Treatment of Warm Antibody Type Autoimmune Haemolytic Anaemia (WAIHA)

Warm antibody type of autoimmune haemolytic anaemia (WAIHA) is characterised by anaemia, reticulocytosis, conjugated hyperbilirubinaemia with the presence of a positive anti-globulin (Coombs’) test (see Diagnosis of haemolytic anaemia). It may be idiopathic or associated with an underlying disease. The underlying disease is usually an autoimmune disease, malignancy or an infection.

Approach to a Patients with WAIHA

The aim of treatment of a patient with WAIHA is twofold

  1. Stabilise the patient
  2. Arrest the haemolysis

Stabilising the Patient

Patients who have symptomatic anaemia need red cell transfusion. The presence of autoantibody makes transfusion challenging because firstly it masks the presence of an alloantibody and secondly reduces the lifespan of the transfused red cells.

    1. Masking of alloantibody: The autoantibodies present in the plasma of patients with WAHIA usually react with antigens on red cells of all donors. Checking compatibility needs additional testing and time. It is possible  that despite all efforts a compatible unit may not be found. The present of an autoantibody may mask an alloantibody that risk of a acute transfusion reaction. The approaches to minimising the risk and consequences of a harmful alloantibody include
      1. Choosing the donors: ABO and Rh-D compatible blood from men who do not have a history of being transfused and women who have not been pregnant and do not have a history of being transfused is least likely to have a harmful antibody. It is preferable to use these are donors for patients with WAIHA.
      2. Extended Phenotype Testing: Extended phenotyping testing is testing for groups other than ABO and Rh-D. These include D, C, E, c, e, K, Jka, Jkb, Fya, Fyb, S, and s. It may not be possible to determine the exact phenotype in a fair proportion of patients (Transfusion. 2002 Nov;42(11):1435-41).
      3. Precautions while transfusing: Symptomatic patients with WAIHA in whom compatible blood can not be found are more at risk of death from WAIHA rather than a transfusion reaction. Patients who are critically ill should be transfused. In order to minimise the consequences of an acute transfusion reaction, red cell transfusion should be initiated slowly and only 20-30 ml of blood transfused. If there is no reaction the rest of the unit can be transfused slowly with close monitoring.
    2. Shortened life of transfused red cells: Patients with WAIHA have a attenuated haemoglobin rise in response to transfusion. It has been estimated that the average rise of haemoglobin in patinents with WAIHA is 0.88g per unit transfused (Asian J Transfus Sci. 2014 Jul;8(2):105-8) as against the usual 1g per unit transfused (Blood Transfus. 2009 Jan; 7(1): 49–64). The autoantibody acts against transfused erythrocytes shortening their lifespan. necessitating more frequent transfusions.

Arresting Haemolysis

Erythrocytes from patients with WAIHA haemolyse because the Fc portion of the autoantibodies interacts with the Fc receptors on reticuloendothelial macrophages, mainly in the spleen. Spleen is also the main source of antibodies. Haemolysis is arrested by inhibiting antibody production and hampering the ability of antibodies to cause haemolysis.

  1. Hampering the ability of antibodies to cause haemolysis: Haemolysis is a consequence of the binding of the Fc portion (except in case of IgM autoantibodies) of the auto-antibody to the Fc receptor on the reticuloendothelial macrophages. Patients may respond to steroids in a matter of days. This period is too short for antibody levels to fall. In the short term steroids appear the hamper Fc receptor function and decreases the destruction of antibody coated cells. Danazol also appears to reduce the Fc receptor on macrophages. Splenectomy removes the main site of erythrocytes destruction and has the same effect. Intravenous immunoglobulins (IVIg) also hamper Fc function but unlike idiopathic thrombocytopenic purpura, WAIHA responds poorly to IVIg. IgM autoantibodies with a high thermal amplitude can cause WAIHA. IgM is a strong compliment activator but detaches from the red cell. The erythrocyte exposed to IgM antibody is opsonised by C3 fragments. Cells opsonised by C3 fragments are destroyed in the reticuloendothelial system of the liver. Splenectomy is of a limited value in patients with IgM autoantibodies.
  2. Inhibiting antibody production: Antibody production can be inhibited by steroids (over a longer use), splenectomy, rituximab and danazol (alters T cell regulations), immunosuppressive therapy (rituximab, azathioprine, cyclophosphamide, cyclosporine, mycophenolate, and alemtizumab).

Drugs used and Doses


Corticosteroids are the first line of treatment for WAIHA. Treatment is initiated at 1-1.5mg/kg of prednisone. Response is usually seen in about 1-3 weeks. Between 50-90% patients respond. Those who do not respond by 3 weeks should be considered to be refractory. Steroids should be tapered once the haemoglobin increases to 10-12g/dL. Usually patients are monitored at weekly interval. The dose should be rapidly tapered to 20mg/day. Thereafter the tapering should be slow, over 4-8 weeks. Patients may be switched to alternate day therapy at a dose of 10mg. About one third of the patients remain in long term remission. About half need a maintainance dose. Methylprednisone 250-1000mg per day for 3 days is used by some but it is not clear if this is superior to oral dose of prednisone discussed above. Pulse dexamethasone therapy (40mg/day for 4 days every 4 weeks) has been used for refractory disease but not primary treatment.

Presence of compensated haemolysis is not an indication for second line therapy. The decision for second line therapy is taken after considering the entire clinical picture. Patients are considered for second line therapies if

  1. Thay do not respond by three weeks
  2. They need a maintainance dose of 20mg or more
  3. They have side effects of steroid therapy


Spleen is the main site of autoantibody production and the main site of destruction of opsonised erythrocytes. Splenectomy reduces haemolysis. About 60-90% of the patients respond. About one third of these relapse in about 1-2 months. Those who benefit from splenectomy most may not need any steroids. The benefit in many patients may be reduction of steroid dose. Some patients with WAIHA have IgM autoantibodies.  Extravascular haemolysisn in patients with IgM autoantibodies is mediated by C3. Reticuloendothelial system of the liver has a greater role in lysing C3 coated cells than the spleen. Patients with IgM autoantibodies are not likely to benefit from splenectomy (Haematologica. 2015 Nov; 100(11): 1388–1395) . Patients with idiopathic WAIHA are more likely to benefit. Patients with splenectomy are at risk of infections (see overwhelming post-spelenectomy sepsis) and need appropriate prophylaxis.


Rituximab is a anti-CD20 chemaric monoclonal antibody that acts against B lymphocytes. It is used in a dose of 375mg/m2 weekly for four weeks. A meta-analysis 21 studies showed an overall response rate of 79% with a complete response of 42%. Response rate is similar for idiopathic and secondary WAIHA. About 50% of the patients relapse. Relapses usually respond to retreatment (Autoimmun Rev. 2015 Apr;14(4):304-13). Rituximab is effective in IgM as well non-IgM autoantibodies

Other treatments

Other therapies that have been used for WAIHA include

  1. Immunosupression: Immunosupresive drugs formed the backbone of second line treatment of WAIHA before the availability of rituximab. The were often used in combination with steroids and occasionally with other immunosuppressive drugs. The drugs that have been used for the treatment of WAIHA include:
    1. Azathioprine: 2-4 mg/kg day
    2. Cyclophosphamide: Two doses of cyclophosphamide have been used. The low dose is 1-2 mg/kg orally and the high dose 50mg/kg iv days 1-4 with G-CSF or 1000mg iv once a week
    3. Cyclosporine: Cyclosporine has been used in a small number of patients refractory to other therapies. It is administered in a dose of 3mg/kg/day orally twice a day to achieve a target cyclosporine levels 200-400ng/ml
    4. Mycophenolate: The experience with mycophenolate is limited. It is used in a dose of 500-1000mh twice a day.
  2. Danazol: Danazol may be administered at a 200mg orally 3-4 times day. It is often administered with cyclosporine and/or steroids.
  3. Alemtuzumab:  fully humanized IgG1-type mAb directed against CD52 expressed on human B and T cells, natural killer cells, eosinophils, and macrophages. It is effective in patients of refractory WAIHA.
  4. Intravenous Immunoglobulin: Unlike immunethrombocytopenia purpura intravenous immulobulin has not been found to be effective in WAIHA.
  5. Stem cell transplant: The data for stem cell transplant in WAIHA is limited and retrospective. Most patients had Evan’s syndrome. Allogenic transplant is more effective than autologous.  European Group of Blood and Marrow Transplantation registry showed a continuous remission in 1 of 7 autologous HSCT and 3 of 7 allogeneic HSCT, with a transplant-related mortality (TRM) of approximately 15% (Haematologica. 2014 Oct; 99(10): 1547–1554)

Supportive care

Patients with haemolytic anaemia have an increased requirement of folic acid and should be administered 1mg of folic acid per day. Patients on long term steroids need calcium, vitamin D and bisphosphonate suplimentations.

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