophilus influenzae B, hepatitis B and seasonal influenza.
  • Vaso-occlusive crises are managed by aggressive rehydration, oxygen therapy, adequate analgesia (which often requires opiates) and antibiotics.
  • Transfusion should be with fully genotyped blood wherever possible.
  • Simple top-up transfusion may be used in a sequestration or aplastic crisis.
  • A regular transfusion programme to suppress HbS production and maintain the HbS level below 30% may be indicated in patients with recurrent severe complications, such as cerebrovascular accidents in children or chest syndromes in adults.
  • Exchange transfusion, in which a patient is simultaneously venesected and transfused to replace HbS with HbA, may be used in life-threatening crises or to prepare patients for surgery.
  • A high HbF level inhibits polymerisation of HbS and reduces sickling. Patients with sickle-cell disease and high HbF levels have a mild clinical course with few crises. Some agents are able to increase synthesis of HbF and this has been used to reduce the frequency of severe crises.
  • The oral cytotoxic agent hydroxycarbamide has been shown to have clinical benefit with acceptable sideeffects in children and adults who have recurrent severe crises.
  • Relatively few allogeneic stem cell transplants from HLA-matched siblings have been performed but this procedure appears to be potentially curative .

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