Pathophysiology

AIHA appears in a variety of forms depending on duration of onset, location of destruction, and extent of antibody/complement and red blood cell interaction. Though the following distinctions do not currently influence the therapeutic approach, they are discussed here because the more informed an owner is about AIHA, the more intelligently owners can discuss their patient's particular circumstances and therapeutic approaches with their vets; thereby increasing quality of care and chances of survival.

Duration of Onset:

AIHA can have an insidious onset, resulting in a slowly developing anemia with the owner noticing weakness and pale gums, or onset can be acute, causing liver compromise and jaundice. Therefore onset of AIHA can be categorized as peracute, acute or chronic.

• Peracute cases result in a fulminating decrease in the hematocrit, with a build up bilirubin (hyperbilirubinemia) and hemoglobin in the blood (hemoglobinemia) and urine (hemoglobinuria). Autoagglutination is presumed since in saline agglutination is frequently seen. Prognosis in these cases is typically poor regardless of prompt and vigorous treatment.
• Acute cases are the most common form. An enlarged spleen or liver is sometimes evident and the anemia is often extremely responsive. White blood cell counts tend to be elevated due to the bone marrow being in overdrive to produce baby red blood cells. Autoagglutination is uncommon and the DAT is usually positive. These cases usually respond well to immunosuppressive drugs.
• Chronic cases are when the hematocrit falls to a constant level and remains there for weeks or months.

Location of Destruction:

Hemolysis can occur intravascularly or extravascularly.

Intravascular hemolysis results when extensive antibody/complement activation doesn't just damage, but efficiently triggers an immune reaction that causes intravascular red blood cell destruction. This type of intravascular hemolysis is sometimes classified as either warm or cold reacting.

• Warm reacting antibodies are usually IgG. Hemolysis occurs when red blood cells are coated with IgG, activating complement to destroy the red blood cell .
• Cold reacting (cryopathic) antibodies are usually IgM and are extremely rare. Hemolysis occurs when IgM antibodies bind to red blood cells at lower temperatures in the body's extremities such as ear tips, paws and tail, resulting in necrosis. The IgM antibodies can be agglutinating or nonagglutinating.

Extravascular hemolysis occurs when the antibody/complement adhering to the red blood cell membrane induces damage, but not destruction, of the red blood cell. This damaged red blood cell, a spherocyte, is highly susceptable to further interactions with the reticuloendothelial system's phagocytic cells in the spleen, liver, or bone marrow. The spleen's unique filtering system allows for prolonged contact between sensitized red blood cells and complement, which efficiently removes the damaged red blood cells from circulation.

Extent of Antibody/Complement and Red Blood Cell Interaction

The immune components can be directly or indirectly attached to the red blood cell membrane. Variable combinations of immunoglobulins (IgG & IgM), and complement are involved in most cases of AIHA. Red blood cells can be coated with just immunoglobulins, immunoglobulins and complement, or complement alone. Several forms of AIHA, based on antibody and red blood cell interaction, include:

• In saline agglutination is represented by antibodies that agglutinate red blood cells outside the body as soon as the blood is drawn and placed on a slide, therefore intravascular agglutination is presumed. Intravascular agglutination occurs when antibodies cause damage to the red blood cell, which is subsequently removed in the spleen or liver in a form of extravascular hemolysis.
• Intravascular hemolysins are antibodies which activate numerous individual sites of complement on the the red blood cell membrane to induce intravascular hemolysis. Hemoglobinemia and hemoglobinuria are usually present.
• Incomplete or nonagglutinating antibodies are the most common form of AIHA. The antibodies bind to the red blood cell membrane, but in insufficient quantity to cause intravascular hemolysis or agglutination. The red blood cell is then damaged, but not destroyed until encountering the phagocytic system of the spleen or liver.
• Cold agglutinins are antibodies that agglutinate red blood cells, but only at temperatures below 32 degrees. Hemoglobulinuria is often present and usually blood agglutinates when placed on a slide and allowed to cool. If the slide is heated to room temperature, agglutination disappears. The DAT is usually negative at room temperature, but positive at colder temperatures.
• Cold acting nonagglutinins are antibodies that bind red blood cells at low temperatures, but don't cause agglutination. Red blood cells are consequently then destroyed in the phagocytic system of the spleen or liver.

An example of progression of the disease is as follows:

An antigen is recognized on the red blood cell membrane by the body's immune system. Antibodies are then formed against the antigen and immunoglobulin (IgG, IgM, with or without complement) is deposited on the red blood cell membrane.

Once the antibodies have coated the red blood cell membrane either intravascular hemolysis, intravascular agglutination or extravascular hemolysis occurs. Phagocytes have receptors for complement and a portion of the antibody. They either completely phagocytize the red blood cell or phagocytize a portion of the red blood cell membrane, resulting in spherocyte formation, which is then destroyed extravascularly.

Hemolysis, the destruction of red blood cells, leads to a decrease in the oxygen carrying capacity of the blood, resulting in hypoxia, a deficiency in the amount of oxygen reaching bodily tissues. The following systems can be affected as the body functions with a decreased oxygen carrying capacity:

• hepatic(liver): if the rate of red blood cell destruction is rapid, the rate of bilirubin formation may exceed the rate of hepatic clearance: the liver becomes overwhelmed which leads to a build up of bilirubin in the blood (hyperbilirubinemia), resulting in visible icterus and increased bile pigments in feces.
• cardiovascular (heart & circulation) effects include an excessively rapid heartbeat and a heart murmur due to low blood viscosity.
• respiratory effects include rapid breathing.
• thromboembolic disease due to hemolytic by-products.
• kidney or liver necrosis.

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