Abstract
Objective—To further classify dysmyelopoiesis as diagnosed by use of a general classification scheme and to determine clinical features and laboratory test results that could be used to differentiate between the various forms of dysmyelopoiesis in cats.
Design—Retrospective case series.
Sample Population—Bone marrow slides from 34 cats.
Procedures—Medical records of cats in which dysmyelopoiesis was diagnosed on the basis of blood and bone marrow analyses from 1996 to 2005 were reviewed. Criteria for inclusion in the study were findings of > 10% dysplastic cells in 1 or more hematologic cell lines in the bone marrow and concurrent cytopenias in the blood. Cats that met these criteria were classified into subcategories of myelodysplastic syndromes or secondary dysmyelopoiesis on the basis of reevaluation of slides.
Results—Of 189 bone marrow slides reviewed, 34 (14.9%) had > 10% dysplastic cells in 1 or more cell lines. Cats were subcategorized as having myelodys-plastic syndrome with excessive numbers of blast cells (n = 13), myelodysplastic syndrome with refractory cytopenias (8), a variant form of myelodysplastic syndrome (1), and secondary dysmyelopoiesis (12). Findings of dysmyelopoiesis and autoagglutination in cats with myelodysplastic syndrome and in those with immune-mediated anemia complicated differentiating between the 2 conditions.
Conclusions and Clinical Relevance—Differentiating cats with myelodysplastic syndromes from cats with immune-mediated hemolytic anemia was difficult because severe anemia and autoagglutination may be concurrent findings in both conditions. Differentiating between myelodysplastic syndrome with excessive numbers of blast cells and myelodysplastic syndrome with refractory cytopenias was useful in predicting clinical outcome.
Dysmyelopoiesis is a general term used to define dysplastic conditions of hematopoietic cells.1 Dysmyelopoiesis is a relatively common finding in dogs and was observed in 12.7% of clinical bone marrow specimens examined at the University of Minnesota Veterinary Medical Center in 1 study.2 Three general types of dysmyelopoiesis have been described in dogs, cats, and humans: MDS, secondary dysmyelopoiesis, and congenital dysmyelopoiesis.1,3-7 Proliferating hematopoietic cells in humans with MDS and cats infected with FeLV are clonal,8,9 indicating that, in those instances, the condition arises from an acquired mutation in hematopoietic stem cells that results in a proliferative advantage for that clone.9 Secondary dysmyelopoiesis has also been described in association with various disease conditions, drug treatments, or toxin exposure.2,10,11 The features thought to be most reliable for differentiating between those conditions are findings of high numbers of bone marrow myeloblasts or rubriblasts in animals with MDS and detection of associated disease conditions or drug exposure in animals with secondary dysmyelopoiesis, but those features are not invariably present.2
Myelodysplastic syndromes were initially classified by the FAB cooperative group in 1976 (Table 1).4 That classification system has been used to classify disease in dogs and cats.5,6,12-14 Subcategories included refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excessive numbers of blast cells (ie, 5% to 20% myeloblasts in bone marrow), refractory anemia with excessive numbers of blast cells in a transitional stage (ie, 20% to 30% myeloblasts in bone marrow), and chronic myelomonocytic leukemia. Humans with > 30% myeloblasts in bone marrow are defined as having acute myelogenous leukemia.4
Classification systems used for characterization of MDSs.
| FAB system | World Health Organization system | Dog and cat system |
|---|---|---|
| Refractory anemia | Refractory anemia | MDS with refractory cytopenia (ie, < 6% myeloblasts) |
| Refractory anemia with ringed sideroblasts | Refractory anemia with ringed sideroblasts | MDS with sideroblastic differentiation (myeloblasts variable) |
| Refractory anemia with excessive numbers of blast cells (5%–20% myeloblasts) | Refractory anemia with excessive numbers of blast cells (5%–10% myeloblasts) | MDS with excessive numbers of myeloblasts (6%–30% myeloblasts) |
| Refractory anemia with excessive numbers of blast cells in transition (20%–30% myeloblasts) | Refractory anemia with excessive numbers of blast cells II (> 10%–20% myeloblasts) | |
| Chronic myelomonocytic leukemia | MDS unclassified |
More recently, the FAB classification system has been modified by the World Health Organization.7 In that system, a finding of 5% to 10% myeloblasts is defined as refractory anemia with excessive numbers of blast cells I and a finding of 10% to 20% myeloblasts is defined as refractory anemia with excess myeloblasts II.7 Acute myelogenous leukemia is defined as > 20% myeloblasts in bone marrow. Chronic myelomonocytic leukemia was not included in the World Health Organization definition of MDS.7
Myelodysplastic syndromes in cats were initially classified into 1 of 2 categories5,12: cats with a bone marrow G:E ratio > 1.0 with blast cells representing < 30% of all nucleated cells were classified as having MDS, and cats with a G:E ratio < 1.0 with < 30% blast cells were classified as having MDS with erythroid predominance.5,12 The diagnosis of MDS in cats has also been classified according to the FAB system.13,14 Other investigators1,6 have modified the FAB classification system for use in dogs and cats (Table 1). In the modified system, MDS-EB was defined as findings of a G:E ratio > 1.0, with myeloblasts constituting from 6% to 30% of all nucleated cells in the bone marrow. Myelodysplastic syndrome with refractory cytopenias was defined as a G:E ratio > 1.0 with < 6% myeloblasts. Myelodysplastic syndrome with erythroid predominance was defined as a G:E ratio < 1.0 with < 6% myeloblasts.6 Because of the similar clinical presentation and outcome of MDSRC and MDS with erythroid predominance in dogs, it has been proposed that these 2 categories be combined.1 The most frequently encountered type of MDS in cats appears to be MDS-EB.3,5,13,15
Dysmyelopoiesis secondary to other disease conditions has been described in dogs.2 Conditions most frequently associated with secondary dysmyelopoiesis include IMHA, immune-mediated thrombocytopenia, and lymphosarcoma. In the present study, records of cats with dysplastic bone marrow changes over a 9-year period were evaluated. On the basis of blood work, bone marrow findings, and medical records, cats were subcategorized into classifications of MDS or secondary dysmyelopoiesis by use of the modified FAB classification system.
Criteria for Selection of Cases
A search of all bone marrow cytology reports generated by the University of Minnesota Veterinary Medical Center Cytology Service from July 1, 1996, to June 30, 2005, was conducted. Criteria for inclusion were findings of > 10% dysplastic cells in 1 or more hematologic cell lines in the bone marrow accompanied by cytopenias in the blood. Anemia was defined as an Hct < 30%. Leukopenia was defined as a leukocyte count < 3,000 cells/μL. Thrombocytopenia was defined as a platelet count < 200,000 platelets/μL. Cats that met those criteria were subcategorized as having MDS or secondary dysmyelopoiesis.
Procedures
A 500-cell differential count was performed on bone marrow slides in which dysplastic features were detected. The percentages of myeloblasts and rubriblasts were expressed as a percentage of all nucleated cells. The G:E ratio, percentage of myeloblasts, percentage of rubriblasts, percentage of dysplastic cells, and percentage of lymphocytes were determined. Bone marrow core biopsy specimens were examined when available. Cellularity and pathologic changes, including necrosis and myelofibrosis, were recorded.
Dysmyelopoiesis was classified on the basis of the modified FAB classification systems.2,6 In the absence of a concurrent disease process, a finding of nonregenerative anemia or multiple cytopenias in blood smears and < 6% myeloblasts in bone marrow specimens was defined as MDS-RC. A finding of cytopenias in the blood and 6% to 30% myeloblasts in bone marrow specimens was defined as MDS-EB. A diagnosis of secondary dysmyelopoiesis was defined as occurring in association with a disease process or drug treatments that may have initiated the hematologic dyscrasia or that was associated with the response to disease-specific drug treatments.
Statistical analysis—Statistical analyses were performed with commercially available software.a Cats with MDS-EB or MDS-RC were compared with cats with secondary dysmyelopoiesis on the basis of Hct, MCV, mean corpuscular hemoglobin concentration, neutrophil count, platelet count, and percentage of myeloblasts and rubriblasts in bone marrow. Data were analyzed by use of ANOVA. Means of interest were compared by use of the Bonferroni-Dunn F test.b Kaplan-Meier survival curves were generated and analyzed with the Wilcoxon rank sum test.c Differences were considered significant at P < 0.05.
Results
The record search yielded 228 bone marrow cytology reports. The slides accompanying 189 of those reports were appropriate for review. Reasons why slides were not reviewed for 39 cases included that specimens were non-diagnostic (n = 7), specimens were cytologically normal (26), and slides could not be found (6). Of 189 slides evaluated, those from 34 cats had > 10% dysplastic cells in 1 or more hematopoietic cell lines in the bone marrow and cytopenias in the blood. Those cases were subcategorized as MDS-EB (n = 13 cats), MDS-RC (8), variant MDS (1), and secondary dysmyelopoiesis (12) on the basis of percentages of myeloblasts and rubriblasts and the presence or absence of coexisting diseases (Table 2).
Hematologic and survival data for 33 of 34 cats with MDS or secondary dysmyelopoiesis.
| Variable | MDS-EB (n = 13) | MDS-RC (8) | Secondary dysmyelopoiesis (12) | Reference interval |
|---|---|---|---|---|
| Age (y) | 9.4 (1–17)* | 8.7 (5–15) | 5.6 (1–8) | NA |
| Median survival time (mo) | 0.7a | 11.7 | 22.4 | NA |
| Hct (%) | 16 ± 2 | 9 ± 1b | 22 ± 4 | 26–46 |
| MCV (fL) | 44.6 ± 2.3 | 67.9 ± 3.0ab | 45.1 ± 2.8 | 39–51 |
| Mean corpuscular hemoglobin concentration (g/dL) | 34.6 ± 0.4 | 34.6 ± 0.5 | 33.1 ± 1.0 | 31.5–36.5 |
| Neutrophils (no. of cells/μL) | 3,200 ± 440b | 2,430 ± 530b | 8,940 ± 1,340 | 1,200–13,200 |
| Platelets (no. of platelets/μL) | 79,830 ± 3,320 | 51,270 ± 2,410 | 117,450 ± 6,660 | 160,000–489,000 |
| Metarubricytosis (%) | 38 | 75 | 17 | 0 |
| Autoagglutination (%) | 46 | 50 | 23 | Negative |
| Bone marrow myeloblasts (%) | 13 ± 3b | 3 ± 1 | 2 ± 1 | < 6% |
| Rubriblasts (%) | 7 ± 2b | 11 ± 5b | 3 ± 1 | < 6% |
| Lymphocytes (%) | 3 ± 3 | 5 ± 4 | 23 ± 7† | 5–9 |
| Dyserythropoiesis (%) | 85 | 100 | 83 | NO |
| Dysgranulopoiesis (%) | 46 | 38 | 33 | NO |
| Dysmegakaryopoiesis (%) | 69 | 75 | 67 | NO |
| Necrosis (%) | 38 | 33 | 0 | NO |
| Fibrosis (%) | 50 | 33 | 0 | NO |
Values given as median (range).
Values available for cats with IMHA and pure red cell aplasia only.
Significant (P < 0.05) difference between cats with MDS-EB and cats with MDS-RC.
Significant (P < 0.05) difference between cats with MDS and cats with secondary dysmyelopoiesis.
NA = Not applicable. NO = Not observed.
MDS-EB—Median age of cats with MDS-EB was 9.4 years, with a range of 1 to 17 years. Twelve cats had severe clinical illness at the time of initial evaluation. All 13 cats were inappetant, weak, and depressed. Weight loss (n = 9), fever (5), vomiting or diarrhea (4), and platelet-related bleeding (4) were less frequently observed. Six cats had positive test results for FeLV infection, but none had positive test results for FIV infection. Of the 7 cats with negative test results for FeLV infection, 5 also had negative direct fluorescent antibody results on bone marrow specimens.
Twelve cats had nonregenerative anemia. The anemia was characterized as macrocytic in 3 cats and hypochromic in 1 cat. Autoagglutination was observed in blood smears of 6 cats, and metarubricytosis was observed in the smears of 5 cats. Ten cats were thrombocytopenic, and 3 were leukopenic.
The bone marrow was normocellular or hypercellular in 12 cats and moderately hypocellular in 1 cat. All cats had 8% to 20% myeloblasts in bone marrow, a range that was significantly (P < 0.01) different from values in cats with secondary dysmyelopoiesis. Features of cellular dysplasia were observed in all cell lines (Figure 1). Features of dysgranulopoiesis included a shift toward immaturity, maturation arrest, hyper-segmentation, hyposegmentation, giant band and segmented neutrophils, and asynchronous maturation of nucleus and cytoplasm. Features of dyserythropoiesis included asynchronous maturation of the nucleus and cytoplasm, binucleation, fragmented or lobulated nuclei, and megaloblastosis. Features of dysmegakaryopoiesis included large megakaryocytes with mature-appearing granulated cytoplasm but poorly lobulated or multiple discrete nuclei; megakaryocytes with mature hyperlobulated nuclei but immature-appearing homogeneous blue cytoplasm; and many small megakaryocytes with single or multiple discrete, round nuclei. Evaluation of bone marrow core biopsy specimens for 8 of the 13 cats with MDS-EB revealed myelonecrosis in 1 cat and myelofibrosis in 5 cats. Necrosis was characterized by diffuse individual cell necrosis. Fibrosis varied from mild to moderate in degree of severity.
Bone marrow aspirate specimen from a cat with MDS-EB. Notice the dysplastic rubricyte (arrow) characterized by large size; an atypical immature nucleus; and mature, fully hemoglobinized cytoplasm. Also notice the high numbers of myeloblasts in the smear. Wright-Giemsa stain; bar = 20 m.
Citation: Journal of the American Veterinary Medical Association 228, 6; 10.2460/javma.228.6.893
All cats with a diagnosis of MDS-EB had short survival times (Figure 2). Nine cats died or were euthanized within 30 days of initial evaluation. One cat survived for 42 days, and 3 cats were lost to follow-up.
Comparison of Kaplan-Meier survival curves for 13 cats with MDS-EB and 8 cats with MDS-RC in a retrospective case series.
Citation: Journal of the American Veterinary Medical Association 228, 6; 10.2460/javma.228.6.893
MDS-RC—Eight cats had a diagnosis of MDS-RC; median age was 8.7 years with a range of 5 to 15 years. Cats with MDS-RC were less severely ill than cats with MDS-EB. Inappetance, weakness, depression, and weight loss were frequently observed clinical signs. Only 2 of 8 cats had FeLV infection on the basis of blood testing, and none of the cats had FIV infection.
All cats had moderate to severe macrocytic normochromic nonregenerative anemia. Mean corpuscular volume was > 70 fL in 6 cats, a value that was significantly (P < 0.01) higher than those in cats with MDSEB or secondary dysmyelopoiesis. Metarubricytosis was observed in 6 cats, and autoagglutination was observed in 4 cats. Six cats were thrombocytopenic, and 2 cats were leukopenic.
Bone marrow was normocellular or hypercellular in all 8 cats. Myeloblasts comprised < 6% of all nucleated cells in all cats, and rubriblasts constituted > 6% of all nucleated cells in 6 cats. Dysplastic features were identified in the erythroid line of all cats, granulocyte line of 3 cats, and megakaryocyte line of 6 cats. Features of dysmyelopoiesis were similar to those seen in cats with MDS-EB (except for the increase in number of myeloblasts), but megaloblastic changes were more numerous in cats with MDS-RC (Figure 3). Evaluations of bone marrow core biopsy specimens were available for 6 of 8 cats and revealed myelonecrosis in 2 cats and myelofibrosis in 2 cats. Myelonecrosis was characterized by diffuse individual-cell necrosis. Myelofibrosis varied from mild to moderate in severity.
Bone marrow aspirate from a cat with MDS-RC. Notice the megaloblastic rubricyte (arrow), characterized by large size and a large nucleus with poor chromatin clumping. Wright-Giemsa stain; bar = 20 μm.
Citation: Journal of the American Veterinary Medical Association 228, 6; 10.2460/javma.228.6.893
Survival time in cats with MDS-RC was variable (Figure 2). The 2 cats that had pancytopenia at the time of diagnosis were euthanized within 1 month of diagnosis. Alternatively, 3 cats with anemia (n = 1) or anemia and thrombocytopenia (2) survived for 1.0, 1.4, and 2.2 years after diagnosis with supportive care. The cats that survived for 1.0 and 1.4 years had positive test results for FeLV infection. Three cats were lost to follow-up.
Variant form of MDS—One variant form of MDS was detected in a 12-year-old cat with a 6-month history of lethargy, inappetance, weight loss, and vomiting. The cat had negative test results for FeLV and FIV infection. Blood samples from that cat were characterized by severe macrocytic normochromic regenerative anemia with autoagglutination and numerous siderocytes. Moderate thrombocytopenia and severe neutropenia were also observed. Results of a direct Coombs' test were negative, and blood lead concentration was below detectable limits. Bone marrow was hypercellular, but the G:E ratio was low. Myeloblasts constituted < 6%, and rubriblasts constituted 12% of all nucleated cells. Sideroblasts were infrequently detected in the bone marrow. Neutrophilic granulocytes were rare, but the percentages of eosinophil and basophil precursors were high and shifted toward immaturity. Dysplastic features were identified in the erythroid line of cells.
The cat was treated with repeated blood transfusions and immunosuppressive doses of prednisone and cyclosporin A. Despite a prolonged survival time, findings of pancytopenia persisted and the anemia became nonregenerative. The tentative diagnosis in this cat was MDS with sideroblastic differentiation. That diagnosis was made on the basis of high numbers of siderocytes, dyserythropoiesis, increased eosinophilopoiesis and basophilopoiesis, and lack of response to immunosuppressive treatment.
Secondary dysmyelopoiesis—Dysmyelopoiesis was classified as secondary in 12 cats on the basis of findings of > 10% dysplastic cells in 1 or more cell lines in bone marrow and concurrent disease conditions (Table 1). Associated disease conditions included IMHA (n = 4 cats), immune-mediated thrombocytopenia (1), pure red-cell aplasia (1), lymphosarcoma (3), chemotherapy for a vaccine-induced sarcoma (1), glomerulonephritis (1), and feline infectious peritonitis (1). All cats with IMHA had nonregenerative anemia at the time of initial evaluation; the anemia was macrocytic in 2 cats, although MCV did not exceed 56 fL. Autoagglutination was observed in 3 cats, results of a direct antiglobulin test were positive in 1 of 2 cats tested, and metarubricytosis was observed in 2 cats.
Bone marrow specimens in all cats with secondary dysmyelopoiesis had normal or increased cellularity. Dysplastic features were most prominent in cells of the erythroid series but were also detected in granulocytes and megakaryocytes. In general, changes were similar to those seen in cats with MDS except that blast-cell numbers were not increased and megaloblastic changes were not as prominent as those noted in cats with MDS-RC. In cats with IMHA and pure red-cell aplasia, small lymphocyte numbers exceeded reference values (5% to 9% of all nucleated cells16), with a median percentage of 26.8%. Lymphoid aggregates were observed in core biopsy sections in 2 of those cats. The diagnosis of pure red-cell aplasia was made on the basis of a complete absence of erythroid precursor cells in bone marrow. Diagnoses of IMHA, immune-mediated thrombocytopenia, and pure red cell aplasia were supported by hematologic recovery and prolonged survival times after prednisone treatment.
Discussion
Dysmyelopoiesis, as diagnosed in 34 of 189 (18%) bone marrow specimens from cats evaluated over a 9-year period at a veterinary teaching hospital, was further categorized as MDS or secondary dysmyelopoiesis. Myelodysplastic syndromes were subcategorized into MDS-EB, MDS-RC, and variant forms. Classifying MDS as MDS-EB or MDS-RC appears to be useful in predicting the severity of clinical signs and prognosis. Cats with MDS-EB had more severe illness when initially evaluated. Fever, vomiting, and diarrhea were signs associated with MDS-EB that were not associated with MDS-RC. Cats with MDS-EB had uniformly short survival times. Conversely, cats with MDS-RC had less-severe clinical signs, and 3 of those 5 cats survived for 1 year or longer. Therefore, detection of increased numbers of myeloblasts in bone marrow of cats appears to be clinically useful in predicting a poor prognosis in cats with MDS.
Myelodysplastic syndromes were difficult to differentiate from secondary dysmyelopoiesis associated with immune-mediated anemias. Both syndromes were characterized by severe nonregenerative anemia, autoagglutination, and metarubricytosis. Several factors were useful in differentiating these conditions. Marked macrocytosis (ie, values of MCV > 65 fL) was a useful indicator of MDS-RC. Dysplastic changes in bone marrow were not sufficiently different to differentiate MDS from secondary dysmyelopoiesis, but megaloblastic changes were more prominent in MDS-RC. Additionally, myeloblasts and rubriblasts comprised < 6% of all nucleated cells in cats with secondary dysmyelopoiesis. Alternatively, all cats with MDS-EB and 75% of cats with MDS-RC had high blast-cell numbers. A high number of small lymphocytes in bone marrow also supports a diagnosis of IMHA or pure red cell aplasia. The finding of increased numbers of small lymphocytes in bone marrow of cats with immune-mediated hematologic diseases has been reported.17,18 Finally, hematologic evaluation of cats after prednisolone treatment supports the diagnosis of IMHA and pure red-cell aplasia. Therefore, response to immunosuppressive treatments may be useful in differentiating immune-mediated hematologic diseases from MDS.
In the present study, only 36% of cats with MDS had positive test results for FeLV infection, a value that was lower than has been previously reported.13-15 In the prior studies, 92%, 94%, and 71% of cats with MDS tested positive for FeLV infection. The difference may be the result of a decreasing prevalence in FeLV infection associated with decreased exposure of cats to infection or to efficacy of vaccination programs. Therefore, the incidence of idiopathic acquired MDS in cats in our study may actually be greater than was reported in the previous studies. Although the number of cats in each group was low, survival did not appear to be affected by cats' FeLV infection status. Cats with MDS-EB had short survival times, irrespective of infection status. Alternatively, the 2 cats with MDS-RC that had FeLV infection as determined by blood testing survived for 1 year or longer.
In conclusion, dysmyelopoiesis in cats was divided into categories of MDS-EB, MDS-RC, and secondary dysmyelopoiesis. The observation of myelodysplastic changes in cats with IMHA and autoagglutination in cats with MDS-EB and MDS-RC confounded the differentiation of these conditions. The finding of increased numbers of myeloblasts in bone marrow distinguished cats with MDS-EB. The finding of marked macrocytosis was useful in distinguishing cats with MDS-RC. The finding of increased numbers of rubriblasts was useful in differentiating MDS-RC from secondary dysmyelopoiesis. Further classification of MDS into MDS-EB and MDS-RC was useful in predicting survival time for affected cats.
| MDS | Myelodysplastic syndrome |
| FAB | French-American-British |
| G:E | Granulocyte-to-erythrocyte |
| MDS-EB | MDS with excessive numbers of blast cells |
| MDS-RC | MDS with refractory cytopenias |
| IMHA | Immune-mediated hemolytic anemia |
| MCV | Mean corpuscular volume |
SAS, version 8, SAS Institute Inc, Cary, NC.
SAS procedures guide, version 8, SAS Institute, Cary, NC.
MINITAB, release 14.1, Imintab Inc, State College, Pa.
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