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.
Highlights
Cold-antibody autoimmune hemolytic anemias are mediated by autoantibodies characterized by a temperature optimum of the antigen-antibody (AgAb) reaction at 0-4oC
According to the recent international autoimmune hemolytic anemias (AIHAs) consensus document [3], cold agglutinin disease (CAD) is defined as “an AIHA characterized by a monospecific direct antiglobulin test (DAT) strongly positive for complement fragment C3d and a cold agglutinin (CA) titer of 64 or higher at 4◦C [3, 12,13,14]
High doses of C1 esterase inhibitor (C1-INH) were shown to block the complement classical pathway, abrogate hemolysis and improve anemia in a patient with a severe, IgM-mediated wAIHA [144], and a similar effect has been reported in a patient with acute, severe cold agglutinin syndrome (CAS) [145]
Summary
Edited by: Wilma Barcellini, Foundation Ca Granda Maggiore Hospital (IRCCS), Italy. Reviewed by: Bruno Fattizzo, IRCCS Ca ’Granda Foundation Maggiore Policlinico Hospital, Italy Geir Erland Tjønnfjord, Oslo University Hospital, Norway. 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 can result in generation of anaphylotoxins, such as complement split product 3a (C3a) and, to some extent, C5a. Therapeutic approaches have been directed against the clonal lymphoproliferation in CAD or the underlying disease in CAS.
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