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Agglutination

From www.haematologyetc.co.uk


Derivation: From latin “fasten with glue”




Description

Erythrocytes linked together to form irregular clumps of varying size.



Appearance: The key points are that the red cell groups are very irregular. In many cases they will include cells that have been damaged by the underlying immunological process (shown here as a spherocyte and irregularly contracted cell with the agglutinated group)..



Significance

Agglutinates arise when antibodies attach to antigens on the membranes of adjacent red cells linking them together. The most common cause is "cold-reactive" IgM antibodies which do not cause overt symptoms. However, in some cases the effects may be clinically significant since antibodies may activate complement causing haemolysis, or the agglutinated cells can cause occlusion of small blood vessels in the cold (acrocyanosis). The clumped cells will sediment more rapidly leading to a raised erythrocyte sedimentation rate (ESR). Finally, the antibodies that cause cold agglutination may indicate an underlying malignancy (particularly lymphoma), or particular infection (see causes).


Pitfalls

Be sure to examine the correct part of the blood film since cells can be grouped in thicker parts of the blood film; also be careful to distinguish the appearance from rouleaux. If agglutination and rouleaux co-exist, then it is important to look for the much more irregular clumping that characterises agglutination. A specific cold-reactive IgG antibody (Donath Landsteiner antibody) causes the clinical disorder Paroxysmal Cold Haemoglobinuria (PCH). It is important to recognise this condition (see images).




1. Causes


Primary Causes
Monoclonal IgM frequently recognising blood group "I", peak incidence in the elderly, but may arise from the 5th decade
Secondary Causes (transient)
Commonly: Mycoplasma pneumoniae or Epstein Barr virus
Other viral including: influenza, HIV, CMV, rubella
Non-viral: bacterial endocarditis, syphilis, malaria
Secondary Causes (sustained)
Commonly: Lymphoma, Waldenstroms macroglobulinaemia, CLL
Rarely: Non-haematological malignancy
Donath Landsteiner antibody

Most commonly seen in chlidren, this IgG antibody recognises the P antigen - the clinical presentation differs: cold haemaglutinin disease (CHAD)

Syphilis (congenital or tertiary syphilis classical but now uncommon)

Viral: measles, mumps, influenza A, adenovirus, CMV, EBV and post-vaccination

Bacterial: H.influenza, Mycoplasma pneumoniae

Chronic idiopathic



Clinical Examples



Clinical Image 1: Several irregular groups of cells are shown, these are very different from the linear structures of rouleaux and can be seen to include dense damaged cells both within the agglutinates and circulating separately. Clinical condition: cold haemagglutinin disease (CHAD)



Clinical Image 2: A low power image shows how the disease is first detected – the agglutinates cause a very irregular distribution of cells that on closer examination can be seen to comprise erythrocytes in irregular clumps. In severe cases these changes can be detected without the need for microscopy. Clinical condition: cold haemagglutinin disease (CHAD).



Clinical Image 3: Agglutinates are clearly shown, and are comprised of normal and damaged erythrocytes. In this case the additional presence of erythrophagocytosis by neutrophils is present – this is characteristic of this condition. Clinical condition: paroxysmal haemoglobinuria (PCH) (see separate discussion in neutrophil section).





Pathobiology


Agglutination is caused by antibodies that link adjacent red cells together and hence are generally caused by antibodies that are polyvalent (IgM or less commonly IgA subclass). Most commonly the antibodies recognise red cell antigens of "I" or "i" groups. Since these antibodies generally only bind antigen at temperatures below normal body temperature, their effects may be reversed if the sample is heated and the blood smear is made on a warmed slide. Cold reactive IgG antibodies may also cause agglutination, but tend to have a different clinical presentation dominated by haemolytic symptoms (Paroxysmal Cold Haemoglobinuria).