Acquired Haemolytic Anaemia

These anaemias may be divided into those due to immune, non-immune, or other causes.
1 Immune destruction of red cells by:
(a) autoantibodies,
(b) drug-induced antibodies,
(c) alloan tibodies.
2 Non-immune destruction of red cells may be due to:
(a) acquired membrane defects, e.g. paroxysmal nocturnal haemoglobinuria ,
(b) mechanical factors, e.g. prosthetic heart valves, or microangiopathic haemolytic anaemia,
(c) secondary to systemic disease, e.g. renal and liver disease.
3 Miscellaneous: Various toxic substances can disrupt the red cell membrane and cause haemolysis, e.g. arsenic, products of Clostridium welchii. Anaemia is frequent in malaria and this is due to a combination of a reduction in red cell survival and reduced production of red cells. Hypersplenism  results in a reduced red cell survival, which may also contribute to the anaemia seen in malaria. Extensive burns result in denaturation of red cell membrane proteins and reduced red cell survival. Some drugs, e.g. dapsone, sulphasalazine, cause oxidative haemolysis with Heinz bodies in normal subjects; some chemicals, e.g. weed killers such as sodium chlorate may cause severe oxidative haemolysis causing acute renal failure.



Autoimmune haemolytic anaemias (AIHA) are acquired disorders resulting from increased red cell destruction due to red cell autoantibodies. These anaemias are characterized by the presence of a positive direct antiglobulin (Coombs’) test, which detects the autoantibody on the surface of the patient’s red cells.
AIHA is divided into ‘warm’ and ‘cold’ types, depending on whether the antibody attaches better to the red cells at body temperature (37°C) or at lower temperatures. The major features and the causes of these two forms of AIHA are shown. In warm AIHA, IgG antibodies predominate and the direct antiglobulin test is positive with IgG alone, IgG and complement or complement only. In cold AIHA, the antibodies are usually IgM. They easily elute off red cells leaving complement which is detected as C3d.
Immune destruction of red cells IgM or IgG red cell antibodies which fully activate the complement cascade cause lysis of red cells in the circulation (intravascular haemolysis).
IgG antibodies frequently do not activate complement and the coated red cells undergo extravascular haemolysis . They are either completely phagocytosed in the spleen through an interaction with Fc receptors on macrophages, or they lose part of the cell membrane due to partial phagocytosis and circulate as spherocytes until they too become sequestered in the spleen. Some IgG antibodies partially activate complement leading to deposition of C3b on the red cell surface and this may enhance phagocytosis as macrophages also have receptors for C3b. Non-complement-binding IgM antibodies are rare and have little or no effect on red cell survival. IgM antibodies which partially rather than fully activate complement cause adherence of red cells to C3b receptors on macrophages, particularly in the liver, although this is an ineffective mechanism of haemolysis. Most of the red cells are released from the macro phages when C3b is cleaved to C3d and then circulate with C3d on their surface.

Causes and major features of autoimmune haemolytic anaemias.
Causes and major features of autoimmune haemolytic anaemias.

IWarml autoimmune haemolytic anaemias


These anaemias may occur at all ages and in both sexes. They can present as a short episode of anaemia and jaundice but they often remit and relapse and may progress to an intermittent chronic pattern. The spleen is often palpable. Infections or folate deficiency may provoke a profound fall in the Hb level.
In more than 30% of cases, the cause remains unknown. These anaemias may be associated with lymphoid malignancies or diseases such as rheumatoid arthritis and SLE or drugs.


SPHEROCYTOSIS is present as a result of red cell damage.
DIRECT ANTIGLOBULIN TEST is positive, with either IgG alone (67%), IgG and complement (20%) or complement alone (13%) being found on the surface of the red cells.
AUTOANTIBODIES may have specificity for the Rh blood group system, e.g. for the e antigen.
AUTOIMMUNE THROMBOCYTOPENIA AND/OR NEUTROPENIA may be associated with the condition (Evans’ syndrome).


Corticosteroids (e.g. prednisolone in doses of 40-60 mg daily for adults) are effective in inducing a remission in about 80% of patients. Steroids reduce both production of the red cell autoantibody and destruction of antibodycoated cells. Splenectomy may be necessary if there is no response to steroids or if the remission is not maintained when the dose of prednisolone is reduced. Other immunosuppressive drugs, such as azathioprine and cyclophosphamide, may be effective in patients failing to respond to steroids and splenectomy.

Antiglobulin (Coombs') tests.
Antiglobulin (Coombs’) tests.

Cold’ autoimmune haemolytic anaemias

These disorders are due to antibodies, usually of the IgM ,’Fe, that attach to red cells at low temperatures and cause agglutination of red cells in the cold peripheries of the body. Activation of complement may cause intravascular haemolysis when the cells return to the higher temperatures in the core of the body.
Low titres of IgM cold agglutinins reacting at 4°C are normally present in serum and are harmless. After certain ections (such as Mycoplasma, cytomegalovirus (CMV), Epstein-Barr virus (EBV)) there is increased synthesis of polyclonal cold agglutinins with a higher thermal range and they may produce transient mild to moderate haemolysis if the thermal range reaches peripheral body temperatures (30-32°C).

This usually occurs in the elderly with a gradual onset of haemolytic anaemia due to the production of monoclonal IgM cold agglutinins. After exposure to cold the patient develops an acrocyanosis similar to Raynaud’s  due to red cell autoagglutination.


RED CELLS agglutinate in the cold or at room temperature. Agglutination is sometimes seen in the sample tube after cooling but is more easily seen on the peripheral blood film made at room temperature. The agglutination is reversible after warming the sample.DIRECT ANTIGLOBULIN TEST is positive with complement alone.
AUTOANTIBODIES often have specificity for the Ii blood group system, usually for the I antigen.


The underlying cause should be treated, if possible. Patients should avoid exposure to cold. Treatment with steroids, aIkylating agents and splenectomy is usually ineffective.


This is a rare condition associ-red with common childhood infections, such as measles, mumps and chickenpox, but was originally described in association with syphilis. Intravascular haemolysis is associated with polyclonal IgG complement-fixing antibodies. These antibodies are biphasic, reacting with red cells in the cold in the peripheral circulation with lysis occurring due to complement activation when the cells return to the central circulation. The antibodies have specificity for the P red cell antigen.
The lytic reaction is demonstrated in vitro by incubating the patient’s red cells and serum at 4°C and then warming the mixture to 37°C tDonath-Landsteiner test). Haemolysis is self-limiting but supportive transfusions may be necessary.

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