Abstract
VII. Summary: Immune-mediated hemolytic anemia and immune-mediated thrombo-cytopenia in dogs, a prospective study (1997 ý1999)
In this prospective study all patients with immune-mediated thrombocytopenia (ITP) and immune-hemolytic anemia (IHA), which were presented within two years (January 1997 - January 1999) at the Clinic for Small Animals, Free University of Berlin, were studied and clinical findings, diagnostics and treatment results were evaluated.
Immune-mediated thrombocytopenia
Thrombocytopenia (< 150,000/µl) was observed in 268 dogs, primary ITP was diagnosed in 15 of these dogs (5,6 %). The diagnosis pITP was based on low platelet counts, exclusion of other diseases and a positive platelet-bound antibody test result and response to immunosuppressive therapy. The dogs belonged to 11 different breeds, Cocker Spaniels (n=3) and Golden Retrievers (n=3) were overrepresented. The age when first signs of disease were noted, ranged from 0.5 ý 10.0 years (mean 7.3 years). Four dogs were male, 10 female and 1 female-spayed. Clinical signs of hemorrhage were observed in 12 dogs: petechiae (n=10), gingival bleeding (n=4), melaena (n=3), ecchymoses (n=1) and epistaxis (n=1). Platelet counts ranged from 0 ý 74,000/µl (mean 10,400/µl), 93 % of the dogs had platelet counts
< 30,000/µl. The mean platelet volume (MPV) measured in 6 dogs ranged from 5.6 to 9.1 fl (mean 7.4 fl; reference range 3.9-6.1 fl). Five dogs were anemic (Hematocrit < 35 %). Radiography and ultrasonography revealed splenomegaly in 7 dogs, hepatomegaly in 1 and hepatosplenomegaly in 2 dogs.
The patients were treated with prednisolone (n=9), prednisolone/azathioprine (n=3) and prednisolone/azathioprine/vincristine (n=3). An increase of platelet counts above 50,000/µl was noted in 13 dogs after 2 to 11 days (mean 4.4 days). In 1 dog, platelet counts never exceeded 25,000/µl during course of disease, 1 dog had an initial platelet count > 50,000/µl.
In 5 dogs with increasing platelet counts the follow-up period was short (9 to 38 days, mean 20.4 days). All of these dogs were alive approximately 1 year after the end of the study.
Two dogs showed a decrease in platelet counts under therapy, 2 dogs after finishing drug ther-apy. Recurrence rate was 27 % for all patients, and 40 % if only the 10 patients, which were followed for a longer period (59 to 588 days, mean 234 days), were included.
Five dogs showed no recurrence of disease under therapy (59 to 208 days) and had platelet counts in the normal range after finishing therapy (48 to 580 days, mean 356 days) or under immunosuppressive therapy.
One dog was euthanized due to pancreatitis and DIC. The mortalitiy rate was 6.7 %.
An underlying disease was diagnosed in 17 dogs (platelet counts 1,400 to 119,000/µl, mean 31,200/ µl) with a positive platelet-bound antibody test result suggesting a secondary ITP (sITP). Twelve of the 17 dogs had an infectious disease (babesiosis, ehrlichiosis, leishmaniasis, abscess, prostatits), 4 had neoplasia (lymphoma, liver or splenic tumor) and 1 dog developed thrombocytopenia after a blood transfusion. In 9 of 12 dogs with infections platelet counts increased after treatment of the underlying disease, 3 dogs with ehrlichiosis also received prednisone.
The platelet-bound antibody test was negative in 15 dogs (platelet-numbers 11,000-110,000/µl, mean 54,300/µl) with splenic tumor/hemangiosarcoma (4), DIC (3), lymphatic leukemia (2), hemophilia (2), lymphoma under chemotherapy (1), rodenticide intoxication (1), splenic hematoma (1), and splenic torsion (1).
In 42 healthy control dogs the platelet-bound antibody test was negative.
Immune-mediated hemolytic anemia
352 dogs were anemic (Hematocrit, Hct < 35 %), 15 of these dogs (4.3 %) had a primary immune-mediated anemia (pIMHA). The diagnosis pIMHA was based on a positive Coombsý test (n=13), macroscopic slide agglutination (n=15), spherocytes (n=10), exclusion of other diseases and response to immunosuppressive treatment. In 2 dogs the Coombsý test was negative. In these dogs the diagnosis pIMHA was based on slide agglutination (n=2), spherocytes (n=1), response to immunosuppressive treatment (n=2) and exclusion of other diseases (n=2).
The dogs belonged to 6 different breeds, 6 dogs were mixed-breed. The Cocker Spaniel (n=2) and bobtail (n=2) were overrepresented. At the time of first presentation the dogs were between 1 to 10 years (mean 5.3 years) old. Nine animals were male or male-castrated, 6 female or female-castrated. The Hct ranged from 10 to 23 % (mean 17 %); 10 dogs had a severe anemia with a Hct < 20 %. Nine dogs were thrombopenic (patelet counts from 11,800 to 143,000/µl), 3 due to DIC.
The antibody classes of the differentiated Coombsý test (n=12) were IgG (n=7), IgG + C3 (n=4), and IgG + IgM + C3 (n=1). An undifferentiated Coombsý test was performed in one dog (positive result). The IgG titres were determined for 7 patients. The IgG titers ranged from 1:40 to 1:1280, the C3 titres from 1:20 to 1:40. No correlation was found between antibody class and antibody titer of the Coombsý test and the course and severity of the disease.
The corrected reticulocyte counts ranged from 0 to 23.6 % (mean 4.0 %); in 5 dogs with reticulocyte counts < 1.0 % the anemia was non-regenerative at the time of first presentation. Eleven dogs had elevated serum bilirubin levels (0.7 to 33 mg/dl, mean 4.6 mg/l). Fourteen dogs had extravascular, one dog intravascular hemolysis. Serum activity of several liver enzymes (AP, ALT, AST, GLDH) were elevated in 12 dogs. Based on radiography and ultrasonography, 7 dogs had splenomegaly, 4 hepatomegaly and 2 had hepatosplenomegaly.
The dogs were treated with different immunosuppressive drugs: prednisolone (n=6), prednisolone/azathioprine (n=8) and prednisolone/cyclophosphamide (n=1). In 2 dogs, azathioprine was replaced by cyclophosphamide or cyclosporine.
In four dogs, the course of disease could be followed only for a short time (10 to 39 days, mean 19 days). A rise of the Hct > 25 % was noted in the second (n=2), the third (n=1) or the fourth (n=1) week after beginning therapy. All of these dogs were still alive at the end of the study. Five dogs died or were euthanized before an increase of the Hct was noted.
Six dogs were followed for a longer period (10 to 89 weeks, mean 32.7 weeks). A Hct rise
> 25 % was noted in the second (n=4) or the third (n=2) week. Two dogs had recurrence of disease 12 or 20 weeks after beginning of therapy. One dog was euthanized with respiratory symptoms. The other patient was treated for 34 weeks, 10 weeks after finishing therapy the Hct was stable. The rate of recurrence was 13 %. The recurrence rate was 33 %, however, if only dogs were included that could be followed for a longer period. One dog was treated for 25 weeks, 64 weeks after finishing therapy the Hct was stable. Three dogs with increasing or normal Hct still received immunosuppressive drugs at the end of the study.
Overall 6 dogs died or were euthanized. The mortalitiy rate was 40 %.
In 7 dogs (Hct 17 to 28 %, mean 24 %) with a positive Coombsý test, secondary IMHA
(sIMHA) was suggested. The patients suffered from leishmaniasis (n=2), leishmaniasis/babesiosis (n=1), ehrlichiosis (n=1), liver necrosis (n=1), liver cell carcinoma (n=1) or received drugs (phenobarbital n=1). All dogs with sIMHA showed slide agglutination, which persisted in one dog at 4 °C. Two dogs had spherocytes.
In 25 anemic dogs (Hct 11 to 35 %, mean 22 %) with pITP (n=8), babesiosis (n=3), ehrlichiosis (n=3), chronic renal insufficiency (n=3), gastrointestinal tumor (n=3), hemophilia (n=2), hemorrhagic gastroenteritis (n=1), lymphoplasmacellular enteritis (n=1), and lymphatic leukemia (n=1) the Coombsý test was negative.
Immune-mediated thrombocytopenia and immune-mediated hemolytic anemia (Evansý
Syndrom)
A pITP and pIMHA was diagnosed in 9 dogs. The dogs belonged to 3 different breeds and 4 were mixed-breed. The age when first signs of disease were noted ranged from 2 ý 14 years (mean 7.3 years). Five of the dogs were male, 3 female and 1 female-spayed. Five dogs showed an increased bleeding tendency with melaena (n=2), petechiae and ecchymoses, hematoma, hemorrhagic diarrhoe and bloody vaginal discharge (each n=1). The platelet counts ranged from 10,000 ý 143,000/µl (mean 46,900/µl). Five dogs had platelet counts
< 30,000/µl. The results of the platelet-bound antibody test were positive in all 9 dogs. The MPV measured in 5 dogs ranged from 1.8 to 5.3 fl (median 3.3 fl). All 9 dogs were anemic. Six dogs had a severe anemia with a Hct < 20 %. Nine of the dogs showed macroscopic slide agglutination, five dogs had spherocytes. The antibody classes of the differentiated Coombsý test were IgG (n=8) and IgG + C3 (n=1). All patients showed an extravascular hemolysis. The corrected reticulocyte counts ranged from 0.4 to 6.8 % (mean 3.5 %), in one dog the anemia was non-regenerative. Two dogs had elevated serum bilirubin levels. Based on radiography and ultrasonography, 5 dogs had a splenomegaly and 2 had a hepatosplenomegaly.
The patients were treated with prednisolone (n=2), prednisolone/azathioprine (n=7) and in 1 dog azathioprine was replaced by cyclosporine. An increase of platelet counts above 50,000/µl was noted in 7 dogs after 2-6 days (mean 3.4 days). A rise of Hct was noted in 9 dogs in the first (n=1), the second (n=6) or the third (n=2) week after beginnig of treatment.
In one dog, the course of disease could be followed only for a short time (13 days). This dog was lost for follow-up.
Three dogs, that still received immunosuppressive treatment at the end of the study showed a decrease in platelet counts after 16, 84 and 119 days. Two dogs had a decrease in Hct at the same time. The third dog showed a decrease in Hct 18 weeks after decreasing platelet counts. One dog had recurrence of disease (platelet counts and Hct decrease) 26 weeks after finishing therapy. The rate of recurrence (platelet counts and Hct decrease) was 50 %. Three dogs with increasing platelet counts and Hct and the 4 dogs with recurrence of disease still received immunosuppressive drugs at the end of the study.
One dog with increasing platelet counts and Hct was euthanized due to incontinence. The mortality rate was 11 %.
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