Overview

Haemolytic anaemia describes premature destruction (haemolysis) of red blood cells (RBCs) leading to anaemia. Normally RBCs have a lifespan of around 120 days, but this can be as short as 5 days in haemolytic anaemia.

There are many different causes of anaemia, each with different management steps, however, they all share some common features.

It may be helpful to look at the chapter on Anaemia: Data Interpretation alongside reading this section to help wrap your head around when to suspect what type of anaemia.

Mechanisms of Haemolysis

Extravascular haemolysis

Extravascular haemolysis describes the destruction of RBCs by macrophages in the spleen. RBCs are degraded and the products are kept within macrophages, therefore, haemoglobinaemia and haemoglobinuria are not seen. Extravascular haemolysis is always going on normally to recycle old RBCs but can become excessive.

Causes of excessive extravascular haemolysis include:

Therefore, overall, extravascular haemolysis is associated with splenomegaly.

Intravascular haemolysis

Intravascular haemolysis describes the destruction of RBCs within blood vessels due to trauma or lysis mediated by complement proteins. This leads to their contents being released into the circulation (such as haemoglobin and bilirubin).

Causes of intravascular haemolysis include:

Lesions within a blood vessel (such as clots) can cause RBCs to shear against them and be destroyed

Overall, intravascular haemolysis is associated with bilirubinaemia, increased lactate dehydrogenase, and decreased haptoglobins, and is less associated with splenomegaly compared to extravascular haemolysis.

Causes of Haemolysis

Acquired causes

Acquired causes of haemolytic anaemia include:

  • Non-immune causes (direct antiglobulin (Coombs’) test negative):
    • Infection (e.g. malaria)
    • Traumatic (e.g. disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, haemolytic uraemic syndrome, mechanical heart valves)
    • Paroxysmal nocturnal haemoglobinuria
    • Hypersplenism
  • Immune causes (direct antiglobulin (Coombs’) test positive):

Congenital causes

Congenital causes of haemolytic anaemia include:

  • RBC membrane disorders:
    • Hereditary spherocytosis
    • Hereditary elliptocytosis
  • RBC enzyme deficiencies:
    • G6PD deficiency
    • Pyruvate kinase deficiency
  • Haemoglobinopathies:
    • Sickle-cell anaemia
    • Thalassaemia

Presentation

General features of anaemia include:

Features suggesting haemolytic anaemia include:

  • Jaundice – due to haemolysis leading to bilirubin release
    • Jaundice is generally seen once bilirubin is higher than around 30 mmol/L (3 mg/dL)
  • Gallstones – due to persistent bilirubin release
  • Haemoglobinuria
    • Suggests intravascular haemolysis
  • Bleeding and bruising
  • Splenomegaly
    • Suggests extravascular haemolysis

Investigations

Initial tests include:

  • Full blood count:
    • Shows reduced haemoglobin
    • Platelets may be low in some causes
  • Mean cell volume:
    • Typically normal
  • Reticulocyte count:
    • Increased – bone marrow tries to create new immature cells
  • Blood film:
    • May show abnormal cells
    • Examples can be schistocytes, spherocytes, bite cells etc.
  • Markers of haemolysis:
    • Bilirubin – raised due to haemoglobin breakdown
    • Lactate dehydrogenase (LDH) – raised but not specific
    • Haptoglobin – low as it binds to free haemoglobin
  • Urinalysis/dipstick:
    • Positive for haemoglobin in intravascular haemolysis
  • Urea and electrolytes (U&Es):
    • May help identify the underlying cause (e.g. HUS)
  • Direct antiglobulin test (Coombs’ test):
    • Positive in immune haemolytic anaemia
  • Haemoglobin electrophoresis:
    • If haemoglobinopathies (e.g. sickle cell disease) are suspected
  • G6PD assay:
    • If G6PD deficiency is suspected

Data Interpretation Approach

Reticulocytes are immature red blood cells and are a measure of the bone marrow’s ability to produce new red blood cells. A high reticulocyte count suggests that the bone marrow is attempting to make new red blood cells to compensate. A low reticulocyte count suggests the bone marrow cannot make enough new red blood cells. Therefore:

  • High reticulocyte counts suggest haemolysis or blood loss
  • Low reticulocyte counts suggest bone marrow suppression or failure

Further investigations can help with identifying the underlying cause. The following can be used to differentiate between haemolysis and acute blood loss:

  • Tests associated with haemolysis:
    • Bilirubin – elevated in haemolysis (bilirubin is a product of haemolysis)
    • Lactate dehydrogenase – elevated in haemolysis
    • Haptoglobins – reduced (free haemoglobin is released in haemolysis which binds to haptoglobins)

If haemolysis is likely, the next step is to determine whether the haemolysis is immune-mediated or not:

  • Direct antiglobulin (Coombs’) test:
    • Positive – immune-mediated haemolysis
    • Negative – immune-mediated haemolysis

The next step is to look at the blood film, which may show signs that correlate to a specific disorder.

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