Is This a Hemolytic Transfusion Reaction?

Is This Intravascular Immune Hemolysis?

The term "immune" implies that the hemolysis is antibody-related. Because the type and antibody screen and the DAT were negative, the hemolysis was probably not immune in nature. The word "intravascular" suggests that the red cell destruction was occurring within the blood vessels rather than extravascularly, by the macrophages of the reticucloendothelial system of the spleen and liver.

Some causes of acute immune intravascular hemolysis are discussed below. See Figure 2 for a summary of DAT-positive intravascular hemolysis.

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Figure 2.

Differential diagnosis for causes of intravascular hemolysis resulting in a positive DAT. DAT = direct antiglobulin test; PCH = paroxysmal cold hemoglobinuria; WAHA = warm autoimmune hemolytic anemia; MT-AIHA = mixed-type autoimmune hemolytic anemia; CAS = cold agglutinin syndrome.

IgM intravascularly hemolyzing heterologous antibodies include those of the ABO system, Bombay (those that lack the fucose moiety making the H in group O), anti-Tj^a (anti-PP₁P^k)m and anti-Vel. These IgM antibodies may bind complement and cause an acute in vivo intravascular immune hemolysis if red cells with the corresponding antigens are transfused or in vitro when performing a cross-match with incompatible red cells. The plasma or serum of the patient or of the blood specimen can be pink to red if sufficient numbers of red cells are destroyed intravascularly when complement is activated through the membrane attack complex (C5-C9).

It is also possible for the autologous IgM anti-I and anti-i to hemolyze a patient's own red blood cells when the titer of these antibodies increases and their thermal range is expanded from below room temperature to body temperature of 37°C, in conditions that can cause cold autoimmune hemolytic anemia. This can occur for anti-I, in the presence of Mycoplasma pneumoniae, and for anti-i, in the presence of Epstein-Barr virus, parainfluenza 3, and other influenza viruses.

In most instances of virally related cold autoimmune hemolytic anemia, the IgM autoantibody causes complement coating of the red cells, but the process does not continue through the membrane attack complex and stops at C3a. The C3a is eventually broken down to C3bd. C3-coated red cells are removed extravascularly by the reticuloendothelial system of the liver and spleen. Extravascular hemolysis does not cause red plasma and is not as extreme a condition as intravascular hemolysis.

Another unusual condition, a biphasic IgG auto-anti-P antibody called the Donath-Landsteiner antibody can cause cold autoimmune hemolysis.^[1] This IgG Donath-Landsteiner antibody attaches to red blood cells in the peripheral circulation, where temperatures are less than 30°C. The resulting complement-mediated hemolysis occurs when the red blood cells subsequently travel to an area of warmer temperature (37°C) in the central circulation. The Donath-Landsteiner antibody can occur in patients with late-stage syphilis or in patients recovering from a variety of viral illnesses.

Cold autoimmune hemolytic anemia was also not a consideration because the DAT was negative. Furthermore, keeping the specimen at 37°C did not prevent the hemolysis or clotting from occurring.

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