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22nd July 2024

Haemolytic anaemia

Overview of haemolytic anaemia

This is anaemia secondary to premature destruction of RBCs. It can range in severity and be acute or chronic. There are various underlying causes, but useful distinctions include whether or not the process is immune-system driven and whether it occurs in intra- or extravascular space(s), the latter including the spleen, liver and bone marrow. If haemolysis is not compensated for by increased RBC production, then it is likely to cause symptomatic anaemia with fatigue and jaundice.

Results indicating a haemolytic process include raised reticulocytes, low haptoglobin (this binds to free haem released from lysed RBCs), raised LDH (lactate dehydrogenase) and raised unconjugated bilirubin.

Intravascular haemolysis is suggested by positive urinary tests:

  • Haemoglobinuria: free haemoglobin rather than whole RBCs
  • Haemosiderinuria: free haemoglobin which has been filtered and stored as haemosiderin in the renal tubules is then excreted in the urine; this can stay positive for ~1 week

Splenomegaly is associated with extravascular haemolysis, and patients may have a history of recurrent pigment gallstones due to excess unconjugated bilirubin.

Hereditary haemolysis

RBC membrane defects

Hereditary spherocytosis

An autosomal dominant condition most prevalent in people descended from Northern Europe. There is a deficiency of cell membrane proteins leading to a more spherical RBC compared to the normal biconcave shape, with a raised mean corpuscular haemoglobin concentration (MCHC) (typically >36 g/dL). The abnormal RBCs, called spherocytes (Figure 5) have a reduced lifespan as well as reduced mechanical stability and deformability, which can cause membrane loss and phagocytosis within the spleen. In turn, this leads to an even more spherical shape and reduced mobility through the circulation leading to haemolysis.

A diagnosis can be made clinically and patients often have a family history as well as bloods consistent with a chronic haemolytic anaemia. If there is uncertainty, the specific EMA (eosin-5′-maleimide) binding test can be used. Osmotic fragility testing is possible but has poor sensitivity and specificity. Acute exacerbations can occur secondary to infection, nutritional deficiencies or pregnancy, due to either increased haemolysis or inadequate RBC production.

Treatment aims to minimise complications and may include folic acid supplementation, RBC transfusions, erythropoietin, splenectomy and cholecystectomy (patients are at risk of pigment gallstones made up of bilirubin). Following splenectomy patients will have signs of reduced splenic function, for example Howell-Jolly bodies (nuclear remnants within RBCs) and are more at risk of infection from encapsulated bacteria.

Hereditary elliptocytosis

An autosomal dominant condition with a similar pathophysiology to hereditary spherocytosis, but is rarer and often asymptomatic or causes only mild disease.

MRCP Part 2 - Blood film showing spherocytes with no central pallor

Image Source: Wikimedia Commons (2010). Hereditary Spherocytosis smear 2010-03-17, Licensed under a creative commons licence. Available for free at: https://upload.wikimedia.org/wikipedia/commons/6/69/Hereditary_Spherocytosis_smear_2010-03-17.JPG (Accessed: 16 January 2024)

Enzyme deficiencies

Glucose-6-phosphate dehydrogenase (G6PD) deficiency

G6PD deficiency is an X-linked recessive condition, which therefore generally affects males, often of Mediterranean, African or middle and far Eastern descent. There is mainly intravascular haemolysis.

It can present in the newborn, commonly with neonatal jaundice, or with episodes of acute haemolysis secondary to triggers including ​​drugs (primaquine, sulfonamides, henna dye), fava beans and intercurrent illness, or with chronic haemolytic anaemia.

Investigations include those mentioned previously to assess for haemolysis. The blood film may show bite cells (semicircular indent on RBC) and blister cells (vacuole on the edge of the RBC membrane), and Heinz bodies. A G6PD enzyme assay should be performed. This needs to be done 8-12 weeks after an acute haemolytic crisis to avoid a falsely elevated result, as reticulocytes have high levels of the enzyme, but levels decrease as RBCs mature.

Treatments include RBC transfusion if symptomatic anaemia or severe haemolysis and avoidance of triggers.

Pyruvate kinase (PK) deficiency

This is an autosomal recessive condition which often presents with neonatal jaundice, followed by unexplained chronic anaemia later in life with splenomegaly ± gallstones. There is mainly extravascular haemolysis.

Investigations include an enzyme assay to assess PK activity as well as genetic testing.

Treatment is often supportive with folic acid and RBC transfusions if needed. Splenectomy can help reduce haemolysis if there is severe disease.

Haemoglobinopathies

These include thalassaemia and sickle cell anaemia.

Acquired haemolysis

Autoimmune haemolytic anaemia (AIHA)

In AIHA, extravascular haemolysis occurs due to the presence of autoantibodies against RBCs. This is categorised as either warm or cold AIHA according to the temperature at which this occurs.

Haemolytic markers are raised, and a positive Coombs test is expected.

 
Warm AIHA Cold agglutinin disease (most common cold AIHA)
Mediated by IgG – binds to RBC antigens at ~37°C Mediated by IgM – bind to RBC antigens at <4°C
Commonly idiopathic or can be secondary to lymphoproliferative or autoimmune disease Can be idiopathic or secondary to lymphoproliferative disease or infection
May present with symptomatic anaemia

Chronic compensated haemolysis, jaundice and splenomegaly are common

 Often presents with symptoms induced by exposure to cold temperatures, e.g. acrocyanosis

Chronic compensated haemolysis
Spherocytes are seen due to RBC membrane destruction by splenic phagocytes No significant spherocytosis as the haemolysis is due to complement activation, which leads to phagocytosis of the whole RBC
First-line treatment is oral steroids (prednisolone 1 mg/kg) and consideration of rituximab

Second-line treatment includes other immunosuppressants (e.g. azathioprine or cyclophosphamide) or IVIg

Splenectomy can be considered in resistant cases

Treatment of the underlying cause can improve symptoms but may take some time to have an effect

 First-line treatment is rituximab and warm RBC transfusion if severe anaemia

Other treatments include avoidance of cold conditions, treatment of the underlying disorder or plasmapheresis in severe cases

Drug-induced haemolysis

Many drugs have been found to cause haemolysis, and these can occur by immune (i.e. AIHA) or non-immune mechanisms. Examples include penicillins, cephalosporins, NSAIDs, sulfasalazine, quinine and rifampicin.

Microangiopathic haemolytic anaemia (MAHA)

This is a type of intravascular haemolysis where RBCs are damaged and haemolyse due to mechanical damage whilst circulating. This can be caused by endothelial abnormalities within blood vessels leading to microthrombi, which causes trauma to the RBCs.

Causes include disseminated intravascular coagulation (DIC), haemolytic uraemic syndrome (HUS), thrombotic thrombocytopaenic purpura (TTP), eclampsia/HELLP (haemolysis, elevated liver enzymes and low platelets) syndrome, mechanical valves and vasculitides.

The blood film will show schistocytes (a fragmented part of an RBC) (Figure 6) and there is marked reticulocytosis.

Clinically, it can present differently depending on the primary cause, and treatment will depend on the diagnosis.

MRCP Part 2 - Blood film with arrows highlighting examples of schistocytes

Image Source: Wikimedia Commons (2014). Microangiopathic haemolytic anaemia_(Schistocytes_and_spherocytes, Licensed under a creative commons licence. Available for free at: https://commons.wikimedia.org/wiki/File:Microangiopathic_haemolytic_anaemia_(Schistocytes_and_spherocytes).jpg (Accessed: 16 January 2024)

Thrombotic thrombocytopaenic purpura

This is often thought of as a pentad of clinical features: haemolytic anaemia, thrombocytopaenia, renal injury, fever and neurological symptoms.

Reduced functional levels of ADAMTS13 (the enzyme that cleaves large multimers of von Willebrand factor, vWF, into smaller molecules) leads to platelet aggregation on the endothelium of small vessels and, therefore, thrombosis. This causes thrombocytopaenia due to increased platelet consumption. This can be acquired (with autoantibodies directed at ADAMTS13) or a hereditary deficiency of the enzyme. Levels can be checked, however treatment will need to be instigated urgently before results are available.

First-line treatment is plasma exchange, and medical treatment can include glucocorticoids, rituximab and caplacizumab (anti-vWF).

Haemolytic uraemic syndrome

This is defined by the triad of microangiopathic haemolytic anaemia, thrombocytopaenia and acute kidney injury.

It is more commonly found in children than in adults and is predominantly caused by shiga toxin-producing E. coli (STEC) 0157:H7, and mostly associated with diarrhoea, although this usually resolves prior to the development of other features. This can be confirmed with a stool culture or PCR for STEC and a stool assay for shiga toxin.

The infection is self resolving, and treatment is mostly supportive with IV fluid replacement, RBC or platelet transfusion and dialysis if required. In severe or atypical cases other treatments may be required, depending on the underlying cause. HUS is a notifiable disease.

Infections

A variety of infections can cause haemolytic anaemia. These include malaria (most commonly falciparum), babesiosis, bartonellosis and viral infections (e.g. dengue, yellow fever, Epstein-Barr virus, EBV).

Paroxysmal nocturnal haemoglobinuria (PNH)

PNH is a rare, acquired clonal abnormality in haematopoietic stem cells, which have reduced complement inhibitors (CD55 and CD 59) on their surface. This leaves cells derived from these stem cells prone to haemolysis through the complement system.

Patients can present with a wide range of symptoms, classically with more noticeable dark urine in the morning (although haemolysis does occur at lower levels throughout the day as well), symptomatic anaemia, jaundice, and unusual sites of venous thrombosis (e.g. abdominal or cerebral). It can also be associated with bone marrow failure and, therefore, symptoms of pancytopaenia such as recurrent infection, bleeding or bruising.

Specific investigations for PNH include sending blood for flow cytometry to detect reductions in CD55 and CD59 and bone marrow biopsy to evaluate any degree of bone marrow failure.

Treatment options include eculizumab (anti-complement monoclonal antibody) and anticoagulation and in patients with co-existing bone marrow failure, stem cell transplant is a curative option.

References

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