Peculiarities of anemias in cats (Proceedings)

Anemia is an extremely common clinical problem in cats and is associated with many different conditions, many very different from those in dogs.  Bleeding disorders are less common than in dogs, but may frequently complicate hepatic disorders. Hemolysis has many different causes in cats, but is rarely caused by IMHA.  Non-regenerative anemias are most common. The different types of anemias will covered and illustrated with case examples. Moreover, specific treatments including transfusions will be addressed.

Despite severe anemia many cats may only show mild clinical signs or only pallor particularly when chronic.  In order to recognize the type, degree, and regeneration of the anemia in cats, it is important to appropriately appreciate the hematological peculiarities of cats.  When compared to dogs, the normal packed cell volume in cats is lower (PCV 32-48%), feline red blood cells are considerably smaller (MCV 38-50fl), central red cell pallor is small, bone marrow iron stores are lacking, and there are mostly mild regenerative responses observed.

There are aggregate reticulocytes which are short-lived in circulation (like the typical reticulocytes in dogs), but cats also have punctate reticulocytes, which may linger around in circulation for a couple of weeks. The best parameter to assess a regenerative bone marrow response is the absolute reticulocyte count; normally <50,000/μl, which refers to the presence of aggregate reticulocytes and is equal to the degree of polychromasia observed.  Note nucleated red blood cells may be proportionally seen with reticulocytes or may occur independently due to bone marrow endothelial damage as in lead poisoning and sepsis. 

While the evaluation of PCV, total protein, and blood smear is most valuable, a complete blood cell count and specific tests are generally required to reach a definitive diagnosis and monitor the response to therapy.  These may include for instance chemistry screen, urinalysis, bone marrow cytology or core biopsy, hemostatic tests, iron parameters, infectious disease screenings, toxicological analyses, and Coombs', and specific genetic tests.

Although kidney failure and some infections (flea infestation, FeLV infection and hemobartonellosis) are likely the most common causes of anemia, there are many other differential diagnoses to consider, such as bleeding disorders, toxicity, metabolic disturbances, hereditary defects, and immune-mediated hemolytic anemias. It is crucial to carefully assess the feline patient by history taking, physical exam and specific laboratory tests in order to determine the cause and offer the most appropriate treatment.

In contrast to dogs, external blood loss anemias are less commonly observed in cats, albeit they happen with trauma and surgery.  In fact, many cats drop their PCV during and shortly after surgery which may in part be blood loss but also unexplained lysis and sequestration (frequently resolves 1-2 days after anesthesia).  Moreover, external blood loss can rapidly result in iron deficiency particularly in the very young kittens (even with repeat phlebotomies for diagnostic purposes), however, the classic microcytosis and hypochromasia with iron deficiency may be very difficult to appreciate due to small feline red cells.  The most common reason for blood loss is flea infestation, while ticks and intestinal hookworms are less likely leading to major blood loss.  Skin and other tumors may also cause local bleeding.  Blood loss anemias are generally regenerative after 3-4 days and remain regenerative even when iron deficient.

While in the above cases hemorrhage was caused by vascular injury, there are also a variety of bleeding disorders to consider. Thrombocytopenia is rare in cats but may be induced by drugs (methimazol) and rarely infection and cancer. Also, immune-mediated thrombocytopenia seems to occur rarely in cats and is likely due to a secondary trigger.  Accurate platelet counts can be difficult to obtain due to the large size of feline platelets and their tendency to aggregate.  Thus, any platelet count needs to be confirmed with an estimate from a blood smear examination (20,000 platelets/μl equals 1 platelet seen on a high power microscopic field).  Cats with with any thrombocytopenia rarely bleed uless they have other bleeding tendencies (vasculopathy and coagulopathy). 

Thrombopathia – impaired platelet function - may be triggered by aspirin or similar more potent drugs inhibiting platelet function.  Cats appear particularly sensitive to platelet injury, but less likely develop aspirin- or steroid-induced ulceration).  Hereditary thrombopathias are extremely rare. 

Similarly coagulopathies are less common in cats than dogs.  Compared to dogs anticoagulant rodenticide poisoning is less commonly observed in cats, however, coagulopathies due to hepatic failure are much more severe in cats than dogs.  Most feline hepatopathies are diffuse such as hepatic lipidosis, cholangiohepatitis, amyloidosis, lymphoma, mast cell tumor, feline infectious peritonitis.  Hence diagnostic liver biopsies are frequently associated with serious hemorrhage unless surgically done or as an ultrasound guided or laparoscopic biopsy.   Part may be due to an inability to absorb vitamin K and thus parenteral vitamin K1 supplementation for a few days may improve hemostasis. 

Furthermore, there are several hereditary coagulopathies such as hemophilia A and B in male domestic and Himalayan cats as well as a vitamin K-dependent coagulopathy in Devon Rex cats.  Interestingly, domestic and exotic shorthair cats often have a coagulation factor XII deficiency; while this causes a markedly prolonged partial thromboplastin time, this is not associated with a bleeding tendency.  Generally the prothrombin and partial thromboplastin times provide sufficient information to differentiate the coagulopathies, although specific factor analyses may be needed.

Hemolytic anemias in cats are often hard to recognize as the degree of regeneration and the evidence of bilirbinuria and hyperbilirubinemia are often mild. Note any bilirubinuria is important in a cats.  In fact, icterus in cats is much more likely due to hepatic failure than hemolysis in cats.  While the normal feline spleen is very small, it can get fairly enlarged in cases of hemolytic anemia (like increased osmotic fragility).  In contrast to dogs immune-mediated hemolytic anemia seems rare in cats.  Nevertheless, there are several important differential diagnoses, and, thus, treatment options depend on the cause of hemolysis. 

Various triggers such as drugs and chemicals can be rapidly removed.  However, other diagnoses may require special tests at reference laboratories, such as for infectious disease serology and real-time PCR, and genetic red cell tests.  It is, therefore, not unusual to start with prednisolone and doxycycline to cover the bases until test results are back and the proper therapy can be instituted.  Note PCR tests for infectious organisms turn quickly negative after treatment and thus samples for diagnostics should collect prior to treatment even if only submitted later.  For hereditary hemolytic anemias, it is most important to avoid harmful treatments as these cats may in fact have a good life-expectancy.

Lastly, non-regenerative anemias due to decreased erythro- or overall hematopoiesis can be associated with a variety of disorders.  Indeed, mild non-regenerative normochromic normocytic anemia is commonly seen with many organ diseases and is well tolerated.  However, many middle-aged to older cats with chronic renal failure develop a moderate to severe anemia.  The main cause is a lack of renal production of erythroproietin, but uremic toxins affecting red cell stability and bone marrow production as well as blood loss from ulcers also play a role.  Transfusion or human recombinant erythropoietin can reverse the anemia and associated clinical signs.  However, repeat transfusions are generally needed and cats may become refractory, as they develop alloantibodies against the transfused red cells. 

Moreover, cats can develop antibodies against the recombinant human erythropoietin, which cross-reacts with feline endogenous erythropoietin and leads to a severe and hardly reversible pure red cell aplasia (darbepoetin is seemly preferred over epogen).  Some may appear resistant to erythropoietin supplementation only to be found also iron deficient.  Renal transplantation from a carefully selected donor cat has effectively reversed not only the anemia, but also restored kidney function.  While rarely truly deficient, iron, folate, and cobalamin may be replenished as needed.   FeLV infections may end in a pure red cell aplasia (C type) or myelodysplasia to aplasia, while FIV exhibits less effects on the bone marrow.  Cancer associated anemias may have many causes, but may result in aplastic or myelophistic bone marrows.

Transfusion support is also critical for the feline patient, most commonly to correct anemia and less often bleeding.   Nevertheless, blood transfusions are overall still less frequently administered to cats than dogs for a variety of reasons.  Compared to canine transfusion medicine, cats can tolerate anemia better, they still get somewhat less medical attention, except for rodenticide toxicity and hepatopathies they bleed less severely, recruiting healthy donors is more difficult (occult heart disease, viral infections), blood collection requires sedation and special small bag collection systems, component therapy is less commonly practiced in clinics, cats have important naturally occurring alloantibodies and may experience life-threatening complications with a first transfusion, and the anemic cat is more sensitive to volume overload.  There is no specific trigger PCV, but rather the overall clinical picture with a PCV of <20% is used. 

Blood typing

The major feline blood group system thus far generally recognized is known as the feline AB blood group system and contains 3 alleles: type A, type B, and the extremely rare type AB.  Type A is dominant over B.  Thus, cats with type A blood have the genotype a/a or a/b, and only homozygous b/b cats express the type B antigen on their erythrocytes.  In the extremely rare AB cat, a third allele recessive to the a allele and/or codominant to b allele leads to the expression of both A and B substances.  AB cats are not produced by mating of a type A to a type B cat unless the A cat carries the rare AB allele.  Cats with type AB blood have been seen in many breeds and domestic shorthair cats.

Most domestic shorthair cats have type A blood, but the proportion of type B cats can be substantial in certain areas.  The frequency of A and B blood types of domestic shorthair cats differs geographically (Table 2).  The frequency of A and B blood types varies greatly between different breeds, but likely not much geographically in purebred cats (Table 2).  Kitten losses due to A-B incompatibility and changes in breeding practices influence the frequency of A and B in various breeds.  Most blood donors have type A blood, but some places also keep cats with the rare type B and type AB as donors.  All blood donors must be typed.  Naturally-occurring alloantibodies have been well documented in type A and type B cats and require that blood typing be performed prior to both blood transfusion and breeding to assure appropriate blood compatibility.  Cats have naturally-occurring alloantibodies.  All type B cats have very strong naturally-occurring anti-A alloantibodies, which can be detected by hemolysis and hemagglutination assays.      

Kittens receive alloantibodies through the colostrum from type B queens and develop high alloantibody titers (>1:32) after a few weeks of age.  These alloantibodies are strong hemolysins and hemagglutinins, and are of the IgM and, to a lesser extent, IgG classes.  They are responsible for serious transfusion reactions and neonatal isoerythrolysis in type A or AB kittens born to type B queens.  Type A cats have weak anti-B alloantibodies, and their alloantibody titer is usually very low (1:2), nevertheless they can also cause hemolytic transfusion reactions, but have not been associated with NI.  Type AB cats have no alloantibodies.  Furthermore additional blood group systems are being identified such as the Mik red cell antigen in Domestic shorthair cats.

Serological testing relies on identification of surface antigens, leading to agglutination and hence can distinguish A, AB or B phenotypes. Several different reagents may be used for this. Serum from type B cats is often used as an anti-A reagent owing to the presence of strong alloantibodies in all type B cats. Serum from type A cats has previously been used as an anti-B reagent but this produces variable results owing to the often-weak alloantibodies present. The lectin from Triticum vulgaris is now commonly used as an anti-B reagent as it preferentially agglutinates erythrocytes expressing the B antigen, only agglutinating type A erythrocytes at higher concentrations. More recently monoclonal antibodies against the type A and type B antigen have been developed.  A genetic test is now available for identification of the b allele, allowing identification of type B cats and carriers of this allele, but not distinguishing A or AB phenotypes.

There are no universal donor cats.  Donor and patient need to be typed, even if it is “only” a domestic shorthair cat.  However additional blood groups are likely being identified; we recent found a Mik red cell antigen in Domestic shorthair cats, and Mik-negative cats may also produce naturally occurring alloantibodies.  Simple AB blood typing cards (DMS Laboratories, 2 Darts Mill Road, Flemington, NJ) and cartridges (Alvedia DME, Lyon France) are available for in practice use. 

Blood incompatibilities, unrelated to the AB blood group system, have also been recognized following blood transfusion through crossmatching cats or as a result of acute hemolytic transfusion reactions.  Utilizing standard tube and novel gel column crossmatching techniques, the presence of a clinically relevant alloantibody, formed against a newly discovered feline red blood cell antigen, and referred to as Mik red cell antigen has been identified.  Additional studies to determine both the frequency of Mik red cell antigen-negative cats and the presence of anti-Mik alloantibodies in the general feline population are needed as is molecular characterization of the Mik-red cell antigen.   Screening feline blood donors and patients for the presence of this apparently common red cell antigen and corresponding alloantibody may prove necessary in clinical practice. 

Blood crossmatching tests

The major crossmatch tests for alloantibodies in the recipient's plasma against donor cells, whereas the minor crossmatch test looks for alloantibodies in the donor's plasma against the recipient's red blood cells.  Mixing a drop of donor/recipient blood with donor/recipient plasma will detect A-B incompatibilities if typing is not available.  However, proper techniques for crossmatching and experience are required to detect other less severe incompatibilities.  Standrad tube and the novel gel column (saline and feline Coombs gel card, DiaMed) technique are used in laboratories and a tube gel column test (DMS) has been introduced to permit crossmatching in clinical practice.  The presence of autoagglutination or severe hemolysis may preclude the crossmatch testing. 

A major crossmatch incompatibility is of greatest importance because it predicts that the transfused donor cells will be attacked by the patient's plasma, thereby causing a potentially life-threatening acute hemolytic transfusion reaction. As fatal reactions may occur with <1ml of incompatible blood, compatibility testing by administering a small amount of blood is not appropriate. This has been shown in experimental studies to result in fatal reactions.  The major and minor crossmatch can show incompatibility prior to any transfusion due to the presence of naturally occurring alloantibodies in cats, not only for the AB but also the Mik and possibly other blood group systems.

Previously transfused cats should always be crossmatched, even when receiving blood from the same donor.  The time span between the initial transfusion and incompatibility reactions may be as short as 4 days and lasts for many years (i.e., years after the last transfusion alloantibodies may be present).  Obviously, a blood donor should never have received a blood transfusion to avoid sensitization. 

Feline blood donors

There are few commercial blood bank that offer feline blood products.  Many hospitals have a small in-house colony and/or involve the staff's cats.  Healthy, young adult (1-8 years) good tempered cats of at least 4 kg lean body weight can be recruited. Due to the infectious disease risks indoor cats free of fleas and intestinal parasites are selected.  A freely roaming cat in a veterinary hospital would not be a good donor candidate because of the potential of having acquired some infections.

Blood donors must have no history of prior transfusion; have been regularly vaccinated and are healthy as determined by history, physical examination, and laboratory tests (complete blood cell count, chemistry screen, and fecal parasite examination every 6-12 months) as well as free of infectious diseases (testing depends on geographic area but may include regular FeLV, FIV, FIP, hemomycoplasma testing.  Donors should receive a well-balanced, high performance diet, and may be supplemented twice weekly with ferrous sulfate (Feosal, 10 mg/kg), if bled every 4 weeks.  Packed cell volume (PCV) or hemoglobin (Hb) should be >30% and >10 g/dl in cats.

Blood collection

Cats are regularly sedated with a combination of ketamine (10 mg), diazepam (0.5 mg), and atropine (0.04 mg) by intravenous injection.  Some sedatives, such as acepromazine, interfere with platelet function and induce hypotension, hence they should not be used.  Blood is collected aseptically by gravity or blood bank vacuum pump from the jugular vein over 5 to 10 minute period.  Large plastic syringe containing 1 ml CPD-A1 or 3.8% citrate per 9 ml blood and connected to a 19 gauge butterfly needle is commonly used for cats.  This represents an open collection system in which connections allow exposure of blood to the environment; because of the potential risk for bacterial contamination, blood collected via an open system should not be stored for more than 48 hours.  The maximal blood volume to be donated is 40-50 ml blood (one typical feline unit) per ≥ 5 kg cat.

We have developed a closed blood collection system that permits component preparation into packed re blood cells and fresh frozen plasma as well as storage (28 days of red cells, 1 year FFP). Blood components are prepared from a single donation of blood by simple physical separation methods such as centrifugation generally within 4 hours from collection.  The separation of blood components from a single donation of blood is performed according to the Technical Manual of the American Association of Blood Banking and does require some expertise and equipment.  Fluctuations in storage temperature significantly alter the length of storage; thus, temperature controlled and alarmed blood bank refrigerators and freezers are ideal, but others are acceptable as long as the temperature is monitored and the refrigerator/freezer are not too frequently opened.  Blood components that have been warmed to room or body temperature should not be recooled and cannot be stored again.  Similarly, opened blood bags should be used within 24 hours because of the risk of contamination. 

Blood administration 

The regular principles used in transfusing cats are applied in cats. No food is given during the transfusion, and blood is administered separately without any drugs or other fluids.  Because of the volumes shorter tubing with a small filter are used instead of the large infusion sets.  Despite assuring blood compatibility particular attention is given to the first few milliliters infused. Monitoring is done like in dogs.

Table 1. Feline hemolytic anemias

• Infections

• Mycoplasma hemofelis, hemominutum, turecesis

• Cytauxzoon felis

• Feline Leukemia Virus infection (A type)

• Feline Infectious Peritonitis

• Immune

• Autoimmune hemolytic anemia

• Secondary (drugs [methimazol], infection, cancer)

• Toxic

• Drugs: Acetaminophen, lidocain spray, propofol, etc.

• Onions

• Metabolic

• Hypophosphatemia (D. mellitus, hepatopathy, hyperalimentation)

• Hereditary

• Pyruvate kinase deficiency (Abyssinian, Somali, DSH cats)

• Increased osmotic fragility (Abyssinian, Somali, DSH cats)

• Porphyria (Siamese, DSH cats)

Table 2. Blood type A and B frequency in cats in certain countries and breeds*

  Percentage     Percentage   Domestic shorthaired cats Type A Type B Purebred cats Type A Type B Northeast 99.7 0.3 Abyssinian 84 16 North Central 99.6 0.4 Am. shorthair 100 0 Southeast 98.5 1.5 Birman 82 18 Southwest 97.5 2.5 British shorthair 64 36 West Coast 95.3 4.7 Burmese 100 0 Argentina 97 3 Cornish rex 67 33 Australia 73.7 26.3 Devon rex 59 41 India (Bombay) 88 12 Exotic shorthair 73 2759 Europe     Himalayan 94 76 Austria 97 3 Japanese bobtail 84 16 England 97 3 Maine coon 97 3 Finland 100 0 Norwegian Forest 93 7 France 85 14 Oriental shorthair 100 0 Germany 94 6 Persian 86 14 Hungary 100 0 Scottish Fold 81 19 Italy 89 11 Siamese 100 0 Netherlands 96 4 Somali 82 18 Scotland 97 3 Sphinx 83 17 Switzerland 100 0 Tonkinese 100 0