AIHA can be caused by different antibody classes with
IgG and
IgM antibodies being the primary antibody types. IgA autoantibodies can also rarely cause AIHA. Pathophysiology of warm or IgG mediated AIHA differs from cold or IgM mediated AIHA. Warm AIHA means immune haemolysis is caused by auto-antibodies which bind to red cells at body temperature (37 degree Celsius). These are usually IgG but can be IgM in rare cases. In warm AIHA, red cells coated by IgG undergo antibody mediated cell death in the reticuloendothelial system of liver and spleen leading to extravascular haemolysis. These IgG antibodies are also capable of activating the complement cascade with variable efficacy, further leading to opsonisation and destruction of red cells in reticuloendothelial system (RE) system or intravascular haemolysis via terminal complement. Red cell autoantibodies causing cold agglutinin disease are of IgM class. These bind to RBC antigens at lower temperatures (e.g. in the acral parts of body such as hands, feet, ears, nose). The antibody/RBC antigen complex then activates the classical complement pathway leading to complement mediated hemolysis of RBCs in RE system. Rarely, a biphasic IgG antibody leads to complement mediated intravascular lysis. This antibody binds to red cells in acral regions along with first two components of complement. As the blood moves to central regions of the body and warms up, the IgG dissociates but the complement remains attached to red cell causing intravascular hemolysis. The antibody causing this biphasic hemolysis is commonly IgG but IgM and IgA have also been reported. Paroxysmal Cold Hemoglobinuria (PCH) is primarily a pediatric disease and usually occurs with Mycoplasma pneumonia infection or other viral infections. It can also occur with chronic lymphocytic leukemia and lymphomas in adults. Pathophysiologic mechanisms involved in drug induced haemolysis include: drug-dependent autoantibodies due to an immuno-allergic mechanism, drug-independent autoantibodies due to molecular mimicry, or nonspecific stimulation of the immune system. AIHA cannot be attributed to any single autoantibody. To determine the autoantibody or autoantibodies present in a patient, the
Coombs test, also known as the antiglobulin test, is performed. There are two types of Coombs tests, direct and indirect; more commonly, the direct antiglobulin test (DAT) is used. Classification of the antibodies is based on their activity at different temperatures and their etiology. Antibodies with high activity at physiological temperature (approximately 37 °C) are termed warm autoantibodies. Cold autoantibodies act best at temperatures of 0–4 °C. Patients with cold-type AIHA, therefore, have higher disease activity when body temperature falls into a hypothermic state. Usually, the antibody becomes active when it reaches the limbs, at which point it opsonizes RBCs. When these RBCs return to central regions, they are damaged by complement. Patients may present with one or both types of autoantibodies; if both are present, the disease is termed "mixed-type" AIHA. When DAT is performed, the typical presentations of AIHA are as follows. Warm-type AIHA shows a positive reaction with
antisera to IgG antibodies with or without complement activation. Cases may also arise with complement alone or with
IgA, IgM or a combination of these three antibody classes and complement. Cold-type AIHA usually reacts with antisera to complement and occasionally to the above antibodies. This is the case in both cold agglutinin disease and cold paroxysmal hematuria. In general, mixed warm and cold AIHA shows a positive reaction to IgG and complement, sometimes IgG alone, and sometimes complement alone. Mixed-type can, like the others, present unusually with positive reactions to other antisera. ==Laboratory features and diagnosis==