A prospective cohort study to identify clinical diagnostic and prognostic markers of primary immune thrombocytopenia in dogs.

BACKGROUND: Primary immune thrombocytopenia (pITP) in dogs presents a diagnostic challenge, and clinical markers of severity are lacking. OBJECTIVES: Identify clinicopathologic features that differentiate pITP from secondary ITP (sITP) and markers related to bleeding severity, transfusion, and survival of dogs with pITP. ANIMALS: Ninety-eight thrombocytopenic dogs (58 pITP and 40 sITP). METHODS: Client-owned dogs with platelet counts <50 000/µL were enrolled in a prospective, multi-institution cohort study. History and treatment information, through a maximum of 7 days, was recorded on standard data forms. Bleeding severity was scored daily using a bleeding assessment tool (DOGiBAT). At-admission blood samples were collected for CBC, biochemistry, C-reactive protein concentration, and coagulation panels, and to measure platelet surface-associated immunoglobulin G (PSAIg) and expression of platelet membrane proteins and phospholipids. Dogs with evidence of coincident disease were classified as sITP. RESULTS: No definitive pITP diagnostic test was found. However, pITP cases were characterized by lower platelet counts, D dimer concentrations, and platelet membrane protein expression than sITP cases. Differentiation between pITP and sITP was further enhanced using logistic regression modeling combining patient sex, coagulation profile, platelet count, D dimer, and PSAIg. A second model of pITP severity indicated that low hematocrit and high BUN concentration were associated with non-survival. Low hematocrit at admission, but not platelet count or DOGiBAT score, was associated with transfusion. CONCLUSIONS AND CLINICAL IMPORTANCE: Pending validation studies, models constructed from at-admission clinicopathologic findings may improve differentiation of pITP from sITP and identify the most severe pITP cases at the time of presentation.

Divergent veterinarian and cat owner perspectives are barriers to reducing the use of cefovecin in cats.

OBJECTIVE: To understand veterinarian and cat owner perspectives on antimicrobial use in cats, reasons for prescribing cefovecin, and barriers to improving antimicrobial stewardship, including veterinarian and cat owner perspectives of giving oral medication to cats. SAMPLE: 21 New York veterinarians and 600 cat owners across the US. METHODS: Cat owners were surveyed about their preferences for and experiences in giving oral medications to cats and their experiences with antimicrobials specifically. Veterinarians were interviewed about antimicrobial use decisions in cats, benefits and drawbacks of cefovecin, and their perspectives on antimicrobial resistance. RESULTS: Many veterinarians reported feeling pressure to prescribe antimicrobials, while 41% of cat owners reported requesting antimicrobials. Although veterinarians are aware of the downsides of prescribing cefovecin, many prescribed cefovecin in situations where an antimicrobial was not needed or cefovecin may not have been the best choice. Veterinarians thought that 20% of cat owners could not give oral medications, but < 10% of cat owners had a cat that was impossible to medicate. CLINICAL RELEVANCE: The disconnect between veterinarians' assessment of and cat owners' reported abilities in administering oral medication may contribute to cefovecin use. Demonstrating for cat owners how to give oral medication may help improve compliance and reduce the use of parenteral long-acting formulations. Structural and educational interventions are needed to address other contributors to inappropriate antimicrobial use. This research provides the specific considerations about barriers and motivations for cat owners and veterinarians that are required to guide strategic, tailored interventions for both audiences to advance stewardship.

Pathways to sustainable antimicrobial use in cats.

Antimicrobial stewardship encompasses all the individual and collective actions that medical professionals take to preserve the efficacy of antimicrobials. It is a one-health problem, affecting animals and humans. The current state of antimicrobial use in cats, particularly (1) the overuse and improper use of cefovecin, which belongs to the third-generation cephalosporin class that is critically important to human health, and (2) use of antimicrobials when they are not needed, poses unsustainable risks of antimicrobial resistance. This paper describes the principles of antimicrobial stewardship and stewardship challenges faced by feline veterinarians, including (1) poor adherence to or awareness of antimicrobial use guidelines, (2) lack of access to affordable diagnostic tests and antibiograms, (3) lack of access to materials and tools for clients that may facilitate more sustainable antimicrobial use and help cat owners understand resistance risks, (4) underestimating the ability of cat owners to administer oral antimicrobials, and (5) limited time and resources to support stewardship efforts. Based on research described in this paper; an original research article by Cazer et al, JAVMA, December 2023; and a Currents in One Health article by Cobo-Angel et al, AJVR, December 2023, several solutions are proposed to advance antimicrobial stewardship in feline medicine. Many of these proposals were expressly requested by veterinarians interviewed in Cazer et al, JAVMA, December 2023. Education and training of veterinarians and cat owners is an essential step toward sustainable antimicrobial use, but it must be complemented with innovations in diagnostic testing, antimicrobial drug development, structural changes, and technological supports.

Factor XII deficiency is common in domestic cats and associated with two high frequency F12 mutations.

Factor XII (FXII) is a coagulation protein that initiates surface-activation of the coagulation cascade in vitro. The protein's in vivo role, however, remains poorly defined. Factor XII deficiency, or Hageman trait, is a rare hereditary disorder that is not associated with bleeding, and wide variations in FXII activity (FXII:C) exist among healthy people. While FXII-deficient knockout mice appear to be resistant to arterial thrombosis, human F12 polymorphisms that influence FXII:C have not been associated with thrombotic risk in population surveys. Factor XII deficiency is a naturally occurring hereditary trait in domestic cats. We undertook phenotypic and genotypic analyses of FXII-deficient cats for comparative studies with the human disease counterpart. A retrospective review of feline submissions to our laboratory revealed that FXII deficiency is common in domestic cats, and also present in many different breeds. The trait has a geographic bias toward the Midwestern United States. Clinical history, coagulation assays, and samples for F12 sequencing were obtained from 26 FXII deficient cats. None of the cats had experienced abnormal bleeding and their residual FXII:C was related to F12 mutation number and mutation-type. We found 2 high frequency F12 mutations: an exon 13 missense mutation (c.1631G > C) and an exon 11 deletion mutation (c.1321delC), and additional sequence variants throughout the gene. Factor XII deficiency in pet cat populations provides an animal model system to help clarify the biologic actions and clinical relevance of FXII protein.

Randomized placebo-controlled study of the effects of Yunnan Baiyao on hemostasis in horses.

OBJECTIVE To determine effects of oral administration of Yunnan Baiyao on platelet activation, coagulation, and fibrinolysis in healthy horses. ANIMALS 12 healthy adult horses. PROCEDURES In a randomized blinded crossover study that included a 4-week washout period between treatments, horses were orally administered a paste containing Yunnan Baiyao (15 mg/kg) or placebo at 12-hour intervals for 3 days. Blood samples were collected before start of treatment (time 0) and at 24 and 72 hours for a CBC, measurement of fibrinogen concentration, coagulation screening tests, and a panel of assays to assess platelet activation (including ADP- and collagen-induced aggregation and closure times, flow-cytometric variables of platelet-leukocyte aggregates, platelet membrane P-selectin and phosphatidylserine expression, and microparticle release), von Willebrand factor (vWF) concentration, and cofactor activity. In addition, thrombelastography was used to evaluate fibrin formation in tissue factor-activated whole blood and plasma and to assess tissue plasminogen activator-induced plasma fibrinolysis. For each treatment, values obtained before and 72 hours after start of administration were compared by use of Wilcoxon signed rank tests. RESULTS Yunnan Baiyao treatment had no significant effect on any hemostatic variable, compared with results for the placebo treatment. CONCLUSIONS AND CLINICAL RELEVANCE Administration of Yunnan Baiyao at a dosage typically used in clinical practice had no effect on in vitro measures of platelet or vWF function and no enhancement of fibrin-clot formation or stability. Any hemostatic actions of Yunnan Baiyao may require higher dosages or result from cell-surface interactions at sites of vascular and tissue injury not examined in this study.

Effects of clopidogrel on horses with experimentally induced endotoxemia.

OBJECTIVE: To evaluate the effects of clopidogrel on clinical and clinicopathologic variables in healthy horses with experimentally induced endotoxemia. ANIMALS: 12 adult mares. Procedures-Horses were assigned with a randomization procedure to receive clopidogrel (4 mg/kg, once, then 2 mg/kg, q 24 h; n = 6) or a placebo (6) through a nasogastric tube. After 72 hours of treatment, horses received lipopolysaccharide (LPS; 30 ng/kg, IV). Heart rate, respiratory rate, rectal temperature, CBC variables, plasma fibrinogen concentration, serum tumor necrosis factor-α concentration, plasma von Willebrand factor concentration, and measures of platelet activation (including ADP- and collagen-induced platelet aggregation and closure times, thrombelastography variables, and results of flow cytometric detection of platelet membrane P-selectin, phosphatidylserine, and microparticles) were determined at various times before and after LPS administration by investigators unaware of the treatment groups. Statistical analyses were performed with repeated-measures ANOVA. RESULTS: 4 of 6 clopidogrel-treated horses had significant decreases in ADP-induced platelet aggregation before and after LPS administration. Heart rate increased significantly after LPS administration only for the placebo group. No significant differences were detected between groups for CBC variables, closure time, and plasma concentration of fibrinogen or serum concentration of tumor necrosis factor-α, and no clinically relevant differences were detected for other hemostatic variables. CONCLUSIONS AND CLINICAL RELEVANCE: In this study, administration of LPS did not induce platelet hyperreactivity in horses on the basis of measures of platelet adhesion, aggregation, degranulation, and procoagulant activity. Administration of clopidogrel was associated with variable platelet antiaggregatory activity and attenuated some clinical signs of endotoxemia.

Effects of clopidogrel on the platelet activation response in horses.

OBJECTIVE: To evaluate the platelet activation response before and after treatment with clopidogrel in horses. ANIMALS: 12 healthy adult mares. PROCEDURES: In a masked study, horses (6/group) were randomly allocated to alternately receive placebo or clopidogrel via nasogastric tube at a loading dose of 4 mg/kg followed by 2 mg/kg every 24 hours. Blood samples were collected before and 72 hours after initiation of treatment for ADP- and collagen-induced light transmission aggregometry; determination of closure time in collagen-ADP cartridges; modified thrombelastography for comparison of maximal amplitudes generated by kaolin, reptilase, and reptilase plus ADP activation; and flow cytometric tests to detect platelet fibrinogen binding, P-selectin expression, and phosphatidylserine externalization before and after ex vivo stimulation with thrombin, convulxin, thrombin with convulxin, and calcium ionophore. RESULTS: Clopidogrel administration induced a significant decrease in mean aggregation response to 5 µM and 10 µM ADP stimulation; however, 2 horses had resistance to clopidogrel's inhibitory action. Significant differences after clopidogrel treatment were not found in any other tests of platelet function. CONCLUSIONS AND CLINICAL RELEVANCE: Assays using commercially available reagents were configured to measure different variables of the platelet activation response; however, clopidogrel's platelet inhibitory action was only detected by ADP-induced light transmission aggregometry. Results also suggested that horses, like humans, have interindividual variability in response to clopidogrel that may influence the drug's clinical efficacy as an antiplatelet agent.