Autoimmune hemolytic anemia (AIHA)

Autoimmune hemolytic anemia

Divided into disorders of autoantibodies and those caused by alloantibodies.

May be due to IgG or IgM immunoglobulin autoantiantibodies against red blood cell membrane antigens.

They are usually of the IgG class.

Incidence 0.8/100,000 people per year (Klein NP et al).

Warm antibody autoimmune hemolytic anemia is the most common autoimmune hemolytic anemia with an in incidence of 1:50,000-1:100,000.

Prevalence 17 per 100,000 people per year (Eaton WW et al).

Can occur as an idiopathic or secondary condition associated with defined illnesses or drug therapy.

Seen in 3-10% of patients with CLL.

Seen in 1-6% of patients with lymphoma.

With alloantibodies foreign red blood cell antigen exposure results in antibody formation directed against a specific antigen leading to red cell destruction.

Most of the complement mediated RBC destruction occurs through phagocytosis  of complement fragment C3b-coated cells by extravascular hemolysis.

To a lesser extent, cleavage of C5 and activation of the terminal complement cascade may occur with formation of a membrane attack complex and intravascular hemolysis.

AIHA pathogenesis involves the T lymphocytes system.

Polymorphisms of the CTLA-4 gene can confer a predisposition to immunologic disorders including auto immune cytopenias.

The programmed cell death 1 signal pathway is another checkpoint for immune tolerance and its inhibition carries an increase risk of auto immune disease.

In warm AHIA  antibodies have the highest affinity to the antigen at 37°C.

In warm AHIA , the autoantibodies are polyclonal.

There is autoantibody production again surface antigens expressed on red blood cells.

Autoimmune categories of disease include warm antibody autoimmune hemolytic anemia, cold autoimmune hemolytic anemia, paroxysmal cold hemoglobinuria and drug induced hemolytic anemia.

Warm IgG antibodies predominately bind to RBC surface antigens at body temperature and cause warm AIHA.

Cold IgM agglutinins bound to RBCs fix complement the temperature is below 37C and can cause cold agglutinin hemolysis.

These anti-RBC auto antibodies can be detected using the direct anti-globulin test, also called the Coombs test.Red blood cell destruction may occur intra or extravascularly.

Extravascular hemolysis occurs when IgG or complement coats red blood cells and these cells are recognized by liver and spleen macrophages and the interaction of the Fc component of the immunoglobulin and the Fc receptor in the macrophage remove part of red blood cell membrane with damage to the erythrocyte cytoskeleton.

The mononuclear phagocytosis system in the spleen plays a major role in the breakdown of erythrocytes: extravascular hemolysis.

The complement system, activated by the classical pathway, is involved in approximately half the cases of warm AIHA.

Red blood cells damaged extravascularly become spherocytes and are more sensitive to destruction in the circulation.

Associated with spherocytosis and reticulocytosis.

Intravascular hemolysis occurs when immunoglobulins capable of activating the complement system are at sufficient concentration of the red blood cell surface.

Attachment of antibody to red blood cell membrane leads to deposition of complement components C5-9 causing leakage of erythrocyte membrane cellular contents.

Most cases idiopathic in etiology.

In nearly 50% of cases of warm AIHA no underlying disorder can be identified, and the hemolytic process is classified as primary.

About 50% of cases are secondary to immunological lymphoproliferative disorders such as CLL, SLE, or common variable immunodeficiency.

Associated with disturbances in regulatory and autoreactive B and T cells.

Occasionally, a lymphoproliferative disorder may manifest several years after the diagnose of AIHA.

The presence of CTLA-4 G allele strongly associated with AIHA, paticularly in CLL.

May be associated with methyldopa or penicillin drugs, viral infections such as mononucleosis, collagen vascular diseases such as SLE, and hematologic malignancies.

May be related to use of nucleoside analogues such as fludarabine.

Associated with a 2-3 times increase in lymphoproliferative disorders.

Of 107 patients with AIHA 18% later developed a malignant lymphoproliferative disorder at a median of 26 months after the onset of the hemolysis (Sallah S et al).

One-third of cases associated with an enlarged spleen.

Patients may be asymptomatic or have symptoms and signs of anemia.

Diagnosis based on hemolysis with reticulocytosis, low haptoglobin, increased LDH, elevated indirct bilirubin, and positive direct antiglobulin test.

Diagnostic test most commonly uses is the direct Coombs’ test (direct antiglobulin test).

Management is to prevent hemolysis.

In the acute setting transfusion may be required with severe disease, advanced age and impaired clinical status.

Blood matching may be difficult due to the presence of antibodies against red blood cell antigens.

Diagnosis is on the basis of hemoglobin level and serum LDH, unconjugated bilirubin, and haptoglobin.

Reticulocytosis supports the presence of hemolysis, but may be normal or low, probably because of autoantibody activity against erythrocytes precursors or a existing bone marrow disorder.

The autoimmune pathogenesis is detected by the means of the direct anti-globulin test (DAT,Coombs test).

A positive test indicates immunoglobulin, complement, or both on the erythrocyte surface.

complement components, most often C3d, are detected in nearly half of the cases of warm autoimmune hemolytic anemia because of complement activation.

DAT is negative in 3 to 10% of patients with AIHA.

Standard treatment is with the use of corticosteroids, with about an 80% chance of complete remission or partial remission with initial treatment.

Failure to respond to corticosteroids suggests the presence of an underlying disease.

Splenectomy is second line treatment with short-term efficacy and short-term complete or partial remission in about 2/3 of patients.

Splenectomy is recommended for patients who do not have a response to primary or secondary therapies, and/or who have had a relapse after Rituximab therapy.

Rituximab is an effective as second line therapy; no response rate of 78% has been reported with immediate time to response of 3 to 6 weeks.

The addition of rituximab to steroids almost doubles long-term responses and is recommended by some as initial therapy in patients with severe disease with a hemoglobin of less than 8 g/dL.

Cyclophosphamide can be used in refractory cases.

Mycophenolate mofetil effective in refractory patients.

Third line agents also include azathioprine, cyclosporine and bortezomib.

For emergencies, high-dose intravenous steroids, immunoglobulins, complement C1 inhibition, plasma exchange, splenectomy, splenic embolization have been tried with some success.

Blood transfusion should not be withheld in cases of life-threatening anemia.

Pre-transfusion screening for antibodies will be positive and cross matching identical blood will show incompatibility.

Phenotyping for Rh sub groups, Kell, MNS, kidd, S/s, and Duffy antigens should be performed.

Transfusion should be tested within in vivo compatibility test with a rapid infusion of 20 mL of red blood cells, observation for 20 minutes and then if no reaction further infusion at the usual rate.

Erythropoietin can increase hemoglobin levels.

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