Immune-mediated hemolytic anemia (Proceedings)


Immune-mediated hemolytic anemia (Proceedings)

Nov 01, 2009

Disease conditions that lead to anemia can be divided into two general categories: regenerative and nonregenerative. Immune-mediated hemolytic anemia (IMHA) can fall under either category but is more commonly regenerative. Because the disease has a rapid onset and can quickly lead to severe illness or death, early diagnosis and treatment is necessary. The following discussion will review the causes, clinical signs, diagnosis, and current therapy of IMHA in dogs and cats. Preliminary results from a retrospective study will be included in the presentation.


The immune system recognizes or "tolerates" normal body tissues including red blood cells as harmless. During formation of lymphoid cells early in development, potentially self-reacting cells are destroyed or not allowed to mature. In some animals, a few of these cells escape and become "autoimmune", waiting for a trigger to start attacking normal tissue. Autoimmune responses can be divided into primary (idiopathic) and secondary (due to infectious disease, neoplasia, drugs, toxins, etc.). Other classifications take into account warm vs. cold antibody disease and various other factors (more relevant in human medicine).

In IMHA, IgG and IgM antibodies, which are normally produced in response to infectious organisms, are produced by plasma cells and directed against the membranes of red blood cells (rbcs). IgG-coated rbcs are detected as abnormal by macrophages, which primarily are in the spleen. As these rbcs circulate through the spleen, they are phagocytosed and removed from the bloodstream. This process results in extravascular hemolysis by the mononuclear phagocyte system (MPS) and leads to splenomegaly as well as loss of rbcs. As more rbcs are tagged with IgG, the liver begins participating in erythophagocytosis. When both IgG and IgM bind to rbcs, agglutination occurs (sticking together) which also leads to extravascular hemolysis in the spleen and liver.

Another mechanism in IMHA involves complement. Complement binds to Ig-coated rbcs, which activates the complement cascade. This arm of the innate immune system destroys its targets by forming membrane attack complexes, which "punch holes" in the rbc membranes and allow water and electrolytes to enter the cell, causing swelling and lysis. If this occurs in the circulation, it is called intravascular hemolysis. Complement-coated rbcs are also recognized in the spleen and liver and subject to phagocytosis (extravascular). Rbcs bound with IgM are more likely to be destroyed by complement-mediated destruction.

When the MPS removes only a portion of the rbc membrane instead of phagocytosing the entire cell, a spherocyte is formed. This is a damaged red cell with a spherical shape rather than concave disk, and it is likewise trapped in the spleen and destroyed. Spherocytes may be seen on blood smears which helps with diagnosis.

The trigger or underlying cause of immune-mediated hemolytic anemia (IMHA) is identified in 25-40% of canine cases and most of the feline cases. If a cause is found, it must be resolved before the immune-mediated rbc destruction stops. Therefore, a thorough diagnostic workup is necessary to rule in or rule out other diseases. Among the triggers are:

  • Infections

     o Viral (FeLV, FIV, FIP)
     o Bacterial and fungal (leptospirosis, hemobartonellosis, histoplasmosis, endotoxemia, endocarditis, clostridial)
     o Parasitic (babesiosis, leishmaniasis, heartworm disease (caval syndrome), hookworms, ehrlichiosis, anaplasmosis, cytauxzoonosis)
  • Neoplasia (leukemia, lymphoma, multiple myeloma, hemangiosarcoma, solid tumors)
  • Other immune disorders (systemic lupus erythematosus, immunodeficiencies)
  • Drugs (sulfas, cephalosporins, penicillins, vaccines, propylthiouracil, methimazole, procainamide, benzocaine, heparin, dipyrone, levamisole, phenylbutazone, quinidine, phenothiazines)
  • Toxins (zinc, copper, propylene glycol, onion, garlic, rye grass, maple, castor bean, methylene blue, beestings)
  • Intrinsic defects (methemoglobin reductase, pyruvate kinase, or phosphofructokinase deficiencies, idiopathic Heinz body anemia)
  • Microangiopathic (disseminated intravascular coagulation, vasculitis, uremia)

Young to middle-aged dogs and cats are at higher risk. Breeds with a higher incidence include American Cocker Spaniels, Old English Sheepdogs, Doberman Pinschers, German Shepherds, Miniature Poodles, Miniature Schnauzers, Bichon Frises, Irish Setters, Collies, and English Springer Spaniels. This suggests that genetics play a role in the development of IMHA. Different breeds of dogs were found to have different major histocompatibility complexes (dog leukocyte antigen haplotypes) in one study of IMHA. While spayed females are suggested in some studies to be most susceptible, true gender differences or hormonal influences are difficult to determine. In cats, no particular breed or gender is associated.