The autoimmune hemolytic anemias (AIHA) are rare but important hematologic diseases. They can range in severity from mildly symptomatic illness to a rapidly fatal syndrome. The incidence of AIHA is estimated to be between 0.6 and 3 cases per 100,000 persons.1,2 AIHA is mediated by antibodies, and in the majority of cases immunoglobulin (Ig) G is the mediating antibody. This type of AIHA is referred to as "warm" AIHA because IgG antibodies bind best at body temperature. "Cold" AIHA is mediated by IgM antibodies, which bind maximally at temperatures below 37°C (Table 1). This article series reviews the most common types of AIHA, with an overview of evaluation and diagnosis presented in this article and management of warm, cold, and drug-induced AIHA reviewed in a separate article.
Pathogenesis
In most cases, the ultimate etiology of AIHA is unknown. In warm AIHA, the target epitopes in most cases are Rh proteins.2 What leads the immune system to target these proteins is unidentified, but one theory is that an initial immune response to a foreign antigen starts to cross-react with the Rh proteins and the immune system fails to suppress this autoreactive response, leading to hemolysis. In IgG-mediated (warm) hemolysis, the red cells become coated with IgG molecules, which mark the cells for uptake and destruction by splenic macrophages.3 In "cold" AIHA, IgM molecules fix complement to the surface of red blood cells. Rarely, this can lead to activation of the full complement cascade, resulting in red cell lysis, but more often it is stopped at the C3 stage, leading to C3-coated red cells which are then taken up by hepatic macrophages.4
Suspecting the Diagnosis
In many patients, it is the symptoms and signs of anemia that lead to suspicion of hemolysis. Older patients often present earlier in the course of the disease due to lack of tolerance of anemia, especially if there is a sudden drop in the red blood cell count. Dark, cola-colored urine resulting from the presence of free hemoglobin may be noted by some patients. Patients with rapid-onset hemolysis may note lumbar back pain, and those with cold agglutinins often note symptoms related to agglutination of red cells in the peripheral circulation, such as the development of acrocyanosis in cold weather.5 In rare cases, patients will have abdominal pain when eating cold food due to ischemia related to agglutination of red cells in the viscera. Some patients with cold agglutinins can have an exacerbation of their hemolysis with cold exposure.
Unlike patients with immune thrombocytopenia, those with AIHA may have mild splenomegaly on exam. The presence of enlarged lymph nodes or massive splenomegaly should raise concern about concomitant lymphoma or chronic lymphocytic leukemia.
Making the Diagnosis
The 2 key steps in diagnosis are (1) demonstrating hemolysis and (2) demonstrating the autoimmune component.
Laboratory Evaluation for Hemolysis
Hemolysis is proven by finding evidence of both red cell breakdown and the compensatory increase in red cell production this stimulates (Table 2). The following sections discuss the laboratory tests that are performed to investigate hemolysis.
Lactate Dehydrogenase
When red cells undergo hemolysis, they release their contents, which are mostly comprised of hemoglobin but also include lactate dehydrogenase (LDH), an enzyme found in high concentration in red cells. Most patients with hemolysis will have an elevated LDH level, making this a sensitive test. However, because many other processes, including liver disease and pneumonia, also raise the serum LDH level, this finding is not specific for hemolysis.