22nd May 2023

Classification of anaemia

Aetiology of anaemia

The World Health Organisation defines anaemia as a haemoglobin level <120g/L for women and <130g/L for men. Due to variations in normal haemoglobin ranges with age and sex, as well as between laboratory instruments, anaemia is widely defined as a haemoglobin below the reference range provided by the testing laboratory.

Haematopoeitic stem cells in the bone marrow differentiate into reticulocytes, which in turn are released into the circulation to develop into mature red blood cells. The average lifespan of a red blood cell is 120 days before it is removed from the circulation by macrophages.

Anaemia can present clinically with pallor of skin and mucous membranes, tiredness, exertional dyspnoea, palpitations, dizziness, exacerbation of existing angina or heart failure, or symptoms of the underlying cause of anaemia.

Anaemia can be classified by mechanism or by morphology. Mechanisms of anaemia include:

• Decreased production of red blood cells
• Increased loss of red blood cells
• Dilutional

Classification of anaemia by morphology is more commonly used clinically and is defined by the size of red blood cells, measured by mean corpuscular volume (MCV):

• Macrocytic (MCV>100fL)
• Normocytic (MCV 80-100fL)
• Microcytic (MCV<80fL)

Macrocytic anaemia

Macrocytosis is defined as an MCV>100fL, and when associated with anaemia is termed macrocytic anaemia. It can be subdivided into megaloblastic and non-megaloblastic anaemia.

Megaloblastic anaemia

Megaloblastic anaemia is named due to the presence of enlarged, immature red blood cells (megaloblasts) and hypersegmented neutrophils on blood film. This results from impaired DNA synthesis or maturation during red blood cell production, which delays the progression of the cell cycle from the G2 growth stage to mitosis, leading to continuing cell growth and enlarged red blood cells.

Causes of megaloblastic anaemia can be divided into those resulting in vitamin B12 deficiency and folate deficiency.

Common causes of vitamin B12 deficiency include:

• Pernicious anaemia – autoimmune destruction of gastric parietal cells causing reduced production of intrinsic factor, a glycoprotein required for B12 absorption in the terminal ileum.
• Post-gastrectomy or post-terminal ileum resection e.g. due to Crohn’s disease
• Proton-pump inhibitors e.g. omeprazole
• Bacterial overgrowth
• Decreased intake e.g. vegan diet without vitamin B12 supplementation

Common causes of folate deficiency include:

• Decreased intake e.g. alcohol dependence, elderly, anorexia nervosa
• Decreased absorption e.g. coeliac disease
• Increased demand e.g. pregnancy, malignancy, chronic inflammation
• Excessive urination e.g. in congestive heart failure or dialysis
• Drugs e.g. phenytoin, methotrexate, trimethoprim, sulfasalazine, cholestyramine

Non-megaloblastic anaemia

Non-megaloblastic anaemias (also known as normoblastic anaemias) comprise other causes of macrocytosis without impairment of DNA synthesis. Therefore, megaloblasts and hypersegmented neutrophils do not feature on the blood film in non-megaloblastic anaemia.

Causes of non-megaloblastic anaemia include:

• Alcohol excess
• Reticulocytosis – reticulocytes are large, immature red cells. Reticulocytosis can be seen when there is increased bone marrow activity to replace red blood cell loss, such as in haemolysis or haemorrhage.
• Liver disease
• Hypothyroidism
• Tyrosine-kinase inhibitors e.g. imatinib
• Myelodysplasia
• Multiple myeloma

Normocytic anaemia

Anaemia associated with an MCV between 80fL and 100fL is termed normocytic.

Causes of normocytic anaemia include:

• Large volume acute blood loss
• Anaemia of chronic disease e.g. chronic kidney disease, rheumatoid arthritis
• Pregnancy
• Bone marrow failure e.g. aplastic anaemia
• A combination of conditions producing both a microcytic and macrocytic anaemia

Microcytic anaemia

Microcytosis is defined as an MCV<80fL, and when associated with anaemia is termed microcytic anaemia.

Causes of microcytic anaemia include:

• Iron deficiency
• Anaemia of chronic disease
• Thalassaemia
• Sideroblastic anaemia – results from impaired incorporation of iron into haemoglobin molecules. This can be congenital or secondary to alcohol excess, drugs (isoniazid, chloramphenicol), or myelodysplasias. The MCV is low or normal in congenital forms but can sometimes be raised in acquired forms.
• Lead poisoning