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Treatment of primary immunemediated hemolytic anemia with mycophenolate mofetil in two cats

Journal of Veterinary Emergency and Critical Care 21(1) 2011, pp 45–49 Treatment of primary immune-mediated hemolytic anemia with mycophenolate mofetil in two cats Lenore M. Bacek, DVM and Douglass K. Macintire, DVM, MS, DACVIM, DACVECC Objective – To describe the use of oral mycophenolate mofetil (MMF) as an adjunctive therapy in 2 cats withprimary immune-mediated hemolytic anemia.
Case Series Summary – Two cats suffering from presumptive primary immune mediated hemolytic weretreated with MMF as part of their treatment regimens. Both cats had improved complete blood countsfollowing therapy.
New or Unique Information Provided – This is the first reported use of oral MMF as adjunctive treatment forcats with immune-mediated hemolytic anemia. Outcome was favorable in both cats and no adverse effectswere noted from the MMF.
(J Vet Emerg Crit Care 2011; 21(1): 45–49) doi: 10.1111/j.1476-4431.2010.00606.x Keywords: immunosuppressive agents, feline IMHA, purine analog ommended immunosuppressive agent for this condi-tion. Initial prednisolone doses of 2–4 mg/kg have been Primary immune-mediated hemolytic anemia (IMHA) reported.4,5 Other drugs, such as cyclosporine, cyclo- occurs less frequently in cats than in dogs. In cats, phosphamide, and chlorambucil have been adminis- hemolytic anemia is more frequently caused by infec- tered along with glucocorticoids in nonresponsive or tious diseases (eg, Mycoplasma infection), exposure to chemicals or toxins (eg, onions, acetaminophen), severe Mycophenolate mofetil (MMF) is the prodrug form of hypophosphatemia, drug reaction (eg, methimazole), mycophenolic acid: a fermentation product derived neoplasia (eg, lymphoma), or immune reactions against from several Penicillium species. It is a selective inhib- transfused red blood cells (RBC).1 IMHA due to anti- itor of the enzyme inosine monophosphate dehydro- body production against the host’s own RBC is more genase (IMPDH), which is necessary in the de novo uncommon in cats.2 A diagnosis of primary (ie, idio- cellular pathway of purine synthesis. Unlike most cells, pathic) IMHA is made when the inciting cause for an- lymphocytes are unable to use the salvage pathways for tibody formation cannot be identified. Secondary purine synthesis. Therefore, lymphocytes are depen- IMHA in cats is often triggered by infectious diseases, dent on IMPDH activity and the de novo pathway.7–9 such as Mycoplasma spp., feline leukemia virus (FeLV), Two forms of IMPDH (types I and II) have been iden- feline immunodeficiency virus (FIV), and feline infec- tified with MMF having a 5 times greater affinity for the type II isoform. The type II isoform is expressed in ac- Supportive care for feline primary IMHA is generally tivated T- and B-cell lymphocytes, whereas the type I similar to treatments used in dogs, including the use isoform is expressed in most cell types.8 Mycophenolic of RBC transfusions. Glucocorticoids are the initial rec- acid inhibits T- and B-cell proliferation and decreasesantibody production.10 MMF is most commonly used to From the Department of Clinical Sciences, College of Veterinary Medicine, prevent organ rejection in human transplant patients.7–9 Auburn University, Auburn, AL 36849.
There has recently been increased interest in using The authors declare no conflict of interest.
MMF in dogs with autoimmune disorders such as my- Address correspondence and reprint requests to asthenia gravis7,11 but the drug has not been critically Dr. Douglass K. Macintire, Department of Clinical Sciences, College of evaluated in veterinary medicine. Nevertheless, my- Veterinary Medicine, Auburn University, Auburn, AL 36849, USA.
cophenolate was used successfully in treatment of aplastic anemia in a single canine case report12 and in & Veterinary Emergency and Critical Care Society 2011 treatment of warm-type IMHA in a small number of FIP), toxins (eg, onions), or chemicals/drugs (eg, acet- human trials.13–15 There are no reports of using MMF in aminophen). An infectious disease (flea and tick) PCR feline primary IMHA. In this report we describe the use panele was submitted and results were negative for of oral MMF in 2 cats with severe primary IMHA.
Anaplasma phagocytophilum, Bartonella henselae, Bartonellaclarridgeaie, Bartonella quintana, Ehrlichia spp., Mycoplasmahaemofelis, Mycoplasma haemominutum, Mycoplasma turicen- sis, Rickettsia rickettsii, and Rickettsia felis. Dexamethasonef A 2-year-old female spayed domestic short hair cat, (0.3 mg/kg, IV, q 12 h) was initiated while awaiting the weighing 4.2 kg was presented to the Auburn Univer- results of the infectious disease panel.
sity emergency service for evaluation of acute onset The following morning, a recheck CBC showed a lethargy and anorexia. The cat had no previous medical strongly regenerative severe anemia (HCT 10.4 L/L problems, was retrovirus (FeLV and FIV) negative, and [10.4%], reference interval 30–45 L/L [30–45%]; ret- lived indoors only. She was current on vaccinations and iculocyte count 234.1 Â 109/L [234.1 Â 103/mL], refer- was not on any other medications. On presentation, ence interval 15–81 Â 109/L [15–81 Â 103/mL]), a mild the cat was lethargic with an increased respiratory rate mature neutrophilia (21.58 Â 109/L [21.58 Â 103/mL], (60/min) and had pale mucous membranes. The reference interval 2.5–12.5 Â 109/L [2.5–12.5 Â 103/ remainder of the physical exam was unremarkable in- mL]), moderate RBC autoagglutination, marked poly- cluding a rectal exam. Initial CBC demonstrated a chromasia, marked anisocytosis, and few ghost RBC. A strongly regenerative severe anemia (HCT 15.9 L/L platelet count was not determined due to clumping of [15.9%], reference range 30–45 L/L [30–45%]; reticulocyte the sample. However, it appeared to be within normal count 200.4 Â 109/L [200.4 Â 103/mL], reference range 15– limits upon examination of the blood smear. Treatment 81 Â 109/L [15–81 Â 103/mL]), severe regenerative throm- with doxycycline and famotidine were continued and bocytopenia (platelet count 44 Â 109/L [44 Â 103/mL], injectable dexamethasone was switched to predniso- reference range 200–700 Â 109/L [200–700 Â 103/mL]; mean platelet volume 29.1 fL, reference range 10.8– On the third day of hospitalization, a recheck CBC 19.8 fL), and a moderate leukocytosis characterized by a demonstrated a sustained regenerative response (HCT mature neutrophilia and mild left shift (WBC 33.8 Â 109/ 10.5 L/L [10.5%], reference interval 30–45 L/L [30–45%]; L [33.8 Â 103/mL], reference range 5.5–19.5 Â 109/L [5.5– reticulocyte count 444.1 Â 109/L [444.1 Â 103/mL], ref- 19.5 Â 103/mL]; neutrophils 28.05 Â 109/L [28.05 Â 103/ erence range 15–81 Â 109/L [15–81 Â 103/mL]), 4 nucle- mL], reference range 2.5–12.5 Â 109/L [2.5–12.5 Â 103/mL]; ated RBC per 100 WBC, a mild thrombocytopenia bands 0.338 Â 109/L [0.338 Â 103/mL], reference range 0– (163 Â 109/L [163 Â 103/mL], reference interval 200– 0.3 Â 109/L [0–0.3 Â 103/mL]). Cell morphology included 700 Â 109/L [200–700 Â 103/mL]), a mild mature neu- marked anisocytosis, marked polychromasia, and occa- trophilia (18.15 Â 109/L [18.15 Â 103/mL], reference sional ghost RBC. No autoagglutination was noted. Initial interval 2.5–12.5 Â 109/L [2.5–12.5 Â 103/mL]), marked biochemical profile revealed mild hypoalbuminemia (25 g/L [2.5 g/dL], reference interval 28–42 g/L [2.8– marked anisocytosis, and many ghost RBC. MMFh 4.2 g/dL]), mild hyperglobulinemia (46 g/L [4.6 g/dL], (10 mg/kg, PO, q 12 h) treatment was initiated due to a reference interval 24–44 g/L [2.4–4.4 g/dL]), increased lack of response to immunosuppressive steroid therapy.
alanine transaminase (170 U/L, reference interval 26–77 Doxycycline and prednisolone were continued as de- U/L), and increased bilirubin (21.88 mmol/L [1.28 mg/ dL], reference interval 1.70–3.42 mmol/L [0.1–0.2 mL/dL]).
Throughout the fourth through seventh day of hos- Urinalysis was unremarkable. The cat’s blood type was pitalization, the cat clinically became brighter and determined via a point-of-care card-based systema and it respiratory rate normalized. No further packed RBC was determined that the cat had A type blood. Initial transfusions were required. A recheck CBC on the day treatment consisted of a packed red blood transfusion of discharge revealed a strongly regenerative moderate (30 mL) over 4 hours after which the cat’s respiratory rate anemia (HCT 21 L/L [21.0%], reference interval 30– decreased and the PCV increased to 21%. Two-view tho- 45 L/L [30–45%]; reticulocyte count 520.2 Â 109/L racic radiographs and abdominal radiographs were ob- [520.2 Â 103/mL], reference interval 15–81 Â 109/L tained and were within normal limits. Doxycyclineb [15–81 Â 103/mL]), 26 nucleated RBC per 100 WBC, a (5 mg/kg, PO, q 12 h), famotidinec (0.5 mg/kg, PO, q normal platelet count (298 Â 109/L [298 Â 103/mL], ref- 12 h), and IV Normosol Rd (45 mL/kg/d) were initiated.
erence interval 200–700 Â 109/L [200–700 Â 103/mL), a Differential diagnoses for the regenerative anemia at that mild mature neutrophilia (16.8 Â 109/L [16.8 Â 103/mL], time included primary IMHA or secondary IMHA caused reference interval 2.5–12.5 Â 109/L [2.5–12.5 Â 103/mL]), by infectious diseases (eg, Mycoplasma spp., Bartonella spp., marked polychromasia, marked anisocytosis, and & Veterinary Emergency and Critical Care Society 2011, doi: 10.1111/j.1476-4431.2010.00606.x few ghost RBC. There was no evidence of autoagglu- hen). An infectious disease (flea and tick) PCR panel tination. The cat was discharged on prednisolone, was submitted and results were negative for A.
famotidine, doxycycline, and MMF at the above phagocytophilum, B. henselae, B. clarridgeaie, B. quintana, dosages with a recheck examination scheduled for 1 Ehrlichia spp., M. haemofelis, M. haemominutum, M.
turicensis, R. rickettsii, and R. felis. The cat was found Recheck CBC obtained 7 days after discharge re- to be type B on the blood type card.a Dexamethasone vealed a normal HCT (35.3 L/L [35.3%], reference in- (0.3 mg/kg, IV, q 12 h) was initiated while results of the terval 30–45 L/L [30–45%]), a thrombocytosis (968 Â infectious disease panel were pending. The patient also 109/L [968 Â 103/mL], reference interval 200–700 Â 109/L received a whole blood transfusion of 40 mL of type B [200–700 Â 103/mL]), with slight RBC autoagglutination blood over 4 hours. The PCV after the transfusion was and slight polychromasia. Further follow-up lab work while tapering drugs, has showed a continued normal The following morning, a recheck CBC showed a HCT (44.2 L/L [44.2%], reference interval 30–45 L/L nonregenerative anemia (HCT 14.3 L/L [14.3%], refer- [30–45%]) and a normal platelet count (408 Â 109/L ence interval 30–45 L/L [30–45%]; reticulocyte count [408 Â 103/mL], reference interval 200–700 Â 109/L 39.3 Â 109/L [39.3 Â 103/mL], reference interval 15– [200–700 Â 103/mL]) with no evidence of autoaggluti- 81 Â 109/L [15–81 Â 103/mL]), slight polychromasia, nation 2.5 months postdischarge. The prednisolone was slight anisocytosis, and slight rouleaux. Treatment with being slowly tapered and the MMF was discontinued doxycycline, famotidine, and dexamethasone were con- after 2 months of therapy. According to the owner, the tinued. MMF (10 mg/kg, PO, q 12 h) was initiated be- cat has been clinically normal at home and is currently cause the HCT was not maintaining posttransfusion. A only on prednisolone (0.5 mg/kg, PO, q 12 h).
bone marrow aspirate was performed that revealednormal cellularity with no infectious agents or neoplas-tic cells seen. The following day (day 3), the cat was transitioned from dexamethasone to prednisolone A 10-year-old female spayed Himalayan cat, weighing 3.4 kg was presented to the emergency service for fur- Over the third through eighth day of hospitalization, ther evaluation of anemia. The cat was retrovirus (FeLV the cat became brighter. No further packed RBC trans- and FIV) negative and lived indoors only. She had been fusions were required. A recheck CBC on the day be- diagnosed previously with asthma and was maintained fore discharge demonstrated a strongly regenerative on once daily montelukasti (2 mg, PO, q 24 h). She was moderate anemia (HCT 21.4 L/L [21.4%], reference in- terval 30–45 L/L [30–45%]; reticulocyte count 185.9 Â On presentation, the cat was quiet with pale mucous 109/L [185.9 Â 103/mL], reference interval 15–81 Â 109/L membranes. The remainder of the physical exam was un- [15–81 Â 103/mL]), 3 nucleated RBC per 100 WBC, a mild remarkable including a rectal exam. Initial CBC showed a mature neutrophilia (20.13 Â 109/L [20.13 Â 103/mL], ref- strongly regenerative severe anemia (HCT 10.2 L/L erence interval 2.5–12.5 Â 109/L [2.5–12.5 Â 103/mL]), [10.2%], reference interval 30–45 L/L [30–45%]; ret- moderate anisocytosis, slight polychromasia, and slight iculocyte count 163.6 Â 109/L [163.6 Â 103/mL], reference rouleaux. There was no evidence of autoagglutination.
interval 15–81 Â 109/L [15–81 Â 103/mL]). Cell morphol- The cat was discharged on prednisolone, famotidine, ogy included moderate anisocytosis, moderate polych- doxycycline, and MMF at the above dosages with a re- romasia, and mild hypochromia. Initial biochemistry Recheck CBC obtained 6 days after discharge re- (1513 U/L, reference interval 26–77 U/L), increased vealed a strongly regenerative moderate anemia (HCT bilirubin (12.83 mmol/L [0.75 mg/dL], reference interval 21.9 L/L [21.9%], reference range 30–45 L/L [30–45%]; 1.7–3.4 mmol/L [0.1–0.2 mg/dL]), and increased BUN reticulocyte count 136.4 Â 109/L [136.4 Â 103/mL], ref- (15.4 mmol/L [43.0 mg/dL], reference interval 1.79– erence interval 15–81 Â 109/L [15–81 Â 103/mL]), slight 10.7 mmol/L [5–30 mg/dL]). Two-view thoracic radio- polychromasia, and moderate anisocytosis. At the graphs and abdominal ultrasound were performed and following recheck 2 weeks later, CBC demonstrated a were within normal limits. Doxycycline (5 mg/kg, PO, q 12 h) and famotidine (0.5 mg/kg, PO, q 12 h) and IV 30–45 L/L [30–45%]) with slight polychromasia. Fur- Normosol R (45 mL/kg/d) were initiated. Differential ther follow-up lab work while tapering drugs, has diagnoses for the regenerative anemia at that time in- showed a continued normal HCT (35.2 L/L [35.2%], cluded primary IMHA or secondary IMHA caused by reference interval 30–45 L/L [30–45%]) and a normal infectious diseases (Mycoplasma spp., Bartonella spp., alanine transaminase (66 U/L, reference range 12– FIP), toxins (onions), or chemicals/drugs (acetaminop- 130 U/L) approximately 2 months postdischarge.
& Veterinary Emergency and Critical Care Society 2011, doi: 10.1111/j.1476-4431.2010.00606.x Unfortunately, the cat developed a severe esophageal performed in cats evaluating adverse effects but the stricture (most likely from doxycycline after the most common adverse effects noted in dogs include owner switched from liquid to tablets) and subse- weight loss, gastrointestinal upset, and mild allergic quently died during anesthesia to place a gastrostomy reactions during parenteral administration.21,k No ad- verse effects were noted in the cases reported here.
MMF is available in 250 and 500 mg capsules and our pharmacy compounds a 100 mg/mL oral solution. To the authors’ knowledge, this is the first report of cats sufferingfrom primary IMHA treated with MMF as an adjunct im- Cats with primary IMHA are usually treated with munosuppressive. The dose of MMF for cats with primary prednisolone. There is little information on the use of IMHA has not been established. The dosage administered cytotoxic drugs. In a retrospective study by Husbands to cats in this report was extrapolated from an oral dose et al,5 records of 25 cats with idiopathic IMHA were reported by Dewey et al,22 (5–20 mg/kg, PO, q 12 h).
reviewed. Seven of the cats did not respond to pred- Based on these clinical results, it is difficult to deter- nisolone therapy alone or relapsed and were treated mine the exact effect of MMF on outcome due to con- with cyclophosphamide and cyclosporine or splenec- current steroid treatment. However, the drug was well tomy or both.5 In another retrospective study of 19 cats tolerated and no adverse effects were noted making this with primary IMHA, 15 of the 19 cats receiving only an a promising potential adjunctive therapy. A prospec- immunosuppressive dose of prednisolone experienced tive, randomized-clinical trial is indicated to more an increase in PCV above 25% within 8–42 days after definitively establish the benefit of MMF in IMHA starting treatment.7 For 2 of the 19 cats, follow-up could not be carried out and the other 2 of the 19 cats wereeuthanized after days 9 and 63.7 In dogs, azathioprine is commonly used in conjunction with prednisone to treat IMHA.16,17 Azathioprine is con- Rapid Vet-H, DMS Laboratories Inc, Flemington, NJ.
traindicated in cats because of its high potential for bone Doxycycline Suspension, Pfizer Inc, New York, NY.
marrow toxicity.18 Other drugs that have been used as Famotidine Injection, Baxter Heathcare Corp, Deerfield, IL.
Normosol R, Hospira Inc, Lake Forest, IL.
immunosuppressive agents in cats include cyclosporine, FastPanel PCR, Antech Diagnostics, Los Angeles, CA.
Dexamethasone SP Injection, Butler Animal Health, Columbus, OH.
Cyclophosphamide can have severe side effects such as Prednisolone Oral Solution, Amneal Pharmaceuticals, Glasgow, KY.
Cellcept, Roche Laboratories Inc, Nutley, NJ.
myelosuppression, hemorrhagic cystitis, and gastro- Singulair, Merck & Co., Whitehouse Station, NJ.
enteritis.19 Cyclosporine requires drug monitoring to Cellcept (package insert), Roche Laboratories Inc.
Dewey C, Boothe DM, Wilkie WS. Pharmacokinetics of single-dose oral maintain therapeutic drug levels because of marked in- and intravenous mycophenolate mofetil administration in normal dogs dividual variation.19 Leflunomide is expensive and there (abstr). J Vet Intern Med 2001;15(3):304.
are only anecdotal reports of its use with IMHA.
Chlorambucil is a relatively weak immunosuppressivedrug and may not be effective in refractory cases of IMHA. It also is associated with myelopsuppression.19 1. Werner LL, Gorman NT. Immune-mediated disorders of cats. Vet MMF is formulated for both IV and oral dosing allow- Clin North Am Small Anim Pract 1984; 14(5):1039–1064.
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long-term therapy.11 The 2 cases reported here suggest Textbook of Veterinary Internal Medicine, 7th ed. Philadelphia: that MMF may have a benefit as an adjunctive agent in WB Saunders Co; 2010, pp. 761–772.
severe primary IMHA in cats. While the time frame from 3. Scott DW, Schultz RD, Post JE. Autoimmune hemolytic anemia in the cat. J Am Anim Hosp Assoc 1973; 9:530–539.
the start of therapy to the onset of improvement as seen 4. Kohn B, Weingart C, Eckmann V, et al. Primary immune-mediated on blood work is not known, it has been shown that after hemolytic anemia in 19 cats: diagnosis, therapy and outcome oral administration, maximal inhibition of IMPDH oc- (1998–2004). J Vet Intern Med 2006; 20(1):159–166.
5. Husbands BD, Smith SA, Weiss DJ. Idiopathic immune-mediated curs approximately 2–4 hours after dosing suggesting hemolytic anemia (IMHA) in cats. In: Proceedings of the American College of Veterinary Internal Medicine; 2002: Dallas, USA.
Reported adverse effects of MMF in people include 6. Abrams-Ogg, Wood RD, Cheung A. Idiopathic non-regenerative anemia in cats: a retrospective study. In: Proceedings of the primarily gastrointestinal upset but also increased sus- American College of Veterinary Internal Medicine; 2007: Seattle, ceptibility to infection, teratogenic effects, increased risk of lymphoma, allergic reaction, headache, and ne- 7. Dewey CW, Cerda-Gonzalez S, Fletcher DJ, et al. Myco- phenolate mofetil treatment in dogs with serologically diagnosed utropenia that occurs most often between 31 and 180 acquired myasthenia gravis. J Am Vet Med Assoc 2010; 236(6): days following start of therapy.j No studies have been & Veterinary Emergency and Critical Care Society 2011, doi: 10.1111/j.1476-4431.2010.00606.x 8. Allison AC, Eugui EM. Mechanisms of action of mycophenolate 16. Grundy SA, Barton C. Influence of drug treatment on survival of mofetil in preventing acute and chronic allograft rejection. Trans- dogs with immune-mediated hemolytic anemia: 88 cases (1989– plantation 2005; 80(2 suppl):181–190.
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9. Schneider-Gold C, Hartung HP, Gold R. Mycophenolate mofetil 17. Piek CJ, Junius G, Dekker A, et al. Idiopathic immune-mediated and tacrolimus: new therapeutic options in neuroimmunological hemolytic anemia: treatment outcome and prognostic factors in diseases. Muscle Nerve 2006; 34(3):284–291.
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18. Beale KM, Altman D, Clemmons RR, et al. Systemic toxicosis as- Clin Transplant 1996; 10(1 part 2):118–123.
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20. Langman LJ, Shapiro AM, Lakey JR, et al. Pharmacodynamic as- 12. Yuki M, Sugimoto N, Otsuka H, et al. Recovery of a dog from sessment of mycophenolic acid-induced immunosuppression by aplastic anaemia after treatment with mycophenolate mofetil.
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15. Howard J, Hoffbrand AV, Prentice HG, et al. Mycophenolate mo- 22. Dewey C, Boothe DM, Rinn K, et al. Treatment of a myasthenic fetil for the treatment of refractory auto-immune hemolytic anae- dog with mycophenolate mofetil. J Vet Emerg Crit Care 2000; mia and auto-immune thrombocytopenia purpura. Br J Haematol & Veterinary Emergency and Critical Care Society 2011, doi: 10.1111/j.1476-4431.2010.00606.x

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