Clinical Pearls & Morning Reports
Published October 6, 2021
Autoimmune hemolytic anemia (AIHA) is defined as increased destruction of red cells through autoimmune mechanisms, usually mediated by autoantibodies against erythrocyte surface antigens. Read the NEJM Review Article here.
Q: Do the histologic and genetic features of cold agglutinin disease differ from those of lymphoplasmacytic lymphoma?
A: Cold agglutinin disease is an AIHA in which the autoantibody is a cold agglutinin and no underlying clinical disorder is present. Newer studies have shown that affected patients, who previously would have received a diagnosis of primary or idiopathic cold agglutinin disease, have a clonal lymphoproliferative bone marrow disease that can be difficult to recognize. The histopathological picture has often been interpreted as several types of low-grade non-Hodgkin’s lymphoma, such as lymphoplasmacytic or marginal-zone lymphoma, but a relatively uniform disease, cold agglutinin–associated lymphoproliferative bone marrow disorder, is now thought to be the underlying condition. The MYD88 L265P mutation, present in nearly all cases of lymphoplasmacytic lymphoma (the bone marrow disorder seen in Waldenstrom’s macroglobulinemia), is usually not found in cold agglutinin disease.
Q: What is the difference between cold agglutinin disease and secondary cold agglutinin syndrome?
A: The distinction between cold agglutinin disease (a well-defined entity, as explained above) and secondary cold agglutinin syndrome has been increasingly accepted. The latter is a rare, heterogeneous group of cold agglutinin–mediated AIHA disorders that are secondary to other diseases — most often, specific infections (Mycoplasma pneumoniae infection, Epstein–Barr virus infection, cytomegalovirus infection, SARS-CoV-2 infection, and others) or cancers (typically, aggressive B-cell lymphoma).
A: In warm AIHA, antibodies have the highest affinity to the antigen at 37°C. The autoantibodies are polyclonal (i.e., produced by nonclonal B lymphocytes and plasma cells). They are usually of the IgG class, but IgM warm antibodies may be involved, and in rare cases, IgA warm antibodies may be involved. The pathogenesis of warm AIHA is complex. The mononuclear phagocytic system in the spleen plays a major role in the breakdown of opsonized erythrocytes (extravascular hemolysis). The complement system, activated by the classical pathway, is involved in approximately half the cases. In nearly 50% of cases of warm AIHA, no underlying or associated disorder can be identified, and the hemolytic disease is classified as primary. Slightly more than 50% of the cases are secondary to immunologic or lymphoproliferative disorders (e.g., chronic lymphocytic leukemia, systemic lupus erythematosus, or common variable immunodeficiency). Occasionally, a lymphoproliferative disease develops several years after the diagnosis of AIHA.
A: Hemolytic anemia induced by drugs is usually mediated by immunologic mechanisms. More than 150 drugs have been implicated as causes of this condition, which nonetheless remains rare. Cases can be classified into two subtypes. In the drug-dependent subtype, autoantibodies are produced in response to a neoantigen formed by the binding of a drug to a cell-surface structure. In the drug-independent subtype, the offending drug can induce an autoimmune response that persists even in the absence of the drug. Historically, methyldopa and large doses of penicillin were the most frequent causes of drug-induced hemolytic anemia. Today, most cases are caused by ceftriaxone, other cephalosporins, piperacillin, or nonsteroidal antiinflammatory drugs. Fludarabine, chlorambucil, and even bendamustine can increase the risk of autoimmune hemolysis when they are used to treat chronic lymphocytic leukemia, especially as monotherapy. Not unexpectedly, checkpoint inhibitors that are used to treat cancer, in particular PD-1 inhibitors, can also induce AIHA.