What steps are involved in red blood cell production?

Erythropoiesis, the production of red blood cells (RBCs), occurs within the bone marrow. Erythrocytes differentiate through several cell types during their development:

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  The starting point is the common pluripotent haemopoietic stem cell. This stem cell differentiates into myeloid progenitor stem cells dedicated to erythropoiesis, first called burst-forming unit erythroid (BFU-E) cells, before becoming colony-forming unit erythroid (CFU-E) cells.

  
  
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  CFU-E cells then pass through a series of erythroblast phases in the bone marrow. Erythroblasts require both vitamin B₁₂ and folate for their DNA synthesis.

  
  
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  Erythroblasts synthesise haemoglobin (Hb) from the early stages of their maturation. Globin chains are produced in the cytoplasm, whilst the haem moiety, which requires iron, is synthesised in the mitochondria.

  
  
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  The penultimate cell type is the reticulocyte. By this stage of maturation, the cell has lost its nucleus. However, Hb continues to be synthesised by the residual ribosomal RNA within the cytoplasm.

  
  
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  At 1–2 days following their release into the circulation, reticulocytes lose their RNA (and therefore their ability to synthesise Hb) and become mature erythrocytes.

Erythropoiesis is controlled by the hormone erythropoietin (EPO). EPO is a glycoprotein secreted mainly by the kidney in response to hypoxaemia.¹ EPO increases erythropoiesis by stimulating the differentiation of BFU-E and CFU-E progenitor cells. A negative-feedback loop is therefore created: hypoxaemia stimulates EPO production, which increases RBC production, which increases O₂-carrying capacity, counteracting the initial hypoxaemia.

Why do patients become anaemic?

Anaemia is defined as an Hb concentration below the expected value when gender, pregnancy and altitude have been taken into account. The World Health Organization defines anaemia as Hb < 130 g/L in men and Hb < 120 g/L in non-pregnant women. The prevalence of anaemia in the surgical population has been found to be as high as 60%.

Anaemia occurs when RBC loss exceeds RBC production. There are many causes of anaemia, which may be classified as follows.

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  Insufficient RBC production. Examples include:

  
  
  
  
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     – Iron-deficiency anaemia. Deficient haem synthesis results in a reduced number of microcytic and hypochromic RBCs.

     
     
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     – Folic acid and vitamin B₁₂ deficiency. RBCs produced are megaloblastic.

     
     
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     – End-stage renal disease. Insufficient EPO is produced by the kidneys; RBCs are normocytic.

     
     
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     – Anaemia of chronic disease. This is now thought to result from cytokine-mediated (especially interleukin-6) hepatic synthesis of a protein hormone called hepcidin. Hepcidin blunts the response of the erythropoietic progenitor cells to EPO and reduces the gastrointestinal (GI) absorption of iron (see later).

  
  
  
  
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  RBC haemolysis. RBCs are haemolysed either intravascularly or (more commonly) extravascularly within the spleen. Examples include:

  
  
  
  
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     – Inherited abnormalities of RBCs; for example, hereditary spherocytosis. Abnormally shaped RBCs are taken out of circulation by the spleen, reducing their lifespan.

     
     
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     – Inherited abnormalities of Hb; for example, sickle cell disease. The spleen haemolyses sickle-shaped cells, significantly reducing the average RBC lifespan.

     
     
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     – RBC enzyme deficiencies; for example, glucose-6-phosphate dehydrogenase deficiency causes some Hb in the ferrous state (Fe²⁺) to be oxidised to the ferric state (Fe³⁺), forming MetHb (see Chapter 8). RBCs containing MetHb are haemolysed by the spleen.

     
     
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     – Transfusion reactions; transfusion of ABO-incompatible blood leads to an antibody-mediated intravascular haemolysis reaction (see Chapter 73).

     
     
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     – Autoimmune haemolytic anaemia; RBCs are haemolysed by autoimmune attack.

     
     
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     – Mechanical trauma to RBCs; for example, cardiopulmonary bypass and valvular dysfunction may result in traumatic haemolysis.

  
  
  
  
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  Bleeding. This may be acute (e.g. postpartum haemorrhage) or chronic (e.g. colonic carcinoma, menstruation). In critical care patients, repeated arterial blood sampling is a major contributor to anaemia.