24th May 2023

Immune-mediated haemolytic anaemia

ABO and Rhesus Incompatibility

Typically, this is due to an immune response from the host to foreign allogenic RBC antigens from donor blood. It can also be less commonly due to plasma containing antibodies in donor blood that act against host RBC antigens.

Individuals with group A, B and O blood types develop IgM antibodies that react with the antigens they lack due to molecular mimicry following exposure to intestinal microorganisms that are similar to type A and type B antigens.

There are antibodies to other antigens on RBC (e.g. Kidd, Kell, Duffy) that can be present due to previous transfusions, pregnancy, or intravenous needle sharing. The presence of these can cause acute or delayed haemolytic transfusion reactions (HTR) depending on the titre of antibodies present. Acute HTR occurs during the transfusion, whereas delayed HTR can happen one week or more following the transfusion.

Both intravascular and/or extravascular haemolysis can occur in ABO incompatibility. Intravascular haemolysis is due to activation of complement when an antibody binds to the RBC antigen. Extravascular haemolysis occurs when the antibody opsonises the RBC causing phagocytosis in the reticuloendothelial system (namely, the liver and spleen).

Rhesus antigens are non-glycosylated transmembrane proteins in the RBC membrane. They are inherited independently of the ABO alleles. Rhesus incompatibility can cause haemolysis and Rhesus phenotyping is particularly important in pre-transfusion testing and prenatal care. Preventing alloimmunisation in Rhesus negative women of childbearing age is particularly important to reduce the risk of haemolytic disease of the newborn in a Rhesus positive pregnancy.

Warm Autoimmune Haemolytic Anaemia (AIHA)

Haemolytic anaemia due to autoantibodies that are active at body temperature is termed warm AIHA. It is the most common type of AIHA and can be spontaneous, or secondary to medication and illness.

Primary warm AIHA occurs with no precipitating or underlying condition.

Secondary warm AIHA can be associated with the following:

• Infection
  • HIV, CMV, VZV, Hepatitis C, pneumococcal infection, leishmaniasis, tuberculosis
• Autoimmune conditions
  • SLE, Sjogren’s, scleroderma, ulcerative colitis, sarcoidosis
• Immunological conditions
  • Combined variable immunodeficiency
• Lymphoproliferative disorders
• Pregnancy

Clinical features – jaundice, fatigue, pallor, shortness of breath, splenomegaly

Laboratory bloods – low haemoglobin, raised reticulocytes, low haptoglobin, raised lactate dehydrogenase

Blood film – spherocytes, reticulocytes

Direct Antiglobulin Test – positive, typically anti-Ig and/or anti-C3 (Note – Indirect antiglobulin test is not used to evaluate warm AIHA)

Management – transfusion in the acute setting, intravenous immunoglobulins or plasma exchange in critical situations, prednisolone and/or rituximab, azathioprine can be used as 3rd line, splenectomy in refractory cases of anaemia not responding to immunosuppression.

Cold Agglutinin Disease (CAD)

This is an autoimmune haemolytic anaemia that causes agglutination and extravascular haemolysis of RBCs at below core body temperatures. Cold agglutinins are typically IgM and recognise antigens on RBC in colder temperatures. Much like warm AIHA, it can be primary i.e. idiopathic, or secondary.

The causes of secondary CAD vary depending on the age of patients. Younger patients tend towards autoimmune and infective causes, while older patients may have underlying malignancy.

• Infection – Mycoplasma pneumoniae, Epstein-Barr virus
• Malignancy/Lymphoid disorders – lymphoma, Waldenstrom’s macroglobulinaemia, chronic lymphocytic leukaemia, monoclonal gammopathy of undetermined significance

Clinical presentation – Raynaud’s phenomenon, cold-induced acrocyanosis, symptoms of anaemia and haemolysis, splenomegaly, livedo reticularis, cutaneous ulceration or necrosis is severe cases

Laboratory bloods – As seen with other AIHA if significant haemolysis

Blood film – RBC agglutination

Red blood cell agglutination.

Image Source: Wikimedia Commons (2014). Red blood cell agglutination, Licensed under a creative commons licence. Available for free at: https://commons.wikimedia.org/wiki/File:Red_cell_agglutination.jpg (Accessed on: 10 January 2023).

Direct Antiglobulin Test – Positive for C3, usually negative for immunoglobulin

Cold agglutinin titre – measured in suspected CAD, > 64 at 4 degrees Celsius

Management – Cold avoidance, treatment of underlying condition, blood transfusion in severe and symptomatic anaemia, plasmapheresis and intravenous IG as a temporary measure in acute haemolytic crises, rituximab for transfusion dependent/symptomatic anaemia/severe circulatory symptoms