Haematology - Red cell membrane disorders

The features of these disorders and an overview of management. By Dr Andrew Hearn and Professor Swee Lay Thein.

Jaundice is commonly seen in patients with hereditary spherocytosis (Photo: SPL)
Jaundice is commonly seen in patients with hereditary spherocytosis (Photo: SPL)

In order to pass through the tightest points of the capillary network, red blood cells (RBCs) must be able to change in morphology, mediated by the high elasticity of the membrane. Any abnormality results in a reduced ability to pass through these tight capillaries, as well as loss of the biconcave shape that is essential for optimal oxygen delivery.

Red cell membrane disorders can be divided into those resulting from structural protein loss (hereditary spherocytosis (HS), hereditary elliptocytosis (HE) and hereditary ovalocytosis) and membrane transport dysfunction (hereditary stomatocytosis).

All RBC membrane disorders share common features: loss of surface area, change in morphology and the resultant tendency to splenic sequestration and extravascular haemolysis resulting in chronic anaemia of variable severity.1-3

Hereditary spherocytosis
HS is the most common red cell membranopathy in developed countries, with a prevalence of one in 2,000 to one in 5,000.1,2 It is recognisable by the typical blood film appearance of dense spherical RBC.

Autosomal dominant mutations predominate (75%), with recessive forms leading to more severe phenotypes. The condition is more common in people of northern European origin and highly variable in severity.

In its mild form, the haemolysis is well compensated such that patients have normal or very mildly reduced Hb (11-15g/dl) and mild reticulocytosis (3-6%). These patients are likely to represent the majority but will often be missed due to the near normal appearance of their FBC, and will tend to present late in life with gall stones predisposed by the chronic increase in bilirubin.3

Patients with moderately severe anaemia account for about 60% of identified cases. Typically these patients have Hb 8-11g/dl and a reticulocyte count >8%. Splenomegaly becomes detectable during childhood.1,2 Gall stones and jaundice are common and incidence of cholecystectomy is high.2

Hereditary elliptocytosis
HE is characterised by the presence of elliptical RBC secondary to a highly unstable membrane.

HE is relatively less common than HS in white patients, but equal in frequency to HS in black African populations. Similar to sickle cell disease, its distribution mirrors that of malaria,1,2 indicating that elliptocytes confer a survival advantage in the form of malarial resistance.

Like HS, its presentation ranges from incidental findings on blood profiles to death in utero.

However, most patients are asymptomatic, with only 10% displaying a severe phenotype.1,3

Hereditary ovalocytosis
Hereditary ovalocytosis is most prevalent in south-east Asia. It is characterised on blood film by presence of oval RBC with up to two longitudinal ridges or slits due to increased rigidity of the membrane.1

Hereditary stomatocytosis
Hereditary stomatocytosis is rare. It is characterised by large stomatocytes on blood films, with moderate to severe anaemia. More commonly, the blood film is unremarkable apart from macrocytosis and polychromasia. Pseudohyperkalaemia may occur due to rapid leakage of potassium ions from RBC at room temperature. Splenomegaly, if present, is moderate.

A major complication for patients is iron overload due to increased GI absorption.

Management options
The primary care physician needs to rule out a red cell membranopathy in patients with a positive family history of haemolytic anaemia. Autoimmune haemolysis must first be ruled out with a negative direct antiglobulin test.

Patients then require a blood film for diagnosis. Management depends on the severity of the anaemia. Patients with a known red cell membranopathy of mild severity require little management but the clinician should be alert to their predisposition to gall stones. Co-inheritance of Gilbert's syndrome (present in about 30% of individuals) further increases predisposition to gall stones.

Patients presenting at an early age or with severe anaemia require referral to specialist haematology services. Well-compensated anaemias are safely managed in primary care. All patients require folate supplementation.

Splenectomy reduces the severity of anaemia in HS and HE. Patients with moderately severe HS warrant splenectomy before puberty; those with severe HS will require splenectomy after the age of six.2 Splenectomy is contraindicated in some HS patients, however.

Post splenectomy patients require immunisation against pneumococcus and prophylactic antibiotics.

  • Dr Hearn is a second year academic foundation doctor and Professor Thein is consultant haematologist and professor of molecular haematology, King's College Hospital, London

REFERENCES

1. An X, Mohandas N. Br J Haematol 2008; 141: 367-75.

2. Barcellini W, Bianchi P, Fermo E et al. Blood Transfus 2011; 9: 274-7.

3. Gordon-Smith EC, Mohandas N. Hereditary disorders of the red cell membrane. In: Green AR, Hoffbrand AV, Catovsky D et al (eds). Postgraduate Haematology. Oxford, Wiley-Blackwell, 2010.

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