In this mechanism, the drug does not bind to the RBCs directly. Instead, drug-antidrug (antigen-antibody) complexes form and circulate in the plasma. The antibody involved is often IgM but IgG may also be present. These immune complexes bind non-specifically to the red cells and activate complement. Complement sensitizes the red cell, which may lead to intravascular hemolysis. The complex may dissociate after complement activation and bind to other red cells.
Patients may present with hemoglobinemia and hemoglobinuria. Renal failure occurs in 50% of the cases. The DAT is usually positive with complement antisera only. Other blood bank tests such as the antibody screen and crossmatches will be negative, unless an alloantibody is present. This is because the antibody is specific to the drug and not an RBC antigen. The eluate is usually non-reactive. Confirmation of the drug-induced positive DAT can be obtained by incubating the patient's serum with a solution of the drug and reagent/donor ABO compatible red cells. Hemolysis would be expected after incubation as well as positive DAT with anti-C3. Confirmatory testing is usually not required when the patient has a history of taking the drug and a positive DAT.
Medications commonly implicated in the immune complex mechanism include: