Case 86 – part B2

Thanks for joining in with this short case. We reviewed the blood film of an 82 year old. The FBC was done for diabetes monitoring. There was no recent transfusion and no new medications.

Cold agglutination - annotated

The film showed red cell agglutination(3) along with a normal neutrophil(1), lymphocyte(2) and monocyte.

Cold agglutination of red cells occurs due to an IgM antibody attaching to the red cells (often on the I antigen (occasionally on the i antigen (if EBV-related) or P antigen). The antibody generally only attaches in the cold (hence why we see this on the blood film (unless it is 37 degrees Celsius where you work!). The antibody can cause red cell agglutination as we see on the blood film or red cell lysis or both. If patients become cold the antibody binds (mostly in the peripheries). Cold agglutination can occur in:

  • Infections e.g. mycoplasma, EBV – Mostly polyclonal IgM antibodies which develop in response to infective organisms and cross react with RBC antigens. Haemolysis 2-7/52 after infection – mild and self-limiting. Can also see in other autoimmune disease and solid organ malignancy(Sometimes called secondary CHAD or cold agglutinin syndrome)
  • Non-Hodgkin lymphoma with an associated IgM kappa paraprotein e.g. lymphoplasmacytic lymphoma/Waldenström’s macroglobulinaemia
  • Cold haemagglutinin disease – there is an IgM kappa paraprotein – usually at low level which does not meet the criteria for lymphoma (often  monotypic B cells can be found by flow of bone marrow)



  • Acrocyanosis – purple extremities secondary to stasis and agglutination.
  • Livedo reticularis
  • Raynaud’s phenomenon
  • Jaundice; mild splenomegaly
  • Worse in cold – get anaemic
  • Features of haemolysis e.g. haemoglobiniuria
  • No symptoms – incidental finding
  • Erroneously elevated MCV (red cells stick together and low RBC with raised MCHC – repeat at 37oC resolves this


Laboratory – need to think of the following questions

  1. Is the patient haemolysing?
    • Check FBC/film/bilirubin/haptoglobin/DAT/LDH/reticulocytes
  2. Is the haemolysis immune
    • Check DAT – in cold haemolysis the DAT will usually only be positive for C3d and not IgG (the IgM antibody leaves the red cell leaving complement 3d)
    • Check red cell panel to see if underlying specificity to I antigen etc.
  3. Is there an underlying cause
    • E.g. recent viral infection or lymphoma (may want to check viral serology, immunoglobulins/serum protein electrophoresis and work up for lymphoma e.g. CT scan and bone marrow if concerns)

If cold haemolysis is suspected a direct agglutination test should be done and titre (if the cold antibody is >1:500 this suggests CHAD). Thermal amplitude can also be performed and if CHAD it is usually ≥30°C.

Our patient

He had evidence of red cell agglutination on the blood film but had a normal FBC (once warmed at 37oC) and no biochemical evidence of haemolysis. The DAT was positive for C3d but the antibody was <1:64 and thermal range was low. He had no symptoms or signs of lymphoma but did have an IgM kappa paraprotein at low level consistent with MGUS. He was advised to stay warm in the cold and report any features of anaemia or haemolysis (and if required a transfusion this should be through a blood warmer). Otherwise no further treatment was advised for his asymptomatic cold agglutinins.


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