Pathogenesis and mechanisms of antibody-mediated hemolysis

Abstract

Background: The clinical consequences of antibodies to red blood cells (RBCs) have been studied for a century. Most clinically relevant antibodies can be detected by sensitive in vitro assays. Several mechanisms of antibody-mediated hemolysis are well understood. Such hemolysis after transfusion is reliably avoided in a donor-recipient pair, if one individual is negative for the cognate antigen to which the other has the antibody.

Study design and results: Mechanisms of antibody-mediated hemolysis were reviewed based on a presentation at the Strategies to Address Hemolytic Complications of Immune Globulin Infusions Workshop addressing intravenous immunoglobulin (IVIG) and ABO antibodies. The presented topics included the rates of intravascular and extravascular hemolysis; immunoglobulin (Ig)M and IgG isoagglutinins; auto- and alloantibodies; antibody specificity; A, B, A,B, and A1 antigens; A1 versus A2 phenotypes; monocytes-macrophages, other immune cells, and complement; monocyte monolayer assay; antibody-dependent cell-mediated cytotoxicity; and transfusion reactions due to ABO and other antibodies.

Conclusion: Several clinically relevant questions remained unresolved, and diagnostic tools were lacking to routinely and reliably predict the clinical consequences of RBC antibodies. Most hemolytic transfusion reactions associated with IVIG were due to ABO antibodies. Reducing the titers of such antibodies in IVIG may lower the frequency of this kind of adverse event. The only way to stop these events is to have no anti-A or anti-B in the IVIG products.

Figure 1

Antibody-mediated destruction or alteration of a red blood cell (RBC). An effector cell recognizes an RBC by antibodies that are bound to the RBC’s cell membrane. Three mechanisms can lead to the RBC’s destruction or alteration: (i) An RBC is engulfed by a macrophage (MΦ) and lysed intracellularly (phagocytosis). (ii) An RBC is partially phagocytized (fragmentation), but the altered RBC (spherocytes) escapes the immune attack by the macrophage (MΦ) and remains circulating. (iii) An RBC is attacked by a macrophage (MΦ) and lysed extracellularly (ADCC, antibody-dependent cell-mediated cytotoxicity). Modified from Garratty.

Figure 2

Organ distribution of blood group antigens. A schematic representation for the antigen distribution of some clinically relevant blood group systems is shown. ABO antigens are formed by carbohydrates expressed on the surfaces of many cells in the human body. When an individual carries active ABO genes, the ABO antigens are expressed on red blood cells (RBC) and even more strongly on some tissues other than RBC, such as kidney, lung, liver and intestine. The ABO antigens are also soluble in the plasma of persons and then attach passively to cells that do not express the ABO antigens by themselves. Modified from Nydegger et al. and reprinted with permission.

Figure 3

Schematic simplified model of the glycosylation patterns in the A1 and A2 blood group phenotypes. The elongated, branched and repetitive carbohydrate structures on the RBC surface end in various types of H and A antigens: In an A1 phenotype (upper panel), most of the H antigens (types 2 to 4) are transformed to their A antigen analogues (types 2 to 4). The A type 4 antigen represents the A1 antigen. In an A2 phenotype (lower panel), many H type 2 antigens remain unchanged and are the targets of anti-H lectins; also, most H type 4 antigens remain unchanged. Hence, the number of A type 2 and 3 antigens is reduced and the A type 4 antigen is lacking in an A2 phenotype. The Secretor/Lewis antigens (H and A type 1 antigens, not shown) are adsorbed from plasma onto the RBC surface in Le(a-b-) secretors and occur in ratios like the H and A type 4 antigens. The antigens are shown as glycolipids in their simplest form; the same antigens also exist on glycoproteins and commonly as large extended glycans with greater than 60 residues (not shown). The ratios among the antigens are not absolute but for demonstration purposes only. Modified from Flegel and Wagner according to Svensson et al.