Peripheral Blood Film Features (Fig. 20.1)

• reticulocytes (active marrow) – haemolysis or chronic blood loss
  
• anisocytes (variation in red cell size) or poikilocytes (variation in red cell shape) – iron deficiency
  
• target cells (‘Mexican hat’ cells) – thalassaemia
  
• rouleau formation (clumping together of red cells) – raised ESR (check for myeloma)
  
• burr cells (echinocytes with irregular ‘crinkled’ red cell membrane) – renal failure, carcinoma
  
• hypersegmented polymorphs – vitamin B₁₂ or folic acid deficiency
  
• Howell–Jolly bodies (remnants of nuclear material) – splenectomy (or non-functioning spleen)
  
• blast cells (immature cells) – acute leukaemia
  
• eosinophilia – parasitic infection, allergy, occasionally systemic vasculitis or Hodgkin’s disease

Figure 20.1 Morphology of red cells. (From Mehta and Hoffbrand (2009) Haematology at a Glance, 3rd edition Wiley-Blackwell, Oxford.)

Reticulocytes

Normocytic Anaemia

Microcytic Anaemia

Macrocytic Anaemia

Anaemia Secondary to Chronic Disease

Pancytopenia

This is a rare combination of anaemia, leucopenia and thrombocytopenia. It is caused by either:

• reduced production of cells, caused by:

bone marrow infiltration (leukaemia, myeloma, carcinoma, myelofibrosis)

bone marrow aplasia: idiopathic or drug-induced (e.g. NSAIDs, chloramphenicol, chemotherapy for malignancy); severe vitamin B₁₂ or folate deficiency

• increased destruction of cells, caused by hypersplenism; or autoimmune disease (e.g. SLE).

Bone marrow examination is the most important investigation in distinguishing these causes.

Marrow Suppression

Erythrocyte Sedimentation Rate (ESR)

Anaemia

Laboratory Investigation (Table 20.1)

The peripheral blood count shows hypochromia (MCH < 27 pg) and microcytosis (MCV < 80 fl), possibly with poikilocytosis (variation in shape) and anisocytosis (variation in size). The serum iron is low and the transferrin raised, with a low saturation. The serum iron is also low in anaemia secondary to chronic disease, but normal in haemoglobinopathies and, usually, thalassaemia minor (p. 329). Serum ferritin reflects the state of the iron stores and is therefore low. There is a reduction in stainable iron in the marrow. The bone marrow shows adequate iron in macrophages but reduced amounts in developing erythroblasts. Thalassaemia (p. 329) also causes hypochromic, microcytic anaemia.

Table 20.1 Haematological reference values in anaemia. A significant difference between one Hb reading and the next is 1 g/dl. If you are attempting to analyse anaemia and are looking at a Coulter-style full blood count, first check the MCV. See if the cells are normal (normocytic), small (microcytic) or large (macrocytic)

Management

In the absence of active bleeding, ferrous sulphate 200 mg b.d. before food is usually all that is required. The reticulocyte count rises first and then the haemoglobin (at about 1 g/week), but iron should be continued for another 3 months to replenish the stores.

NB Hypochromic anaemia, unresponsive to oral iron therapy, occurs in:

• incorrect diagnosis or mixed deficiency
  
• continued bleeding (reticulocytosis persists), e.g. microscopic from tumour of the bowel
  
• patients who do not take their tablets
  
• rheumatoid arthritis (p. 270)
  
• malabsorption (p. 136)
  
• thalassaemia (p. 329)
  
• myelodysplastic syndrome (p. 330) – refractory anaemia (if ringed sideroblasts present in marrow, sideroblastic anaemia – p. 330).

Hazards of Blood Transfusion

• Transfusion reaction – minimise risk by cross-matching patient’s serum with donor blood. If clinical manifestations of a transfusion reaction occur (fever, backache, hypotension and haemoglobinuria), stop the transfusion immediately and initiate supportive treatment to alleviate shock.
  
• Transmission of infection – blood is screened for hepatitis B and C and human immunodeficiency virus (HIV).
  
• Circulatory overload – give furosemide with transfusion in patients at risk of heart failure.
  
• Coagulation defects and electrolyte abnormalities – particularly hyperkalaemia (red cell breakdown releases potassium) where large volumes are transfused.

Vitamin B₁₂ Deficiency (Usually Pernicious Anaemia)

Vitamin B₁₂ is present in liver, and small amounts also in milk and dairy products, and requires intrinsic factor for absorption. The most common cause of vitamin B₁₂ deficiency in the UK is lack of intrinsic factor as a result of parietal cell and intrinsic factor antibodies. It is associated with other organ-specific autoimmune disorders. Achlorhydria is invariably present. Rare causes of B₁₂ deficiency include gastrectomy, intestinal blind loops (in which bacteria multiply using up B₁₂), a vegan diet, Crohn’s disease involving the absorbing surface in the terminal ileum, other causes of malabsorption and Diphyllobothrium latum Finnish tapeworm that consumes B₁₂. Stores of B₁₂ last 3–4 years.

Clinical Features

Pernicious anaemia occurs in the middle-aged and elderly and is more common in women. Exhaustion and lethargy are the most common presenting complaints, although pallor may be noticed incidentally, or the blood picture noticed in the laboratory.

In chronic, severe B₁₂ deficiency, which is uncommon, the skin has a pale lemon tint, the hair is snow white and the sclera may be slightly jaundiced as a result of mild haemolysis. The tongue may be tender, smooth and red because of atrophy of the mucosa. Peripheral neuropathy may be the presenting feature with pain, soreness or numbness of the feet on walking. Later, features of subacute combined degeneration of the cord may develop. Cardiac failure is common if the anaemia is marked. The spleen is sometimes palpable. There is an increased incidence of gastric carcinoma.

Diagnosis

The haemoglobin may be very low, i.e. 3–4 g or less. The blood film shows macrocytes usually with anisocytosis and poikilocytosis, and the MCV is usually > 100 fl. The total white blood cell (WBC) count may fall because of reduced numbers of both lymphocytes and neutrophils (Table 20.2). Some neutrophils may show hypersegmentation of the nuclei (> 5 lobes). There may also be a moderate fall in the platelet count. Reticulocytes are generally not increased until treatment is started.

Table 20.2 White cells. Normal White Cell Count: 4–10×10⁹/l

The marrow is hypercellular, with giant metamyelocytes and megaloblasts present – evidence that anaemia is in part caused by suppression of cell release. Megaloblasts (Fig. 20.2) are found only rarely in the peripheral blood. They are characterised by a large and inactive nucleus (maturation arrest) in a relatively hypermature, and even haemoglobinised, cytoplasm. They are not present in normal marrow and their presence denotes vitamin B₁₂ or folate deficiency, which may be secondary to antifolate or phenytoin therapy. If sufficiently severe, vitamin B₁₂ and folate deficiencies produce depression of all the marrow elements, including neutrophils and platelets. There is usually some haemolysis with a raised unconjugated serum bilirubin. The haptoglobins are reduced. Urobilinogen is present in the urine as a result of reduced red cell survival and ineffective erythropoiesis. Antibodies to parietal cells are present in > 90% of patients and to intrinsic factor in approximately 55%. Not all individuals who have parietal cell antibodies have pernicious anaemia.

Figure 20.2 (a) Peripheral blood in megaloblastic anaemia, showing a hypersegmented neutrophil (A), oval macrocytes and poikilocytosis (variation in red cell shape). (b) Bone marrow in megaloblastic anaemia showing megaloblasts. (c) Megaloblasts with developing myeloid cells; the cell with a C-shaped nucleus (arrow) is a giant metamyelocyte. From Mehta and Hoffbrand (2009) Haematology at a Glance, 3rd edn. Wiley-Blackwell, Oxford.

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