Red Blood Cell Destruction in Autoimmune Hemolytic Anemia: Role of Complement and Potential New Targets for Therapy

Abstract

Autoimmune hemolytic anemia (AIHA) is a collective term for several diseases characterized by autoantibody-initiated destruction of red blood cells (RBCs). Exact subclassification is essential. We provide a review of the respective types of AIHA with emphasis on mechanisms of RBC destruction, focusing in particular on complement involvement. Complement activation plays a definitive but limited role in warm-antibody AIHA (w-AIHA), whereas primary cold agglutinin disease (CAD), secondary cold agglutinin syndrome (CAS), and paroxysmal cold hemoglobinuria (PCH) are entirely complement-dependent disorders. The details of complement involvement differ among these subtypes. The theoretical background for therapeutic complement inhibition in selected patients is very strong in CAD, CAS, and PCH but more limited in w-AIHA. The optimal target complement component for inhibition is assumed to be important and highly dependent on the type of AIHA. Complement modulation is currently not an evidence-based therapy modality in any AIHA, but a number of experimental and preclinical studies are in progress and a few clinical observations have been reported. Clinical studies of new complement inhibitors are probably not far ahead.

Complement Deposition and IgG Binding on Stored Red Blood Cells Are Independent of Storage Time

“…Phagocytosis of untreated and NHS-opsonized RBCs was comparable, but low compared to RhD-opsonized RBCs. Others have shown before that in case of allo- or autoantibodies, as occurring in a transfusion reaction or autoimmune hemolytic anemia, RBCs are cleared from the circulation by macrophages via Fc receptors and/or complement receptors [26,27]. It seems that the extent of C3 deposition and/or IgG binding on stored RBCs observed in our study was not sufficient for phagocytic uptake by macrophages.…”

Clinical characteristics and outcome of patients with autoimmune hemolytic anemia uniformly defined as primary by a diagnostic work‐up

“…In 16/18 cases, the LD was detected by the BM biopsy in the absence of other clinical manifestations. As previously described [5], the BM involvement by clonal B lymphocytes was usually limited and these patients, defined as having a primary cold agglutinin disease [5] showed a high response rate, 85.71% with a rituximab-based-chemoimmunotherapy. This observation confirms the benefit of chemoimmunotherapy in these cases [6].…”

Warm autoimmune hemolytic anemia: experience from a single referral center in Mexico City

“…The estimated annual incidence of this disease is 1–3 per 100,000 individuals, with a mortality rate of 11% in patients without treatment [1]. According to the characteristic temperature reactivity of the RBC, AIHA is classified into warm AIHA (wAIHA), cold AIHA (cAIHA), and mixed AIHA [2345]. Depending on the underlying cause of the disease, AIHA can be further classified as primary (or idiopathic) or secondary [6].…”

“…The wAIHA represents 60% of AIHA cases, and 50% of the patients with secondary wAIHA have lymphoproliferative neoplasia or other autoimmune disorders as the underlying cause [123]. Alternatively, cAIHA is subdivided into primary and secondary cold agglutinin syndrome and paroxysmal cAIHA [5].…”