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Hemolytic anemia caused by hereditary pyruvate kinase deficiency in a West Highland White Terrier dog. Inherited erythrocytic pyruvate kinase PK deficiency is an autosomal recessive hemolytic disorder described in dogs and cats. Pyruvate kinase is one of two key-regulatory enzymes in the anaerobic glycolytic pathway, and its deficiency causes premature destruction of the ATP-depleted red cells.

This case study reports the clinical and laboratory findings in a West Highland White Terrier WHWT dog with a life-long history of weakness and exercise intolerance from Brazil. The dog was found to have persistently profound pallor, a highly regenerative hemolytic anemia and osteosclerosis. The dog was euthanized at 20 months of age due to the deterioration of its clinical condition including anemia and blood incompatibility.

Hereditary red cell defects are important differential diagnoses for chronic hemolytic anemias in younger animals after excluding immune-mediated and infectious causes. Furthermore, purebred dogs for which DNA tests for hereditary diseases are available should be screened prior to breeding in order to limit the spread of the mutant allele and to avoid future production of PK-deficient animals.

Key words : pyruvate kinase, erythroenzymopathies, genetic disease, regenerative anemia. The natural occurrence of hereditary blood disorders in animals provides a unique opportunity to study the biochemical and molecular pathogenesis of these diseases and to investigate possible therapeutic options Giger et al , Sewell et al Several hereditary erythrocytic disorders that cause hemolytic anemia and additional unique features have been described in dogs and cats, including membrane defects and enzyme deficiencies; however, interestingly enough no hemoglobinopathies have been discovered in companion animals.

Enzyme deficiencies may involve: 1 heme synthesis causing porphyria in cats Clavero et al a,b , 2 heme reduction by methemoglobin reductase causing cyanosis, and Harvey et al 3 glycolytic erythroenzymopathies. If either pyruvate kinase PK or phosphofructokinase PFK , the two key regulatory enzymes in anaerobic glycolysis, is deficient, erythrocytic ATP production will be impaired and red blood cells RBCs will have a shortened survival.

Pyruvate kinase deficiency is the most common erythroenzymopathy in humans, dogs and cats. In dogs, PK deficiency causes a severe chronic and highly regenerative hemolytic anemia with progressive osteosclerosis, while in cats it is characterized by an intermittent hemolytic anemia without osteosclerosis. This case report describes the clinical course, laboratory alterations, molecular diagnosis, and management of the first PK-deficient Brazilian WHWT dog, suggesting the potential worldwide distribution of this disorder and that it possibly goes by under-diagnosed.

Historically the puppy was weak, has episodes of syncope and constantly showed pale gums on routine clinical examination. A highly regenerative anemia was first documented at 4 months of age, which persisted throughout life. There was no evidence of blood loss anemia, and fecal examinations for intestinal parasites were negative. Thus, a hemolytic anemia caused by an infection, immune-mediated process or toxicity was considered.

In previous clinical visits babesiosis was suspect due to severe anemia and also giardiasis because the puppy had some episodes of loose and greennish faeces. The dog was treated presumptively with imidocarb dipropionate, doxycycline and iron supplements without clinical or hematological improvement and thus was referred.

On blood smear evaluation anisocytosis, marked polychromasia, and normoblastosis were present. However, no spherocytes, Heinz bodies, poikilocytes or infectious agents were detected, and the direct Coomb's test was negative for IgG antibodies on RBCs. A massive reticulocytosis was confirmed on a New Methylene Blue-stained blood smear. Leukopenia and thrombocytopenia was also noted and could be explained by the possible myelofibrosis, common in dogs with this disorder permission for a bone marrow biopsy was not received.

The clinical chemistry profile showed mild hyperbilirubinemia 0. An abdominal ultrasound examination revealed hepatosplenomegaly, and abdominal radiographs indicated mildly increased medullary bone opacity of the ischiatic bone. Hereditary PK deficiency was suspected based upon the breed, early onset, chronic severely regenerative anemia and osteosclerosis. Briefly, DNA was extracted from nucleated cells from a small aliquot of the EDTA blood and specific primers were used to amplify the region surrounding the known mutation in WHWT with a polymerase chain reaction.

The dog reported here was found to have this same mutation thereby confirming PK deficiency. Based upon the clinical signs and anemia a transfusion was deemed necessary.

The dog had been previously transfused without blood typing and crossmatching. In order to assure a safe transfusion, compatibility testing was performed. Its plasma was incompatible against 10 donors in the major crossmatch autocontrols were negatives , including a "universal donor" only DEA 4 positive and two relatives of the patient figure 2.

Thus, alloantibodies against DEA 1. Due to the severity of clinical signs and anemia, the dog was still transfused with fresh whole blood from the "universal donor" DEA 4 positive only. Some clinical improvement was observed within a day, but the PCV did not rise. However, the anemia did not improve, and the animal's overall condition deteriorated to the point where the owners elected euthanasia.

Permission to perform a necropsy was not received. The diagnosis of PK deficiency was suspected in the WHWT described here, because of the breed, young age of anemia, persistence of the highly regenerative anemia and osteosclerosis and was confirmed by a simple DNA mutation test.

Due to the postnatal development of the RBC metabolism, the clinical signs of PK deficiency in dogs are not detected until approximately 4 months of age, as seen in this puppy.

Indeed, many PK-deficient dogs are not diagnosed until one to several years of age, as the animals can often adapt well to the severe chronic anemia. Affected dogs may be first discovered only because of very pale mucous membranes on routine examination. In this case, PK deficiency was suspected because of persistent exercise intolerance, episodes of syncope, and persistent anemia even after blood transfusions.

The illness may also become evident during a crisis triggered by a concurrent illness, such as an infection or toxicity, or stressful situation including strenuous exercise. The leukopenia and thrombocytopenia in the WHWT described here is not typical of PK deficiency and may indicate a secondary illness affecting the bone marrow. Also, the patient was treated for secondary diseases such as giardiasis and babesiosis, without clinical response.

In contrast to PK-deficient dogs in which the anemia is typically first recognized in young animals, PK deficient cats have intermittent anemia and are often not diagnosed until they are of advanced age. Cats exhibit intermittent lethargy, pale mucous membranes and have intermittently mild to moderately severe anemia which may be complicated by bilirubin bile calculi Giger , Harvey et al , Kohn and Fumi , Van Geffen et al , Giger Because PK deficiency causes a distal metabolic block in the anaerobic glycolytic pathway, the proximal glycolytic metabolites, including 2,3-diphosphoglycerate 2,3-DPG , tend to accumulate, while distal metabolites like ATP become depleted in erythrocytes.

The high erythrocytic content of 2,3-DPG facilitates the easy release of oxygen from hemoglobin by the lower hemoglobin-oxygen affinity, which in turn improves oxygen delivery and enhances tissue oxygenation, thereby ameliorating the clinical signs of the severe anemia.

Indeed, this likely explains why most PK-deficient dogs can cope so well, despite a persistently severe anemia Chapman and Giger , Giger and Noble , Giger For yet unexplained reasons, all PK-deficient dogs develop a progressive myelofibrosis and then osteosclerosis, as seen in this case, though PK-deficient cats and humans do not experience osteoclerosis.

However, the increased iron uptake due to hemolytic anemia caused by PK-deficiency is common to all species and can lead to hemosiderosis and eventually hemochromatosis, particularly after patients are transfused large iron source Schaer et al Thus, PK-deficient patients and for that matter any animals with hemolytic anemia should not be supplemented with oral or parenteral iron. This was unfortunately done in this case, which emphasizes the importance of classifying the regenerative anemia into hemolytic versus blood loss anemia and reaching a definitive diagnosis.

Many animals with hemolytic anemia are initially misdiagnosed and treated for infectious diseases e. Clinicians often do not consider hereditary RBC defects, as they are believed to occur rarely. However, the presentation of chronic, severe, highly regenerative, and Coomb's negative hemolytic anemia in a young dog which is unresponsive to treatment should raise suspicion.

Moreover, in certain breeds, PK deficiency, just like other hereditary disorders and genetic predispositions to disease, may occur commonly due to the breeding of carrier animals Harvey , Sewell et al , Giger While in the past PK-deficiency was diagnosed by erythrocytic enzymatic activity test, assessment of oxygenhemoglobin dissociation curve, and level of intermediates of the glycolytic pathway, such as 2,3-DPG, a definitive diagnosis in this case was established simply with the PCR mutation-specific test.

Unfortunately, no information of the breeder or related dogs was available to further trace this dog's ancestors and to identify related potential carrier or affected dogs. Different causative PK mutations have been identified in different breeds such as Basenjis, Beagles, WHWT, while within a breed all affected dogs have the same mutation.

Mutation-specific genetic tests permit the identification of homozygous and carrier dogs. For all the other canine breeds, detailed enzymatic activity tests that include the characterization of the isoenzymes or heat-lability are necessary.

In addition, normoblasts are released into the circulation. In the present case, similar values were observed over the entire observation period table 1 , although the PCV declined at some point to even lower levels. It should be noted that the fall in PCV observed in the last month of life was associated with a diminished bone marrow response, as shown by both the lower absolute reticulocyte count and reticulocyte production index. As there was also a decline in platelet and leukocyte counts, a hematopoietic failure for other reasons than PK-deficiency may have been present.

The degree of osteosclerosis was radiographically mild, but the marrow was not histopathologically examined. Dogs with PK deficiency often have normal white blood cell counts. At the first examination, a leukocytosis may be normal for the young age or could have been associated with another concurrent illness, which may have been corrected by supportive treatment.

Usually the dogs that live longer develop severe liver disease with hemosiderosis. In this report, the dog did not show any hepatosplenomegaly, hepatic disease or iron accumulation, but a hepatic biopsy and iron assessment were not carried out. While PK-deficient cats and humans may also develop bilirubin calculi and gall bladder blockade, this has not been reported in PK-deficient dogs. Radiographs from this WHWT terrier described here revealed only a mildly decreased bone radiopacity of the pelvic bones, probably due to the young age of the animal Chapman and Giger , Harvey et al , Van Geffen et al No clinically practical specific treatment has yet been established for PK-deficient animals.

However, experimentally successful bone marrow transplantation from compatible donors has been described in dogs and gene therapy has been attempted. In veterinary clinics, it is more important to recognize PK deficiency in order to avoid excessive diagnostic procedures for the affected dogs and unnecessary or even harmful treatments with medications such as immunosuppressive agents and iron supplementation.

The treatment is mostly supportive and any other illnesses, stress or excessive exercise should be avoided. Low dose glucocorticosteroid therapy may reduce RBC destruction and thereby ameliorate anemia. The splenomegaly seen in this case could be explained because the spleen is the major site of RBC destruction, and thus splenectomy may slow the premature elimination of PK-deficient RBCs.

In humans, splenectomy can reduce the degree of hemolysis in some patients, but PK-deficient Basenji dogs did not improve clinically after surgery. Thus, splenectomy may only be considered as a last resort in dogs that are persistently severely anemic or have frequently severe crises and are transfusion dependent. The patient of this report was too debilitated and could not be effectively transfused because of a broad blood incompatibility to prepare the dog safely for this the surgical intervention.

As noted in this case, transient improvements and clinical stabilization can be observed. While the patient was undergoing treatment, there was apparently slight clinical improvement, but hematological parameters never returned to normal range Weiden et al , Giger and Noble , Giger Blood transfusions from compatible donors are sometimes needed when the anemia becomes most severe and the PK-deficient animal shows major clinical signs.

Unless a hemolytic crisis develops, transfusions are rarely needed in PK-deficient dogs and cats, as they adapt quite well and can live in good health as house pets, sometimes for years without treatment. In fact, considering the high mortality rate of dogs with immune-meditated hemolytic anemia, PK deficiency may offer a better prognosis.

In the case described here, the dog was severally anemic and symptomatic, and thus had been repeatedly transfused. Unfortunately, the dog became incompatible even to a "universal donor" and its littermates, and thus must have developed an alloantibody against a yet to be identified common red cell antigen. While dogs do not generally have any clinically relevant naturally occurring alloantibodies, they can develop antibodies against blood groups and a common red cell antigen following transfusion, as seen in this case.

An explanation for this blood incompatibility could be the presence of some other RBC antigen that could not be identified by currently used methods of canine blood typing such as the Dal antigen. In this case, the patient could be negative for Dal or another antigen.

Nevertheless, a transfusion was deemed so desperately needed that blood from a "universal donor" was given. Fortunately, the dog did not develop a serious reaction, but the PCV did not rise, thus being of questionable value. Indeed, dogs can become sensitized to other RBC antigens than one can test for and thus be incompatible to even the "universal donor" Callan et al , Blais et al , Kessler et al


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