Hereditary Erythrocyte Defects

Pyruvate Kinase (PK) Deficiency

Erythrocytic PK deficiency occurs commonly in the Abyssinian and Somali breeds and has also been documented in domestic shorthaired cats. Affected cats have chronic intermittent hemolytic anemia, first noted between a few months to several years of age, and mild splenomegaly, but no osteosclerosis (typically seen in dogs). The clinical signs despite severe anemia (PCV 8%) are often mild except for pale or slightly icteric mucous membranes. Crises of anemia may be induced by infection or toxin exposure. The anemia is moderately regenerative and mildly macrocytic-hypochromic, and no poikilocytosis is noted. Erythrocyte PK activity is severely reduced and there is no M-type PK expression. A deletion caused by a splicing transition in the PK gene has been identified, and a molecular screening test has been made available to discover affected and carrier cats. Intermittent prednisone therapy and splenectomy appear to ameliorate the clinical signs of intermittent anemia. The oldest living cat reached 13 years of age.

Increased Osmotic Fragility of Erythrocytes and Splenomegaly

Many Abyssinian and Somali cats as well as a few other cats were found to have severely fragile erythrocytes. A hereditary membrane defect has been suspected but has not been documented. The initial presentation is similar to PK deficiency and waxes and wanes over months to years, but because of the recurrent nature of the anemia, anemic episodes may be mistaken for other diseases. The typical signs of anemia can be associated with severe splenomegaly and weight loss, particularly as the animal ages. A few stomatocytes, and variable degree of hyperglobulinemia, lymphocytosis, increased liver enzymes, and hyperbilirubinuria may be noted. Anticoagulated blood kept cold overnight may be severely lysed the next day. The osmotic fragility test, which measures the stability of erythrocytes to lyse in decreasing saline concentrations, is markedly increased. Treatment with prednisone during hemolytic crises may inhibit the macrophage system and erythrocyte destruction. Splenectomy has been performed in several cats with severe anemia, lethargy, inappetence and splenomegaly. This resulted in regain of appetite and weight, although a moderate anemia often persisted. Particularly in the postoperative period splenectomized cats are prone to develop sepsis.

Immune-Mediated Hemolytic Anemia

Immune-mediated hemolytic anemia (IMHA) arises when an immune response targets directly or indirectly erythrocytes and hemolytic anemia ensues. Until the antierythrocytic antibodies are identified and the pathogenesis is better understood, the nomenclature and classification of IMHA remains imprecise and sometimes confusing. In primary IMHA no inciting cause can be identified, thus the synonyms idiopathic IMHA or autoimmune hemolytic anemia (AIHA). In contrast, secondary IMHA is associated with an underlying condition or triggered by an agent. In addition, alloimmune hemolytic anemias such as neonatal isoerythrolysis (NI) and hemolytic transfusion reactions are caused by antierythrocytic alloantibodies. Whereas primary IMHA is the most common reason for hemolytic anemias in dogs, cats have more likely a trigger or an underlying disease that leads to immune destruction of erythrocytes. In fact there only rare clinical reports of primary IMHA in cats and in these cases a secondary form was not completely ruled out.

The anemia can be mild to life-threatening and the hematocrit may precipitously drop after presentation due to active hemolysis. Although a regenerative, macrocytic-hypochromic anemia would be expected, evidence of ineffective erythropoiesis and erythrophagocytosis may be found on cytologic examination of a bone marrow aspirate. Autoagglutination of erythrocytes are typical findings on blood smears, but feline spherocytes are difficult to recognize due the small size and limited central pallor of normal feline erythrocytes. Serum bilirubin values may only be slightly increased, presumably due to a highly efficient and accelerated bilirubin metabolism. Thus, high serum bilirubin values also may indicate a concomitant hepatopathy; in cats, any degree of bilirubinuria is considered important.

A diagnosis of IMHA must demonstrate accelerated immune destruction of erythrocytes. Thus, beside documenting a hemolytic anemia, a search after antibodies or complement or both directed against erythrocytes is required, i.e., one or more of the following three hallmarks has to be present to reach a definitive diagnosis of IMHA:

1.  Marked spherocytosis is difficult to appreciate

2.  True autoagglutination occurs rarely

3.  Positive direct Coombs' test depends on reagents and laboratory

Feline Neonatal Isoerythrolysis (NI)

Feline neonatal isoerythrolysis is caused by maternal anti-A alloantibodies that gain access to the circulation and destroy type A and type AB erythrocytes. Thus, type A and type AB kittens from matings between a type B queen and a type A or AB tom are at risk. The proportion of kittens at risk for NI varies from 0-25% depending on the frequency of type B cats and, therefore, represents a major and now preventable cause of the neonatal kitten complex in purebred cats. The low titer anti-B alloantibodies of type A queens have not been associated with NI. Cats, as well as dogs, have an endotheliochorial placenta that is impermeable to immunoglobulins from the mother's serum to the fetus. However, feline colostrum as well as milk contains high maternal immunoglobulin concentrations, which pass the gastrointestinal track and are absorbed intact only during the first 16 hours of life.

Thus, type A or type AB kittens produced by type B queens are born healthy. Upon ingestion of colostrum or milk containing anti-A antibodies, the kittens at risk develop clinical signs. They may suddenly die without obvious clinical signs during the first few hours of life. They develop severe pigmenturia that is readily visible when stimulating the neonates to urinate with a moist cotton ball. These kittens fail to thrive, are reluctant to nurse, become anemic and icteric, and rarely survive the first week of life. Some kittens at risk may have a subclinical course or slough their tail tip at 1-2 weeks of age, presumably due to an agglutinin-induced occlusion. The severity of clinical signs depends on the amount of colostral antibodies ingested prior to the kitten's ability to digest proteins and closure of the gut to intact proteins, and varies from kitten to kitten, between queens, litters, and even within a litter. NI can be confirmed by typing the queen and kitten or the tom if the kitten died with suspicious signs.

Chemical-induced Hemolytic Anemia

Many compounds including chemical agents, drugs, and food components and additives can induce oxidative damage to erythrocytes leading to a hemolytic anemia. Many of these agents are derivatives of aromatic organic compounds. In some cases, the chemical itself acts as an oxidative agent, but more often the compound or its metabolite interacts with oxygen to form free radicals and peroxides. Extracellularly produced oxidants injure the membrane, whereas oxidants generated intracellularly attack hemoglobin as well as membrane structures. Thus, a single agent may inflict erythrocyte injury and thereby hemolysis and reduced oxygen delivery to tissue by one of all three of

1.  Oxidation of heme iron resulting in methemoglobin production

2.  Oxidative denaturation of hemoglobin leading to Heinz body formation

3.  Membrane damage causing impaired deformability and ion transport