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.

Daratumumab for disabling cold agglutinin disease refractory to B‐cell directed therapy

“…2 The plasmacytic differentiation and cyclinD1 expression highlight the potential of clonal development, and are likely explained by selection of long-lived plasma cells resistant to B-lymphocyte depleting therapies. 1,5 In our patient, the data do not allow a firm conclusion on this mechanism, but are consistent with such development, providing the most likely explanation for the resistance to B-cell directed therapy and dramatic effect of daratumumab. Although the discrepancy between the significant effect of daratumumab and resistance to bortezomib cannot readily be mechanistically explained, it is wellknown that bortezomib monotherapy is effective in less than half of patients with CAD.…”

“…Cold agglutinins (CA) are autoantibodies, usually of the IgMκ class, which target the I antigen on erythrocyte surface at 4°C, but may also react at temperatures approaching 37°C. 1 An IgMκ gammopathy is typically identified, and a distinct underlying lymphoproliferative disorder (LPD) is recognized, which may be indistinguishable from lymphoplasmacytic lymphoma (LPL). [2][3][4] Bone marrow examination usually shows intraparenchymal nodules with small CD20 + , CD38 − , CD5 +/− IgMκ + monoclonal B-cells and surrounding monoclonal IgM + ,κ + plasma cells.…”

“…4 A subpopulation of clonal, long-lived chemoimmunotherapy-resistant plasma cells is assumed to exist. 1,5 Therapy has been directed at the underlying clone by using rituximab, often in combination with bendamustine, fludarabine, or bortezomib. 3 Upstream complement inhibition is an emerging therapy, but circulatory symptoms are not complement-mediated and persist.…”

“…3 Cold-induced, agglutination-mediated, circulatory symptoms are recorded in 40%-90% of patients. 1,2 We present a Caucasian male, aged 48, who was diagnosed with CAD in 2011. At the outset, the hemolysis was well-compensated (Figures 1 and 2), with a presence of an IgM CA, and direct antiglobulin test strongly positive for C3d, with CA titre 1024 at 2°C-8°C.…”

COVID-19 and Cold Agglutinin Hemolytic Anemia

“…When cold agglutinin autoantibodies are produced in association with an underlying hematologic malignancy or infection, this is called cold agglutinin syndrome. 11 Patients with cold agglutinin syndrome present with laboratory evidence of hemolysis (high LD, high bilirubin, and low haptoglobin) and positive direct coombs test. 6 Clinically, they can present with acral ischemia, especially after exposure to cold.…”