An 8-year-old 4.2-kg (9.2-lb) spayed female Yorkshire Terrier (dog 1) was evaluated after being administered 25 mg of cyclophosphamide daily for 11 days, which was consistent with a daily dose of 98 mg of cyclophosphamide/m2 and a cumulative dose of 1,078 mg of cyclophosphamide/m2. The dog had been treated for > 1 year with a brand-name cyclosporinea for atopic dermatitis. Because of a manufacturing shortage of the brand-name cyclosporine, the veterinarian prescribed 25-mg capsules of a generic cyclosporine for the dog through a local community pharmacy. The pharmacy erroneously dispensed 50-mg tablets of cyclophosphamide with instructions to give the dog half a tablet daily.
The owner noticed that the dog had become lethargic within 2 days after initiation of cyclophosphamide administration, and the lethargy progressed daily. The dog became anorexic 7 days after initiation of cyclophosphamide administration and was evaluated by its primary-care veterinarian 4 days later (ie, 11 days after initiation of cyclophosphamide administration), at which time the pharmacy mistake was identified. The dog was referred to the University of Tennessee Veterinary Medical Center for further evaluation.
During initial evaluation at the university hospital, the dog was hyperthermic (39.66°C [103.4°F]; reference interval, 37.5° to 39.16°C [99.5° to 102.5°F]) and was hyperactive with signs of extreme anxiety. No other abnormalities were identified during physical examination. Results of a CBC revealed leukopenia (800 leukocytes/μL; reference interval, 5,100 to 14,000 leukocytes/μL), neutropenia (260 neutrophils/μL; reference interval, 2,650 to 9,800 neutrophils/μL), lymphopenia (400 lymphocytes/μL; reference interval, 1,100 to 4,600 lymphocytes/μL), monocytopenia (70 monocytes/μL; reference interval, 165 to 850 monocytes/μL), and thrombocytopenia (25,000 platelets/μL; reference interval, 147,000 to 423,000 platelets/μL). The Hct was 44.8% (reference interval, 41% to 60%), and total protein concentration was 7.7 g/dL (reference interval, 5.7 to 7.9 g/dL). A serum biochemical analysis revealed no clinically important abnormalities. A urinalysis was not performed because the dog did not urinate when walked, and a cystocentesis was not performed because of the severe thrombocytopenia.
The dog was not hospitalized because of its apparent stability at home and concerns regarding its severe anxiety and susceptibility to nosocomial infection. Medications prescribed were mirtazapine (0.83 mg/kg [0.38 mg/lb], PO, q 24 h) to stimulate appetite, amoxicillin trihydrate (23 mg/kg [10.5 mg/lb], PO, q 12 h) and enrofloxacin (8 mg/kg [3.6 mg/lb], PO, q 12 h) as prophylaxis against a secondary bacterial infection subsequent to neutropenia, and G-CSF (5 μg/kg [2.3 μg/lb], SC, q 12 h) to stimulate neutrophil production.
The dog was reevaluated 4 days after the initial evaluation, at which time the owner reported a slight improvement in the dog's lethargy and hyporexia. The only pertinent physical examination findings were hyperthermia (39.94°C [103.9°F]) and signs of anxiety. Abnormal CBC findings were leukopenia (2,700 leukocytes/μL), neutropenia (1,240 neutrophils/μL), and thrombocytopenia (16,000 platelets/μL); the Hct was 47.7%, and total protein concentration was 7.8 g/dL. The dog was discharged to the owner with instructions to continue the medications as previously prescribed.
Eleven days after the initial evaluation, the physical examination findings remained unchanged with hyperthermia (40.16°C [104.3°F]) and signs of anxiety. The owner reported that the dog's lethargy and hyporexia had resolved and that it had been clinically normal for 48 hours prior to reevaluation. Pertinent CBC findings were leukocytosis (37,000 leukocytes/μL), neutrophilia (28,490 neutrophils/μL) with band neutrophils (3,300 band neutrophils/μL; reference interval, 0 to 300 band neutrophils/μL), and thrombocytopenia (65,000 platelets/μL); the Hct was 43.8%, and total protein concentration was 8.1 g/dL. All medications were discontinued.
The dog was reevaluated for the last time 25 days after the initial evaluation. The owner reported that the dog was clinically normal. Physical examination findings remained unchanged; the dog was hyperthermic (40.16°C) and had signs of marked anxiety. Results of a CBC revealed that the leukocyte (12,400 leukocytes/μL), neutrophil (7,440 neutrophils/μL), and platelet (299,000 platelets/μL) counts had returned to within reference limits. The Hct was 46.8%, and the total protein concentration was undeterminable because of lipemia.
A 5-year-old 9.4-kg (20.7-lb) castrated male West Highland White Terrier (dog 2) was evaluated after being administered 50 mg of cyclophosphamide daily for 9 days, which was consistent with a daily dose of 120 mg of cyclophosphamide/m2 and a cumulative dose of 1,080 mg of cyclophosphamide/m2. The dog was being treated with cyclosporine for atopic dermatitis, and cyclophosphamide instead of cyclosporine was inadvertently dispensed by a community pharmacy.
Two days after the first dose of cyclophosphamide was administered, the dog developed anorexia, lethargy, and diarrhea, which continued until the dog was evaluated by its primary-care veterinarian 9 days after cyclophosphamide administration was initiated. The pharmacy mistake was identified, and the dog was referred to the University of Tennessee Veterinary Medical Center.
During initial examination at the university hospital, the dog was hyperthermic (39.66°C [103.4°F]), and had a grade 3 of 6 left-sided systolic heart murmur, pale pink and tacky mucous membranes (estimated dehydration, 7%), and diarrhea. Results of a CBC revealed severe leukopenia (500 leukocytes/μL), neutropenia (140 neutrophils/μL), lymphopenia (300 lymphocytes/μL), monocytopenia (30 monocytes/μL), and thrombocytopenia (9,000 platelets/μL). The Hct was 44.7%, and the total protein concentration was 6.0 g/dL. Serum biochemical analysis revealed hypoalbuminemia (2.2 μg/dL; reference interval, 3.2 to 4.1 μg/dL), hyperglobulinemia (3.5 g/dL; reference interval, 2 to 3.2 g/dL), hyperglycemia (138 mg/dL; reference interval, 84 to 120 mg/dL), and hypokalemia (2.8 mEq/L; reference interval, 3.1 to 4.8 mEq/L). Urinalysis revealed no hematuria or active sediment and, despite clinical dehydration, a urine specific gravity of 1.010; however, the urine sample was obtained after initiation of IV fluid therapy and administration of furosemide.
The dog was hospitalized and treated with an electrolyte solutionb (4.8 mL/kg/h [2.2 mL/lb/h], IV) for dehydration; G-CSF (5 μg/kg, SC, q 12 h) to stimulate neutrophil production; ampicillin sodium (21 mg/kg [9.5 mg/lb], IV, q 8 h), enrofloxacin (10 mg/kg [4.5 mg/lb], IV, q 24 h), and metronidazole (10 mg/kg, IV, q 12 h) as prophylaxis against secondary bacterial infection subsequent to neutropenia; and furosemide (2 mg/kg [0.9 mg/lb], IV, q 12 h) as prophylaxis against hemorrhagic cystitis. After 2 days of hospitalization, the dog was normothermic (38.33°C [101°F]) and rehydrated but remained anorexic and lethargic and had developed epistaxis and melena. Results of a CBC indicated leukopenia (500 leukocytes/μL), neutropenia (120 neutrophils/μL), lymphopenia (300 lymphocytes/μL), monocytopenia (30 monocytes/μL), thrombocytopenia (9,000 platelets/μL), and nonregenerative anemia (Hct, 31.1%; reticulocyte count, 3,500 reticulocytes/μL; reference interval, 12,500 to 93,000 reticulocytes/μL) with a total protein concentration of 6.0 g/dL. The dog was administered a cryopreserved platelet concentrate transfusion (100 mL, IV) and dolasetron mesylate (0.6 mg/kg [0.27 mg/lb], IV, q 24 h) in addition to continued administration of G-CSF, ampicillin, enrofloxacin, metronidazole, and furosemide.
On the third day of hospitalization, the dog began eating well and remained normothermic (38.94°C [102.1°F]); however, it still had epistaxis and melena, and hemorrhage was observed at the sites where the G-CSF was injected SC. In the morning, the PCV was 24% and the total protein concentration was 5.2 g/dL; both increased throughout the day, and by evening, the PCV was 29% and the total protein concentration was 6.2 g/dL. Because the dog was eating and its heart and respiratory rates were within reference limits, a blood transfusion was not administered. Owing to evidence of continued hemorrhage, the dog was premedicated with diphenhydramine hydrochloridec (2.6 mg/kg [1.2 mg/lb], PO) and administered a second platelet concentrate transfusion (100 mL, IV).
On the fourth day of hospitalization, the dog became hyperthermic (39.8°C [103.8°F]) and the melena and epistaxis continued. The PCV had stabilized at 27%, and the total protein concentration was 6.2 mg/dL. The medications administered were continued unchanged, and the dog was administered a third platelet concentrate transfusion (100 mL, IV).
The dog was much less lethargic and continued to eat well on the fifth day of hospitalization. The melena persisted but was less frequent, and the epistaxis was noted only when the dog became excited. Because the anemia had worsened (PCV, 18%; total protein concentration, 6.0 g/dL), 125 mL of packed RBCs was administered IV. After the RBC transfusion, the PCV was 34% and the total protein concentration was 6.8 g/dL.
On the seventh day of hospitalization, the dog was no longer lethargic and continued to eat well despite being hyperthermic (40.16°C [104.3°F]). The dog still had epistaxis and melena, although the frequency of each had decreased from that during the earlier stages of hospitalization. Results of a CBC revealed leukopenia (600 leukocytes/μL), neutropenia (200 neutrophils/μL), lymphopenia (400 lymphocytes/μL), monocytopenia (20 monocytes/μL), thrombocytopenia (5,000 platelets/μL), and anemia (Hct, 31.6%). Because the dog had improved clinically and peripheral venous access could no longer be achieved, it was discharged for continued treatment at home. The owner was instructed to measure the dog's rectal temperature once daily and administer enrofloxacin (10.8 mg/kg [4.9 mg/lb], PO, q 24 h), amoxicillin with clavulanic acidd (26.5 mg/kg [12.0 mg/lb], PO, q 12 h), metronidazole (13.3 mg/kg [6.0 mg/lb], PO, q 12 h), furosemidee (2 mg/kg, PO, q 12 h), and G-CSF (5 μg/kg, SC, q 12 h).
The dog was reevaluated 3 days after discharge from the hospital. The owner reported that the dog had remained normothermic (mean temperature, 38.9°C [102°F]) and was hyporexic at home; no epistaxis or hematuria was observed, and melena, which was observed when the dog initially went home, had resolved. Physical examination revealed that the dog's temperature (39°C [102.2°F]) and heart and respiratory rates were within reference limits, and no melena was detected during rectal examination. The dog had bruises at previous SC injection sites. Results of a CBC indicated that the leukocyte (8,700 leukocytes/μL), neutrophil (7,310 neutrophils/μL), band neutrophil (260 band neutrophils/μL), and monocyte (260 monocytes/μL) counts were all within their respective reference limits, despite persistent lymphopenia (870 lymphocytes/μL), thrombocytopenia (14,000 platelets/μL), and anemia (PCV, 36.7%; total protein concentration, 7.5 g/dL). Abnormalities detected on serum biochemical analysis included hypoalbuminemia (2.7 g/dL), hyperglobulinemia (4.4 g/dL), and high alkaline phosphatase activity (408 U/L, reference interval, 15 to 164 U/L). Administration of enrofloxacin was discontinued at this time.
On the seventh day after discharge from the hospital, the owner reported that the dog's activity and appetite had returned to levels similar to those prior to the intoxication. The bruises that were detected during the previous examination were resolving, and the grade 3 of 6 heart murmur that was detected during the initial physical examination was no longer present. Findings of a CBC included leukocytosis (38,100 leukocytes/μL), neutrophilia (35,811 neutrophils/μL) with a left shift (760 band neutrophils/μL), thrombocytopenia (29,000 platelets/μL), and regenerative anemia (Hct, 37.3%; reticulocyte count, 133,200 reticulocytes/μL; total protein concentration, 6.7 g/dL). Administration of amoxicillin with clavulanic acid and G-CSF was discontinued, but administration of furosemide was continued.
During reevaluation 14 days after discharge from the hospital, the owner reported that the dog was clinically normal at home. Physical examination revealed no abnormalities, and the previously noted bruises at the injection sites had almost completely resolved. Results of a CBC revealed leukocyte (9,100 leukocytes/μL), neutrophil (7,700 neutrophils/μL), lymphocyte (730 lymphocytes/μL), and monocyte (640 monocytes/μL) counts within their respective reference limits and thrombocytopenia (66,000 platelets/μL) and anemia (Hct, 32.3%; total protein concentration, 6.4 g/dL). Results of a CBC performed 24 days after discharge from the hospital indicated that all cell counts were within their respective reference limits except for the platelet count, which was slightly low (135,000 platelets/μL).
The dog was examined for the final time 34 days after discharge from the hospital. The owner reported that the dog was clinically normal, and physical examination findings were unremarkable. Results of a CBC revealed that the leukocyte (7,000 leukocytes/μL), neutrophil (5,740 neutrophils/μL), lymphocyte (840 lymphocytes/μL), monocyte (280 monocytes/μL), and platelet (211,000 platelets/μL) counts and Hct (49.9%) were within their respective reference limits. Results of a serum biochemical analysis were all within reference limits except for the presence of mild hyperglycemia (122 mg/dL). Urinalysis revealed a urine specific gravity of 1.029 and inactive sediment.
Discussion
Cyclophosphamide is an alkylating agent used in veterinary medicine to treat cats and dogs with neoplastic and immune-mediated diseases1–3 and to prepare dogs for bone marrow transplants.4 The dose of cyclophosphamide ranges from 50 to 300 mg/m2 depending on the route of administration, whether it is given as a single dose or divided over multiple days, and the indication for administration.1,5 When administered orally, the recommended dose of cyclophosphamide is 50 mg/m2 daily for 4 days with a 3-day interval between treatment regimens.5 The 8-year-old spayed female Yorkshire Terrier of this report (dog 1) was administered 98 mg of cyclophosphamide/m2 daily for 11 days, and the 5-year-old castrated male West Highland White Terrier (dog 2) was administered 120 mg of cyclophosphamide/m2 daily for 9 days. The amount of cyclophosphamide administered to those 2 dogs was 2 to 2.5 times the recommended daily dose and 3.5 to 4 times the recommended weekly dose. The most common toxicoses associated with cyclophosphamide include dose-dependent bone marrow suppression, hemorrhagic cystitis, and gastroenteritis.1 For dogs treated with cyclophosphamide, the leukocyte nadir generally occurs between 7 and 14 days after administration and bone marrow recovery typically requires 18 to 25 days.1 The granulocyte counts for the dogs of the present report recovered to within reference limits by 10 to 11 days after administration of the last dose of cyclophosphamide, which is quicker than the time required for granulocyte recovery reported by investigators of another study.1 The dogs of the present report were administered G-CSF, which could have contributed to the rapid recovery of the granulocyte count. Granulocyte colony-stimulating factor is a hematopoietic agent used to increase the proliferation, differentiation, and activation of progenitor cells in the neutrophil-granulocyte line. It has been used to accelerate hematopoietic recovery in dogs with lymphoma that have undergone chemotherapy in preparation for autologous bone marrow transplant.4,6 The recommended dose of G-CSF for dogs varies; however, administration of 5 μg of G-CSF/kg was associated with a > 10-fold increase in the neutrophil count within 2 weeks.7 Adverse effects were not observed in dogs treated with 5 μg of G-CSF/kg twice daily for 7 days in preparation for a bone marrow transplant.6
Both dogs of the present report were hyperthermic during the initial physical examination. However, dog 1 remained hyperthermic throughout the subsequent 25-day evaluation period despite the fact that its leukogram returned to within reference limits, which suggested that the hyperthermia was caused by stress and anxiety during examination at the hospital. Ideally, had the owner routinely measured dog 1's rectal temperature at home, we might have been able to determine whether the hyperthermia was indeed a consequence of stress associated with the visit to the hospital. For dog 2, the hyperthermia was suspected to be secondary to sepsis because it resolved following antimicrobial treatment.
Although both dogs developed severe thrombocytopenia, dog 1 did not have any apparent bleeding disorders, whereas dog 2 developed epistaxis and melena and eventually required platelet and RBC transfusions. In humans, the severity of clinical hemorrhage depends on the platelet count.8,9 Patients with equivalent platelet counts often have substantially different bleeding times; factors that affect bleeding times in such patients include differing causes of thrombocytopenia or imprecision of the method used to determine the platelet counts, concurrent hemostasis disorders, and anemia.10 Results of 1 study11 indicate a correlation between anemia and prolonged bleeding time; thus, in retrospect, dog 2 might have benefitted from a transfusion of packed RBCs early during the course of treatment.
Studies conducted to evaluate the prophylactic use of platelets or the optimal platelet dose required to control thrombocytopenia-induced hemorrhage in dogs are lacking. At our hospital, platelet transfusions are considered for patients with thrombocytopenia alone or with concurrent life-threatening hemorrhage. Cryopreserved platelets were administered to dog 2 because it had thrombocytopenia and spontaneous multifocal hemorrhage.
Cyclophosphamide administration can cause sterile hemorrhagic cystitis because of the production of acrolein, one of its metabolites.12 Acrolein has an inflammatory effect on the lining of the bladder, which causes submucosal edema, hemorrhage, necrosis, and fibrosis of the bladder epithelium. For dogs, risk factors for sterile hemorrhagic cystitis include patient age, anesthetic induction protocol used, and cumulative dose of cyclophosphamide administered.13 For dogs with lymphoma that were administered cyclophosphamide orally as part of a chemotherapy protocol, the mean time to onset of sterile hemorrhagic cystitis ranged from 79 to 120 days after the first dose of cyclophosphamide, and cyclophosphamide was still being administered to all dogs when signs of sterile hemorrhagic cystitis developed.13 The dogs in that study13 were administered a higher cumulative dose of cyclophosphamide (1,200 to 1,900 mg/m2), albeit over a 5-month period, than were the dogs of this report (1,100 mg/m2). To our knowledge, the duration of time that a patient is at risk for sterile hemorrhagic cystitis after cessation of cyclophosphamide administration is unknown. Long-term follow-up was not performed for the 2 dogs of the present report, with the dogs last examined at 25 and 34 days after administration of the last dose of cyclophosphamide. It is possible that the dogs developed sterile hemorrhagic cystitis after those examinations.
Results of another study14 indicate that administration of furosemide to dogs with lymphoma that are being treated with a chemotherapy protocol that includes cyclophosphamide decreases the incidence of sterile hemorrhagic cystitis. In human patients, administration of mesna, a thiol compound, significantly decreases the incidence of sterile hemorrhagic cystitis15 by combining with acrolein in the bladder to form an inert, nontoxic product.16,17 To our knowledge, the efficacy of furosemide or mesna administration for prevention of hemorrhagic cystitis after prolonged oral administration of cyclophosphamide in dogs is unknown. Mesna was not administered to the dogs of the present report because neither dog had clinical signs of hemorrhagic cystitis and because of the lack of data regarding the drug's efficacy and its cost. Furosemide was administered to dog 2 as a prophylactic measure against hemorrhagic cystitis because it is a relatively safe and inexpensive drug.
Accidental cyclophosphamide intoxication has been reported in 2 other dogs.18,19 One dog chewed open its owner's bottle of cyclophosphamide and subsequently developed sterile hemorrhagic cystitis and pancytopenia.18 That dog was treated with enrofloxacin and sodium penicillin for 9 days, during which time the severity of hematuria decreased and the leukocyte, RBC, and platelet counts gradually increased.18 Further follow-up was not provided for that dog.18 The other dog had signs of cystitis, and initial diagnostic testing revealed pancytopenia.19 The dog's owner, a physician, had written a prescription for cyclosporine for the treatment of atopic dermatitis for the dog, and cyclophosphamide was inadvertently dispensed and administered for 3 weeks.19 The cumulative dose of cyclophosphamide administered to the dog in that report19 was 1,521 mg/m2, which was higher than the cumulative cyclophosphamide doses administered to the dogs of the present report. The dog was hospitalized for 4 days and treated with clindamycin and enrofloxacin; on the fifth day, the dog was discharged and prescribed G-CSF.19 Two days after discharge from the hospital (day 7), the dog was reevaluated because of hyporexia and lethargy; results of a CBC revealed the continued presence of pancytopenia.19 The dog was treated with packed RBC transfusions on days 7, 10, and 12 and a fresh-frozen plasma transfusion on day 12.19 On day 13, the dog was hospitalized and treated with prednisolone sodium succinate, imipenem, methadone hydrochloride, and a transdermal fentanyl patch.19 The dog's condition continued to deteriorate, and because the owner declined to have the dog euthanized, it remained hospitalized and was treated with escalating doses of methadone.19 On day 19, the dog died because of suspected sepsis, anemia, and methadone overdose.19
Both dogs of the present report were erroneously dispensed cyclophosphamide instead of cyclosporine by a pharmacy. Instead of 25-mg tablets, 50-mg cyclophosphamide tablets were dispensed for dog 1, and the owner was instructed to cut the tablets in half. The Tennessee Pharmacy Standards of Practice20 states that a pharmacist can substitute a medication with a different strength than that prescribed as long as the amount directed to be given to the patient is therapeutically equivalent to the prescribed amount. Although not detailed in the Pharmacy Standards of Practice,20 it is recommended that tablets containing a chemotherapeutic agent not be cut because it can expose individuals other than the intended patient (ie, pet owners) to the agent. Neither pharmacy that inadvertently dispensed the cyclophosphamide to the dogs of the present report appropriately labeled the prescriptions as hazardous or recommended the wearing of gloves for drug administration, which is a violation of the Tennessee Pharmacy Standards of Practice.20 To our knowledge, studies of the incidence of pharmacy errors in veterinary medicine are lacking. In a study21 of 50 US community pharmacies in 6 cities, the overall dispensing error rate for prescription drugs was 1.57% (91/5,784), and 77% (70/91) of those errors occurred when prescriptions were manually inspected instead of dispensed by use of an electronic barcode system. In the United States, the human mortality rate because of medication errors is estimated to range between 44,000 and 98,000 deaths/y.22 The prescriptions for both of the dogs of the present report were communicated to the pharmacy by telephone, which is more likely to result in communication error. The submission of written prescriptions with clear and legible orders without abbreviations to pharmacies could decrease prescription errors.
To our knowledge, the present report is the first to describe the treatment and survival of dogs after inadvertent prolonged administration of cyclophosphamide subsequent to pharmacy dispensing errors. Although both dogs of the present report were administered similar cumulative doses of cyclophosphamide on an mg/m2 basis, the severity of the intoxication and the treatment required for each dog differed. Dog 1 did not require hospitalization and never developed severe adverse intestinal effects or hemorrhage associated with bone marrow suppression, whereas dog 2 developed severe adverse effects, which necessitated several days of hospitalization and platelet and packed RBC transfusions. Dogs, even those with severe clinical signs and extreme bone marrow suppression, can recover from prolonged cyclophosphamide intoxication with appropriate supportive care.
ABBREVIATIONS
| G-CSF | Granulocyte colony-stimulating factor |
Atopica, Novartis Animal Health Inc, Greensboro, NC.
Normosol R, Hospira Inc, Lake Forest, Ill.
Benadryl, McNeil Consumer Healthcare, Fort Washington, Pa.
Clavamox, Pfizer Animal Health, Exton, Pa.
Lasix, Intervet/Merck Animal Health, Summit, NJ.
References
1. Stanton ME, Legendre AM. Effects of cyclophosphamide in dogs and cats. J Am Vet Med Assoc 1986; 188: 1319–1322.
2. Lana S, U'Ren L & Plaza S, et al. Continuous low-dose oral chemotherapy for adjuvant therapy of splenic hemangiosarcoma in dogs. J Vet Intern Med 2007; 21: 764–769.
3. Elmslie RE, Glawe P, Dow SW. Metronomic therapy with cyclophosphamide and piroxicam effectively delays tumor recurrence in dogs with incompletely resected soft tissue sarcomas. J Vet Intern Med 2008; 22: 1373–1379.
4. Frimberger AE, Moore AS & Rassnick KM, et al. A combination chemotherapy protocol with dose intensification and autologous bone marrow transplant (VELCAP-HDC) for canine lymphoma. J Vet Intern Med 2006; 20: 355–364.
5. Plumb DM. Plumb's veterinary drug handbook. 7th ed. Ames, Iowa: Blackwell Publishing Professional, 2011.
6. Lane AE, Chan MJ, Wyatt KM. Use of recombinant human granulocyte colony stimulating factor prior to autologous bone marrow transplantation in dogs with lymphoma. Am J Vet Res 2012; 73: 894–899.
7. Lothrop CD Jr, Warren DJ & Souza LM, et al. Correction of canine cyclic hematopoiesis with recombinant human granulocyte colony-stimulating factor. Blood 1988; 72: 1324–1328.
8. Rodgers RP & Levin J. A critical reappraisal of the bleeding time. Semin Thromb Hemost 1990; 16: 1–20.
9. De Caterina R, Lanza M & Manca G, et al. Bleeding time and bleeding: an analysis of the relationship of the bleeding time test with parameters of surgical bleeding. Blood 1994; 84: 3363–3370.
10. Abrams-Ogg AC. Triggers for prophylactic use of platelet transfusions and optimal platelet dosing in thrombocytopenic dogs and cats. Vet Clin North Am Small Anim Pract 2003; 33: 1401–1418.
11. Valeri CR, Khuri S & Ragno G. Nonsurgical bleeding diatheses in anemic thrombocytopenic patients: role of temperature, red blood cells, platelets, and plasma clotting proteins. Transfusion 2007; 47: 206S–248S.
12. Cox PJ. Cyclophosphamide cystitis-identification of acrolein as the causative agent. Biochem Pharmacol 1979; 28: 2045–2049.
13. Gaeta R, Brown D & Cohen R, et al. Risk factors for development of sterile haemorrhagic cystitis in canine lymphoma patients receiving oral cyclophosphamide: a case-control study [published online ahead of print Oct 19, 2012]. Vet Comp Oncol doi:10.1111/vco.12009.
14. Charney SC, Bergman PJ & Hohenhaus AE, et al. Risk factors for sterile hemorrhagic cystitis in dogs with lymphoma receiving cyclophosphamide with or without concurrent administration of furosemide: 216 cases (1990–1996). J Am Vet Med Assoc 2003; 222: 1388–1393.
15. Brade WP, Herdrich K & Varini M. Ifosfamide—pharmacology, safety and therapeutic potential. Cancer Treat Rev 1985; 12: 1–47.
16. Sarosy G. Ifosphamide—pharmacologic overview. Semin Oncol 1989; 16: 2–8.
17. Goren MP, Houle JM & Bush DA, et al. Similar bioavailability of single-dose oral and intravenous mesna in the blood and urine of healthy human subjects. Clin Cancer Res 1998; 4: 2313–2320.
18. Marin MP, Samson RJL, Evangeline RJ. Hemorrhagic cystitis in a dog. Can Vet J 1996; 37: 240.
19. Wimpole JA, Vogelnest LJ & Krockenberger MB, et al. Fatal cyclophosphamide dosing causing sterile haemorrhagic cystitis and panleucopaenia in a dog. Aust Vet Pract 2010; 40: 148–153.
20. Tennessee Board of Pharmacy. Rules of the Tennessee Board of Pharmacy. Feb 2009 (revised). Available at: www.tn.gov/sos/rules/1140/1140-03.20090207.pdf. Accessed Nov 18, 2013.
21. Flynn EA, Dorris NT & Holman GT, et al. Medication dispensing errors in community pharmacies: a nationwide study, in Proceedings. Hum Factors Ergon Soc 46th Annu Meet 2002; 1448–1451.
22. Kohn LT, Corrigan JM, Donaldson MS, eds. To err is human: building a safer health system. Washington, DC: National Academy Press, 2000.
