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22nd July 2024

Haemoglobinopathies

Sickle cell anaemia (SCA)

Overview of sickle cell anaemia

SCA is an autosomal recessive disorder affecting the Hb beta chain, causing HbS to be produced rather than HbA. It is most commonly seen in people of African ethnicity or descent. Sickle trait (HbAS) is protective against malaria.

In the UK, screening is available for pregnant women in high-risk groups, as well as neonatal screening. Children usually only become symptomatic after around 4 months, when HbS production takes over from foetal Hb (HbF). When exposed to reduced oxygen levels HbS deforms and forms sickle cells, which have poorer flow through vessels and can cause occlusion and sickle crises.

Investigations may show chronic haemolysis, anaemia, raised reticulocytes and bilirubin. The blood film shows sickle cells, nucleated RBCs and Howell-Jolly bodies (indicate hyposplenism). A sickle solubility test will be positive; however, electrophoresis is required to confirm the diagnosis and differentiate between HbSS and HbAS.

Long-term complications include anaemia, iron overload (secondary to transfusions), pigment gallstones, avascular necrosis, chronic kidney disease, pulmonary hypertension, hyposplenism, retinopathy and impaired growth.

MRCP Part 2 - Blood film showing characteristic sickle cells

Image Source: Wikimedia Commons (2011). Stomach blood supply, Licensed under a creative commons licence. Available for free at: https://upload.wikimedia.org/wikipedia/commons/7/70/Sickle_Cell_Blood_Smear.JPG (Accessed: 16 January 2024)

Management of chronic sickle cell anaemia

Long-term management of sickle cell disease includes hydroxyurea to reduce HbS levels and increase HbF, prophylactic antibiotics (usually started in childhood), and vaccinations (pneumococcal and influenza) because of functional asplenism (due to repeated splenic infarction) that occurs whilst patients are young and increases the risk of severe infections from encapsulated bacteria.

Management of sickle cell crises

There are multiple acute manifestations of sickle cell anaemia. In general, these crises occur when HbS RBCs deform due to hypoxia, acidosis, dehydration, hypothermia or infection. This produces sickle-shaped cells, which can occlude vessels and are more prone to haemolysis. Patients are often well outside of crises.

A general approach to a patient with sickle cell disease presenting acutely to hospital will aim to identify any potential triggers or early signs of a sickle cell crisis and reduce the risk of patients developing a crisis:

  • Supportive measures: adequate hydration, target sats >94%, keep warm
  • Send a group and save and consider transfusion if the patient is anaemic below their baseline
  • Check blood tests for signs of increased haemolysis
  • Consider sending a HbS%
  • Adequate analgesia
  • Screen for infection and have a low threshold to perform a septic screen and start empirical antibiotics

Key clinical facts about specific types of sickle cell crises are as follows:
Acute chest crisis Episodes can occur with no specific trigger, however they are commonly triggered by infection, vaso-occlusive pain, fat embolism and asthma exacerbations.

It presents with chest pain, shortness of breath, fever, cough and wheeze, and can lead to multiorgan failure if not treated rapidly. Pulmonary infiltrates on chest X-ray are classical but initially may not be present.

Acute management includes analgesia, oxygen, incentive spirometry to prevent further atelectasis, IV antibiotics (typically cefotaxime and azithromycin), RBC transfusion or exchange transfusion to reduce HbS% to <30, and possible early escalation for consideration of non-invasive (NIV) or mechanical ventilation.
Vaso-occlusive (VOC) or painful crisis Microvascular occlusion often triggered by cold, dehydration, hypoxia or infection. Generally affects bones containing marrow, but other sites include mesenteric ischaemia, central nervous system (CNS) (strokes, cognitive impairment or seizures), avascular necrosis of the femoral head, leg ulcers and priapism (urological aspiration and irrigation may be required).

It is important to use the patient’s and their relative’s reports to assess pain. Analgesia should be administered within 30 minutes, and patients often have a personalised treatment plan, however IV morphine can be used if not. Reassessment following this is important as patients may need additional doses. Adequate hydration helps to improve symptoms, and exchange transfusion can be used to treat neurological complications, including an acute stroke, due to a VOC.
Aplastic crisis Bone marrow suppression due to parvovirus B19 infection causing reduction in RBCs and reticulocytes. This is self limiting and usually resolves within 14 days, but supportive RBC transfusion may be needed.
Sequestration crisis Pooling of blood, often in the spleen or liver, which worsens anaemia and can cause hypovolaemic shock. This often occurs in children whose spleens have not yet infarcted and become fibrotic. Viral infections can be a trigger.

Management includes fluid resuscitation and cautious RBC transfusion (sequestered blood may re-enter the circulation and lead to hyperviscosity).
Haemolytic crisis A rapid fall in Hb due to haemolysis, which can be associated with infections and other sickle crises. Management involves RBC transfusions and treatment of the underlying cause.

Thalassaemia

Thalassaemias are disorders of haemoglobin production with a reduced production of one type of globin chain (alpha or beta). This leads to an excess of the unaffected chain, which ultimately damages RBCs in the bone marrow and causes haemolysis. Thalassaemia is more common in patients from the Mediterranean, northern Africa and parts of the Middle and Far East.

FBC will show a microcytic anaemia, with blood film findings including tear drop cells, target cells and nucleated RBCs. Raised bilirubin, LDH and reticulocytes indicate haemolysis.

Beta thalassaemia

Mutations of the beta globin gene on chromosome 11 lead to β⁺ (reduced beta chain production) or β⁰ (absence of beta chain production). Various combinations of mutations are possible leading to different phenotypes.

Beta thalassaemia major (two defective genes)

This presents in early childhood with impaired growth, abdominal distention (hepatosplenomegaly), frontal bossing of the skull (extramedullary haematopoesis) and severe anaemia.

Hb electrophoresis shows significantly reduced or absent HbA (adult haemoglobin, the most common haemoglobin tetramer), with elevated HbF and HbA₂. X-rays of the skull can show the ‘hair-on-end’ sign due to bone marrow hyperplasia and widening of the medullary cavity in order to aid haematopoesis (this can also be seen, but generally to a lesser extent, in other causes of bone marrow hyperplasia, e.g. hereditary spherocytosis and sickle cell disease). Genetic testing is used to confirm the diagnosis and evaluate the nature of the mutation and can also be used to assess for carrier status in relatives.

Patients need lifelong RBC transfusions (2-4 weekly) to reduce extramedullary haematopoeisis and, therefore, need to be monitored for iron overload with 3-monthly ferritin levels. If iron chelation is indicated (criteria include ferritin >1000 ug/L, liver iron concentration >3 mg/g of dry weight on MRI, cardiac T2* <20 ms), subcutaneous (SC) desferrioxamine is first line, and patients should undergo 3-monthly monitoring of side effects including visual and auditory neurotoxicity, growth impairment, renal and liver failure and increased susceptibility to Yersinia infections.

Splenectomy is indicated if there are increasing transfusion requirements. Hydroxycarbamide can increase HbF and improve symptoms. Bone marrow transplantation offers a cure but is rarely done due to the associated risks.

Beta thalassaemia intermedia (mild homozygous mutations or heterozygotes with another haemoglobinopathy)

This causes moderate anaemia but patients are not usually transfusion dependent.

Beta thalassaemia minor or trait (heterozygous with one functioning gene)

Patients are usually asymptomatic, although Hb can drop in pregnancy. They are likely to have mild anaemia, with a similar picture to iron deficiency but with significantly low MCV (< 75). Electrophoresis shows HbA2 >3.5% with a mildly raised HbF.

Alpha thalassaemia

Alpha globin chains are coded for by two separate genes on each copy of chromosome 16 (normal alleles are designated αα/αα). There are 4 distinct phenotypes of alpha thalassaemia:

  • Silent carrier (1 affected gene): asymptomatic with normal Hb
  • Alpha thalassaemia trait (2 affected genes): asymptomatic with mild microcytic anaemia
  • HbH disease (3 affected genes): moderate anaemia and haemolysis with jaundice and hepatosplenomegaly, and failure to thrive in infancy
  • Hb Bart or hydrops fetalis syndrome (deletion of all 4 alpha globin genes): death in utero

References

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