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Autoimmunity is a disorder in which an organism loses its ability to recognize the self and non-self antigen, which would further lead to immune response against its own cells and tissues. Diseases that results from such abnormal immune responses are termed as autoimmune diseases. Autoimmune hemolytic anemia (AIHA) is an autoimmune disorder in which endogenous antibodies are directed against the red blood cells and upregulated leading to erythrocyte death. This review article focuses on the types of AIHA based on the classification of the antibodies and the temperature at which they are active i.e warm AIHA, cold AIHA and mixed AIHA , based on the age of its occurance i.e adult or pediatric AIHA, causes, diagnostic techniques, diseases which may cause AIHA as a secondary disorder, treatment and its aftereffects, current and future prospectives of its studies.
Abbreviations: AIHA - Autoimmune hemolytic anemia, WAIHA - Warm autoimmune hemolytic anemia, CAIHA - Cold autoimmune hemolytic anemia, RBCs - Red blood cells, DAT - Direct antiglobin test.
Autoimmune hemolytic anemia (AIHA) is a disorder in which the auto-antibodies are directed against the persons own red blood cells (1). It is a relatively uncommon but not a rare disorder. It has an estimated incidence of 1 to 3 cases per 100,000 population per year (1). There are three types of AIHA based on the temperature of activity of the autoantibodies i.e warm AIHA, cold AIHA and mixed type AIHA of which warm AIHA has the most common occurance (more than 70%) followed by cold AIHA (about 20%) and mixed type has least occurance (2). Further AIHA is classified on the basis of age of the patient suffering from the disorder i.e pediatric AIHA and adult AIHA. Pediatric AIHA is from the age group of 1 to 16 (or 18) years and mostly has no underlying causes (2). Adult AIHA is from 18 years and above and is mostly associated with some underlying primary diseases. Sometimes AIHA is caused due to administration of some drugs and is called drug induced AIHA. AIHA may also be of secondary or idiopathic type. The further description of the different types of AIHA is explained below.
TYPES OF AIHA:
Based on the temperature at which the auto-antibodies are active:
Warm autoimmune hemolytic anemia (WAIHA)
It the most common type of AIHA. Warm auto-antibodies are usually IgG. It is called warm autoimmune hemolytic anemia because the antibodies have their peak activity at 370C. IgG effectively binds to the FC receptor of phagocytic cells. Hence the destruction of RBCs takes place mostly by phagocytosis. IgG may or may not fix complement. Hemolysis of RBCs also takes place in spleen. WAIHA may be idiopathic i.e when there is no primary infection causing the disorder or secondary to lymphoproliferative diseases, autoimmune diseases, viral infections, immune deficiency etc (1)(2)(3)(6).
Cold autoimmune hemolytic anemia (CAIHA)
Cold auto-antibodies are usually IgM antibodies. Rarely IgG or IgA antibodies can act as cold auto-antibodies. It is so called because the antibodies have their peak activity at temperature ranging from 0-40 C (1)(2)(3)(6). IgM antibodies are potent classical complement pathway activators. Hence causes complement mediated lysis of RBCs.
Paraxysmal cold hemoglobinurea a form of CAIHA, is caused by cold active IgG hemolysin. It was usually associated with some underlying diseases like syphilis, measles, mumps or other viral diseases (1)(2)(6).
Mixed autoimmune hemolytic anemia
Both warm auto-antibodies and cold auto-antibodies are present the blood. It is more fatal than the WAIHA and CAIHA. Detection and diagnosis is also more difficult than the earlier types (1)(2)(3)(4)(6).
Based on the age of the patient suffering from the disorder AIHA is classified as:
Affects the age group of 1-16 years, with a higher incidence of occurance in the first four years of life (1). It may spontaneously resolve on its own. It shows a good response to the steroid treatment. It has a severe onset and less morbity rate. Males are more prone to pediatric AIHA (2).
Affects the age group of 18 years and above. It is more often associated with the underlying lymphoproliferative, autoimmune and infectious diseases. Treatment is steroid therapy or spleenectomy. Has higher morbity rate compared to adult AIHA because of the difficulty or inability in treating the underlying disease (2).
Based on the cause of its occurance, following are the types of AIHA:
It is mainly caused due to some underlying diseases like bacterial, fungal or viral infections. The primary underlying diseases that may cause secondary AIHA are Sjogren's syndrome (10), lymphoproliferative and autoimmune diseases (2).Treatment of the secondary AIHA would also include the treatment of the underlying primary disease, for its complete remission (1).
Has no particular underlying causes like infections or primary diseases for its occurance. Mortality rate is comparatively less than that of secondary AIHA (1).
Drug induced AIHA
Cause of occurance are drug molecules that binds to the surface of the RBC membrane, acts as non-self antigens, thus inducing the autoantibodies against the RBCs and further leads to hemolysis (2). Examples of the drugs that cause drug induced hemolytic anemia are Ibuprofen, Diclofenac, L-dopa, Procainamide (6).
In majority of the cases AIHA is caused due to some primary underlying diseases like lymphoproliferative, autoimmune and infectious diseases (2). For example, after the M.suis infection in pigs, warm IgG autoantibodies are directed against the RBCs and destroys it. In this case actin was the active component that played a vital role in inducing an autoimmune response. Actin acted as a target protein for the autoreactive antibody during the acute phase of the M.suis infection. The autoreactive antibody production is induced by a misguided upregulation of the naturally occurring B cells specific for self antigens, appearance of previously cryptic antigens, occurance of altered self antigens, tolerance to self antigens due to molecular mimicry. The autoimmune epitopes (in this case actin) on the RBCs may be due to contact with the proteolytic enzymes. Cytoskeleton of the RBCs gets modified by the attachment and invasion of the infectious agent. Also the infectious agent causes damage to the RBCs making the hidden cytoskeletal proteins of the RBCs accessible for the circulating antibodies. Due to all the above mentioned reasons the antibodies recognizes them as non-self and elicit an immune response (3).
There are several other causes which may lead to AIHA other than due to a primary infections. For example higher incidence of occurance of AIHA after allogenic hematopoetic stem cell transplantation in adult patients. Further studies proved that the chances of development of AIHA is more in patients with HSCT from unrelated donors and also that they develop chronic extensive graft versus host disease (GVDH). In such cases it was observed that AIHA was never the primary cause of death, rather it was due to infection of GVDH (5). In some rare cases, liver transplantation or solid organ transplantation leads to the development of AIHA (11)(14)(15).
The destruction or removal of red blood cells from the circulation before their normal life span of 120 days is called 'Hemolysis'. Hemolysis manifests itself as acute or chronic anemia, reticulocytosis or jaundice. Intravascular hemolysis refers to the destruction of red blood cells in the blood with the release of contents into plasma. This is then followed by direct membrane degradation and cell destruction caused by mechanical trauma from a damaged endothelium, complement fixation and activation on the cell surface. On the other hand, extravascular hemolysis refers to the removal and destruction of red blood cells with membrane alterations by the macrophages of the spleen and liver. The hemolysis can be categorized broadly into the following types:
Due to infections (6)
Drug induced (2) (6)
Immune complex or Auto-antibody (6)
Drug absorption (hapten induced) (6)
Delayed transfusion reaction (6)
Acute transfusion reaction (6)
Flow chart 2: Broad classification of autoimmune hemolytic anemia.
Since all the above said categories of hemolytic anemias have many similar symptoms and expressions, efficient diagnostic techniques should be developed to detect the correct category of hemolytic anemia for its appropriate treatment.
Basic diagnosis for hemolysis on the basis of laboratory and peripheral smear findings:
Reticulocytosis which is the normal response of the bone marrow to the peripheral loss of blood cells is an important characteristic laboratory feature of hemolysis. Checking for the presence of reticulocytosis can be used for diagnosis of hemolysis. Review of the peripheral blood smear with an assessment for pathognomic red blood cell morphologies (spherocytes or schistocytes) along with examination of WBCs and platelets is very important for the evaluation of any anemia (6).
Increased unconjugated bilirubin, increased lactate dehydrogenase, and decreased haptoglobin levels are characteristic feature of the distruction of RBCs and thus can be used for diagnosis of hemolysis (6).
c) In addition to the above tests, urinary tests are also be performed (6)
After diagnosis of the basic hemolysis, its etiology is determined by performing further diagnostic tests. This review article focuses on the diagnostic techniques specific for AIHA. Microspherocyte on a peripheral smear and positive direct antiglobin test (DAT) is a characteristic feature of AIHA (1). The direct antiglobin test ,is also known as direct Coombs test (8). It demonstrates the presence of antibodies or complement on the surface of red blood cells which is the hallmark of autoimmune hemolysis (8). In this technique, the patients red blood cells are mixed with rabbit or mouse antibodies against human IgG or C3. The test would give a positive result if an agglutination reaction between the patients antibody or complement coated red blood cells by anti-IgG or C3 is observed. RBC agglutination with anti-IgG serum indicates warm AIHA and RBC agglutination with anti-C3 indicates the cold AIHA. However further efficient and very specific diagnostic techniques should be developed to distinguish mixed AIHA and paraxysomal cold hemoglobinuria from the other types. Also the present diagnostic techniques many a times failed to give an errorless distinction between these two types of AIHA (4).
The three types of drug induced anemia based on their mechanism of their mechanism of action can be detected by a positive DAT and its type can be identified by the intravascular or extra-vascular hemolysis that it produces (6).
Treatment mainly depends upon the type of AIHA i.e warm antibody type, cold antibody type, mixed antibody type or paraxysomal cold hemoglobinuria and also on the secondary or the idiopathic forms. The following are the treatment options for AIHA. However each treatment stratergies has its own advantages and disadvavtages.
Warm antibody autoimmune hemolytic anemia -
The initial therapeutic agent used for treatment of WAIHA patients are the corticosteroids.
There is a rapid onset of response. This therapy is usually maintained for 1-3 weeks, however sudden ceasation of therapy may result in prompt relapse of hemolysis. The adverse effects of long term use of corticosteroids as a therapeutic agent would include pulmonary aspergellosis, central nervous system hemorrhage (2), osteoporosis, avascular necrosis, susceptibility to infection, abnormalities in glucose and lipid metabolism and growth suppression in children (7).The gluocorticoids may inhibit antimicrobial activity of macrophages thus showing side effects when treated with it (2). In cases of pediatric anemia, prednisolone along with folic acid supplementation was used for therapy which showed a positive response in 81% of the patients (8).
Splenectomy is mainly considered in patients who donot respond to the corticosteroid therapy. The main advantage of splenectomy is that it has a potential for a complete and long term remission. The adverse effect of spelectomy would include overwhelming postspelectomy infection (OPSI) which may result in serious morbity or mortality in a small percentage of patients after spelectomy (2)(7)(8).
iii) IMMUNOSUPPRESSIVE DRUGS
This is the third therapeutic option after both corticosteroid therapy and spelectomy. Examples of the immuno-suppressive drugs would include azathioprine, cyclosporine (8), rituximab (9)(11) etc.
It is an attenuated androgen with good responses and comparatively lesser side effects (2)(7).
v) INTRAVENOUS IMMUNOGLOBIN
In patients who doesnot respond to the corticosteroids, it is used as a second line therapy. However, intravenous immunotherapy is expensive (2)(7).
vi) PLASMA EXCHANGE
Used for acute reversal of severe hemolysis along with other therapeutic agents.
Cold antibody autoimmune hemolytic anemia
The simplest and the possible way for reducing the severity of CAIHA is avoidance of cold. Plasma exchange showed a temporary benefit in a small percentage of patients. Any other therapeutic options involved more potential risks than probable benefits.
Paroxysmal cold hemoglobinuria
In most of the cases hemolysis terminates spontaneously and hence only supportive care is required. Sometimes transfusion of RBCs and corticosteroid therapy may have a positive impact on the treatment.
Atmost care should be taken in case of secondary autoimmune hemolytic anemia i.e the underlying diseases like chronic lymphocytic leukemia, systemic lupus erytromatous, lymphomas etc should be treated for complete remission from AIHA (7).Combinational therapy was used in some cases of AIHA as secondary infection. Example, a case in which AIHA was found in association with Plasmodium vivax infection was treated with chloroquine and primaquine (for P.vivax infection), prednisolone and transfusion of least incompatible RBCs (for AIHA) (12).
This review article gives a very short explanation about autoimmunity as a disorder. It mainly focused on auto-immune hemolytic anemia which is a subset of autoimmunity. The types of AIHA, causes, diagnosis and possible treatment stratergies were discussed. The future area of research under this topic is in finding out more efficient and specific diagnostic techniques to detect mixed and paroxysmal cold hemoglobinuria and treatment options with maximum results and minimum side-effects. Drugs like Bortizomib (13), Alemtuzumab (humanized monoclonal antibody targeting CD52 antigen) etc are still under research for the treatment of hemolytic anemia (16).