Autoimmune hemolytic anemia overview
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Assosciate Editor(s)-In-Chief: Prashanth Saddala M.B.B.S; Shyam Patel [2], Irfan Dotani [3]
Overview
Autoimmune hemolytic anemia is a type of hemolytic anemia where the body's immune system attacks its own red blood cells, leading to their destruction (hemolysis). Antibodies and associated complement system components become fixed onto the red blood cell surface. These antibodies can be detected with the Coombs test or direct Coombs test. Autoimmune hemolytic anemia can also be induced by infections such as Mycoplasma pneumoniae, drugs such as methyldopa and fludarabine, or malignancies such as chronic lymphocytic leukemia or non-Hodgkin lymphoma. Autoimmune hemolytic anemia is classified into 3 broad categories. These include warm-antibody type, cold-antibody type, and mixed-antibody type. Each category is characterized by a different autoantibody (IgG or IgM) and different optimal binding temperatures (37 degrees Celsius or 4-18 degrees Celsius). A variety of conditions comprise the differential diagnosis of autoimmune hemolytic anemia. These include microangiopathic hemolytic anemia, paroxysmal cold hemoglobinuria, paroxysmal nocturnal hemoglobinuria, hereditary spherocytosis, pernicious anemia, and chronic lymphocytic leukemia. The risk factors for autoimmune hemolytic anemia include systemic lupus erythematosus and immunotherapeutic medications. The natural history of autoimmune hemolytic anemia begins with the hemolytic event. A diagnostic workup is typically initiated soon after the hemolytic event, and the hemolysis subsides after the start of corticosteroids. Most patients will generally achieve remission with no long-term complications. Complications of autoimmune hemolytic anemia usually include infection, thrombosis, iron overload, and end-organ damage from impaired oxygen delivery. Patients with autoimmune hemolytic anemia have a gradual onset of fatigue and can develop shortness of breath and decreased exercise tolerance. The symptoms of autoimmune hemolytic anemia depend on the severity of the disease. Laboratory findings in patients with autoimmune hemolytic anemia include anemia, positive Coombs test, positive indirect antiglobulin test, hemoglobinuria, low haptoglobin, increased spherocytes, and elevated lactate dehydrogenase (LDH). Not all patients will have all of these findings. The severity of hemolysis will determine the degree of laboratory abnormalities. The mainstay of therapy for autoimmune hemolytic anemia is immunosuppression, since the pathophysiology of autoimmune hemolytic anemia involves immunological activation which leads to the destruction of red blood cells. Suppression of the immunological activation via medications has been the cornerstone of therapy for many decades. Medications include corticosteroids, azathioprine, rituximab, mycophenolate mofetil, cyclosporine A, and cyclophosphamide. Splenectomy is the only surgical management option for patients with autoimmune hemolytic anemia. The response rate is moderately high. Assessment for candidacy for splenectomy involves evaluation of the surgical risk and the risk of sepsis from encapsulated organisms. Proper vaccinations must thus be given prior to splenectomy. The primary prevention strategies for autoimmune hemolytic anemia include avoidance of exposure to precipitants.
Historical Perspective
The history of studies on autoimmune hemolytic anemia begins in the early 20th century with the description of clinical syndromes involving low hemoglobin in the setting of a circulating antibody. Various groups reported on the production of antibodies that could bind to red blood cells at either warm or cold temperatures. Over the years, diagnostic tests were developed and optimized to determine the exact type of antibody involved in hemolysis. Treatment modalities were developed, beginning with corticosteroids. Other immunosuppressive medications, such as rituximab, were soon found to be effective in patients with hemolytic anemia.
Classification
Autoimmune hemolytic anemia is classified into 3 broad categories. These include warm-antibody type, cold-antibody type, and mixed-antibody type. Each category is characterized by a different autoantibody (IgG or IgM) and different optimal binding temperatures (37 degrees Celsius or 4-18 degrees Celsius). Each condition is associated with different triggers, including infections, medications, and malignancies. The warm-antibody type is the most common, and the mixed-antibody type is rare and not well characterized.
Pathophysiology
The pathophysiology of autoimmune hemolytic anemia is different for warm-antibody type and cold-antibody type anemia. The pathophysiology of warm-antibody type autoimmune hemolytic anemia involves the coating of red blood cells with IgG, followed by extravascular hemolysis by splenic macrophages. The pathophysiology of cold-antibody type autoimmune hemolytic anemia involves the coating of red blood cells with IgM, followed by intravascular hemolysis. The complement system has a significant role in autoimmune hemolytic anemia and involves the binding of classical complement proteins on the red blood cell surface, followed by cell lysis by the membrane attack complex. In summary, a variety of cell-mediated immunologic mechanisms underlie the pathophysiology of autoimmune hemolytic anemia.
Causes
Autoimmune hemolytic anemia is caused by primary and secondary conditions. Secondary conditions that cause autoimmune hemolytic anemia include malignancies, autoimmunity, and medications. Malignancies that cause autoimmune hemolytic anemia include chronic lymphocytic leukemia and non-Hodgkin lymphoma. Autoimmune conditions that cause autoimmune hemolytic anemia include systemic lupus erythematosus, primary biliary cirrhosis, and others. Medications that cause autoimmune hemolytic anemia include methyldopa and fludarabine.
Differentiating Autoimmune Hemolytic Anemia from Other Diseases
A variety of conditions comprise the differential diagnosis of autoimmune hemolytic anemia. These include microangiopathic hemolytic anemia, paroxysmal cold hemoglobinuria, paroxysmal nocturnal hemoglobinuria, hereditary spherocytosis, pernicious anemia, and chronic lymphocytic leukemia. The diagnosis of autoimmune hemolytic anemia can sometimes be made by first ruling out these other causes. It is important to distinguish amongst these conditions since the prognosis and treatment of each condition is different.
Epidemiology and Demographics
Overall, the incidence and prevalence of autoimmune hemolytic anemia are low. This condition affects a very small proportion of the population. Autoimmune hemolytic anemia affects men and women equally. There is no racial predilection for autoimmune hemolytic anemia.
Risk Factors
The risk factors for autoimmune hemolytic anemia include systemic lupus erythematosus and immunotherapeutic medications. Systemic lupus erythematosus is thought to be a strong risk factor for autoimmune hemolytic anemia. However, immunotherapeutic medications may become a more prevalent risk factor in the coming years as these agents are becoming used increasingly for a variety of cancers. These medications include anti-PD-1 antibodies and anti-CTLA-4 antibodies.
Screening
Screening for autoimmune hemolytic anemia is not currently done routinely.
Natural History, Complications, and Prognosis
Natural History
The natural history of autoimmune hemolytic anemia begins with the hemolytic event. A diagnostic workup is typically initiated soon after the hemolytic event, and the hemolysis subsides after the start of corticosteroids. Most patients will generally achieve remission with no long-term complications.
Complications
For patients who develop complications, these complications include infection, thrombosis, iron overload, and end-organ damage from impaired oxygen delivery.
Prognosis
The prognosis of autoimmune hemolytic anemia depends on the severity of the immune activation. The prognosis is overall favorable for most patients.
Diagnosis
History and Symptoms
Patients with autoimmune hemolytic anemia have a gradual onset of fatigue and can develop shortness of breath and decreased exercise tolerance. The symptoms of autoimmune hemolytic anemia depend on the severity of the disease.
Physical Examination
Physical exam findings in patients with autoimmune hemolytic anemia vary depending on the severity of the disease. Examination findings include pallor, clubbing, jaundice, scleral icterus, splenomegaly, and abdominal tenderness.
Laboratory Findings
Laboratory findings in patients with autoimmune hemolytic anemia include anemia, positive Coombs test, positive indirect antiglobulin test, hemoglobinuria, low haptoglobin, increased spherocytes, and elevated lactate dehydrogenase (LDH). Not all patients will have all of these findings. The severity of hemolysis will determine the degree of laboratory abnormalities.
CXR
There is no primary role for chest X-ray in diagnosis or evaluation of autoimmune hemolytic anemia, but chest X-ray can be useful to help diagnose other conditions associated with autoimmune hemolytic anemia, such as volume overload states from frequent transfusions.
CT scan
CT scan is useful as an adjunct in the workup of autoimmune hemolytic anemia but is not used in the primary evaluation.
MRI
There is no primary role for MRI in the evaluation of autoimmune hemolytic anemia, but MRI can be helpful in assessing for spleen size or iron overload.
Ultrasound
Ultrasound of the abdomen is useful in patients with autoimmune hemolytic anemia to assess for spleen size and mesenteric thrombosis.
Other Imaging
An echocardiogram can be done in patients with autoimmune hemolytic anemia to assess for high-output cardiac failure and to assess for iron overload.
Other Diagnostic Studies
There are no other diagnostic studies used in the primary evaluation of autoimmune hemolytic anemia.
Treatment
Medical Therapy
The mainstay of therapy for autoimmune hemolytic anemia is immunosuppression, since the pathophysiology of autoimmune hemolytic anemia involves immunological activation which leads to the destruction of red blood cells. Suppression of the immunological activation via medications has been the cornerstone of therapy for many decades. Medications include corticosteroids, azathioprine, rituximab, mycophenolate mofetil, cyclosporine A, and cyclophosphamide.
Surgery
Splenectomy is the only surgical management option for patients with autoimmune hemolytic anemia. The response rate is moderately high. Assessment for candidacy for splenectomy involves evaluation of the surgical risk and the risk of sepsis from encapsulated organisms. Proper vaccinations must thus be given prior to splenectomy.
Prevention
The primary prevention strategies for autoimmune hemolytic anemia include avoidance of exposure to precipitants. There is no significant role for secondary prevention of autoimmune hemolytic anemia.