Normocytic normochromic anaemia is a type of anaemia in which the red blood cells (RBCs) have a normal size (normocytic) and normal colour (normochromic) but are few and cannot function properly.¹ Haemolysis is the early destruction of red blood cells in the body. It is one of the common causes of normocytic anaemia.²

Normocytic anaemia has two types:

• Non-haemolytic anaemias
• Haemolytic anaemias

Haemolytic anaemias are further classified according to:

• The cause of haemolysis (intrinsic and extrinsic to the RBCs, i.e., inside or outside of RBCs)
• The location of haemolysis (may be intravascular or extravascular, meaning inside the blood vessels or in organs such as the spleen and liver)²

In this article, we will understand the two significant types of haemolytic normocytic anaemias: autoimmune haemolytic anaemia and hereditary spherocytosis. We are going to learn all about their signs, symptoms, types, and treatments.

What is haemolysis?

Haemolysis is defined as ‘haeme’, meaning red blood cells, and ‘lysis’, meaning destruction. In haemolysis, the RBCs are destroyed earlier than their average lifespan.

By BruceBlaus. When using this image in external sources it can be cited as:Blausen.com staff (2014). "Medical gallery of Blausen Medical 2014". WikiJournal of Medicine 1 (2). DOI:10.15347/wjm/2014.010. ISSN 2002-4436. - Own work, CC BY 3.0, Link

The RBCs are produced in the bone marrow. After maturing, they start circulating in the bloodstream. Red blood cells have an average circulating life span of 115 -120 days.²  When their average life span is completed, they are damaged and worn out. They are then eaten by macrophages and undergo lysis in the liver, spleen, and bone marrow. 

Haemolysis and normocytic anaemia 

How does early red blood cell destruction cause anaemia?

In haemolytic normocytic anaemia, the RBCs are broken down before their average life span, causing a low number of circulating RBCs. They are destroyed faster than they can be produced and replaced, leading to decreased oxygen supply to the body organs and tissues, which can lead to anaemia.²

In normocytic anaemia, the mean corpuscular volume (MCV), which tells us about the size of RBCs, is within the normal range between 80-100 fL. Haemolytic anaemia is characterised by low haemoglobin (Hb) in RBCs. Haemoglobin is a protein responsible for carrying oxygen to the body tissues. Haemolytic anaemia occurs due to the early destruction of Hb in the RBCs.² The World Health Organisation (WHO) criteria for anaemia are Hb less than 13g/dl in men and less than 12g/dl in women.

Symptoms of haemolytic normocytic anaemia²

• Fatigue
• Pale skin
• Shortness of breath
• Weakness
• Jaundice (yellowish skin due to low Hb)
• Haemoglobinuria 
• Inability to do physical activities 

Autoimmune haemolytic anaemia (AIHA)

What is autoimmune haemolytic anaemia?

Autoimmune haemolytic anaemia (AIHA) is a rare immune disorder found in people all around the world. In AIHA, the body produces antibodies that mistakenly target and attack its red blood cells.³ It happens when the body mistakes them for foreign substances and destroys them, leading to a lower number of RBCs in the circulating blood (anaemia).³

Treatment of AIHA is done after determining the cause and type of the underlying condition. AIHA is life-threatening if not treated on time, so early diagnosis and treatment are important.³

What is primary and secondary autoimmune haemolytic anaemia AIHA?

AIHA can be classified into two types based on the cause of the disease. If AIHA is present without any other associated conditions, then it is known as primary autoimmune haemolytic anaemia.³

AIHA is called secondary autoimmune haemolytic anaemia when it is associated with other ongoing conditions in the body. It can be present with a blood cancer such as lymphoma, medications such as cephalosporins, a viral infection or other immune disorders.³

Secondary autoimmune haemolytic anaemia is often associated with the following conditions:³

• autoimmune disorders, the most common of which is systemic lupus erythematosus or lupus (SLE)
• chronic lymphocytic leukaemia (CLL)
• epstein-Barr virus (EBV)
• cytomegalovirus (CMV)
• non-Hodgkin lymphoma (NHL) and other blood cancers
• human immunodeficiency virus (HIV)
• hepatitis

What are the three different types of autoimmune haemolytic anaemia AIHA?

There are three main types of AIHA depending on the temperature at which the autoantibodies and the complement systems are most active in the destruction of red blood cells. A positive result in the direct agglutinin test (DAT) confirms the presence of antibodies in the following types:³

• Warm AIHA
• Cold AIHA
• Mixed AIHA

By SA1590 - Own work, CC BY-SA 4.0, Link

Warm AIHA

In warm AIHA, the IgG antibodies bind with red blood cells at body temperature 38 degrees Fahrenheit and destroy them extravascularly in the spleen, leading to haemolysis.³ It is the most common type of primary AIHA and accounts for almost two-thirds of all cases.³

It is often seen in SLE and CLL and with certain drugs (e.g. beta-lactams and methyldopa).

Common features³

• Gradual onset
• Pale skin
• Fatigue 
• Headache 
• Jaundice 
• Splenomegaly (enlarged spleen)
• Positive DAT with IgG, C3d, or both³

Treatment³ 

• Glucocorticoids
• Steroids 
• Intravenous immunoglobulins (IVIG)
• Rituximab (when steroids no longer work)
• Splenectomy (if refractory, i.e. not responding to treatment)

Cold AIHA or cold agglutinin disease (CAD)

Cold AIHA occurs mostly in people older than 50 years.³ In this type, the IgM antibodies react with RBCs at lower temperatures and cause extravascular haemolysis.³

Cold AIHA can become active when hands and feet are at lower temperatures, such as 32- 50 degrees Fahrenheit (0 to 15 degrees Celsius).²

Cold agglutinin syndrome is a secondary condition of cold AIHA and is associated with CLL, Mycoplasma pneumoniae infections, infectious mononucleosis, and other autoimmune disorders.³

Common features³

• Breathing difficulties 
• Jaundice 
• Raynaud’s phenomenon
• Chest pain
• Headache 
• Acrocyanosis (discolouration of hands and limbs)
• Sudden onset of symptoms in cold temperatures
• DAT positive with C3d only 

Treatment³

• Avoid cold temperatures
• Keep the body warm
• Rituximab 

Mixed AIHA

It is marked by the presence of both warm and cold-type autoantibodies (IgG, IgM, and complement C3d) that destroy RBCs at various temperatures.³ It is a rare condition and is often idiopathic or associated with lymphomas, SLE, and other viral infections.³

Common features

• DAT positive for both IgG and C3d
• Rare, severe, and difficult to treat³

Treatment

• Appropriate measures of both warm and cold type AIHA³

Hereditary spherocytosis 

What is hereditary spherocytosis?

Hereditary spherocytosis (HS)  is an inherited condition in which the red blood cells are spherical rather than biconcave (doughnut-shaped) in shape. It is the most common cause of haemolytic anaemia. The red blood cells cannot maintain their shape due to genetic mutations in the cell membrane protein.⁴

By Prof. Osaro Erhabor - Prof. Osaro Erhabor, CC0, Link

What does the word “spherocyte” mean?

Normal red blood cells are biconcave in shape, which helps them in their elasticity in the blood vessels. However, in HS, the red blood cells are abnormally spherical, and this decreases their elasticity and makes them fragile. They break easily when passing through blood vessels in the spleen, leading to haemolytic anaemia.² The typical age at which the symptoms start showing is 3-8 years old. Some people do not have any symptoms until they are in their 30s.

By Joan-Lluis Vives-Corrons, Elena Krishnevskaya - https://www.researchgate.net/publication/349926118_Rare_anemias_in_adolescents Joan-Lluis Vives-Corrons, Elena Krishnevskaya. Rare anemias in adolescents. February 2021. DOI:10.23750/abm.v92i1.11345 LicenseCC BY 4.0, CC BY 4.0, Link

Symptoms of HS

• Yellowish skin and eyes due to increased bilirubin in the blood (jaundice) 
• Gallstones
• Splenomegaly
• Tredness, fatigue
• Dizziness
• Haemolytic anaemia
• Pale skin⁴

How to diagnose hereditary spherocytosis?

Most people suffering from HS have a positive family history. This disease should be suspected in any child with a positive family history, enlarged spleen (splenomegaly), anaemia, and hyperbilirubinemia (increased levels of bilirubin in circulating blood). It is most common in Northern Europe and North America.² If a person presents with these symptoms, then a blood test is performed. In HS, your MCHC is increased more than normal (more than 35-36 g/dl), MCV (mean cell volume) is less than 80 fL, and an increase in reticulocyte count is seen.⁴ Doctors also look for the shape of RBCs in the lab findings. The DAT test is performed to rule out autoimmune haemolytic anaemia in these patients.³

Treatment of hereditary spherocytosis

The treatment options for HS depend upon the severity of the case. Folic acid supplements are prescribed for anaemia in children and adults. The haemoglobin levels are maintained above 7-8 g/dl in children. Mild cases usually need no treatment. In children with moderate cases, blood transfusions are done. If the child has gallstones and splenomegaly, then both the gallbladder and spleen are removed in severe cases.⁴

Gallstones are the most common complication in 10-30 years of age. In such cases, the gallbladder is removed surgically. If the patient comes with an enlarged spleen (splenomegaly) and jaundice, then the spleen is removed. After spleen removal, patients should be vaccinated against certain bacteria to prevent infections.⁴

Comparing AIHA and HS

Both AIHA and HS cause early red blood cell breakdown, leading to normocytic haemolytic anaemia. However, the key difference to remember is that the autoimmune haemolytic anaemia is an immune disorder, whereas HS is a genetic disorder (passed down in families) with a defect in the red cell membrane.

When to see a doctor for AIHA and HS?

If someone you know is suffering from persistent jaundice, fatigue, chest pain, or tiredness, then they should consult a doctor to rule out AIHA and other causes of anaemia. A family with a positive history of HS should inform their doctor when planning a child. If a child suffers from a high fever (more than 101 degrees Fahrenheit), has jaundice, and an enlarged spleen (splenomegaly), then urgent medical care should be provided.⁴

Summary

Haemolysis is an important, but often hidden, cause of anaemia. Always look out for your symptoms of fatigue, paleness, and jaundice. Proper diagnosis and treatment are possible for both autoimmune haemolytic anaemia and HS. With awareness and treatment, most people can manage well. Always consult your doctor if you notice unexplained fatigue and jaundice, followed by above mentioned symptoms in yourself and your family members.