Haemolytic anaemia

Haemolytic anaemias are a form of anaemia characterized by the pathologically increased breakdown of RBCs (haemolysis), reducing their to less than the normal 120 days. To compensate for increased turnover of RBCs the bone marrow can increase the output of RBCs 6 – 8-fold. Anaemia only manifests if the rate of destruction exceeds this increased production rate.

There exist many types of haemolytic anaemia, both congenital and acquired.

Types

Here are some of the most important:

Congenital haemolytic anaemias:

• Haemoglobinopathies – characterised by defects of haemoglobin. These defects often cause haemoglobin to precipitate in the cell, which alters its shape.
  • Sickle cell anaemia
  • Thalassaemia
• Membranopathies – diseases characterised by abnormal RBC membrane
  • Hereditary spherocytosis
  • Paroxysmal nocturnal haemoglobinuria
• Enzymopathies
  • Glucose 6-phosphate dehydrogenase deficiency
  • Pyruvate kinase deficiency

Acquired haemolytic anaemias:

• Immune-mediated haemolytic anaemias
  • Warm antibodies (idiopathic or secondary to autoimmune disease or haematological malignancy)
  • Cold antibodies (idiopathic or secondary to autoimmune disease or haematological malignancy)
  • Haemolytic disease of the newborn (a problem of neonates)
• Non-immune-mediated haemolytic anaemias
  • Microangiopathic haemolytic anaemias (TTP/HUS)
  • Macroangiopathic haemolytic anaemias
    • Prosthetic heart valves
    • Severe aortic stenosis
  • Drugs
  • Infection
  • Paroxysmal nocturnal haemoglobinuria

Corpuscular and extracorpuscular haemolysis:

We can classify haemolytic anaemias as corpuscular and extracorpuscular based on whether the cause of haemolysis is inside or outside the RBCs.

• Corpuscular haemolytic anaemias
  • RBC membrane defects
  • Enzymopathies
  • Haemoglobinopathies
• Extracorpuscular haemolytic anaemias
  • Immune-mediated haemolytic anaemias
  • Non-immune-mediated haemolytic anaemias

Pathomechanism

RBCs are broken down by macrophages of the mononuclear phagocyte system (MPS), also called the reticuloendothelial system (RES). The majority of the breakdown occurs in the spleen. Haemoglobin is split into the globin part and the heme part. The globin part is broken down to amino acids while the heme part is converted to indirect bilirubin. Indirect bilirubin is then converted to direct bilirubin in the liver and so on.

We distinguish between intravascular haemolysis and extravascular haemolysis depending on where the haemolysis happens. In intravascular haemolysis pathological haemolysis occurs in vessels while in extravascular haemolysis the physiological haemolysis in the MPS is pathologically increased.

Clinical features

In addition to features of anaemia, haemolysis may cause jaundice and gallstones. Some types of haemolytic anaemia may cause specific symptoms. Haemolysis may occur continuously or intermittently.

Diagnosis and evaluation

A protein called haptoglobin is important in the diagnosis of haemolysis. Haptoglobin is a plasma protein which binds to free haemoglobin in the plasma. When there is haemolysis, more haemoglobin is released into the plasma. Haptoglobin in the plasma will bind to the released haemoglobin. This decreases the amount of free circulating haptoglobin, which is what’s measured in the lab.

• Laboratory tests
  • In both types of haemolysis
    • Haptoglobin ↓
    • Lactate dehydrogenase ↑
    • Indirect bilirubin ↑
    • Reticulocytes ↑ – due to increased erythropoiesis
    • Urinary urobilinogen ↑
  • Only in intravascular haemolysis
    • Free haemoglobin in plasma ↑ (only in severe cases)
    • Brown-coloured urine – due to haemoglobinuria or haemosiderinuria
• Peripheral blood smear
  • Spherocytes – Small, spherical RBCs with no central pallor

It can be difficult to differentiate intravascular and extravascular haemolysis on a lab test as no one parameter is different in the two. In extravascular haptoglobin can be normal, and there is rarely free haemoglobin in the plasma.

The Coombs test is essential in the diagnosis of antibody-mediated anaemias. There are two types of Coombs test, the direct type and the indirect type. The direct Coombs test is positive if there are autoantibodies against the patient’s own RBCs bound to the RBCs in the patient’s blood. The direct Coombs test is positive in immune-mediated haemolytic anaemias.

The indirect Coombs test is positive if there are autoantibodies against foreign (not the patient’s) RBCs in the patient’s blood. The indirect Coombs is used to check if the patient’s blood contains anti-D antibodies, which would cause haemolytic disease of the newborn due to ABO or Rh incompatibility.