New Insights in the Pathogenesis and Therapy of Cold Agglutinin-Mediated Autoimmune Hemolytic Anemia

Abstract

Autoimmune hemolytic anemias mediated by cold agglutinins can be divided into cold agglutinin disease (CAD), which is a well-defined clinicopathologic entity and a clonal lymphoproliferative disorder, and secondary cold agglutinin syndrome (CAS), in which a similar picture of cold-hemolytic anemia occurs secondary to another distinct clinical disease. Thus, the pathogenesis in CAD is quite different from that of polyclonal autoimmune diseases such as warm-antibody AIHA. In both CAD and CAS, hemolysis is mediated by the classical complement pathway and therefore can result in generation of anaphylotoxins, such as complement split product 3a (C3a) and, to some extent, C5a. On the other hand, infection and inflammation can act as triggers and drivers of hemolysis, exemplified by exacerbation of CAD in situations with acute phase reaction and the role of specific infections (particularly Mycoplasma pneumoniae and Epstein-Barr virus) as causes of CAS. In this review, the putative mechanisms behind these phenomena will be explained along with other recent achievements in the understanding of pathogenesis in these disorders. Therapeutic approaches have been directed against the clonal lymphoproliferation in CAD or the underlying disease in CAS. Currently, novel targeted treatments, in particular complement-directed therapies, are also being rapidly developed and will be reviewed.

Keywords: autoimmune hemolytic anemia; cold agglutinin disease; complement; inflammation; lymphoproliferative; therapy.

Figure 1

CAD-associated lymphoproliferative disorder. (A) shows the nodular infiltration pattern. (B) highlights the resemblance to marginal zone B cell infiltration. (C) shows the typical flow cytometry finding of a monoclonal κ+ B-cell population (gated on CD19+ B-cells). Courtesy of U. Randen. First published in Clin Adv Hematol Oncol 2020 by S. Berentsen et al. (41), reused under Creative Commons Attribution Non-Commercial License. Copyright: S. Berentsen, A. Malecka, U. Randen, and G.E. Tjønnfjord.

Figure 2

Blood smear in a patient with CAD. Agglutination of erythrocytes dominates the picture. Courtesy of G.E. Tjønnfjord. First published in Clin Adv Hematol Oncol 2020 by S. Berentsen et al. (41), reused under Creative Commons Attribution Non-Commercial License. Copyright: S. Berentsen, A. Malecka, U. Randen, and G.E. Tjønnfjord.

Figure 3

Classical complement pathway-mediated hemolysis in CAD. Only relevant steps and components are shown. Black arrows, major pathways. Gray/dotted arrows, minor pathways. Lightning symbol indicates anaphylotoxin properties. C1, C2, etc., complement proteins; CA, cold agglutinin; Ig, immunoglobulin; MAC, membrane attack complex.

Figure 4

Severity of anemia in cold agglutinin disease (percentages of patients). Severity of anemia correlates nicely with markers of hemolysis (LDH and bilirubin levels), but not with IgM levels, which may be associated with complement-independent RBC agglutinating activity as well as complement-mediated hemolysis. Hb, hemoglobin level; LDH, lactate dehydrogenase; LLN, lower limit of normal (Hb 11.5 g/dL in women and 12.5 g/dL in men). Based on data from Berentsen et al. (18).