Feline Anemias-A Diagnostic Challenge
WSAVA 2002 Congress
Urs Giger, Diplomate, ACVIM & ECVIM
University of Pennsylvania
Philadelphia, PA, USA
penngen@vet.upenn.edu
P: 215-573-2162(office)
F: 215-573-2162
www.vet.upenn.edu/penngen

Anemias are commonly observed in cats and could be due to a primary blood disorder, but are more often associated with other organ disorders. Based upon the pathophysiology, anemias are conveniently divided into reduced hematopoiesis, blood loss, and hemolysis, albeit some diseases may involve overlapping reasons that lead to anemia. The degree of regeneration may be mild and the site of bleeding may not be obvious. Although inadequate erythropoiesis and blood loss anemias have been considered to be the most common forms of anemia in cats, many causes of feline hemolytic anemias have been known for decades, whereas others have only recently been discovered. Some clinical examples are presented.

Reduced Hematopoiesis

 Idiopathic:

 Aplastic anemia (all cell lines)

 Pure red cell aplasia

 Immune:

 Human Epogen therapy

 Idiopathic

 Infectious:

 Viral (FeLV and FIV)

 Anemia of chronic disease

 Organ failure: Chronic renal failure

 Nutritional:

 Folate deficiency (rare)

 Cobalamin deficiency (rare)

 Iron deficiency (most are regenerative)

 Neoplasia:

 Lymphoma

 Leukemia

 Myelophthisis

 Toxic:

 Chemotherapy

 idiosyncratic drug reactions

 Radiation therapy

Anemia due to reduced hematopoiesis is characterized by a low reticulocyte count (<0.4% or 40,000/µl). Most of them are normocytic and normochromic. Macrocytosis is seen with some non-regenerative forms of FeLV-associated anemias and the rare folate deficiency. Microcytosis may be seen with iron deficiency and hepatic shunts. Serum iron is low in iron deficiency anemia and some cases of chronic renal failure. Serum erythropoeietin concentrations are exponentially elevated according to the degree of the anemia, but are inappropriately low in cats with chronic renal failure. A bone marrow aspirate or core biopsy may be required to further define the cause of the anemia, albeit a careful history and evaluation of other routine laboratory results are often sufficient to define the cause.

Causes of Blood Loss Anemia

 Inherited:

 Coagulopathies:

 Hemophilia A(Factor VIII def.): males, many cat breeds

 Hemophilia B(Factor IX def.): males, many cat breeds

 Vitamin K-dependent coagulopathy: Devon rex

 Factor XII deficiency-no bleeding

 Domestic shorthair cats

 Oriental shorthair cat

 Thrombopathias (rare)

 von Willebrand disease (rare)

 Acquired:

 Aspirin and other NSAIDs

 Thrombocytopenia (rare, mostly secondary)

 Anticoagulant rodenticides

 Heparin and Warfarin therapy

 Liver disease (including hepatic shunts, amyloidosis)

 Renal failure

 Neoplasia (Lymphoma, leukemia, myeloma, metastatic carcinomas)

 Disseminated Intravascular Coagulation (DIC)

 Vasculopathies

In contrast to dogs, cats are much less commonly presented with hemorrhage due to acquired as well as hereditary bleeding disorders. It is important to determine the cause of hemorrhage prior to treatment as particularly transfusion support may affect hemostatic tests and appropriate blood components are best chosen based upon test results. Furthermore, superior techniques for collection and handling of appropriate blood samples are crucial in order to receive valid results and be able to correctly interpret the data.

Another session will cover in detail the diagnostic approach to a bleeding patient. Platelet estimates or/and platelet counts are determined to identify quantitative platelet problems, but severe thrombocytopenia (<40,000/µl) is rarely observed. Platelet function is difficult to assess in clinical practice; buccal mucosal bleeding time (sedation/anesthesia) and platelet aggregation studies are rarely done in cats. The Activated Clotting Time (ACT tube) is an inexpensive and reliable in-practice screening test to assess coagulation. Recently there are some point of care instruments that can determine the Partial Thromboplastin Time (PTT) and Prothrombin Time (PT) on fresh citrated whole blood, whereas laboratories require immediate separation and cooling of plasma until analysis. Schistocytes and positive fibrin split products or d-dimers may suggest disseminated intravascular coagulation.

Causes for Hemolytic Anemia in Cats

 Inherited:

 Pyruvate kinase (PK) deficiency: Abyssinian, Somali, DSH

 Increased erythrocyte osmotic fragility: Abyssinian, Somali, DSH

 Porphyria: Siamese, DSH

 Immune:

 Primary: Idiopathic (primary AIHA) is rare in cats

 Secondary:

 Drug allergy (PTU, methimazole, others)

 Infection-induced hemolysis (viral, bacterial, parasitic)

 Neoplasia-associated hemolysis

 Alloimmune:

 Neonatal isoerythrolysis

 Acute hemolytic transfusion reactions

 Infectious:

 Hemobartonellosis

 FeLV (subtype A) infection

 Cytauxzoonosis

 Babesiosis

 Anemia of inflammation

 Chemical:

 Heinz body anemia

 Methemoglobinemia

 Zinc, drugs, food components (onions)

 Other:

 Hypophosphatemia

 Microangiopathic anemia

 Hepatopathy

A diagnosis of hemolytic anemia may be difficult to reach: icterus is more likely to result from feline hepatopathies than hemolysis in the cat, and although cats are capable of conjugating bilirubin, bilirubinuria may be hard to identify. Furthermore, the regenerative response as assessed by the degree of reticulocytosis-differentiate between aggregate and punctate reticulocytes-is generally milder in cats than dogs. Idiopathic (auto-) immune-mediated hemolytic anemia (AIHA), the most common cause of hemolysis in dogs, has only very rarely been documented in cats, but other immune-mediated disorders such as neonatal isoerythrolysis and acute transfusion reactions due to A-B blood type incompatibilities and hematologic drug (PTH, methimazole) allergies have recently been described in cats. Simple blood typing and crossmatching procedures are now readily available to avoid blood incompatibility reactions (see therapy for blood typing). Some of the cases with presumptive AIHA, but negative direct Coombs' test, may in fact have an inherited erythrocytic defect. Erythrocyte pyruvate kinase (PK) deficiency has now been recognized in several Abyssinians and Somalis with intermittent, regenerative anemias (without osteosclerosis). Increased osmotic fragility of erythrocytes causing hemolytic crises with macrocytic regenerative anemia and splenomegaly has also been documented in Abyssinians and Somalis. All these cats with hereditary hemolytic anemias, which have been tested in our laboratory, exhibited intermittent anemia and weight loss, and the clinical signs appear to be ameliorated by splenectomy. The diagnosis of feline parasitic hemolytic anemias (hemobartonelosis, cytoxzoonosis, and babesiosis) has evolved from blood smear evaluation to polymerase chain reaction tests and will be covered elsewhere. Heinz body anemia and methemoglobinemia caused by drugs, zinc, and food components (propylene glycol, onions) have recently been well characterized. Finally, hypophosphatemia, another cause of intravascular hemolysis associated with diabetes mellitus and hepatic lipidosis, has also been reported. Some of these newer disorders will be discussed in this chapters in more detail.

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

Methemoglobin can accumulate because of a hereditary deficiency of the cytochrome b5 reductase enzyme, or because of exposure to oxidative agents. Although many compounds are capable of inducing methemoglobin formation, benzocaine-containing skin products and laryngeal or nasopharyngeal sprays, phenozopyridine (a urinary analgesic) as well as acetaminophen produce within minutes to hours of exposure severe methemoglobinemia in cats. For several reasons, cats appear more susceptible to oxidative agents. In fact, as little as a baby, Tylenol tablet (65 mg) may be lethal for a debilitated cat, whereas 10-fold higher doses are required to induce toxicity characterized by hepatic failure in other species.

Heinz bodies represent irreversibly denatured and precipitated hemoglobin in erythrocytes. Eccentrocytes may be noted instead which are characterized by shifting of hemoglobin to one side of the cell and leaving a clear moon-shaped zone outlined by membrane. Heinz body hemolytic anemia has been associated with a variety of conditions, many of which also cause methemoglobinemia and membrane injury. Ingestion of dietary onions, whether raw, cooked or dehydrated (onion powder) and usually as part of table scraps fed by owners, can result in up to 90% Heinz body formation within a day followed by hemolysis leading to severe anemia by 5 days. Administration of various drugs, including methylene blue, DL-methionine, phenacetin, and vitamin K3 (>5 mg/kg/day) can lead to Heinz body hemolytic anemia. The previously mentioned agents, acetaminophen, benzocaine-containing products and phenazopyridine that induce severe methemoglobinemia can also cause Heinz body formation. Furthermore, increased numbers of Heinz bodies have been associated with various organ disorders in cats including hyperthyroidism, lymphoma and other cancers, and diabetes mellitus, particularly when ketoacidotic.

Hypophosphatemia-induced Hemolysis

Severe hypophosphatemia causing hemolysis has been associated with diabetes mellitus, hepatic lipidosis, and primary hyperparathyroidism as well as with enteral and parenteral hyperalimentation (starvation-refeeding syndrome) and oral administration of phosphate-binding antacids. During insulin, fluid and bicarbonate treatment of (ketoacidotic) diabetic animals, the phosphate value in plasma declines precipitously. Hypophosphatemia occurs due to intracellular phosphate shifts, enhanced renal losses, and reduced intestinal absorption of phosphate. In addition to myopathy and cardiac and neurologic dysfunction, acute hemolytic anemia, characterized by a rapid drop in PCV and mild intravascular lysis and Heinz body formation is observed in animals with hypophosphatemia. Serum phosphate measurements may underestimate the phosphate depletion in these disease states and can erroneously be higher because of hemoglobinemia and hyperbilirubinemia. The pathogenesis of the hypophosphatemia-induced anemia is likely related to depletion of erythrocytic ATP and GSH, which leads to decreased deformability and increased osmotic fragility as well as susceptibility to oxidative injury.

Speaker Information
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Urs Giger, ACVIM & ECVIM
University of Pennsylvania
Philadelphia, PA, USA


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