Hemolytic anemia is characterized by the premature death of red blood cells, which is often caused by antibodies attacking them. If the autoantibodies are produced by the host, the disease can be labeled autoimmune hemolytic anemia—one type of which is cold agglutinin disease.
“Autoimmune hemolytic anemia has always been considered the simplest and most scholastic example of antibody-mediated autoimmune disease,” Barcellini and Fattizzo wrote in Frontiers in Immunology.
This is because the mechanisms of this disease are straightforward: antibodies from the host mistakenly attack its own red blood cells, resulting in anemia and associated symptoms. The directed attack of autoantibodies against red blood cells can sometimes be mediated by complement activation. Compared with malignant hematological diseases, autoimmune hemolytic anemia is relatively easy to treat.
When autoimmune hemolytic anemia is suspected, the gold standard test for diagnosis is the direct antiglobulin test, which allows clinicians to determine the thermal characteristics and the isotype of the antibodies. Warm autoimmune hemolytic anemia represents around 60% to 70% of cases, while cold autoimmune hemolytic anemia makes up the remaining 20% to 25% of cases. The term “cold agglutinin disease” is used to refer to cold antibodies secondary to clonal lymphoproliferative disorder.
Read more about cold agglutinin disease etiology
Autoimmune hemolytic anemia has an estimated incidence of only 1 to 3 cases per 100,000/year, making it an extremely rare disease. It commonly occurs in early childhood or in adults above the age of 40. If the disease is diagnosed in adulthood, the risk of frequent relapses is more common, especially if the disease is associated with lymphoproliferative or autoimmune disorders.
Autoimmune hemolytic anemia has considerable clinical heterogeneity. Hence, it is challenging to predict disease course and outcomes.
However, studies have illuminated a few facts about this disease with regard to its typical clinical course. For example, the lower the hemoglobin level is at disease onset, the higher the hazard ratio for a relapse is.
In a literature review published in the Journal of Clinical Medicine, Barcellini and colleagues reported that the survival among adult patients at 1 year is 91%; at 5 years, it is 75%; and at 10 years, 73%. Studies also demonstrate that mortality is around 4%, mainly due to infections, acute renal failure, Evans syndrome, and major thrombotic events.
However, the mortality rate differs according to how well the patient’s condition is managed and how severely ill a patient becomes when experiencing a relapse. Studies have demonstrated that patients with very severe relapses have a mortality rate close to 60%. This highlights the importance of routine care and recognizing the early signs of a relapse before the patient becomes severely ill.
Aiming for Optimal Care
The main feature of autoimmune hemolytic anemia is, as the name suggests, anemia. If the patient is symptomatic, they should receive blood transfusions to raise their hemoglobin to acceptable levels. “In the setting of [autoimmune hemolytic anemia], treating the underlying condition (such as infection, malignancy or removing causative drugs) is required,” Palmer and Seviar wrote in the Clinical Medicine Journal.
The first-line therapy for warm autoimmune hemolytic anemia is corticosteroids, which are used to stop the production of autoantibodies that destroy red blood cells. Corticosteroids are also used in cold autoimmune hemolytic anemia, but these patients tend to respond less well to them.
Read more about cold agglutinin disease treatment
If corticosteroids fail to produce the desired clinical effect, rituximab is often prescribed. Rituximab works by targeting CD20 on B cells to suppress autoantibody production. Rituximab, a relatively new therapy, achieves a response in 80% to 90% of cases, with a median duration of around 2 years. Studies have suggested that the combination of corticosteroids and rituximab can achieve relapse-free survival in 68% of patients at the 3-year mark.
Splenectomy is another therapeutic option for treating autoimmune hemolytic anemia, although it is often seen as a last resort. It works by removing the site at which antibody production and red blood cell destruction occur. It is typically not recommended for older adults with comorbidities or underlying immunodeficiency. However, it may be suitable as a second-line treatment for young patients and females who desire to become pregnant.
“The drawbacks of splenectomy are the lack of reliable predictors of outcome, the associated surgical complications, and most importantly, infectious and thrombotic complications,” wrote Barcellini and colleagues.
A host of new drugs are being investigated, including B cell-directed therapies and complement inhibitors. These drugs may play a major role in the fight against autoimmune hemolytic anemia in the future.
Palmer D, Seviar D. How to approach haemolysis: haemolytic anaemia for the general physician. Clin Med (Lond). 2022;22(3):210-213. doi:10.7861/clinmed.2022-0142
Barcellini W, Fattizzo B. The changing landscape of autoimmune hemolytic anemia. Front Immunol. 2020;11:946. doi:10.3389/fimmu.2020.00946
Barcellini W, Zaninoni A, Giannotta JA, Fattizzo B. New insights in autoimmune hemolytic anemia: from pathogenesis to therapy stage 1. J Clin Med. 2020;9(12):3859. doi:10.3390/jcm9123859