ACVIM consensus statement on the treatment of immune thrombocytopenia in dogs and cats.

Management of immune thrombocytopenia (ITP) in dogs and cats is evolving, but there are no evidence-based guidelines to assist clinicians with treatment decisions. Likewise, the overall goals for treatment of ITP have not been established. Immunosuppressive doses of glucocorticoids are the first line treatment, but optimal treatment regimens beyond glucocorticoids remain uncertain. Additional options include secondary immunosuppressive drugs such as azathioprine, modified cyclosporine, and mycophenolate mofetil, usually selected based on clinician preference. Vincristine, human IV immunoglobulin (hIVIg), and transfusion of platelet or red blood cell-containing products are often used in more severe cases. Splenectomy and thrombopoietin receptor agonists are usually reserved for refractory cases, but when and in which patient these modalities should be employed is under debate. To develop evidence-based guidelines for individualized treatment of ITP patients, we asked 20 Population Intervention Comparison Outcome (PICO) format questions. These were addressed by 17 evidence evaluators using a literature pool of 288 articles identified by a structured search strategy. Evidence evaluators, using panel-designed templates and data extraction tools, summarized evidence and created guideline recommendations. These were integrated by treatment domain chairs and then refined by iterative Delphi survey review to reach consensus on the final guidelines. In addition, 19 non-PICO questions covering scenarios in which evidence was lacking or of low quality were answered by expert opinion using iterative Delphi surveys with panelist integration and refinement. Commentary was solicited from multiple relevant professional organizations before finalizing the consensus. The rigorous consensus process identified few comparative treatment studies, highlighting many areas of ITP treatment requiring additional studies. This statement is a companion manuscript to the ACVIM Consensus Statement on the Diagnosis of Immune Thrombocytopenia in Dogs and Cats.

Consensus on the Rational Use of Antithrombotics in Veterinary Critical Care (CURATIVE): Domain 3-Defining antithrombotic protocols.

OBJECTIVES: To systematically examine the evidence for use of a specific protocol (dose, frequency, route) of selected antithrombotic drugs, in comparisons to no therapy or to other antithrombotic therapies, to reduce the risk of complications or improve outcomes in dogs and cats at risk for thrombosis. DESIGN: Standardized, systematic evaluation of the literature, categorization of relevant articles according to level of evidence (LOE) and quality (Good, Fair, or Poor), and development of consensus on conclusions via a Delphi-style survey for application of the concepts to clinical practice. SETTINGS: Academic and referral veterinary medical centers. RESULTS: Databases searched included Medline via PubMed and CAB abstracts. Eight different antithrombotic drugs were investigated using a standardized Patient, Intervention, Comparison, Outcome (PICO) question format both for dogs and cats, including aspirin, clopidogrel, warfarin, unfractionated heparin (UFH), dalteparin, enoxaparin, fondaparinux, and rivaroxaban, generating a total of 16 worksheets. Most studies identified were experimental controlled laboratory studies in companion animals (LOE 3) with only four randomized controlled clinical trials in companion animals (LOE 1). CONCLUSIONS: Overall, evidence-based recommendations concerning specific protocols could not be formulated for most antithrombotic drugs evaluated, either because of the wide range of dosage reported (eg, aspirin in dogs) or the lack of evidence in the current literature. However, clopidogrel administration in dogs and cats at risk of arterial thrombosis, notably in cats at risk of cardiogenic thromboembolism, is supported by the literature, and specific protocols were recommended. Comparably, aspirin should not be used as a sole antithrombotic in cats with cardiomyopathy. Using the available safety profile information contained in the literature, the panel reached consensus on suggested dosage schemes for most antithrombotics. Significant knowledge gaps were highlighted, which will hopefully drive novel research.

Consensus on the Rational Use of Antithrombotics in Veterinary Critical Care (CURATIVE): Domain 2-Defining rational therapeutic usage.

OBJECTIVES: To systematically review available evidence to determine when small animals at risk of thrombosis should be treated with antiplatelet agents and anticoagulants, which antiplatelet and anticoagulant agents are most effective, and when multimodal therapy is indicated. DESIGN: Standardized, systematic evaluation of the literature, categorization of relevant articles according to level of evidence (LOE) and quality (Good, Fair, or Poor), and development of consensus on conclusions via a Delphi-style survey for application of the concepts to clinical practice. Draft recommendations were presented at 2 international veterinary conferences and made available for community assessment, review, and comment prior to final revisions and publication. SETTINGS: Academic and referral veterinary medical centers. RESULTS: Databases searched included Medline via PubMed and CAB abstracts. Twelve Population Intervention Comparison Outcome questions were devised and generated corresponding worksheets investigating indications for use of antithrombotic drugs in small animals. Seventy-eight studies were reviewed in detail. Most studies assessed were experimentally controlled laboratory studies in companion animals (56 LOE 3) with smaller numbers of LOE 2 (1), LOE 4 (5), LOE 5 (6), and LOE 6 (4) studies assessed. Only 5 randomized controlled clinical trials were identified (LOE 1, Good-Fair). The 12 worksheets generated 21 guidelines with 17 guideline statements that were refined during 3 rounds of Delphi surveys. A high degree of consensus was reached across all guideline recommendations during the Delphi process. CONCLUSIONS: Overall, systematic evidence evaluations generated 2 strong recommendations, 19 weak recommendations (formulated as suggestions), 9 situations where the evidence was insufficient to make strong recommendations, and 8 situations where no relevant evidence was retrieved to aid guideline generation. Numerous significant knowledge gaps were highlighted by the evidence reviews undertaken, indicating the need for substantial additional research in this field.

A prospective evaluation of oral Yunnan Baiyao therapy on thromboleastographic parameters in apparently healthy dogs.

OBJECTIVE: To determine the effect of Yunnan Baiyao (YB) on hemostatic parameters measured by thromboelastography (TEG) in healthy dogs administered 1 capsule of YB orally twice daily for 1 week. DESIGN: Prospective study of client-owned dogs at a small animal specialty hospital. SETTING: Private referral center. ANIMALS: Eighteen client-owned adult dogs weighing at least 15 kg. INTERVENTIONS: Dogs had a baseline TEG performed and then each dog was administered 1 capsule of YB twice daily by mouth for 1 week and the TEG was reevaluated. Any side effects attributed to YB were noted at this time. MEASUREMENTS AND MAIN RESULTS: All 18 enrolled dogs completed the study. Dogs that received 1 capsule (250 mg/capsule) of YB orally twice daily had significantly increased G as well as A30 and A60 values. There was also a significantly decreased LY30 and LY60 values after 1 week. The YB appeared well tolerated as only one dog developed mild diarrhea. CONCLUSIONS: The results of this study suggest that YB at 1 capsule orally twice daily in healthy medium to large breed dogs increases the strength of the clot as measured by TEG and that YB was apparently well tolerated in the study population reported here. Larger prospective studies in different disease states are warranted to further evaluate these preliminary findings.

B genome specific polymorphism in the TdDRF1 gene is in relationship with grain yield.

MAIN CONCLUSION: A and B genome copies of DRF1 gene in durum wheat were isolated and sequenced using gene variability. B genome specific polymorphism resulted, in a RIL population, in relationship with grain yield mainly in drought condition. Drought tolerance is one of the main components of yield potential and stability, and its improvement is a major challenge to breeders. Transcription factors are considered among the best candidate genes for developing functional markers, since they are components of the signal transduction pathways that coordinate the expression of several downstream genes. Polymorphisms of the Triticum durum dehydration responsive factor 1 (TdDRF1) gene that belongs to DREB2 transcription factor family were identified and specifically assigned to the A or B genome. A panel of primers was derived to selectively isolate the corresponding gene copies. These molecular information were also used to develop a new molecular marker: an allele-specific PCR assay discriminating two genotypes (Mohawk and Cocorit) was developed and used for screening a durum wheat recombinant inbred line population (RIL-pop) derived from the above genotypes. Phenotypic data from the RIL-pop grown during two seasons, under different environmental conditions, adopting an α-lattice design with two repetitions, were collected, analyzed and correlated with molecular data from the PCR assay. A significant association between a specific polymorphism in the B genome copy of the TdDRF1 gene and the grain yield in drought conditions were observed.

Retrospective evaluation of pimobendan and sildenafil therapy for severe pulmonary hypertension due to lung disease and hypoxia in 28 dogs (2007-2013).

Pulmonary hypertension (PH) is the persistent abnormal increase in pulmonary artery (PA) pressure and in dogs is usually secondary to congenital disease causing pulmonary over circulation, chronic respiratory disease and elevated left atrial pressure. Sildenafil (SF) is a phosphodiesterase (PDE) V inhibitor that causes pulmonary artery (PA) vasodilation by increasing pulmonary vascular concentrations of cyclic guanosine monophosphate which subsequently increases the activity of endogenous nitric oxide. Pimobendan (PB) is a PDE III inhibitor with calcium sensitizing effects thereby exerting positive inotropy and vasodilation. The purpose of this retrospective study was to evaluate the long-term survival of dogs with severe PH treated with SF and PB compared to SF alone. The use of PB in combination with SF did not result in a statistically significant increase in survival times in dogs with pulmonary hypertension secondary to chronic respiratory disease compared to SF alone.

Use of Yunnan Baiyao and epsilon aminocaproic acid in dogs with right atrial masses and pericardial effusion.

OBJECTIVE: To describe the utility of Yunnan Baiyao (YB) alone or in combination with epsilon aminocaproic acid (EAC) for the treatment of dogs with echocardiographically identified right atrial (RA) masses and pericardial effusion (PE). DESIGN: Retrospective case-controlled study. SETTING: Two private practice referral hospitals. ANIMALS: Client-owned dogs with RA masses and PE identified echocardiographically over a 3-year period. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: There were 67 dogs identified with RA masses and PE during the study period. Sixteen dogs were treated with YB alone while 8 dogs were treated with YB in combination with EAC in addition to pericardiocentesis. Forty-three dogs were treated with pericardiocentesis alone and were considered to be the control group. There was no difference between the groups in regards to signalment, physical examination abnormalities, and diagnostic test results on presentation. There was no significant difference between the 2 groups with respect to number of pericardiocenteses performed and there were no side effects attributed to the YB or EAC in any of the dogs. Median time to recurrence of clinical signs was not significantly different between the treatment (12 d, range 1-186 d) and control group (14.5 d, range 1-277 d). The median survival of dogs treated with YB alone or in combination with EAC (18 d, range 1-186 d) was also not significantly improved compared to dogs treated with pericardiocenteses alone (16 d, range 1-277 d). CONCLUSIONS: This study suggests YB alone or in combination with EAC is relatively safe but does not significantly delay recurrence of clinical signs or improve survival in dogs with RA masses and PE. Due to the small cohort size, further prospective studies evaluating these drugs and their effects on hemostasis in dogs with RA masses and PE are warranted.

Evaluation of the safety and tolerability of rivaroxaban in dogs with presumed primary immune-mediated hemolytic anemia.

OBJECTIVE: To evaluate the safety and tolerability of rivaroxaban (RIV), an oral direct factor Xa inhibitory drug, in dogs with presumed primary immune-mediated hemolytic anemia (pIMHA). DESIGN: Prospective, multicenter, positive-controlled, unblinded clinical trial. Client-owned dogs were enrolled between October 2012 and March 2014. SETTING: Private referral centers. ANIMALS: Twenty-four client-owned dogs with pIMHA. Enrolled dogs were randomized in 2 treatment groups to receive by mouth RIV or clopidogrel (CL) and low-dose aspirin (LDA). All dogs were monitored for 90 days from the enrollment in the study. INTERVENTIONS: Enrolled dogs were given a standardized immunosuppressive protocol and RIV or CL and LDA. MEASUREMENTS AND MAIN RESULTS: There was no identifiable adverse drug reaction, evidence of hemorrhage, significant prolongation of prothrombin time or activated partial thromboplastin time, or increase in transfusion requirements associated with RIV therapy compared to CL and LDA in dogs with pIMHA. There was no significant difference between treatment groups with respect to thrombotic events, survival rates to discharge, at 1 month and 3 months from diagnosis. CONCLUSIONS: This study suggests that RIV at a median dose of 0.89 mg/kg by mouth once daily was safe and well tolerated in a small group of dogs with presumed pIMHA able to tolerate oral medications and treated with a standardized immunosuppressive treatment protocol. Conclusions regarding the relative efficacy of RIV as compared to CL and LDA cannot be made due to the small size of the treatment groups and because pharmacodynamic effects were not assessed.

Use of enoxaparin in dogs with primary immune-mediated hemolytic anemia: 21 cases.

OBJECTIVE: To describe the complications and frequency of thrombosis associated with the use of enoxaparin, a low molecular weight heparin, in dogs with primary immune-mediated hemolytic anemia (IMHA). DESIGN: Retrospective case series. SETTING: Two privately owned veterinary referral hospitals. ANIMALS: Twenty-one client-owned dogs with primary IMHA. INTERVENTIONS: Dogs were treated with enoxaparin (0.8 mg/kg subcutaneously every 6 h) as the sole anticoagulation therapy starting at admission to the hospital. MEASUREMENTS AND MAIN RESULTS: Only 2 dogs had minor hemorrhagic complications associated with enoxaparin therapy. Frequency of thrombosis was not assessed. Long-term survival was comparable to other anticoagulation protocols reported for dogs with primary IMHA. CONCLUSIONS: The use of enoxaparin was safe in a small group of dogs with primary IMHA. Whether enoxaparin therapy can reduce mortality and thrombotic complications in dogs with primary IMHA compared with other anticoagulation protocols remains unknown.

Presumptive immune-mediated thrombocytopenia secondary to massive Africanized bee envenomation in a dog.

OBJECTIVE: To describe a case of immune-mediated thrombocytopenia (IMT) after massive Africanized bee envenomation in a dog. CASE SUMMARY: While boarding at a kennel, a dog was stung by approximately 300 Africanized bees. During initial veterinary examination, the dog was deemed to be in shock, characterized by collapse, with hypotension, bradycardia, and hypoglycemia. In addition, severe diffuse erythema and edema were noted over the entire body. Supportive care, including IV crystalloid and colloid fluids, dextrose, fresh frozen plasma, oxygen therapy, broad spectrum antimicrobials, dexamethasone, and diphenhydramine was initiated. The dog's condition stabilized over the next 2 days. Forty-eight hours after admission the dog developed hematemesis and hematochezia, and severe thrombocytopenia was identified. Extensive diagnostic investigation revealed no likely trigger other than the Africianized bee exposure, and a diagnosis of IMT was made. Following a red blood cell transfusion and immunosuppressive doses of dexamethasone and gastroprotectant therapy, the dog's condition stabilized, and the platelet count returned to normal after 7 days from initiation of therapy. NEW OR UNIQUE INFORMATION PROVIDED: IMT is a possible sequelae of massive Africanized bee envenomation in the dog.

Postresuscitation myocardial dysfunction in a dog.

OBJECTIVE: To describe a clinical case of postresuscitation myocardial dysfunction in a dog. CASE SUMMARY: An 11-month-old, 2.37 kg female spayed Chihuahua was referred for management post CPR after suffering cardiopulmonary arrest. Postresuscitation a gallop rhythm was identified and an echocardiogram revealed severe left ventricular dilation and severely impaired myocardial contractility with a mild eccentric jet of mitral regurgitation on color Doppler interrogation. The primary differentials were idiopathic or nutritional dilated cardiomyopathy, end-stage myocarditis, or postresuscitation myocardial dysfunction. Echocardiogram was repeated 48 hours later and showed normal left ventricular dimensions and contractility assessed as consistent with postresuscitation myocardial dysfunction. NEW OR UNIQUE INFORMATION PROVIDED: Postresuscitation myocardial dysfunction is a common complication of CPR in human medicine and is associated with a worse outcome. This is the first clinical report of postresuscitation myocardial dysfunction in a dog.

Therapeutic options for immune-mediated thrombocytopenia.

OBJECTIVE: To review the therapeutic options for immune-mediated thrombocytopenia (IMT). DATA SOURCES: Original research publications and review articles using the PubMed search engine for the phrases "immune-mediated thrombocytopenia" or "immune thrombocytopenic purpura" or "immune thormbocytopenia." VETERINARY AND HUMAN DATA SYNTHESIS: There are a number of therapeutic options for adult-onset immune thrombocytopenia in human medicine with demonstrated efficacy in clinical studies although corticosteroids and immunoglobulin therapy remain the first-line medical treatments. Thrombopoietin receptor agonist therapy and, to a lesser extent, rituximab have shown great promise in initial clinical trials and may become standard of care in human medicine for the management of IMT. Therapeutic options in veterinary medicine are less diverse and only vincristine and human intravenous immunoglobulin therapies have been evaluated in controlled clinical studies. CONCLUSIONS: There are a number of therapeutic options in the management of IMT veterinary medicine, most of which have not been investigated in clinical studies. Further research is warranted to best identify the optimal treatment strategy for IMT in veterinary patients.

Immune-mediated hemolytic anemia and severe thrombocytopenia in dogs: 12 cases (2001-2008).

OBJECTIVE: To identify and characterize the syndrome of immune-mediated hemolytic anemia (IMHA) with concurrent severe thrombocytopenia (

Treatment of Evans' syndrome with human intravenous immunoglobulin and leflunomide in a diabetic dog.

An 11-year-old, spayed female miniature schnauzer with diabetes mellitus was presumptively diagnosed with Evans' syndrome (ES). Because of the potential adverse effects of immunosuppressive doses of glucocorticoids in a diabetic dog, a single infusion of human intravenous immunoglobulin and oral leflunomide were used as first-line immunomodulatory therapy, after informed owner consent was received. This treatment resulted in complete remission of the ES, and leflunomide was discontinued after 10 months of therapy. Over a 19-month follow-up, the dog did not relapse and has remained a well-regulated diabetic.

Presumed primary immune-mediated thrombocytopenia in four cats.

Feline primary immune-mediated thrombocytopenia (pIMT) is a rare hematological disorder. Platelet-bound antibody assays for cats have variable specificity and sensitivity and are not widely available. Diagnosis of pIMT is made on the basis of exclusion of other identifiable causes of thrombocytopenia and the response to immunosuppressive therapy. This report describes four cats with severe thrombocytopenia and no detectable underlying disease. One cat was euthanased because of pulmonary hemorrhage, while the other cats had frequent relapses, two of these cats developed diabetes mellitus due to long-term corticosteroid therapy. In these cats IMT had a chronic course and responded poorly to therapy with prednisolone. Alternative immunomodulatory drugs may be considered in the treatment of feline IMT.

Treatment of severe immune-mediated thrombocytopenia with human IV immunoglobulin in 5 dogs.

BACKGROUND: Glucocorticoids with or without other immunotherapy are the initial treatment of choice for dogs with severe immune-mediated thrombocytopenia (IMT). The majority of treated dogs will have improvements in platelet counts within 5 to 7 days of starting therapy, but complications from hemorrhage often occur before a response is seen. Human IV immunoglobulin (hIVIG) blocks Fc receptors on mononuclear phagocytic cells in dogs; it is used in people with idiopathic thrombocytopenic purpura. HYPOTHESIS: The purpose of this study was to describe adverse effects and benefit of hIVIG in addition to conventional immunosuppressive therapy in dogs with severe IMT. ANIMALS: Five client-owned dogs with severe primary IMT. METHODS: Case series. The hospital database was searched for dogs with primary IMT treated with hIVIG. RESULTS: No adverse effects were noted during or after hIVIG infusion in any treated dog. Over a 6-month follow-up, all dogs were clinically normal when using conventional immunosuppressive therapy. Human IVIG was administered 3 days after initiation of immunosuppressive therapy in 4 dogs, and, after 2 days, in 1 dog. In all dogs, the mean platelet counts pre- and 24 hours post-hIVIG infusion (0.28-0.76 g/kg) were 2,500/pL and 50,600/microL (62,750/microL for the 4 responders), respectively. One dog failed to respond as promptly to hIVIG (0.34 g/kg), and the platelet count increased to 66,000/microL after 9 days of immunosuppressive therapy. The mean duration of hospitalization post-hIVIG in all 5 dogs was 1.8 days (12 hours for responders), and the mean total length of hospitalization was 4.6 days (3.5 days for responders). Active hemorrhage resolved and no packed red blood cell transfusions were required after hIVIG infusion for responders. CONCLUSIONS AND CLINICAL IMPORTANCE: Human IVIG was well tolerated and appeared to be associated with rapid platelet count recovery and amelioration of clinical signs in most dogs with IMT.