BIOLOGICAL VARIATION OF HEMATOLOGY PARAMETERS AND CLINICAL APPLICATION IN AFRICAN ELEPHANTS ().

Detailed knowledge of biological variation can facilitate accurate interpretation of clinical pathology parameters. A recent biological variation study in Asian elephants () found that hematology parameters had high individuality, which suggests that population-derived reference intervals may be an insensitive diagnostic tool. In elephant medicine, sensitive hematology-related diagnostics are crucial for clinical decision-making, particularly in elephants at risk for elephant endotheliotropic herpesvirus hemorrhagic disease (EEHV-HD).

Thrombin generation potential in the presence of concizumab and rFVIIa, APCC, rFVIII, or rFIX: In vitro and ex vivo analyses.

Background: The anti-tissue factor plasma inhibitor monoclonal antibody concizumab is under clinical investigation for subcutaneous prophylaxis of hemophilia A/B (HA/HB) with or without inhibitors. Breakthrough bleeds while on concizumab prophylaxis may be treated with bypassing agents (recombinant activated factor VIIa [rFVIIa] and activated prothrombin complex concentrate [APCC]), or with factor VIII (FVIII) or factor IX (FIX).

Objectives: To evaluate the effect of combining concizumab with rFVIIa, APCC, rFVIII, and rFIX on thrombin generation (TG) potential.

BIOLOGICAL VARIATION OF HEMATOLOGY AND BIOCHEMISTRY PARAMETERS FOR THE ASIAN ELEPHANT (), AND APPLICABILITY OF POPULATION-DERIVED REFERENCE INTERVALS.

The aim of this study was to objectively evaluate the biological variation of healthy Asian elephant () hematology and biochemistry parameters, therefore enabling evidence-based clinical decision-making to improve patient management. Ten clinically healthy elephants had blood samples collected weekly for 5 wk under standardized conditions. The analytical, between- and within-individual variation, index of individuality, and reference change values were calculated using previously reported methods.

SYSTEMATIC EVALUATION OF 106 LABORATORY REFERENCE DATA ARTICLES FROM NONDOMESTIC SPECIES PUBLISHED FROM 2014 TO 2016: ASSESSING COMPLIANCE WITH REFERENCE INTERVAL GUIDELINES.

Population-based reference intervals (RIs) are vital tools used to characterize health and disease based on laboratory values. The science and statistical basis for RI generation have evolved over the past 50 yr. Current veterinary-specific guidelines by the American Society of Veterinary Clinical Pathology exist for establishing RIs from nondomestic and wild animals.

Initial joint bleed volume in a delayed on-demand treatment setup correlates with subsequent synovial changes in hemophilic mice.

Background: Hemophilic arthropathy is a debilitating morbidity of hemophilia caused by recurrent joint bleeds. We investigated if the joint bleed volume, before initiation of treatment, was linked to the subsequent degree of histopathological changes and the development of bone pathology in a mouse model of hemophilic arthropathy.

Methods: FVIII knock-out (F8-KO) mice were dosed with a micro-CT blood pool agent prior to induction of hemarthrosis.

Inflammatory Response of Healthy Horses Subjected to Small Colon Enterotomy and Treated or Not With Heparin.

The acute phase response is a response to injury and depends on the severity of the trauma. Heparin is routinely used for postsurgical treatment of horses to prevent abdominal adhesions; however, its effect on inflammation is unknown. This study aimed to assess systemic inflammatory response of horses subjected to small colon enterotomy and to evaluate heparin effects on postsurgical inflammation.

In vivo fluorescence molecular tomography of induced haemarthrosis in haemophilic mice: link between bleeding characteristics and development of bone pathology.

Background: Haemophilic arthropathy is a chronic and debilitating joint disease caused by recurrent spontaneous joint bleeds in patients with haemophilia. Understanding how characteristics of individual joint bleeds relate to the subsequent development of arthropathy could improve management and prevention of this joint disease. Here, we aimed to explore relations between joint bleed characteristics and development of bone pathology in a mouse model of haemophilic arthropathy by using novel in vivo imaging methodology.

Proteoglycan synthesis rate as a novel method to measure blood-induced cartilage degeneration in non-haemophilic and haemophilic rats.

Introduction: Haemophilic animal models are used to study blood-induced cartilage damage, but quantitative and sensitive outcome measures are needed.

Aim: To develop a novel quantitative method for detecting early cartilage degeneration in a haemophilic rat model of blood-induced joint damage.

Methods: The Sulphate incorporation ( SO assay) was applied to tibial and patellar cartilage of wild-type rats to quantify baseline proteoglycan synthesis and to evaluate the effect of 4-day blood exposure in vitro.

FVIII activity following FVIII protein infusion or FVIII gene transfer predicts the bleeding risk in hemophilia A rats.

Background: Prophylactic replacement therapy in hemophilia A (HA) patients does not adequately prevent bleeds and arthropathic complications. A more refined understanding of the relationship between coagulation factor VIII (FVIII) levels and bleeding risk during protein prophylaxis, or with gene therapy, is needed to improve patient care.

Objectives: Investigate this relationship in the HA rat, a model exhibiting spontaneous bleeds and development of arthropathy similar to HA patients.

Validation of an equine serum amyloid A assay with an unusually broad working range.

Background: Serum amyloid A (SAA) is a major equine acute phase protein and of great value in detection and monitoring of inflammation. A new immunoturbidometric assay based on monoclonal antibodies (VET-SAA, Eiken Chemical Co., Japan) may be useful for SAA measurements in routine diagnostic laboratories.

Rotational thromboelastometry can predict the probability of bleeding events in a translational rat model of haemophilia A following gene-based FVIIa prophylaxis.

Introduction: Monitoring of clinical effectiveness of bypassing agents in haemophilia patients is hampered by the lack of validated laboratory assays. Thromboelastography (TEG) and rotational thromboelastometry (ROTEM) have been evaluated for predicting clinical effectiveness of bypassing agents, however, with limited success.

Aim: Application of a longitudinal model-based approach may allow for a quantitative characterization of the link between ROTEM parameters and the probability of bleeding events.

Enhanced potency of recombinant factor VIIa with increased affinity to activated platelets.

Background: Recombinant factor VIIa (rFVIIa) enhances thrombin generation in a platelet-dependent manner; however, rFVIIa binds activated platelets with relatively low affinity. Triggering receptor expressed on myeloid cells (TREM)-like transcript (TLT)-1 is expressed exclusively on activated platelets.

Objective: To enhance the potency of rFVIIa via binding TLT-1.

TransCon CNP, a Sustained-Release C-Type Natriuretic Peptide Prodrug, a Potentially Safe and Efficacious New Therapeutic Modality for the Treatment of Comorbidities Associated with Fibroblast Growth Factor Receptor 3-Related Skeletal Dysplasias.

TransCon CNP is a C-type natriuretic peptide (CNP-38) conjugated via a cleavable linker to a polyethylene glycol carrier molecule, designed to provide sustained systemic CNP levels upon weekly subcutaneous administration. TransCon CNP is in clinical development for the treatment of comorbidities associated with achondroplasia. In both mice and cynomolgus monkeys, sustained exposure to CNP via TransCon CNP was more efficacious in stimulating bone growth than intermittent CNP exposure.

Gene-based FVIIa prophylaxis modulates the spontaneous bleeding phenotype of hemophilia A rats.

A sizable proportion of hemophilia inhibitor patients fails immune tolerance induction and requires bypass agents for long-term bleed management. Recombinant human-activated coagulation Factor VII (rhFVIIa) is an on-demand bypass hemostatic agent for bleeds in hemophilia inhibitor patients. Prophylactic use of rhFVIIa may enable sustained hemostatic management of inhibitor patients, but the critical relationship of rhFVIIa circulating levels and clinical outcome in that setting remains unclear.

Bleed volume of experimental knee haemarthrosis correlates with the subsequent degree of haemophilic arthropathy.

Background: Haemophilic arthropathy is the main morbidity of haemophilia. The individual pathological response to the same number of clinically evident joint bleeds is highly variable; thus, it remains unknown if certain joint bleeding characteristics are critical for the development of arthropathy.

Aim: To study the relation between bleed volume and subsequent development of arthropathy, we aimed to develop quantitative in vivo imaging of active joint bleeds in a mouse model of haemophilia.

Rapid inflammation and early degeneration of bone and cartilage revealed in a time-course study of induced haemarthrosis in haemophilic rats.

Objectives: Detailed knowledge of the sequential cell and tissue responses following haemarthrosis is important for a deep understanding of the pathological process initiated upon extensive bleeding into the joint causing haemophilic arthropathy (HA). The underlying pathobiology driving haemarthrosis towards HA has been difficult to establish in detail, although animal models have shed light on some processes. Previous studies have focused on a single or a few distant time points and often only characterizing one tissue type of the joint.

C-reactive protein, glucose and iron concentrations are significantly altered in dogs undergoing open ovariohysterectomy or ovariectomy.

Background: There are relatively few studies about the canine surgical stress response, a sequence of events orchestrated by the body in response to a surgical trauma which is sometimes, as shown in human surgery, deleterious to the patient. There is a need to identify objective markers to quantify this response in order to estimate tissue trauma and use the markers as potential early indicators of surgical complications. The study objective was to investigate the surgical stress response, measured by C-reactive protein (CRP), glucose and iron serum concentrations, to gonadectomy in female dogs, and to compare the response to ovariohysterectomy (OHE) with the response to ovariectomy (OVE).

Usefulness of C-reactive protein and serum amyloid A in early detection of postoperative infectious complications to tibial plateau leveling osteotomy in dogs.

Background: Cranial cruciate ligament rupture is a prevalent injury in dogs, and tibial plateau leveling osteotomy (TPLO) is one of the preferred surgical techniques. Surgical site infection is a possible complication following TPLO and measurement of serum acute phase proteins is suggested to be a way to early recognize and distinguish postoperative infectious complications from normal postoperative inflammatory conditions. In this study we investigate the changes in concentrations of the systemic inflammatory markers C-reactive protein (CRP) and serum amyloid A (SAA) following tibial plateau leveling osteotomy (TPLO) in dogs and evaluate if deviations from the changes expectedly induced by the surgical procedure are useful in early detection of post-surgical infections.

THROMBOELASTOGRAPHY IN THE HEALTHY ASIAN ELEPHANT ( ELEPHAS MAXIMUS): REFERENCE INTERVALS AND EFFECTS OF STORAGE.

Hemorrhagic disease associated with elephant endotheliotropic herpesvirus infection is the most-frequent cause of mortality in captive Asian elephants ( Elephas maximus). Survival relies on intensive monitoring of hemostatic status. Thromboelastography (TEG) utilizes whole blood samples containing all the blood components of hemostasis and is therefore a sensitive indicator of the clinical status in the patient.

Engineering of a membrane-triggered activity switch in coagulation factor VIIa.

Recombinant factor VIIa (FVIIa) variants with increased activity offer the promise to improve the treatment of bleeding episodes in patients with inhibitor-complicated hemophilia. Here, an approach was adopted to enhance the activity of FVIIa by selectively optimizing substrate turnover at the membrane surface. Under physiological conditions, endogenous FVIIa engages its cell-localized cofactor tissue factor (TF), which stimulates activity through membrane-dependent substrate recognition and allosteric effects.

Serological biomarkers detect active joint destruction and inflammation in patients with haemophilic arthropathy.

Introduction: Progressive arthropathy caused by recurrent joint bleeds is a severe complication in haemophilia.

Aim: We investigated whether biomarkers of cartilage and bone degradation, and inflammation were altered in haemophilia patients and whether these biomarkers could identify haemophilia patients with arthropathy.

Methods: Serum from 35 haemophilia patients with varying degrees of arthropathy and 43 age- and gender-matched control subjects were analysed.

Measurement of serum C-reactive protein concentration for discriminating between suppurative arthritis and osteoarthritis in dogs.

Background: In a dog with joint pain, it is important to determine whether it has suppurative joint disease, characterized by exudation of neutrophils in the synovial fluid, or not, as this affects choice of diagnostic tests and treatments. The aim of this study was to evaluate whether measurement of serum C-reactive protein (CRP) concentration could be used to discriminate between dogs with suppurative arthritis and osteoarthritis (OA). Furthermore, the concentrations of serum and synovial fluid interleukin (IL) 6 concentrations were measured in dogs with joint disease and in healthy dogs, and were correlated to serum CRP concentrations.

Altered collagen turnover in factor VIII-deficient rats with hemophilic arthropathy identifies potential novel serological biomarkers in hemophilia.

Unlabelled: Essentials Joint bleeding in hemophilia may induce significant remodeling of the extracellular matrix. Biomarkers of collagen turnover were investigated in a F8 rat model of hemophilic arthropathy. Biomarkers of cartilage degradation increased significantly during development of arthropathy.