Haemolytic anaemia I – General features and inherited disorders

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Haemolytic anaemia I – General features and inherited disorders

General features of haemolysis

The term ‘haemolytic anaemia’ describes a group of anaemias of differing aetiology that are all characterised by abnormal destruction of red cells. The hallmark of these disorders is reduced lifespan of the red cells rather than underproduction by the bone marrow.

In classification of the haemolytic anaemias there are three main considerations:

The mode of acquisition of the disease: is it an inherited disorder or a disorder acquired in later life?

The location of the abnormality: is the abnormality within the red cell (intrinsic) or outside it (extrinsic)?

The site of red cell destruction: red cells may be prematurely destroyed in the bloodstream (intravascular haemolysis) or outside it in the spleen and liver (extravascular haemolysis).

The simple classification in Table 14.1 relies upon division of the main clinical disorders into inherited and acquired types. In general, it can be seen that inherited disorders are intrinsic to the red cell and acquired disorders extrinsic. The inherited disorders can be subdivided depending on the site of the defect within the cell – in the membrane, in haemoglobin, or in metabolic pathways. Acquired disorders (discussed in the next section) are broadly divided depending on whether the aetiology has an immune basis.

Table 14.1

Classification of the haemolytic anaemias

Inherited disorders
Red cell membrane	Hereditary spherocytosis and hereditary elliptocytosis
Haemoglobin	Thalassaemia syndromes and sickling disorders
Metabolic pathways	Glucose-6-phosphate dehydrogenase and pyruvate kinase deficiency
Acquired disorders
Immune	Warm and cold autoimmune haemolytic anaemia
Isoimmune	Rhesus or ABO incompatibility (e.g. haemolytic disease of newborn, haemolytic transfusion reaction)
Non-immune and trauma	Valve prostheses, microangiopathy, infection, drugs or chemicals, hypersplenism

Diagnosis of a haemolytic anaemia

Recognition of the general clinical and laboratory features of haemolysis usually precedes diagnosis of a particular clinical syndrome. Where haemolysis leads to significant anaemia the resultant symptoms are as for other causes of anaemia. However, the increased red cell breakdown of the haemolytic anaemias causes an additional set of problems. Accelerated catabolism of haemoglobin releases increased amounts of bilirubin into the plasma such that patients may present with jaundice (Fig 14.1). Where the spleen is a major site of red cell destruction there may be palpable splenomegaly. Severe prolonged haemolytic anaemia in childhood can lead to expansion of the marrow cavity and associated skeletal abnormalities including frontal bossing of the skull.

Fig 14.1 Mild jaundice in a patient with hereditary spherocytosis.

Initial laboratory investigations of haemolysis will include an automated blood count, a blood film and a reticulocyte count. The blood count will show low haemoglobin. Many cases of haemolysis have ‘normochromic normocytic’ red cell indices although some are moderately macrocytic. The latter observation is caused by the increased number of large immature red cells (reticulocytes) in the peripheral blood following a compensatory increase in red cell production by the bone marrow. Reticulocytes have a characteristic blue tinge with Romanowsky stains and their presence in the film causes ‘polychromasia’. A reticulocyte count is performed either manually on a blood film stained with a supravital stain or by the automated cell counter.

Simple laboratory tests to detect increased breakdown of red cells are also useful indicators of haemolysis. In addition to moderately raised serum bilirubin (often 30–50 mol/L), there may be raised levels of urine urobilinogen and faecal stercobilinogen. Bilirubin itself is unconjugated and therefore does not appear in the urine. Haptoglobin, a glycoprotein bound to free haemoglobin in the plasma, is depleted in haemolysis. In intravascular haemolysis, haemoglobin and haemosiderin can be detected in the urine. Haemosiderin is present for several weeks after a haemolytic episode and is simply demonstrated by staining urine sediment for iron.

Examination of the bone marrow is not usually necessary in the work-up of haemolysis but, where performed, will show an increased number of immature erythroid cells. Formal demonstration of reduced red cell survival by tagging of cells with radioactive chromium (⁵¹Cr) and in vivo surface counting of radioactivity to identify the site of red cell destruction are other possible investigations infrequently performed in practice.

Inherited disorders

Disorders of the red cell membrane

Hereditary spherocytosis

This is the most common cause of inherited haemolytic disease in northern Europeans. The disease is heterogeneous with a variable mode of inheritance. There are many possible gene mutations with alterations in spectrin, ankyrin and other membrane proteins. In a blood film the red cells are spheroidal (‘spherocytes’) with a reduced diameter and more intense staining than normal red cells (Fig 14.2). These abnormal red cells are prone to premature destruction in the microvasculature of the spleen.

Fig 14.2 Hereditary spherocytosis.
Spherocytes in a blood film.

The severity of haemolysis is variable and the disease may present at any age. Fluctuating levels of jaundice and palpable splenomegaly are common features. Occasionally, patients develop severe anaemia associated with the transient marrow suppression of a viral infection; this so-called ‘aplastic crisis’, which may intervene in any form of chronic haemolysis, is often caused by parvovirus B19. Prolonged haemolysis may lead to bilirubin gallstones.

Diagnosis is facilitated by the presence of a family history. The combination of general features of haemolysis and spherocytes in the blood is suggestive of hereditary spherocytosis but not diagnostic as spherocytes may also be seen in autoimmune haemolysis. The two haemolytic disorders are distinguished by the direct antiglobulin test, which is negative in hereditary spherocytosis and nearly always positive in immune haemolysis. Useful screening tests for hereditary spherocytosis include measurement of osmotic fragility (Fig 14.3) and flow cytometric analysis of eosin-5-maleimide binding. In difficult cases, gel electrophoretic analysis of red cell membranes is helpful.

Fig 14.3 Increased osmotic fragility in hereditary spherocytosis.
Spherocytes are more fragile than normal red cells and lyse at higher saline concentrations. The sensitivity of the test is increased by incubating the cells at 37°C.

In patients with milder disease folate supplements are considered but no other treatment is required. In more serious cases the spleen is removed. This should ideally be performed after 6 years of age with counselling regarding the infection risk.

Hereditary elliptocytosis

This is generally a mild disorder with similarities to hereditary spherocytosis. There is a variable deficiency of spectrin tetramers. Red cells are elliptical except in the rare subtype hereditary pyropoikilocytosis when they are more distorted and heat labile. Splenectomy may be indicated for severe haemolysis.

Abnormalities of haemoglobin

These disorders are referred to collectively as the ‘haemoglobinopathies’. Thalassaemia and sickle cell syndromes are discussed in later sections.

Abnormalities of red cell metabolism

The red cell has metabolic pathways to generate energy and also to protect it from oxidant stress (Fig 14.4). Loss of activity of key enzymes may lead to premature destruction; there are two common examples.

Fig 14.4 Schematic diagram of red cell metabolism.
This shows the key roles of pyruvate kinase in the Embden–Meyerhof pathway (the cell’s source of ATP) and glucose-6-phosphate dehydrogenase in the hexose-monophosphate shunt (the cell’s protection from oxidant stress). The broken line represents several intermediate steps.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency

G6PD is a necessary enzyme in the generation of reduced glutathione which protects the red cell from oxidant stress. Deficiency is X-linked, affecting males; female carriers show half normal G6PD levels. The disorder is most common in West Africa, southern Europe, the Middle East and South-East Asia. Patients are usually asymptomatic until increased oxidant stress leads to a severe haemolytic anaemia, often with intravascular destruction of red cells. Common triggers include fava beans, drugs (many, including antimalarials and analgesics) and infections. The disease can alternatively present as jaundice in the neonate. Diagnosis requires demonstration of the enzyme deficiency by direct assay – this should not be done during acute haemolysis as reticulocytes have higher enzyme levels than mature red cells and a ‘false normal’ level may result. Treatment is to stop any offending drug and to support the patient. Blood transfusion may be necessary.

Pyruvate kinase (PK) deficiency

In this autosomal recessive disorder patients lack an enzyme in the Embden–Meyerhof pathway. Red cells are unable to generate adequate ATP and become rigid. All general features of haemolysis can be present, but clinical symptoms are often surprisingly mild for the degree of anaemia as the block in metabolism leads to increased intracellular 2,3-DPG levels facilitating release of oxygen by haemoglobin. Splenectomy may help in reducing transfusion requirements.

Haemolytic anaemia I – general features and inherited disorders

‘Haemolytic anaemias’ are caused by abnormal destruction of red cells.

Most inherited haemolytic disorders have a defect within the red cell while most acquired disorders have the defect outside the cell.

Haemolysis causes characteristic clinical features and laboratory abnormalities. It may be intra- or extravascular.

Hereditary spherocytosis and hereditary elliptocytosis are haemolytic disorders caused by a deficiency in the red cell membrane.

Glucose-6-phosphate dehydrogenase and pyruvate kinase are key enzymes in red cell metabolism; inherited deficiency leads to haemolysis.

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