Haemolytic anaemia
Haemolytic anaemia

Haemolytic anaemia

Haemolytic anaemia is a form of anaemia resulting from destruction of RBCs. It can be caused by inherited conditions and acquired conditions both:

Inherited haemolytic anaemias

  1. Spherocytosis
  2. Elliptocytosis
  3. Thalassaemia
  4. Sickle cell anaemia
  5. G6PD deficiency

Acquired haemolytic anaemias

  1. Autoimmune haemolytic anaemia (AIHA)
    1. Warm AIHA
    2. Cold AIHA
  2. Paroxysmal nocturnal haemoglobinuria
  3. MAHA
  4. Prosthetic valve haemolysis

Haemolysis can be either intravascular or extra vascular:

  • Intravascular - destruction of RBCs due to complement-mediated lysis.
  • Extravascular - destruction of RBCs by the reticuloendothelial system due to antibodies targeting them.
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We can also classify haemolytic anaemias as either Coombs positive or Coombs negative:

Coombs positive haemolytic anaemias

  • AIHA
  • Haemolytic disease of newborn
  • Acute haemolytic transfusion reaction

Coombs negative haemolytic anaemias

  • MAHA
  • Prosthetic valve haemolysis
  • Paroxysmal nocturnal haemoglobinuria
  • Malarial haemolysis
  • Hypersplenism
  • Drug-induced haemolysis

😷 Presentation

These are generalised symptoms applicable to most haemolytic anaemias. We will discuss the symptoms of the specific haemolytic anaemias further…

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  • Pallor
  • Jaundice - due to increased RBC destruction.
  • Fatigue
  • Dyspnoea
  • Dizziness
  • Splenomegaly
  • Haemoglobinuria - dark urine
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HEREDITARY SPHEROCYTOSIS/ELIPTOCYTOSIS
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The RBC cytoskeleton is made up of multiple proteins that allow it to maintain its biconcave shape. This shape enables it to pass through vessels and capillaries. Any defect in the membrane may change the shape, causing it to become spherical and this reduces its flexibility. These spherical RBCs are known as spherocytes. Elliptocytosis is very similar, but instead the RBCs are oval in shape. It is autosomal dominant but other than that the presentation and treatment is the same as HS.

Spherocytes are fragile. The spleen also selectively destroys these, increasing the rate of RBC destruction. This leads to splenomegaly, hyperbilirubinaemia and a raised reticulocyte count.

Defects may occur in any of the 5 different membrane skeleton proteins:

  1. Alpha-spectrin
  2. Beta-spectrin
  3. Ankyrin
  1. Band 3 protein
  2. Protein 4.2

⚠️ Risk factors

  • Family history - 75% of cases are dominantly inherited.
  • Northern European ancestry

😷 Presentation

It can range from asymptomatic all the way up to transfusion-dependant anaemia:

  • Fatigue
  • Pallor
  • Jaundice - due to hyperbilirubinaemia.
  • Splenomegaly

If there is a recent parvovirus infection → aplastic crisis.

🔍 Investigations

Plenty of blood tests may be ordered to check for signs of anaemia (non-specifically):

  1. FBC
    1. Hb - may be reduced (or normal).
    2. MCV - may be reduced (or normal).
    3. MCHC - elevated.
  2. Reticulocyte count - elevated.
  3. Blood smear - shows the presence of spherocytes (absence of central pallor). It is important to remember that spherocytes is not limited to hereditary spherocytosis only.
  4. Serum bilirubin and aminotransferases - elevated levels of unconjugated bilirubin will be present and usually normal levels of amintoransferases.
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⭐️ A positive family history, typical features on blood smear and elevated MCHC and reticulocytes usually are sufficient to diagnose HS. However, there are some confirmatory tests that may be done (but not necessary).

  • Eosin-5-maleimide binding test - identifies band 3 protein defects.
  • Acidified glycerol lysis test
  • Sodium dodecyl sulfate-polyacrylamide gel electrophoresis - for identification of the protein abnormality.
  • Genetic analysis

🔢 Classification

We can classify HS clinically by the severity. There are 4 classifications: trait, mild, moderate, severe.

Trait

  • Hb - normal
  • Reticulocytes - <3%
  • Bilirubin - <17umol/L
  • Splenectomy - not required

Mild

  • Hb - 110-150g/L
  • Reticulocytes - 3-6%
  • Bilirubin - 17-34umol/L
  • Splenectomy - not required

Moderate

  • Hb - 80–120g/L
  • Reticulocytes - >6%
  • Bilirubin - >34umol/L
  • Splenectomy - may be necessary before puberty.

Severe

  • Hb - <60-80g/L
  • Reticulocytes - >10%
  • Bilirubin - >51umol/L
  • Splenectomy - necessary (delay until 6 years old if possible).

🧰 Management

Treatment is generally supportive treatment. Transfusion may be given in times of haemolytic crisis.

Long term management includes:

  1. Folate supplementation
  2. Splenectomy
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G6PD DEFICIENCY
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G6PD is another inherited form of haemolytic anaemia that arises due to metabolic stress on RBCs.

Glucose is converted to glucose-6-phosphate (66P) in glycolysis. G6P can be converted to either pyruvate or it can be converted to 6-phosphogluconate in the pentose-phosphate shunt pathway using the enzyme G6PD (glucose-6-phosphate dehydrogenase). In this same reaction, NADP is reduced to NADPH. NADPH is in turn used to produce glutathione.

Glutathione is extremely important as it is the only source of protection for RBCs against oxidative stress. It is a sacrificial molecule that can withstand the stress. In G6PD deficiency, we are unable to generate this NADPH and glutathione → haemolysis.

⚠️ Risk factors

  • Male sex - as it is X-linked.
  • Mediterranean, sub-Saharan Africa, Middle East or Southeast Asian ethnicity
  • Family history
  • Oxidative drugs - we will discuss these further below.
  • Infection - increases oxidative stress on RBCs.
  • Fava beans (broad beans)

😷 Presentation

  1. Neonatal jaundice is often the first presentation of G6PD deficiency.
  2. Dark urine - suggests that there has been intravascular haemolysis.
  3. Pallor
  4. Nausea
  5. Gallstones - due to increased levels of bilirubin due to RBC turnover.
  6. Splenomegaly
  7. Heinz bodies, bite cells, blister cells - these may be seen on peripheral blood smear.
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🔍 Investigations

🏆 G6PD enzyme assay is the gold-standard diagnostic test. Levels are checked 3 months after an acute episode of haemolysis (this is because the RBCs with the most severe reduction of G6PD will have haemolysed and thus this can produce false negatives if checked at the time as the remaining RBCs will be somewhat normal in comparison).

A peripheral blood smear may show Heinz bodies (denatured Hb), blister cells or bite cells as previously mentioned.

🥇 FBC, reticulocyte count, urinalysis, unconjugated bilirubin, lactate dehydrogenase are all first-line options which may show signs of haemolytic anaemia.

🧰 Management

Supportive treatment should be ongoing (fluid intake, diet, antiemetics etc.).

Folic acid supplementation is usually required to promote RBC production.

In cases of acute haemolysis with an Hb <70g/L → transfusion may be provided.

Neonatal jaundice can be managed using phototherapy which essentially converts insoluble unconjugated bilirubin into a water-soluble isomer.

🚨 Triggers

It is important to remember triggers of acute haemolysis in G6PD deficiency, especially for exams.

Antimalarials
Antimicrobials
Infections
Other
Primaquine
Dapsone
Malaria
Fava beans
Ciprofloxacin
Sulph drugs (sulphonamides, sulfonylureas, sulfasalazine)

Antibiotics that may be safe in these individuals include: penicillins, cephalosporins, macrolides, tetracyclines, trimethoprim.

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AUTOIMMUNE HAEMOLYTIC ANAEMIA (AIHA)

AIHA is an autoimmune case of haemolysis due to autoantibodies targeting RBCs. We can divide it into 2 types based on the temperature at which they autoantibodies cause haemolysis:

  1. Warm AIHA
  2. Cold AIHA

They are most commonly idiopathic, but may be secondary to infection, drugs or lymphoproliferative disorders.

Warm AIHA

The most common type. In this case, IgG autoantibodies function best at warmer conditions (around body temperature).

The haemolysis tends to be extravascular (i.e. in the spleen).

It is mostly idiopathic, but other causes of warm AIHA include:

  • Autoimmune conditions - SLE
  • Lymphoproliferative disorders - lymphoma, chronic lymphocytic leukaemia.
  • Drugs - methyldopa, cephalosporins, diclofenac, rifampicin, oxaliplatin.

🔍 Investigations

🥇 FBC, reticulocyte count, urinalysis, unconjugated bilirubin, lactate dehydrogenase are all first-line options which may show signs of haemolytic anaemia.

  • Coombs test positive
    • IgG is suggestive of a warm antibody.
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🧰 Management

  1. 🥇Treatment of underlying disorder
  2. 🥇 Corticosteroids such as prednisolone or dexamethasone
    1. Rituximab can also be given first-line or to patients refractory to corticosteroid therapy
  3. Splenectomy may be considered if patients still do not responds.

Cold AIHA

Also known as cold agglutinin disease. It occurs at temperatures less than 10ºC typically (mostly at 4ºC supposedly). IgM autoantibodies cause agglutination of RBCs which causes haemolysis by the spleen once again but also can activate complement-mediated intravascular haemolysis.

It is typically secondary to conditions such as

  • Lymphoproliferative disorders - lymphoma, leukaemia.
  • Autoimmune conditions - SLE.
  • Infections - mycoplasma, EBV, CMV, HIV.

🔍 Investigations

🥇 FBC, reticulocyte count, urinalysis, unconjugated bilirubin, lactate dehydrogenase are all first-line options which may show signs of haemolytic anaemia.

  • Coombs test positive
    • C3d (complement protein) is suggestive of cold antibody.

🧰 Management

  1. 🥇Treatment of underlying disorder
  2. 🥇 Corticosteroid* such as prednisolone or dexamethasone
    1. Rituximab can also be given first-line or to patients refractory to corticosteroid therapy
  3. Splenectomy may be considered if patients still do not responds.

Patients respond less well to steroids typically.

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PAROXYSMAL NOCTURNAL HAEMOGLOBINURIA (PNH)

PNH is a rare, acquired haematological disorder that results in intravascular haemolysis and thrombophilia.

Pathophysiology

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There is a mutation in the PIG-A gene which codes for the enzyme needed to produce the glycosylphosphatidylinositol anchor. This anchor is found on RBCs and is used to inhibit the complement cascade. However, as this anchor is lost, complement is uninhibited → intravascular haemolysis.

There is an exaggerated activation of complement at night which causes the nocturnal exacerbations.

Haemoglobinaemia results in nitric oxide (NO) binding in tissues which causes smooth muscle contraction → oesophageal spasm and abdominal cramps. NO deprivation can also lead to erectile dysfunction, pulmonary hypertension and renal failure (which is also exacerbated with haemoglobinuric episodes) due to impaired vasodilation.

Complement activation on platelets missing this anchor results in platelet activation → thrombosis (primarily venous but arterial thrombosis may occur).

😷 Presentation

  • Haemoglobinuria - dark urine is the presenting symptom in about 20% of patients. It is often paroxysmal, lasting 2-6 days or can be exacerbated with infections. Due to complement exacerbation at night it can be nocturnal in its presentation (hence the name).
  • Budd-Chiari syndrome - hepatic vein thrombosis → RUQ pain, hepatomegaly, ascites. Occurs in about 10% of PNH patients.
  • Thrombosis - most typically venous (e.g. DVT, hepatic vein, PE), but often in uncommon sites as well.
  • Aplastic anaemia
  • Fatigue - this is because 90% of PNH patients are anaemia with severe intravascular haemolysis. There is also concomitant iron deficiency and bone marrow hypoplasia (as complement attacks HSCs).
  • Abdominal pain - due to smooth muscle dystonia.
  • Dysphagia/odynophagia - due to smooth muscle dystonia.
  • Erectile dysfunction
  • Dyspnoea - if it has manifested pulmonary hypertension.

🔍 Investigations

  1. Urinalysis - shows haemoglobinuria.
    1. Urine microscopy can also show haemosiderinuria due to intravascular haemolysis.
  2. FBC - may indicate anaemia but also leukopenia and thrombocytopenia.
  3. Reticulocyte count - elevated.
  4. Serum lactate dehydrogenase - elevated. It indicates some form of tissue damage (in this case intravascular haemolysis).
  5. Unconjugated bilirubin - elevated.
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🏆 The most sensitive and accurate test is flow cytometry with fluorescent aerolysin (FLAER).

🧰 Management

🥇 Eculizumab - a MAB targeting the C5 component to prevent intravascular haemolysis through suppression of the complement system.

Bone marrow transplantation may be a curative option for patients who do not respond to MAB therapy.

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MICROANGIOPATHIC HAEMOLYTIC ANAEMIA (MAHA)

MAHA occurs when there are structural abnormalities in small vessels that damage the RBCs. It results from physical damage to the red cells following the occlusion of arterioles and capillaries as a result of fibrin deposition or platelet aggregation. Excessive shearing or turbulent circulation leads to the damage of RBCs.

It usually is secondary to conditions such as:

  1. Haemolytic uraemic syndrome
  2. DIC
  3. Thrombotic thrombocytopenic purpura
  4. SLE
  5. Cancer
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PROSTHETIC VALVE HAEMOLYSIS

This is more so a complication than anything. Both bioprosthetic and metallic heart valves can lead to haemolysis due to turbulence of RBCs within the implanted valve.

Cardiology review may be needed if it continues to worsen, otherwise the management includes:

  • Monitoring
  • Iron supplementation
  • Blood transfusion

⭐️ The recommended INR range for prosthetic valves is 2.5 - 3.5.