How do I approach patients with warm-reactive autoantibodies?

W arm-reactive autoantibodies are the most common cause of autoimmune hemolytic anemia, with the incidence of these antibodies increasing with patient age. They have been reported in children as young as a few months of age, and there are two case reports of neonates who seem to have developed warm-reactive autoantibodies in utero. They are a relatively common finding at Arkansas Children’s Hospital, accounting for approximately 15% of all antibodies evaluated in the laboratory. Although warm-reactive autoantibodies are sometimes idiopathic, there are a number of common disease associations including hematopoietic malignancies (e.g., lymphomas and leukemias, especially chronic lymphocytic leukemia), autoimmune disorders (e.g., systemic lupus erythematosus), and chronic inflammatory conditions (e.g., Crohn’s disease and ulcerative colitis). On occasion, a warmreactive autoantibody may be the harbinger of one of these disorders, which only presents in overt form later. This review will focus on the transfusion service laboratory approach to these autoantibodies and applies to pediatric and adult patients equally. I am usually first consulted about a new warmreactive autoantibody by a blood bank technologist. Initially, I strive to obtain information about the serologic nature of the antibody and the clinical status of the patient. With regard to the former, I turn my attention first to the reactive nature of the antibody in the serum (i.e., How strongly reactive is the antibody? Are all of the red blood cells [RBCs] on the antibody identification panel reactive? Are the cells on the panel equally reactive?). I next consider the reactive nature of the direct antiglobulin test (DAT; i.e., What is coating the RBCs in excess: IgG, C3, or both? What is the strength of reactivity of the anti-IgG and anti-C3 reagents?). Having knowledge of the serologic reactivity of the patient’s antibody helps to confirm that it is, indeed, a warm-reactive autoantibody. It also provides important insight into the likelihood that the antibody is resulting in hemolysis—warm autoimmune hemolytic anemia (WAIHA). As examples, it has been well demonstrated that more strongly reactive warm autoantibodies are more likely to be associated with overt hemolysis, although this is by no means a perfect correlation. Similarly, warm-reactive IgG autoantibodies that are also associated with demonstrable C3 on the RBC membrane are more likely to be hemolytic via a synergistic effect. Once I understand the serological presentation of the warm-reactive autoantibody, I turn my attention to determining the clinical significance of the antibody and understanding the patient’s clinical condition. Most important is determining if the antibody is associated with hemolysis. This is a key consideration as this will be the primary determinant of whether or not the patient will need transfusion (now and into the future). This will, in turn, drive the extent to which the antibody is evaluated in the laboratory. To determine the clinical significance of warm-reactive autoantibodies, a number of ancillary laboratory tests are required including the hemoglobin (Hb) and hematocrit (low), the reticulocyte count (generally elevated, but reticulocytopenia can be a harbinger of a difficult patient course), the lactate dehydrogenase value (elevated), and the bilirubin level, particularly the indirect fraction (elevated). A visual inspection of the plasma or urine is low cost and can provide helpful information as to whether hemolysis (if present) is intravascular or extravascular. The latter is expected in cases of WAIHA. A haptoglobin value can be useful (low), but in many laboratories this test is not readily available. In addition, haptoglobin is an acute-phase reactant, so a single value, especially one that is in the normal reference range for the laboratory, may not be useful. Finally, it is always advisable to assess the RBC morphology on review of the peripheral blood smear, because spherocytes are typically identified in cases of WAIHA. If a patient is experiencing hemolysis to the extent that transfusion support is necessary, additional serologic work may be required. The most basic question is this: From the Department of Pathology, University of Arkansas for Medical Sciences College of Medicine and Arkansas Children’s Hospital, Little Rock, Arkansas. Address reprint requests to: Douglas P. Blackall, MD, Department of Pathology, Arkansas Children’s Hospital, 1 Children’s Way, Little Rock, AR 72202; e-mail: dougandcaron@ att.net. Received for publication July 27, 2010; revision received September 10, 2010, and accepted October 15, 2010. doi: 10.1111/j.1537-2995.2010.02985.x TRANSFUSION 2011;51:14-17.