Question 11.2

A 64-year-old woman presents with lethargy, shortness of breath on exertion and jaundice.


64 g/L



102.4 fl



114 X 109/L


White Cell Count

101 X 109/L




2.3 X 109/L




98.7 X109/L














Nucleated RBCs

3.6 per 100 WBC

Reticulocyte count

280 X 109/L


Polychromasia. Poikilocytosis. Spherocytes. Smudge cells.

i. What is your interpretation of the leucocytosis?

ii. What is your interpretation of the anaemia?

iii. What additional test would you perform to help determine the underlying cause of the anaemia?

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College Answer

i. CLL given lymphocytosis and smudge cells.

ii. Jaundice, presence of spherocytes, and reticulocytosis suggest haemolysis.

    Autoimmune haemolytic anaemia associated with warm antibody.

iii. Additional test: Direct Coomb’s test


The real question should read "try to recall the meaning of smudge cells as a blood film abnormality".

That is fairly straightforward. Smudge cells are deformed lymphocytes which are associated with chronic lymphocytic leukaemia. Look, here's a whole bunch of them at the ASH Image Bank.

However, the warm antibody thing is very different. If one were to forget that jaundice formed part of the initial flavour text, one might be tempted to instead jump on the macrocytosis, and ask for B12 and folate studies, or maybe even a bone marrow biopsy.

What do they mean by "warm"? Well, in this instance its a case of an autoimmune haemolytic anaemia with antibodies maximally active at human body temperature. How this spectrum of activity was derived from the clinical history? Probably because cold exposure was never mentioned.According to this article on the topic, the hemolytic anaemia usually associated with leukaemia is indeed a "warm" variety, whereas Waldenstroms and lymphoma tend to cause a "cold" autoimmune haemolytic anaemia.

A good overview of this topic can be found in the American Journal of Haematology.

Their breakdown of the classifications of haemolytic anaemia looks a little like this:


Differential Causes of Autoimmune Haemolytic Anaemia
Warm haemolytic anaemia  Cold haemolytic anaemia
  • Idiopathic primary haemolytic anaemia
  • Viral infections, including HIV
  • Drugs, eg. penicillin, methyldopa, 5-FU, diclofenac, etc...
  • Lymhoproliferative disorders:
    • CLL
    • Lymphoma
    • Multiple myeloma
    • Hodgkins lymphoma
    • Waldenstrom's macroglobulinaemia
  • Autoimmune disorders, particularly SLE and rheumatoid arthritis
  • Post-infectious colad agglutinin disease
    • Syphilis
    • Post-viral
    • Mycoplasma pneumoniae
    • EBV, VZV, CMV, HIV
    • Adenovirus
    • Influenza viruses
  • Paroxysmal cold haemoglobinuria
    • Idiopathic
    • Virus-associated (EBV, CMV, etc)

Additional tests:

Laboratory features common to all haemolytic anaemias

  • Morphologic RBC abnormalities: such as spherocytosis or fragmented RBCs, as well as pathognomonic erythrocytes such as sickle cells.
  • High reticulocyte count: because a normal bone marrow responds to anaemia by ramping up the production of RBCs.
  • High LDH:  lactate dehydrogenase is an enzyme which leaks out of pretty much any damaged cells, and so is not specific for haemolysis. However, nor is bilirubin. Regardless, the college will expect you to mention both in an exam answer.
  • Haptoglobin: the protein responsible for iron transport will usually be low when there is too much iron to transport. It is also an acute phase reactant, which means it does not necessarily have to be low in the presence of haemolysis.
  • Free haemoglobin will be elevated as it spills out of RBCs. There may even be haemoglobinuria.

Laboratory features specific to autoimmune causes of haemolytic anaemia

  • DAT, direct antiglobulin test or direct Coombs Test, demonstrates that the RBCs are coated with antibody and/or complement. .
  • DAT helps discriminate between a  "warm" and a "cold" haemolytic anaemia.
  • When haemolysis is "warm", the autoimmune haemolytic anaemia is caused by antibodies maximally active at human body temperature, and this is usually caused by IgG. The DAT comes back positive for both IgG and C3d, the latter being a complement product
  • Hamolysis caused by IgM usually occurs in cold conditions, and the DAT comes back positive for C3d but not IgG.


Zeerleder, S. "Autoimmune haemolytic anaemia-a practical guide to cope with a diagnostic and therapeutic challenge." Neth J Med 69.4 (2011): 177-84.

Gehrs, Bradley C., and Richard C. Friedberg. "Autoimmune hemolytic anemia."American journal of hematology 69.4 (2002): 258-271.