C1 inhibitor in canine intravascular hemolysis (C1INCH): study protocol for a randomized controlled trial.

BACKGROUND: Immune-mediated hemolytic anemia (IMHA) is a common disease that affects all breeds of dogs and is associated with significant morbidity and mortality. Intravascular hemolysis of erythrocytes in IMHA is caused by complement activation and is often fatal. No current treatments target complement activation in canine IMHA. Human C1 esterase (C1-INH) reduces canine complement-mediated hemolysis in vitro, and a recent pharmacokinetic analysis of an FDA licensed formulation of C1-INH in dogs confirmed that a 50 IU/kg dose of C1-INH is safe to administer to dogs, and effectively inhibits canine complement mediated hemolysis ex-vivo. The C1INCH randomized controlled trial will evaluate the efficacy of this drug in dogs with intravascular hemolysis. METHODS: We will conduct a multicenter, placebo-controlled double-blind randomized clinical trial of C1-INH in dogs with intravascular hemolysis due to IMHA. We will randomize 18 dogs to receive three doses of intravenous C1-INH or saline in 24 h. Immunosuppressive and antithrombotic therapies will be standardized. Primary outcome measures will be changes in plasma free hemoglobin, serum concentrations of LDH, bilirubin, and haptoglobin. Using patient samples, we will evaluate complement activation in canine IMHA using a novel C5b-9 ELISA assay, flow cytometric detection of C3b on RBC, and by measurement of residual plasma complement activity. Secondary outcome measures will be survival to hospital discharge, duration of hospitalization, number and volume of red blood cell transfusions, and rescue therapy requirements. We will monitor dogs for adverse drug reactions. Sample size was estimated from pilot data on LDH and hemolysis index (HI) in dogs with IMHA. To detect 2-way differences between the upper and lower 50% of the LDH and HI values of equivalent size with 80% power at P < 0.05 will require 9 dogs in each arm. DISCUSSION: We anticipate that IV administration of C1-INH will significantly inhibit complement mediated hemolysis in dogs with intravascular IMHA, as determined by blood biomarker measurements (decreased plasma hemoglobin, LDH and bilirubin, increased haptoglobin). We expect this will translate into significant reductions in transfusion requirements and duration of hospitalization. TRIAL REGISTRATION: This trial has been prospectively registered with the AVMA registry (AAHSD005025).

Methylprednisolone alone or combined with cyclosporine or mycophenolate mofetil for the treatment of immune-mediated hemolytic anemia in dogs, a prospective study.

BACKGROUND: Benefit of adding a second-line immunosuppressive drug to glucocorticoids for the treatment of non-associative immune-mediated hemolytic anemia (naIMHA) in dogs has not been defined prospectively. HYPOTHESIS/OBJECTIVES: Evaluate the effectiveness of different immunosuppressive protocols in naIMHA dogs. ANIMALS: Forty-three client-owned dogs. METHODS: Open label, randomized, clinical trial. Dogs were treated with methylprednisolone (M-group), methylprednisolone plus cyclosporine (MC-group) or methylprednisolone plus mycophenolate mofetil (MM-group). Dogs were defined as responders by disappearance of signs of immune-mediated destruction and hematocrit stabilization. Frequency of responders was compared between M-group and combined protocols (MC and MM-group evaluated together), and among the 3 different therapeutic groups at 14 (T14), 30 (T30), 60 (T60) days after admission. Frequency of complications, length of hospitalization and relapse were also compared. Death rate was evaluated at discharge, T60 and 365 (T365) days. RESULTS: Proportion of responders was not significantly different between M-group and combined protocols (MC and MM-groups), nor among the 3 therapeutic groups at T14, T30, and T60 (P > .17). Frequency of relapse, complications, and length of hospitalization were not significantly different between M-group and dogs treated with combined protocols, nor among the 3 treatment groups (P > .22). Death was significantly more common only for MM-group compared with MC-group at T60 (+42.8%; 95% CI: 11.5-67.4; P = .009), and at T365 (+50%; 95% CI: 17.5-73.2; P = .003). CONCLUSIONS AND CLINICAL IMPORTANCE: Combined immunosuppressive therapy did not improve hematological response in naIMHA.

Cytokine Adsorption as an Adjunctive Treatment for Patients with Immune-Mediated Hemolytic Anemia Receiving Therapeutic Plasma Exchange: A Case Series of 3 Dogs.

The use of cytokine adsorption is an emerging treatment for inflammatory diseases in human medicine. There are few reports of this treatment modality in veterinary medicine and no reports of the use of a cytokine adsorbent for immune-mediated hemolytic anemia (IMHA). These case reports illustrate the use of a cytokine adsorbent as an adjunctive treatment during therapeutic plasma exchange (TPE). All dogs were unresponsive to conventional treatment or were severely affected by rapid hemolysis of red blood cells. The aim was to treat all dogs with three sequential TPE sessions; however, one dog died before completion of three sessions and one dog required additional sessions. Preliminary evidence indicates that the use of a cytokine adsorption is well tolerated and can be considered as an adjunct in the management of IMHA that is severe or refractory to traditional treatment.

Retrospective analysis of immunosuppressive and anti-thrombotic protocols in nonassociative immune mediated hemolytic anemia in dogs.

BACKGROUND: Evidence supporting the effectiveness of therapeutic protocols for nonassociative immune-mediated hemolytic anemia (na-IMHA) is weak. HYPOTHESIS/OBJECTIVES: Investigate the efficacy of various drugs in na-IMHA. ANIMALS: Two hundred forty-two dogs. METHODS: Multi-institutional retrospective study (2015-2020). Immunosuppressive effectiveness was determined by time to packed cell volume (PCV) stabilization and duration of hospitalization through analysis by mixed model linear regression. Occurrence of disease relapse, death, and antithrombotic effectiveness, were analyzed using mixed model logistic regression. RESULTS: Use of corticosteroids vs a multi-agent protocol had no effect on time to PCV stabilization (P = .55), duration of hospitalization (P = .13), or case fatality (P = .06). A higher rate of relapse (P = .04; odds ratio: 3.97; 95% confidence interval [CI]: 1.06-14.8) was detected in dogs receiving corticosteroids (11.3%) during follow-up (median: 28.5 days, range: 0-1631 days) compared to multiple agents (3.1%) during follow up (median: 47.0 days, range: 0-1992 days). When comparing drug protocols, there was no effect on time to PCV stabilization (P = .31), relapse (P = .44), or case fatality (P = .08). Duration of hospitalization was longer, by 1.8 days (95% CI: 0.39-3.28 days), for the corticosteroid with mycophenolate mofetil group (P = .01) compared to corticosteroids alone. Use of clopidogrel vs multiple agents had no effect on development of thromboses (P ≥ .36). CONCLUSIONS AND CLINICAL IMPORTANCE: Addition of a second immunosuppressive agent did not alter immediate outcome measures but might be associated with a reduction in relapse. Use of multiple antithrombotic agents did not reduce incidence of thrombosis.

Urinary 11-dehydrothromboxane B2 concentrations in 20 dogs with primary immune-mediated hemolytic anemia.

BACKGROUND: Thromboembolic disease is a major cause of mortality in dogs with immune-mediated hemolytic anemia (IMHA). At present, no reliable biomarkers of individual patient thrombotic risk are available. In human medicine, increased urinary thromboxane concentrations have utility as markers of prothrombotic tendency in various situations. HYPOTHESIS/OBJECTIVES: First, to determine if urinary 11-dehydrothromboxane B2 (u11-dTXB) concentrations are increased in dogs with primary IMHA compared to normal dogs; second, to assess whether u11-dTXB concentration is associated with survival, known prognostic indicators, or frequency of thrombosis in dogs with IMHA. ANIMALS: Twenty client-owned dogs diagnosed with primary IMHA and 17 healthy dogs volunteered by hospital staff. METHODS: Prospective case-control study. A previously validated ELISA was used to measure urine 11-dTXB concentrations, which were normalized to urine creatinine concentration (u11-dTXB:Cr). Samples were obtained at presentation from patients with primary IMHA. Standard clincopathological data at baseline and survival data were collected. Urinary 11-dTXB:Cr was compared between outcome subgroups, and correlated with known markers of disease severity. RESULTS: Baseline u11-dTXB:Cr was significantly higher in dogs with IMHA than in healthy dogs (median, 3.75; range, 0.83-25.36 vs 0.65; 0.24-2.57; P = .003) but did not differ between dogs with IMHA that survived and did not survive to 30 days after presentation, nor between dogs with and without clinical suspicion of thrombotic disease. CONCLUSIONS AND CLINICAL IMPORTANCE: Urinary 11-dTXB:Cr is increased in dogs with IMHA compared to healthy controls, consistent with a prothrombotic state. However, in this IMHA population u11-dTXB:Cr was not associated with survival or suspected thrombosis.

The use of high-dose immunoglobulin M-enriched human immunoglobulin in dogs with immune-mediated hemolytic anemia.

BACKGROUND: The IV use of human immunoglobulin (hIVIG) in dogs with primary immune-mediated hemolytic anemia (IMHA) has been described previously, but herein we describe the use of high-dose IgM-enriched hIVIG (Pentaglobin). HYPOTHESIS/OBJECTIVES: Dogs treated with high-dose Pentaglobin will experience shorter time to remission and hospital discharge and have decreased transfusion requirements compared to dogs receiving standard treatment alone. ANIMALS: Fourteen client-owned dogs diagnosed with primary IMHA at specialist referral hospitals in the United Kingdom. METHODS: All prospectively enrolled dogs received prednisolone, dexamethasone or both along with clopidogrel. Patients were randomized to receive Pentaglobin at 1 g/kg on up to 2 occasions, or to serve as controls. No additional immunosuppressive drugs were allowed within the first 7 days of treatment. Remission was defined as stable PCV for 24 hours followed by an increase in PCV. RESULTS: Ten of 11 dogs from the treatment group and 2 of 3 dogs from the control group achieved remission and survived until hospital discharge. Survival and time to remission were not significantly different between groups. The volume of packed red blood cells transfused, normalized for body weight, was not significantly different between groups. Potential adverse reactions to Pentaglobin occurred in 2 dogs, but their clinical signs may have been related to the underlying disease. CONCLUSIONS AND CLINICAL IMPORTANCE: Treatment with high-dose Pentaglobin was well tolerated by dogs with primary IMHA but no significant advantage was found in this small study. Additional studies examining larger groups and subpopulations of dogs with primary IMHA associated with a poorer prognosis are warranted.

Splenectomy in the management of primary immune-mediated hemolytic anemia and primary immune-mediated thrombocytopenia in dogs.

BACKGROUND: Current reports about the use of splenectomy for the management of immune-mediated hemolytic anemia (IMHA) or immune-mediated thrombocytopenia (ITP) or both in dogs are limited. OBJECTIVES: To retrospectively describe the use of splenectomy as part of the management for IMHA, ITP, and concurrent IMHA and severe thrombocytopenia (CIST) in dogs. It was hypothesized that splenectomy would be beneficial in allowing for reduction of dose of immunosuppressive drugs or discontinuation in 1 or more of these groups. ANIMALS: Seventeen client-owned dogs (7 with IMHA, 7 with ITP, and 3 with CIST) were identified across 7 UK-based referral hospitals from a study period of 2005 to 2016. METHODS: Data were collected retrospectively via questionnaires and included information about diagnosis, management and treatment response before and after splenectomy. Based on clinical outcome, treatment with splenectomy as part of the management protocol was classified as either successful or unsuccessful. RESULTS: Six of 7 dogs with ITP were managed successfully with splenectomy as part of their management protocol (3 complete and 3 partial responses), although 1 subsequently developed suspected IMHA. Of the 7 dogs with IMHA, splenectomy was part of a successful management protocol in 4 dogs (2 complete and 2 partial responses). In the CIST group, 1 case (1/3) responded completely to management with splenectomy as part of the management protocol. CONCLUSIONS AND CLINICAL IMPORTANCE: Splenectomy was considered successful and well tolerated in most cases of isolated ITP. Whether there is a benefit of splenectomy in cases of IMHA and CIST could not be determined in the current study.

Centrifugal therapeutic plasma exchange in dogs with immune-mediated hemolytic anemia (2016-2018): 7 cases.

OBJECTIVE: To describe the technique of centrifugal therapeutic plasma exchange (cTPE) in dogs diagnosed with immune-mediated hemolytic anemia (IMHA) and summarize the outcome of the procedure. DESIGN: Retrospective review of cTPE performed at North Carolina State University from 2016 to 2018, through a search of the institutional database for cTPE and IMHA. SETTING: University teaching hospital. ANIMALS: Seven dogs with confirmed IMHA were presented to a university teaching hospital ICU for cTPE. Six dogs were not responsive to standard medical management with immunosuppressive agents, while 1 dog presented before immunosuppressive agents were begun. INTERVENTIONS: All dogs underwent multiple cTPE procedures using 1 of 2 commercially available apheresis systems. MEASUREMENTS AND MAIN RESULTS: At presentation, the median HCT was 0.15 L/L (15.7%) (range, 0.10-0.19 L/L [10.3%-19%]) and the median total serum bilirubin was 32.5 mmol/L (1.9 mg/dl) (range, 15.4-597 mmol/L [0.9-34.9 mg/dl]). The median number of transfusions before cTPE was 1 (range, 1-4), with a median total of infused RBCs of 12.9 ml/kg (range, 8.8-37 ml/kg). cTPE with an exchange of ≥4 times total plasma volumes was used to decrease the level of circulating autoreactive antibodies. The median total plasma volumes exchanged was 4.5 times (range, 2.5-6.5 times) over 2-4 procedures. Anticoagulation was performed using a combination of systemic heparinization and regional citrate in all dogs. Six of 7 dogs (85.7%) were discharged from the hospital and were alive 90 days after discharge. One dog (14%) did not respond to cTPE (∼6.5 times total plasma volume exchanged) and was euthanized. CONCLUSIONS: cTPE is a feasible and relatively safe bridging treatment option for the management of canine IMHA.

Low serum folate concentrations in dogs with non-associative immune-mediated haemolytic anaemia.

BACKGROUND: Folate deficiency in people can occur in conditions causing increased demand, including haemolytic anaemia. This has not been investigated in dogs with non-associative immune-mediated haemolytic anaemia (IMHA). METHODS: Cohort study of 15 dogs with non-associative IMHA. Haematocrit (HCT) and serum folate concentrations were measured at presentation and each subsequent venipuncture performed for monitoring. The relationship between serum folate concentrations and HCT was investigated using linear and logistic mixed-effects regression models and in paired samples using a one-tailed paired t-test. RESULTS: Low serum folate concentrations occurred in five of 15 dogs. In 126 samples, a significant positive relationship was found between HCT and corresponding serum folate concentrations. A significant relationship was found between dichotomised folate concentrations (below the reference interval or within/above the reference interval) and HCT and between serum folate concentrations and dichotomised HCT (less than or equal/above 0.30 L/L). For paired samples (available in eight dogs), the mean serum folate concentration of samples with the lowest HCT was significantly lower than that of samples in which the HCT first exceeded 0.30 L/L. CONCLUSIONS: Low serum folate concentrations were observed in some dogs with non-associative IMHA. Further studies are needed to determine the cause and investigate whether folate supplementation would be beneficial.

Effectiveness of aspirin vs. clopidogrel in dogs with immune mediated haemolytic anaemia evaluated by serial thromboelastography and platelet mapping.

Most dogs with immune mediated haemolytic anaemia (IMHA) are hypercoagulable, as measured by thromboelastography (TEG). Thromboelastography-platelet mapping (TEG-PM) has been used to assess platelet function in human patients treated with aspirin or clopidogrel. The aim of this study was to compare platelet thromboxane A2-receptor inhibition (TXA2-RI) and platelet adenosine diphosphate (ADP)-receptor inhibition (ADP-RI) as measured by TEG-PM in dogs with primary IMHA receiving aspirin or clopidogrel to determine if TEG-PM might be useful to monitor treatment. Eighteen client-owned dogs with IMHA were enroled in a prospective double blinded study. Dogs were randomised to receive aspirin or clopidogrel in addition to standard therapy. Thromboelastography was measured before, and 1 and 4 days after commencing treatment. Thromboelastography-PM was performed on days 1 and 4. Non-responders were defined as < 50 % platelet thromboxane A2-receptor inhibition (TXA2-RI) in the aspirin group and < 50 % platelet adenosine diphosphate (ADP)-receptor inhibition (ADP-RI) in the clopidogrel group, on day 4. Mean platelet TXA2-RI and platelet ADP-RI were not significantly different between groups at any timepoint (P > 0.05). The overall mean percentage inhibition of TXA2-receptor was 25 % (aspirin 33 %, clopidogrel 15 %), and of ADP-receptor was 82 % (aspirin 83 %, clopidogrel 80 %). On day 4, 6/9 dogs (66 %) in the aspirin group and 2/8 dogs (25 %) in the clopidogrel group were non-responders (P = 0.086). Two dogs defined as responders based on TEG-PM developed thromboembolism. Overall, there was no significant difference in efficacy between aspirin and clopidogrel based on measurement of receptor inhibition using TEG-PM (P > 0.05), and routine TEG was not reliable for monitoring treatment response in dogs with IMHA. In some dogs, there was a discrepancy between TEG-PM results and clinical response. Further investigation of TEG-PM use in dogs, including its usefulness to monitor treatment response and adjust treatment in individual dogs and any effect of anaemia, is warranted.

Immune-mediated haemolytic anaemia and thrombocytopenia in 25 adult equids: 1997-2016.

BACKGROUND: Information concerning clinical presentation, conditions associated with immune-mediated haemolytic anaemia (IMHA) and thrombocytopenia (IMTP) and outcome in equids is lacking. Previous case reports suggest that immune-mediated disease and neoplasia are associated. OBJECTIVES: Characterise the clinical presentation, clinicopathologic data, underlying conditions, treatment and outcome of IMHA and IMTP cases in equids. We hypothesise that IMHA with concurrent thrombocytopenia occurs more often than IMHA or IMTP alone, and that neoplasia is commonly associated with these immune diseases and cases frequently have a poor prognosis. STUDY DESIGN: Retrospective case-control study. METHODS: Medical records were reviewed from 1997 to 2016. Twenty-five equids were diagnosed with IMHA, IMTP or IMHA with thrombocytopenia by Coombs test or flow cytometry. Controls were equids presented for nonimmune-mediated disease immediately prior to and after study animals. Fisher's exact test was used to compare between groups for categorical variables (P < .05). Results reported as odds ratios (OR) and 95% confidence intervals (CI). Unpaired t test and Mann-Whitney test were used to compare between groups for continuous variables (P < .05). RESULTS: Neoplasia incidence was significantly higher in the study population (28%) versus controls (8%) (P = .04). Equids with primary disease were more likely to survive to discharge than equids with secondary disease (8/9 vs 7/16; P = .03; OR = 13.3; 95% CI: 1.3-134.7). Survivors had a significantly lower blood urea nitrogen (BUN) than those that died or were subjected to euthanasia (survivors, 6.1 ± 2.5 mmol/L vs nonsurvivors, 9.9 ± 3.1 mmol/L P = .003). The odds of short-term mortality were higher in horses presenting with increased BUN (OR = 19.5; 95% CI, 1.8-214.1; P = .009). MAIN LIMITATIONS: Retrospective nature of the study, small case numbers and limited long-term follow-up. CONCLUSIONS: Primary IMHA/IMTP cases have a reasonable prognosis and warrant treatment. Secondary cases have a poor prognosis, and are frequently associated with cancer. BUN may have utility as a prognostic indicator for IMHA/IMTP cases.

Breed predispositions, clinical findings, and prognostic factors for death in dogs with nonregenerative immune-mediated anemia.

BACKGROUND: Breed predispositions, survival, and prognostic factors have not been evaluated in dogs with nonregenerative immune-mediated anemia (nrIMA). HYPOTHESIS/OBJECTIVES: To describe clinicopathologic variables, evaluate their associations with survival, and determine breed predispositions for dogs with nrIMA. ANIMALS: Fifty-nine client-owned dogs with nrIMA. METHODS: Referral hospital records were reviewed retrospectively for dogs with primary nrIMA (PCV ≤30%, corrected reticulocyte percentage (CR%) ≤1.0, bone marrow sampling with evidence of immune-mediated destruction, and underlying causes excluded). Breed predispositions were evaluated by calculation of odds ratios in a case control study; prognostic factors by logistic regression in a cohort study. RESULTS: Fifty-nine dogs with nrIMA had a median PCV of 12% (interquartile range [IQR]: 10%-17%) and CR% 0.1 (0%-0.2%). At least ≥1 ACVIM IMHA diagnostic criteria were met by 35 dogs (59%). Whippets, Lurchers, and miniature Dachshunds were predisposed to nrIMA. Median survival time was 277 days (IQR: 37-1925), with 3- and 12-month survival rates 61% and 43%, respectively. Erythroid regeneration and remission were achieved by 88% and 62% of dogs, respectively. Corrected reticulocyte percentage >0.2 was associated with improved survival. CONCLUSION AND CLINICAL IMPORTANCE: Although there is overlap of clinical features between dogs with IMHA and nrIMA, the prognosis for those with nrIMA depends predominantly on the severity of reticulocytopenia.

Pregnancy-associated immune-mediated hemolytic anemia in a dog.

OBJECTIVE: To describe the clinical presentation, diagnostic investigations, and outcome of a dog with pregnancy-associated immune-mediated hemolytic anemia. CASE SUMMARY: A 6-year-old, pregnant Bichon Frise was presented due to lethargy, inappetence, and progressive regenerative anemia with spherocytosis. The dog had been recently receiving ranitidine and amoxicillin/clavulanate. An in-house saline agglutination test identified marked agglutination and a urinalysis identified hemoglobinuria. Thoracic and abdominal imaging, as well as infectious diseases testing, was unremarkable. The bitch started whelping shortly following hospitalization, and the anemia progressively resolved without any other intervention. Ranitidine and amoxicillin/clavulanate were re-introduced within the following 2 months but the anemia did not reoccur. In light of these findings, a diagnosis of pregnancy-associated immune-mediated hemolytic anemia was made. NEW OR UNIQUE INFORMATION PROVIDED: Pregnancy-associated immune-mediated hemolytic anemia should be considered in female dogs that develop severe hemolytic anemia during pregnancy and may resolve spontaneously following parturition.

Suspected hepatopathy and pancreatitis associated with mycophenolate mofetil use in a cat with immune-mediated haemolytic anaemia.

CASE SUMMARY: A 5-year-old spayed female domestic shorthair cat was referred for severe anaemia. Findings on initial work-up were consistent with a diagnosis of idiopathic immune-mediated haemolytic anaemia. A combination of prednisolone and mycophenolate mofetil (MMF) was instituted. On revisit approximately 2 months later, red blood cell parameters were normal, but the plasma was described as icteric, prompting further investigation. Concurrent hepatopathy and pancreatitis were diagnosed, suspected as being adverse reactions to MMF, as has been reported with use of the drug in humans. Resolution of serum biochemistry abnormalities took approximately 2 months, following discontinuing MMF. At the time of writing, the cat remained clinically well 1 year after initial presentation. RELEVANCE AND NOVEL INFORMATION: With increasing use of MMF as an immunosuppressive agent in cats, clinicians should be aware of both common and potentially rare adverse effects, such as those described herein. In addition, suitable monitoring tools need to be in place to facilitate early detection and appropriate management.

Primary immune-mediated haemolytic anaemia: a retrospective long-term study in 61 dogs.

OBJECTIVES: The objective of this study is to describe the course of disease of dogs with primary immune-mediated haemolytic anaemia (pIMHA) with an observation period longer than 90 days in regard to clinical signs, laboratory results and treatment response. MATERIAL AND METHODS: Clinical records between January 2003 and December 2011 were reviewed. Diagnosis of pIMHA was based on the presence of haemolytic anaemia with a packed cell volume of <0.35 L/L, a positive Coombs' test and/or erythrocyte agglutination, spherocytosis and exclusion of an underlying disease. Included were dogs which could be monitored for more than 90 days after initial presentation. RESULTS: Sixty-one dogs with pIMHA were included. The initial packed cell volume ranged from 0.08 to 0.30 L/L (median 0.16). Immunosuppressive treatment included prednisolone in all the cases; 32 dogs successively received cyclosporine (28), cyclophosphamide (5), leflunomide (2) or human intravenous immunoglobulins (2) in addition. In 33/61 dogs, the drugs were discontinued 67-3372 days (median 334) after beginning of therapy; in 28 dogs, the drug dosage was reduced, but not discontinued until the end of the study. Three dogs developed immune-mediated thrombocytopenia (days 132, 156 and 680). The observation period ranged from 96 to 4147 days (median 628). A total of 22.9% (14/61) of the dogs developed a relapse after 94-3972 days (median 517). Five dogs were euthanased due to a relapse after 96-1188 days (median 628). CLINICAL SIGNIFICANCE: Long-term prognosis in dogs with pIMHA is favourable. However, a relapse can occur after many years. Relapse was the most common cause of death in dogs with pIMHA that survive more than 90 days.

Presumed immune-mediated haemolytic anaemia associated with pregnancy in a cat.

CASE SUMMARY: A 7-year-old female entire Birman presented with acute-onset haemorrhagic vulvar discharge. Moderate, normocytic, normochromic, non-/pre-regenerative anaemia, along with a moderate mature neutrophilia, were seen on haematology. Saline test for agglutination was positive. No haemotropic mycoplasmas were identified. Serum biochemistry revealed severe hyperbilirubinaemia. Retroviral testing was negative. Serology for toxoplasmosis revealed a titre of 1:512. Abdominal ultrasound identified a large uterus, containing at least three advanced-stage fetuses, two of which failed to exhibit independent motion or cardiac activity. Ovariohysterectomy was performed. Histology demonstrated mild, multifocal suppurative placentitis, with Gram staining revealing no evidence of bacteria. Complete resolution of the anaemia was seen within 1.5 months of ovariohysterectomy. RELEVANCE AND NOVEL INFORMATION: Immune-mediated haemolytic anaemia (IMHA) in association with pregnancy has not been previously reported in cats. This case represents a potential novel cause for IMHA in cats, which resolved following ovariohysterectomy.

Consensus on the Rational Use of Antithrombotics in Veterinary Critical Care (CURATIVE): Domain 1-Defining populations at risk.

OBJECTIVES: Thrombosis is a well-recognized phenomenon in dogs and cats with a significant impact on morbidity and mortality. Despite growing awareness of thrombosis and increased use of antithrombotic therapy, there is little information in the veterinary literature to guide the use of anticoagulant and antiplatelet medications. The goal of Domain 1 was to explore the association between disease and thrombosis in a number of conditions identified as potential risk factors in the current veterinary literature, to provide the basis for prescribing recommendations. DESIGN: A population exposure comparison outcome format was used to represent patient, exposure, comparison, and outcome. Population Exposure Comparison Outcome questions were distributed to worksheet authors who performed comprehensive searches, summarized the evidence, and created guideline recommendations that were reviewed by domain chairs. Revised guidelines then underwent the Delphi survey process to reach consensus on the final guidelines. Diseases evaluated included immune-mediated hemolytic anemia, protein-losing nephropathy, pancreatitis, glucocorticoid therapy, hyperadrenocorticism, neoplasia, sepsis, cerebrovascular disease, and cardiac disease. SETTINGS: Academic and referral veterinary medical centers. RESULTS: Of the diseases evaluated, a high risk for thrombosis was defined as dogs with immune-mediated hemolytic anemia or protein-losing nephropathy, cats with cardiomyopathy and associated risk factors, or dogs/cats with >1 disease or risk factor for thrombosis. Low or moderate risk for thrombosis was defined as dogs or cats with a single risk factor or disease, or dogs or cats with known risk factor conditions that are likely to resolve in days to weeks following treatment. CONCLUSIONS: Documented disease associations with thrombosis provide the basis for recommendations on prescribing provided in subsequent domains. Numerous knowledge gaps were identified that represent opportunities for future study.

Randomised controlled trial of fractionated and unfractionated prednisolone regimens for dogs with immune-mediated haemolytic anaemia.

METHODS: A randomised non-blinded non-inferiority trial was conducted to determine whether treatment with an unfractionated regimen of oral prednisolone was inferior to a fractionated regimen for dogs with primary immune-mediated haemolytic anaemia. Dogs received the same total daily dose of prednisolone as unfractionated (group 1, starting at 4 mg/kg orally once daily) or fractionated (group 2, starting at 2 mg/kg orally twice daily) doses. Questionnaires were administered to owners to assess adverse effects and quality of life (QoL). End points included survival to eight weeks, and changes in QoL and clinicopathological parameters over time. RESULTS: Thirty-nine dogs were enrolled in the study, of which 5 were withdrawn and 17 were assigned to each group. The number of cases recruited was insufficient to determine whether unfractionated treatment was inferior to fractionated. Total serum bilirubin decreased more rapidly in dogs in group 2, whereas polydipsia improved more rapidly in group 1. Blood pressure and score for polyuria were higher in dogs in group 2 over time, whereas lymphocyte concentration was lower. CONCLUSION: Administration of the same total daily dose of prednisolone as an unfractionated dose resulted in fewer adverse effects but the effect on survival could not be assessed in this study.

ACVIM consensus statement on the treatment of immune-mediated hemolytic anemia in dogs.

Immune-mediated hemolytic anemia (IMHA) causes severe anemia in dogs and is associated with considerable morbidity and mortality. Treatment with various immunosuppressive and antithrombotic drugs has been described anecdotally and in previous studies, but little consensus exists among veterinarians as to the optimal regimen to employ and maintain after diagnosis of the disease. To address this inconsistency and provide evidence-based guidelines for treatment of IMHA in dogs, we identified and extracted data from studies published in the veterinary literature. We developed a novel tool for evaluation of evidence quality, using it to assess study design, diagnostic criteria, explanation of treatment regimens, and validity of statistical methods. In combination with our clinical experience and comparable guidelines for humans afflicted with autoimmune hemolytic anemia, we used the conclusions of this process to make a set of clinical recommendations regarding treatment of IMHA in dogs, which we refined subsequently by conducting several iterations of Delphi review. Additionally, we considered emerging treatments for IMHA in dogs and highlighted areas deserving of future research. Comments were solicited from several professional bodies to maximize clinical applicability before the recommendations were submitted for publication. The resulting document is intended to provide clinical guidelines for management of IMHA in dogs. These guidelines should be implemented pragmatically, with consideration of animal, owner, and veterinary factors that may vary among cases.

The need for independent advocacy for people subject to mental health community treatment orders.

Independent mental health advocacy (IMHA) has been proposed as a way of maintaining peoples' rights in involuntary settings, but little is known about the challenges and opportunities associated with the provision of independent mental health advocacy to those on compulsory treatment orders in the community. In Victoria, Australia, an IMHA service is available to people who are at risk of or subject to compulsory treatment, including those who are subject to Community Treatment Orders. The IMHA service is based on the independent advocacy model developed in the United Kingdom. This paper details the benefits and challenges of providing independent non-legal advocacy to those in the community, drawing on a 15-month independent co-produced evaluation of the IMHA service. With limited publicly available sector level data, the evaluation employed qualitative approaches. Issues raised include the need to better target limited resources in the most effective way and the problem of ensuring timely and adequate access. While advocacy was well received by consumers, tensions specific to the community setting were influenced by the attitudes of clinicians to need, risk and recovery as opposed to a coherent understanding of consumer preference and choice.