Mihir Raval, MD, MPH, comments on the difference between cold agglutinin disease and other autoimmune hemolytic anemias.
Neil Minkoff, MD: Now, you had mentioned that there are other autoimmune hemolytic anemias that would need to be differentiated here. I was wondering if we could discuss some of those, maybe the warm ones or secondary CAS [cold agglutinin syndrome]. Dr Raval, could you potentially lead us in that conversation?
Mihir Raval, MD, MPH: Definitely. Just like Dr Lorber highlighted, cold agglutinin disease or cold agglutinin hemolytic anemia happens from IgM [immunoglobulin M] antibodies, but there are other autoimmune hemolytic anemias, the most common of which is warm autoimmune hemolytic anemia—the most prevalent one. The difference from the cold agglutinin hemolytic anemia is the common antibody type that induces this abnormality is IgG [immunoglobulin G] and not IgM. Thus, when I get asked about type of hemolytic anemia, I always divide them into 4 categories. One is warm autoimmune hemolytic anemia, predominantly happening because of an IgM, which again, can be divided into idiopathic or primary, or secondary. This can happen from other underlying disease like lymphoproliferative disease, like an autoimmune disease. The second category is the cold agglutinin anemia or cold agglutinin hemolytic anemia, which can be, again, divided into 2 categories, the primary cold agglutinin disease, which is believed to be from a monoclonal B cell from the bone marrow producing the IgM, or the secondary, which can be associated with autoimmune disease, lymphoproliferative disorder, or infection such as microplasma or EBV [Epstein-Barr virus] infection. Then, the third category for autoimmune anemia is mixed; there are some patients who can have cold and warm autoimmune mediated hemolysis.
The fourth and the biggest one is drug-induced. There are some commercially available drugs that can also lead to the picture of similar autoimmune hemolytic anemia. Apart from that, there are some other nuances, some very rare diseases that are also known to cause hemolytic anemia. One of them is paroxysmal cold hemoglobinuria, although typically that is intravascular hemolysis. One of the biggest differences between warm autoimmune and the cold autoimmune hemolytic anemia is how would you detect that on the Coombs testing, and we will talk about that later. But many times, those presentations can also be defined by how the patients are presenting, in which environment those antibodies are acting up. Warm antibody actually acts at room temperature, and most of the patients can experience fatigue, tiredness, anemia, and symptoms related to that at room temperature. In contrast, the cold autoimmune hemolytic anemia happens mainly because of the antibody that tags the red blood cell at lower than room temperature, sometimes as low as 3 to 4 °C. Many times, that hemolysis happens due to cold exposure in the extremity that the patient experiences.
Transcript edited for clarity.