Autoimmune hemolytic anemia (AIHA) occurs when a person's immune system produces antibodies directed against their own red blood cells (RBCs). These antibodies attach to red cells, causing them to break down (lyse), and reducing the number of oxygen-carrying red blood cells in circulation (anemia). The antibodies are usually directed against common red cell antigens, therefore they also bind to allogenic or transfused red cells and cause them to lyse. (ref). Autoimmune haemolytic anaemia can be caused by different types of antibodies with reactivity at different temperatures. The one caused by IgG antibodies is called warm-immune haemolytic anaemia and has an incidence of 5-10 cases per million whereas ‘cold agglutinin disease’ is caused by IgM antibodies with an incidence of 1-1.8 cases per million.
The terminology used in this disease is somewhat ambiguous. Although MeSH uses the term "autoimmune hemolytic anemia", some sources prefer the term "immunohemolytic anemia" so drug reactions can be included in this category. The National Cancer Institute considers "immunohemolytic anemia", "autoimmune hemolytic anemia", and "immune complex hemolytic anemia" to all be synonyms.
Signs and symptoms
Symptoms of AIHA may be due to the underlying anemia; including shortness of breath or dyspnea, fatigue, headache, muscle weakness and pallor.
Jaundice is a common sign of haemolytic anemia. It is caused by the accumulation of bilirubin in skin, and sclera. Bilirubin is produced by degradation of heme molecule and as red cells lyse and release intracellular contents, the free heme decomposes to bilirubin causing jaundice. Jaundice can also be accompanied by dark (tea coloured) urine due to free hemoblogin.
In cold agglutinin disease (cold antibody type), agglutination and impaired passage of red blood cells through capillaries in the extremities causes acrocyanosis and Raynaud phenomenon with a rare complication of gangrene
Spherocytes are found in immunologically mediated hemolytic anemias. Signs of hemolysis that are present in AIHA include low hemoglobin (blood count), alterations in levels of cell markers of hemolysis; including elevated lactate dehydrogenase (LDH), decreased haptoglobin and elevated unconjugated bilirubin. Reticulocytosis, or an increase in circulating immature red blood cells, may be seen.
Causes The causes of AIHA are poorly understood. The disease may be primary, or secondary to another underlying illness. The primary AIHA is idiopathic (the two terms used synonymously) and accounts for more than 60% of unselected cases.
Secondary AIHA can result from many other illnesses usually the ones that also affect immune system. The most common causes of secondary AIHA include lymphoproliferative disorders (e.g., chronic lymphocytic leukemia, lymphoma), immune dysregulation disorders such as autoimmune lymphoproliferative syndrome (ALPS) and common variable immunodeficiency (CVID) and other autoimmune disorders (e.g., systemic lupus erythematosus, rheumatoid arthritis, scleroderma, Crohn's disease, ulcerative colitis), infections (as HIV, EBV, hepatitis, mycoplasma, viral pneumonia, and other respiratory infections) and drugs. Less common causes of warm-type AIHA include neoplasms other than lymphoid, and bone marrow / solid organ transplant. Secondary warm type AIHA has been observed in cases of COVID-19. Secondary cold type AIHA is also caused primarily by lymphoproliferative disorders but is also commonly caused by infection, especially by mycoplasma, viral pneumonia, infectious mononucleosis, and other respiratory infections. Less commonly, it can be caused by concomitant autoimmune disorders.
Drug-induced AIHA, though rare, can be caused by a number of drugs. More than 130 drugs have been implicated in causing AIHA.
This is a type II immune response in which the drug binds to macromolecules on the surface of the RBCs and acts as an antigen. Antibodies are produced against the RBCs, which leads to complement activation. Complement fragments, such as C3a, C4a and C5a, activate granular leukocytes (e.g., neutrophils), while other components of the system (C6, C7, C8, C9) either can form the membrane attack complex (MAC) or can bind the antibody, aiding phagocytosis by macrophages (C3b). This is one type of "penicillin allergy".
In about half of cases, the cause of autoimmune hemolytic anemia cannot be determined (idiopathic or primary). This condition can also be caused by or occur with another disorder (secondary) or rarely, occur following the use of certain drugs (such as penicillin) or after a person has a blood and marrow stem cell transplant.
Secondary causes of autoimmune hemolytic anemia include: Autoimmune diseases, such as lupus Chronic lymphocytic leukemia Non-Hodgkin's lymphoma and other blood cancers Epstein-Barr virus Cytomegalovirus Mycoplasma pneumonia Hepatitis HIV
Pathophysiology AIHA can be caused by different antibody classes with IgG and IgM antibodies being the primary antibody types. IgA autoantibodies can also rarely cause AIHA.
Pathophysiology of warm or IgG mediated AIHA differs from cold or IgM mediated AIHA. Warm AIHA means immune haemolysis is caused by auto-antibodies which bind to red cells at body temperature (37 degree Celsius). These are usually IgG but can be IgM in rare cases. In warm AIHA, red cells coated by IgG undergo antibody mediated cell death in the reticuloendothelial system of liver and spleen leading to extravascular haemolysis. These IgG antibodies are also capable of activating the complement cascade with variable efficacy, further leading to opsonisation and destruction of red cells in reticuloendothelial system (RE) system or intravascular haemolysis via terminal complement.
Red cell autoantibodies causing cold agglutinin disease are of IgM class. These bind to RBC antigens at lower temperatures (e.g. in the acral parts of body such as hands, feet, ears, nose). The antibody/RBC antigen complex then activates the classical complement pathway leading to complement mediated hemolysis of RBCs in RE system.
Rarely, a biphasic IgG antibody leads to complement mediated intravascular lysis. This antibody binds to red cells in acral regions along with first two components of complement. As the blood moves to central regions of the body and warms up, the IgG dissociates but the complement remains attached to red cell causing intravascular hemolysis. The antibody causing this biphasic hemolysis is commonly IgG but IgM and IgA have also been reported.
Paroxysmal Cold Hemoglobinuria (PCH) is primarily a pediatric disease and usually occurs with Mycoplasma pneumonia infection or other viral infections. It can also occur with chronic lymphocytic leukemia and lymphomas in adults.
Pathophysiologic mechanisms involved in drug induced haemolysis include: drug-dependent autoantibodies due to an immuno-allergic mechanism, drug-independent autoantibodies due to molecular mimicry, or nonspecific stimulation of the immune system.
AIHA cannot be attributed to any single autoantibody. To determine the autoantibody or autoantibodies present in a patient, the Coombs test, also known as the antiglobulin test, is performed. There are two types of Coombs tests, direct and indirect; more commonly, the direct antiglobulin test (DAT) is used. Classification of the antibodies is based on their activity at different temperatures and their etiology. Antibodies with high activity at physiological temperature (approximately 37 °C) are termed warm autoantibodies. Cold autoantibodies act best at temperatures of 0–4 °C. Patients with cold-type AIHA, therefore, have higher disease activity when body temperature falls into a hypothermic state. Usually, the antibody becomes active when it reaches the limbs, at which point it opsonizes RBCs. When these RBCs return to central regions, they are damaged by complement. Patients may present with one or both types of autoantibodies; if both are present, the disease is termed "mixed-type" AIHA.
When DAT is performed, the typical presentations of AIHA are as follows. Warm-type AIHA shows a positive reaction with antisera to IgG antibodies with or without complement activation. Cases may also arise with complement alone or with IgA, IgM or a combination of these three antibody classes and complement. Cold-type AIHA usually reacts with antisera to complement and occasionally to the above antibodies. This is the case in both cold agglutinin disease and cold paroxysmal hematuria. In general, mixed warm and cold AIHA shows a positive reaction to IgG and complement, sometimes IgG alone, and sometimes complement alone. Mixed-type can, like the others, present unusually with positive reactions to other antisera.
Laboratory features and diagnosis Diagnosis of AIHA should be suspected in a patient presenting with acute onset of anemia. It is essential to consider the secondary causes of AIHA such as infections, lymphoproliferative conditions, drugs, immune dysregulation and autoimmune conditions. Laboratory investigations are performed to determine the aetiology of the anemia. These include complete blood count, reticulocyte count, markers of hemolysis (haptoglobin, LDH and bilirubin) and red cell morphology on peripheral smear.
The diagnosis of AIHA is confirmed by the direct antiglobulin test (DAT), also known as the Coombs test, which determines the presence of IgG or IgM antibodies attached to the surface of red blood cells. The test involves the incubation of red blood cells with antiglobulin reagent at . If positive, further testing is undertaken to determine whether the hemolysis is IgM/complement-mediated or IgG-mediated.
A bone-marrow biopsy can be performed to identify a possible underlying lymphoproliferative disorder.
Classification AIHA can be classified as warm autoimmune hemolytic anemia or cold autoimmune hemolytic anemia, which includes cold agglutinin disease and paroxysmal cold hemoglobinuria. These classifications are based on the characteristics of the autoantibodies involved in the pathogenesis of the disease. Each has a different underlying cause, management, and prognosis, making classification important when treating a patient with AIHA.
Autoimmune hemolytic anemia
Warm AIHA (IgG mediated) Primary (No underlying secondary cause) Secondary (lymphoproliferative disorders, autoimmune disorders, stem cell transplant, infections, immune dysregulation, drugs) Cold AIHA Primary cold agglutinin disease Secondary cold agglutinin syndrome Associated with malignant disease Acute, transient, infection-associated (acute cold antibody mediated AIHA complicating Mycoplasma pneumoniae or viral infections) Chronic (lymphoproliferative disorders) Paroxysmal cold hemoglobinuria Idiopathic Secondary Acute, transient (Infections other than syphilis) Chronic (syphilis) Mixed cold- and warm-antibody type Idiopathic Secondary (lymphoproliferative disorders, autoimmune disorders) Drug-induced immune hemolytic anemia Autoimmune type Drug absorption type Neoantigen type
Evidence for hemolysis The following findings may be present:
Increased red cell breakdown Elevated serum bilirubin (unconjugated) Excess urinary urobilinogen Reduced plasma haptoglobin Raised serum lactic dehydrogenase (LDH) Hemosiderinuria Methemalbuminemia Spherocytosis Increased red cell production: Reticulocytosis Erythroid hyperplasia of the bone marrow Specific investigations Positive direct Coombs test
Treatment