Causes of Anemia

There are many different causes of anemia in companion animals that can be characterized by their mechanism of action. A retrospective study of anemia in 456 dogs showed that the most frequent causes of anemia were inflammatory disease and cancer-associated anemia, which comprised 62% of the total cases, followed by immune-mediated hemolytic anemia (IMHA, 13% of cases). Anemia associated with kidney disease and endocrine diseases were less frequent (8 and 3%, respectively). Anemia of inflammatory disease, cancer- or endocrine disease-associated anemia, and anemia due to renal disease were typically mild to moderate (20-36% hematocrit [HCT] in >90% of cases). More severe anemias (<20% HCT) were seen more frequently in IMHA.

Immune-Mediated Hemolytic Anemia

Immune-mediated hemolytic anemia (IMHA) is most common in the dog but can occur in other species, including cats . Classically these are acutely developing regenerative anemias, in which RBC are coated with antibody and/or complement and are prematurely removed from circulation by macrophages in the spleen (mostly), liver and bone marrow (extravascular hemolysis). In some animals, complement fixation by antibodies can result in a concurrent intravascular hemolysis due to fixation of the membrane attack complex resulting in membrane lysis. In humans, intravascular hemolysis can destroy far more cells than extravascular hemolysis, partially explaining the more severe clinical manifestation of IMHA when there is concurrent intravascular hemolysis. Free hemoglobin is also toxic to the kidney (directly to renal tubules and indirectly via scavenging nitric oxide, causing renal vasoconstriction) and potentially other cells. IMHA can be primary or non-associative or secondary or associative due to drugs (e.g. penicillin) or erythroparasites (e.g. Babesia sp., Mycoplasma haemofelis), with primary or non-associative causes being more common. Certain dog breeds have a higher incidence of IMHA including Cocker Spaniels and Old English Sheepdogs. The antigens on the RBCs that are responsible for antibody binding in animals are not known. There is evidence that IMHA is associated with T cell dysregulation and production of auto-reactive T helper cells and/or suppression of regulatory T cells. Cytokine abnormalities can also help skew the immune response to auto-reactivity, but it is not known if cytokine dysregulation in IMHA is primary or secondary to the inflammation associated with the disorder. In cases of primary IMHA, antigens are thought to be normally expressed on RBC surfaces, whereas in secondary associative IMHA, the primary cause may bind to RBCs (either directly or via immune-complex formation) or foreign proteins may resemble RBC self antigens triggering an antibody response (called “molecular mimicry”).

The ACVIM have established a consensus statement for diagnosis of IMHA and testing for associative conditions. The diagnostic algorithm is first based on evidence of immune-mediated destruction based on two or more of the following: 1) Moderate to many spherocytes (small red blood cell indicating being partially consumed by the immune system), 2) a positive saline agglutination tests without washing, and 3) detection of RBC-bound immunoglobulin or complement with Coombs or flow cytometric testing or a persistent positive saline agglutination test after washing RBCs. The second tier of evidence consists of documentation of 1 or more of the following signs of hemolysis via: 1) hyperbilirubinemia, excessive bilirubinuria or icterus without evidence of hepatic disease or biliary obstruction/rupture or sepsis, 2) hemoglobinemia, 3) hemoglobinuria, or 4) ghost RBCs. However, surveys show that there is variability in the tests used to diagnose IMHA.

Causes of associative IMHA include cancer, infections, drugs, and auto-immunity.

Non-regenerative or precursor-directed immune-mediated anemia

Non-Regenerative Immune Mediated Anemia

Dogs and cats with non-regenerative immune-mediated anemia (also called precursor-directed immune-mediated anemia or PIMA) usually present with severe normocytic normochromic anemia (Hcts, < 15-20%) of long duration, with normal leukocyte and platelet counts. Due to the long duration, affected dogs and cats do not display clinical signs of hypoxia that are typically associated with such severe anemias. There is no evidence of regeneration in blood and RBC morphology is usually normal, although some dogs may have partial spherocytes in peripheral blood. They are usually Coombs negative, although a few dogs may be Coombs positive (weak reactions, i.e. only present at low dilutions of the Coombs reagent). Biochemical panels are typically normal, except for hyperferremia and increased transferrin saturation. Some dogs may concurrently have extravascular hemolysis and associated hematologic (many spherocytes, positive Coombs reaction) and biochemical findings (increased total and indirect bilirubin). Diagnosis requires bone marrow aspiration and ruling out other causes of non-regeneration (e.g. neoplasia). Bone marrow aspiration usually reveals an erythroid hyperplasia, with increased marrow iron (dogs) and a concurrent mild reactive lymphocytosis and plasmacytosis, compatible with an ineffective erythropoiesis. There may be a left-shifted maturation sequence in erythroid progenitors (more immature than mature forms) and erythrophagia (of precursors or mature erythrocytes). Dogs may have secondary reticulin and collagen myelofibrosis, which may prevent a good bone marrow aspirate, necessitating a core biopsy. Secondary myelofibrosis is rare in cats and mild (Black et al 2016). The anemia is presumed immune-mediated as it responds to immunosuppressive therapy, such as a combination of azathioprine in dogs (which can suppress the bone marrow in some dogs), cyclosporine (dogs and cats), mycophenolate and high doses of prednisolone (dogs and cats). A response (increased reticulocytes, hematocrit) is usually observed within 2-4 weeks of treatment. Long-term therapy may be required; do not taper therapy too rapidly, since the disease can recur and become refractory to therapy.. Both NRIMA/PIMA can be considered variants of immune-mediated anemia.

Pure Red Cell Aplasia

Immune-Mediated Anemia Spectrum

Pure red cell aplasia (PRCA) is a more severe form of PIMA, characterized by the absence of identifiable erythroid precursors in marrow (<5% of marrow cells). It has been diagnosed rarely in dogs or cats.

Oxidant-induced hemolytic anemia

Oxidant injury to RBC is caused by various plants, chemicals, minerals, and drugs. Animals with inherited deficiencies in oxidant protection pathways, e.g. glucose-6-phosphate dehydrogenase deficiency in horses, are predisposed to oxidant-induced hemolytic anemias. Many oxidants (e.g. red maple, zinc, copper) cause intravascular as well as extravascular hemolysis.

Iron Deficiency Anemia

An iron deficiency anemia occurs when iron becomes limiting for erythropoiesis. Iron is an essential component of the heme group of hemoglobin and, in the absence of iron, hemoglobin cannot be produced in sufficient quantities. Iron deficiency results in a microcytic hypochromic anemia. Iron deficiency anemias can be regenerative or non-regenerative. The reason why some iron deficiency anemias are regenerative and others are not is unknown. They may be regenerative if dietary iron or iron absorption is sufficient to maintain some degree of erythropoiesis or if the source of blood loss is the upper gastrointestinal tract (where iron and blood may be more likely to be reabsorbed than in the lower intestinal tract). Because of an ample storage pool and strict conservation of iron by the body, iron deficiency in adult animals usually is caused by chronic blood loss rather than by inadequate dietary iron alone. Nursing animals and young, rapidly growing animals develop iron deficiency more easily than adults on an iron-replete diet: iron stores in young animals tend to be marginal, milk is low in iron, and rapid growth demands expansion of blood volume. Baby pigs and calves may develop iron deficiency without abnormal blood loss. Puppies and kittens heavily infested with fleas or hookworms are also likely to be iron deficient. In adult animals, other causes of chronic blood loss become more important (e.g., bleeding from tumors in the gastrointestinal tract, coagulopathies, etc.).

Prognosis

Anemia can be an indication of very serious life-threatening health issues such as cancer, autoimmune diseases, or poisoning. So the prognosis for dogs with anemia varies based upon the availability of effective treatment for the underlying condition.

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