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8.1 What is meant by “intravascular” and “extravascular” haemolysis?
Intravascular haemolysis, destruction of red cells within the circulation, is mainly caused by IgM antibodies, which activate the complement pathway and lyse the cells within the circulation. Most deaths resulting from the transfusion of incompatible blood are associated with strongly lytic antibodies such as anti-A, anti-B, and particularly anti-A,B. Most IgG antibodies, however, bring about red cell destruction outside the circulation (extravascular haemolysis). The IgG antibody molecules on the cell surface are recognized by macrophages, mainly in the spleen, and it is these cells that remove the antibody-coated cells from the circulation.
8.2 Why are some antibodies not considered to be clinically significant?
Although most antibodies have the potential to cause red cell destruction, as a general rule, antibodies that are reactive at 37°C and are detectable by an antiglobulin test are considered to be ‘clinically significant’. Those that fail to react at 37°C are considered not to be clinically significant. Therefore, antibodies to most of the major blood group antigens within the Rh, Kell, Duff y, and Kidd groups, and the Ss antigens are considered significant. Antibodies that react at temperatures below 37°C to Lewis, P and N antigens, for example, are not significant. There are, of course, some antibodies that fall outside this clear definition; the most notable being anti-M—some examples react by IAT, others do not.
8.3 Define the terms “immediate” and “delayed transfusion reactions, and give examples of both.
An immediate transfusion reaction is one that occurs within 12 hours of a transfusion being started, but usually it is obvious within minutes. Immediate reactions are usually caused by ABO incompatibility, such as wrongly giving group A red cells to a group O individual. There are also cases reported of these reactions occurring when group O platelets are given to a group A or B patient, where the platelet preparation contains high-titre anti-A/B. Delayed reactions occur after 12 hours of a transfusion being started and are often not noticed until 5–8 days after the transfusion has been given, when a fall in Hb might be noted. Anti-Jka is most often associated with delayed haemolytic transfusion reactions.
8.4 How do the antibodies that cause warm and cold AIHA cause red cell destruction?
Warm type AIHA is caused by an IgG auto-antibody that reacts in vivo at 37°C. Sometimes, the C3 component of complement is also present on the patient’s red cells. If the red cells are coated with IgG, destruction takes place in the spleen, but if complement has been activated there might be some more rapid cell destruction in the liver of C3b coated cells. In some cases IgM or IgA antibodies may be found in addition to IgG, and very rarely IgA might be present on its own. In cold AHIA, antibodies that are usually considered to be cold-reacting antibodies and clinically insignificant, as they do not react at body temperature, increase in titre and thermal amplitude, becoming active at 30°C. These antibodies could then react with the patient’s own cells in the peripheral capillaries, such as the fingertips, where the blood might be at 30°C rather than 37°C. At these lower temperatures, the antibody binds to the antigen and initiates the complement cascade. As the blood returns to the warmer parts of the body the antibody elutes from the cells, but as the complement cascade has been started it might go to completion, resulting in intravascular lysis or rapid lysis of the C3b-coated cells in the liver. When this happens, the patient can present with haemoglobinuria after exposure to the cold. In less extreme cases, the complement cascade is halted at the C3 stage, and C3d is found on the red cells that probably have a near normal half-life in the circulation.