The role of tissue factor and tissue factor pathway inhibitor in health and disease states

Objective – To review the veterinary and human literature on the role of tissue factor (TF) and tissue factor pathway inhibitor (TFPI) in health and disease states.
Data Sources – Original research articles and scientific reviews from both human and veterinary literature were searched for relevance to TF and TFPI.
Human Data Synthesis – Interest in both TF and TFPI has grown widely over the last several years. The impact TF plays in coagulation, inflammation, angiogenesis, tumor metastasis, and cellular signaling has become apparent. Treatment with TFPI for severe sepsis has been examined and is still currently under investigation. Inhibition of the TF pathway is being studied as an aid in the treatment of neoplasia. The important physiologic and pathophysiologic role these molecules play has only begun to be understood.
Veterinary Data Synthesis – There is a paucity of publications that discuss the importance of TF and TFPI in veterinary medicine. An enhanced understanding of the TF pathway in human medicine, in experimental animal models treating sepsis with TFPI, and in animal models demonstrating the proangiogenic properties of TF provides relevance to veterinary medicine.
Conclusion – It is apparent that TF and TFPI are important in health and disease. An enhanced understanding of the physiologic and pathophysiologic roles of these factors provides better insight into coagulation, inflammation, angiogenesis, disseminated intravascular coagulation, and tumor metastasis. This greater understanding may provide for the development of therapeutics for sepsis, disseminated intravascular coagulation, and neoplasia.     

The ubiquitous role of zinc in health and disease

Objective – To review zinc physiology and pathophysiology and the importance of zinc toxicity and deficiency in veterinary patients.
Data Sources – A review of human and veterinary medical literature.
Human Data Synthesis – There is a significant amount of original research in humans and animals on the role of zinc in multiple organ systems. There is also significant data available on human patients with zinc abnormalities.
Veterinary Data Synthesis – Zinc deficiency has been studied in dogs with genetic disease and dietary deficiency leading to dermatological disease and immune deficiency. Zinc toxicity has been described after ingestion of metallic foreign bodies containing zinc.
Conclusions – Historically, the role of zinc in health and disease has been studied through patients with toxicity or severe deficiency with obvious clinical signs. As the ubiquitous contribution of zinc to structure and function in biological systems was discovered, clinically significant but subtle deficiency states have been revealed. In human medicine, mild zinc deficiencies are currently thought to cause chronic metabolic derangement leading to or exacerbating immune deficiency, gastrointestinal problems, endocrine disorders, neurologic dysfunction, cancer, accelerated aging, degenerative disease, and more. Determining the causal relationships between mild zinc deficiency and concurrent disease is complicated by the lack of sensitive or specific tests for zinc deficiency. The prevalence of zinc deficiency and its contribution to disease in veterinary patients is not well known. Continued research is warranted to develop more sensitive and specific tests to assess zinc status, to determine which patients are at risk for deficiency, and to optimize supplementation in health and disease.     

Apoptosis: A review of pro‐apoptotic and anti‐apoptotic pathways and dysregulation in disease

Objective – To review the human and veterinary literature on the biology of apoptosis in health and disease. Data Sources – Data were examined from the human and veterinary literature identified through Pubmed and references listed in appropriate articles pertaining to apoptosis. Human Data Synthesis – The role of apoptosis in health and disease is a rapidly growing area of research in human medicine. Apoptosis has been identified as a component of human autoimmune diseases, Alzheimer's disease, cancer, and sepsis. Veterinary Data Synthesis – Research data available from the veterinary literature pertaining to apoptosis and its role in diseases of small animal species is still in its infancy. The majority of veterinary studies focus on oncologic therapy. Most of the basic science and human clinical research studies use human blood and tissue samples and murine models. The results from these studies may be applicable to small animal species. Conclusions – Apoptosis is the complex physiologic process of programmed cell death. The pathophysiology of apoptosis and disease is only now being closely evaluated in human medicine. Knowledge of the physiologic mechanisms by which tissues regulate their size and composition is leading researchers to investigate the role of apoptosis in human diseases such as cancer, autoimmune disease and sepsis. Because it is a multifaceted process, apoptosis is difficult to target or manipulate therapeutically. Future studies may reveal methods to regulate or manipulate apoptosis and improve patient outcome.     

Critical role of the vascular endothelial cell in health and disease: a review article

Objective: To review the human and veterinary literature on the role of the vascular endothelial cell in health, as well as during hypoxic and inflammatory disease states. Data sources: Data from human and veterinary literature were reviewed through a Pubmed search and a manual search of the references listed in articles covering some aspect of vascular endothelial cell function. Human data synthesis: The development of techniques that allow the maintenance and growth of endothelial cells in culture has produced an explosion of new research in the area of endothelial cell physiology. This plethora of data has revealed the critical role that vascular endothelial cells play in both health and disease states. Interspecies variations can occur with respect to the vascular endothelial cell physiology and its response to pathologic conditions. Veterinary data synthesis: There is a paucity of information regarding the role of the vascular endothelial cell in health or disease of small animals. Many human studies use species cared for by veterinarians, providing information that may be applied to small animals and that may be used to construct future studies. Conclusion: An organ system itself, the vascular endothelium is an essential component of all organs in the body. The endothelial cell lining functions to maintain selective permeability between the blood and the tissue it supplies, regulate vascular tone, sustain blood fluidity through regulation of coagulation, and modulate interaction of leukocytes with the interstitium and inflammatory reactions. During disease states, the endothelial cell functions locally to limit the boundaries of the disease process. If these functions are not controlled, they can become a part of the pathogenic process, contributing to blood stasis and thrombosis, potentiation of local inflammation and interstitial edema formation, subsequent tissue hypoxia, and multiple organ dysfunction. Pharmacological investigations targeting the modulation of endothelial function during disease states have not yet advanced treatment protocols. Since all critically ill animals are at risk for some degree of endothelial cell dysfunction, treatment regimens should focus on promoting capillary blood flow and tissue oxygen delivery.     

Transfusion medicine in exotic pets

The decision to transfuse a patient should always be based on the packed cell volume and clinical status of the patient. This article discusses indications for transfusion and blood substitutes in exotic animal patients. The administration of blood products requires careful donor selection, knowledge of blood groups, cross-matching, and use of anticoagulants. Collection sites, volume, and administration techniques are given for different species of animals including birds, rabbits, and ferrets. Blood-transfusion therapy is not without risk. The frequency with which transfusion reactions occur in exotic pets is unknown. The most common transfusion reactions seen in small animals, along with suggested treatment, are discussed. The availability of blood products is limited in exotic pet medicine; therefore, the use of blood substitutes (Oxyglobin) has the advantage of long storage potential, no need for cross-matching, and no potential for disease transmission. General principles of blood substitutes and administration techniques will be discussed.     

Measurement of canine blood microparticles by flow cytometry: effect of anticoagulants and staining reagents

Microparticles (MPs) are released from budding plasma membranes into body fluids. The use of flow cytometry for the measurement of MP in canines has not been standardized. In this fundamental study, we compared the effect of anticoagulant agents, such as acid-citrate-dextrose (ACD) and heparin on the measurement of canine MPs in platelet-free plasma (PFP) using flow cytometry. In addition, we used annexin V, carboxyfluorescein succinimidyl ester (CFSE), or calcein tetraacetoxymethyl ester (calcein-AM), and explored the characteristics of the staining reagents in MP detection using flow cytometry. We were able to measure canine MPs in PFP prepared from ACD-anticoagulated blood using flow cytometry, in which the highest positive rate for fluorescent staining was observed when CFSE was used.     

Feline blood transfusions: A pinker shade of pale

PRACTICAL RELEVANCE: blood transfusions are a potentially life-saving procedure that are within the reach of most small animal practitioners. Only minimal equipment is required. PATIENT GROUP: any cat with clinical signs attributable to a reduced red blood cell mass that is affecting oxygen transport (as a result of reduced packed cell volume or acute blood loss) is a potential candidate for a transfusion. CLINICAL CHALLENGES: although the principles of transfusion medicine are not complicated, there can be fatal consequences if certain steps are omitted. DIAGNOSTICS: blood typing kits and blood filters are readily available from veterinary wholesalers, laboratories and blood banking services. EVIDENCE BASE: over the past three decades, a substantial body of clinical research and reports has built up covering feline blood types and transfusion medicine. This article draws on that research to provide clinical guidance aimed at all veterinarians in feline or small animal practice who either currently practise transfusion medicine or plan to do so.     

Eicosanoids in health and in disease: an appraisal

Oxygenation of the 20-carbon polyunsaturated fatty acid, arachidonic acid, which is found in most body cells of all domestic animals, leads to the formation of a group of compounds possessing biological activity. These compounds, collectively known was eicosanoids, currently receive considerable attention owing to their involvement in a wide variety of physiological and pathophysiological processes. Particular interest has been focussed in recent years on the role and control of prostanoids and leukotrienes in inflammatory and allergic conditions in animals and man. Arachidonic acid metabolites are also recognised to be intimately involved in reproductive and perinatal processes; with platelet aggregation and vascular homeostasis; kidney function; fever; certain tumours and many other normal and disease conditions. Eicosanoid research in veterinary medicine is still at a relatively early stage in many respects and in this review an attempt is given to highlight some of the functions of this important series of compounds both in health and in disease. As more evidence comes to light, it is possible that veterinary surgeons may have to consider revising their clinical approach to the treatment of certain disease states where eicosanoids are implicated or where chemotherapy may interfere with their normal physiological activities.     

Canine platelet transfusions

Objective – To review potential platelet storage options, guidelines for administration of platelets, and adverse events associated with platelet transfusions. Data Sources – Data sources included original research publications and scientific reviews. Human Data Synthesis – Transfusion of platelet concentrates (PCs) plays a key role in the management of patients with severe thrombocytopenia. Currently PCs are stored at 22°C under continuous gentle agitation for up to 5 days. Chilling of platelets is associated with rapid clearance of transfused platelets, and galactosylation of platelets has proven unsuccessful in prolonging platelet survival. Although approved by the American Association of Blood Banks, cryopreservation of human platelets in 6% DMSO largely remains a research technique. Pre‐storage leukoreduction of PCs has reduced but not eliminated acute inflammatory transfusion reactions, with platelet inflammatory mediators contributing to such reactions. Veterinary Data Synthesis – Canine plateletpheresis allows collection of a concentrate with a high platelet yield, typically 3–4.5 × 10¹¹ versus <1 × 10¹¹ for whole blood‐derived platelets, improving the ability to provide sufficient platelets to meet the recipient's transfusion needs. Cryopreservation of canine platelets in 6% DMSO offers immediate availability of platelets, with an acceptable posttransfusion in vivo platelet recovery and half‐life of 50% and 2 days, respectively. While data on administration of rehydrated lyophilized platelets in bleeding animal models are encouraging, due to a short lifespan (min) posttransfusion, their use will be limited to control of active bleeding, without a sustained increase in platelet count. Conclusions – Fresh PC remains the product of choice for control of bleeding due to severe thrombocytopenia or thrombopathia. While cryopreservation and lyophilization of canine platelets offer the benefits of immediate availability and long‐term storage, the compromise is decreased in vivo recovery and survival of platelets and some degree of impaired function, though such products could still be life saving.     

Controversies related to red blood cell transfusion in critically ill patients

Objective – To review the evolution of and controversies associated with allogenic blood transfusion in critically ill patients. Data sources – Veterinary and human literature review. Human Data Synthesis – RBC transfusion practices for ICU patients have come under scrutiny in the last 2 decades. Human trials have demonstrated relative tolerance to severe, euvolemic anemia and a significant outcome advantage following implementation of more restricted transfusion therapy. Investigators question the ability of RBCs stored longer than 2 weeks to improve tissue oxygenation, and theorize that both age and proinflammatory or immunomodulating effects of transfused cells may limit efficacy and contribute to increased patient morbidity and mortality. Also controversial is the ability of pre‐ and post‐storage leukoreduction of RBCs to mitigate adverse transfusion‐related events. Veterinary Data Synthesis – While there are several studies evaluating the transfusion trigger, the RBC storage lesion and transfusion‐related immunomodulation in experimental animal models, there is little research pertaining to clinical veterinary patients. Conclusions – RBC transfusion is unequivocally indicated for treatment of anemic hypoxia. However, critical hemoglobin or Hct below which all critically ill patients require transfusion has not been established and there are inherent risks associated with allogenic blood transfusion. Clinical trials designed to evaluate the effects of RBC age and leukoreduction on veterinary patient outcome are warranted. Implementation of evidence‐based transfusion guidelines and consideration of alternatives to allogenic blood transfusion are advisable.     

Stem cells and veterinary medicine: tools to understand diseases and enable tissue regeneration and drug discovery

New sophisticated laboratory techniques, as well as established interactions between basic science, researchers and veterinarians, have led to an exponential increase in our understanding of the animal body in health and disease. The advent of animal cloning, the identification and characterization of stem cells, and publication of the various mammalian genomes has afforded the opportunity to exploit these technologies to better understand disease and develop new therapies. In human medicine, these medical advances are already being translated into clinical practice, the promise being that previously untreatable or incurable chronic diseases will become a thing of the past. In parallel, the veterinary profession is looking to these technologies to explore novel therapies for chronic diseases, such as osteoarthritis in companion animals, and is applying these technologies to enhance food animal production. This review focuses on the emerging area of stem cell biology and explores the potential applications of stem cell technologies to veterinary medicine.     

Increasing patient safety in veterinary transfusion medicine: an overview of pretransfusion testing

Objectives – To review the principles and available technology for pretransfusion testing in veterinary medicine and discuss the indications and importance of test performance before RBC transfusion.
Data Sources – Current human and veterinary medical literature: original research articles and scientific reviews.
Summary – Indications for RBC transfusion in veterinary medicine include severe anemia or tissue hypoxia resulting from blood loss, decreased erythrocyte production, and hemolyzing conditions such as immune-mediated anemia and neonatal isoerythrolysis. Proper blood sample collection, handling, and identification are imperative for high-quality pretransfusion testing. Point-of-care blood typing methods including both typing cards and rapid gel agglutination are readily available for some species. Following blood typing, crossmatching is performed on one or more donor units of appropriate blood type. As an alternative to technically demanding tube crossmatching methods, a point-of-care gel agglutination method has recently become available for use in dogs and cats. Crossmatching reduces the risk of hemolytic transfusion reactions but does not completely eliminate the risk of other types of transfusion reactions in veterinary patients, and for this reason, all transfusion reactions should be appropriately documented and investigated.
Conclusion – The administration of blood products is a resource-intensive function of veterinary medicine and optimizing patient safety in transfusion medicine is multifaceted. Adverse reactions can be life threatening. Appropriate donor screening and collection combined with pretransfusion testing decreases the occurrence of incompatible transfusion reactions.     

Genetics of animal health and disease in cattle

There have been considerable recent advancements in animal breeding and genetics relevant to disease control in cattle, which can now be utilised as part of an overall programme for improved cattle health. This review summarises the contribution of genetic makeup to differences in resistance to many diseases affecting cattle. Significant genetic variation in susceptibility to disease does exist among cattle suggesting that genetic selection for improved resistance to disease will be fruitful. Deficiencies in accurately recorded data on individual animal susceptibility to disease are, however, currently hindering the inclusion of health and disease resistance traits in national breeding goals. Developments in 'omics' technologies, such as genomic selection, may help overcome some of the limitations of traditional breeding programmes and will be especially beneficial in breeding for lowly heritable disease traits that only manifest themselves following exposure to pathogens or environmental stressors in adulthood. However, access to large databases of phenotypes on health and disease will still be necessary. This review clearly shows that genetics make a significant contribution to the overall health and resistance to disease in cattle. Therefore, breeding programmes for improved animal health and disease resistance should be seen as an integral part of any overall national disease control strategy.     

African trypanosomosis: from immune escape and immunopathology to immune intervention

African trypanosomes can cause prolonged chronic infections through a mechanism of antigen variation whereby they manipulate the humoral immune system of their hosts. However, besides antigenic variation these extracellular parasites exert other immunoregulatory activities mainly mediated by innate cells in particular macrophage-like (M) cells. In this review, the modulation of M cells through parasite factors and host cytokines as well as their role in parasite control and immunopathology will be examined. The concept of M cell polarization into distinct activation states (M1, M2) that may contribute to trypanosusceptibility or resistance will be discussed. Finally, the possibility to interfere with such activation states hereby providing new therapeutical modalities in the treatment of this infectious disease will be illustrated.     

Comparative immunological and microbiological aspects of paratuberculosis as a model mycobacterial infection

Paratuberculosis or Johne's disease of livestock, which is caused by Mycobacterium avium subsp. paratuberculosis (MAP), has increased in prevalence and expanded in geographic and host ranges over about 100 years. The slow and progressive spread of MAP reflects its substantial adaptation to its hosts, the technical limitations of diagnosis, the lack of practical therapeutic approaches, the lack of a vaccine that prevents transmission and the complexity and difficulty of the on-farm control strategies needed to prevent infection. More recently evidence has accumulated for an association of MAP with Crohn's disease in humans, adding to the pressure on animal health authorities to take precautions by controlling paratuberculosis. Mycobacterial infections invoke complex immune responses but the essential determinants of virulence and pathogenesis are far from clear. In this review we compare the features of major diseases in humans and animals that are caused by the pathogenic mycobacteria M. ulcerans, M. avium subsp. avium, M. leprae, M. tuberculosis and MAP. We seek to answer key questions: are the common mycobacterial infections of humans and animals useful "models" for each other, or are the differences between them too great to enable meaningful extrapolation? To simplify this, the immunopathogenesis of mycobacterial infections will be defined at cellular, tissue, animal and population levels and the key events at each level will be discussed. Many pathogenic processes are similar between divergent mycobacterial diseases, and at variance between virulent and avirulent isolates of mycobacteria, suggesting that the research on the pathogenesis of one mycobacterial disease will be informative for the others.     

Detection of bacterial contamination and DNA quantification in stored blood units in 2 veterinary hospital blood banks

Blood transfusions in veterinary medicine have become increasingly more common and are now an integral part of lifesaving and advanced treatment in small and large animals. Important risks associated with transfusion of blood products include the transmission of various infectious diseases. Several guidelines suggest what infectious agents to screen for in canine and feline transfusion medicine. However, while the risk of bacterial contamination of blood products during storage and administration has not been documented in veterinary medicine, it has emerged as a cause of morbidity and mortality in human transfusion medicine. Clinical experience shows that the majority of blood component bacterial contaminations are caused by only a few species. Unlike other types of bacteria, psychrotolerant species like Pseudomonas spp. and Serratia spp. can proliferate during the storage of blood units at 4°C from a very low titer at the time of blood collection to a clinically significant level (> 10⁵ CFU/mL) causing clinical sepsis resulting from red blood cell concentrate transfusions in human medicine. The purpose of this report was to describe the detection and quantification procedures applied in 4 cases of bacterial contamination of canine and feline blood units, which suggest the need for further investigations to optimize patients’ safety in veterinary transfusion medicine.     

Transfusion medicine in veterinary emergency and critical care medicine

Transfusion medicine is a vital part of veterinary emergency and critical care medicine. The goals of this article are to review blood banking and the transfusion principles surrounding care of the critically ill or injured small animal, to highlight the differences in emergency/critical care transfusions compared with standard transfusion medicine, and to discuss traumatic blood loss and sepsis as unique entities in emergency and critical medicine.     

Physical examination and preventive care of rabbits.

As rabbits gain increasing popularity as house pets, more rabbit owners are seeking basic preventive veterinary care. Although a knowledge of the unique anatomic and physiologic characteristics of pet rabbits is essential, annual examination and review of diet and husbandry are as important as with any other species. Many disease states can be detected or prevented with routine veterinary care. Despite all the advances in diagnostic testing in veterinary medicine, there will never be a substitute for a complete physical examination.     

A computerized system for retrieval of case information in a veterinary diagnostic laboratory.

Morbidity and mortality data are necessary bases for the decision-making processes relevant to allocation of public funds for animal disease diagnoses and research. A system for information storage and retrieval capable of handling diagnostic data such as results of microbiology, parasitology, necropsy, and histopathology as well as demographic data such as owner, species, sex, breed, or geographic origin of the animal is described. This information is available to veterinarians, epidemiologists, herdsmen, and others involved in disease prevention or control efforts. The system described utilizes natural language, thus overcoming difficulties encountered in systems with numerical intermediates. Used and revised for the last 10 years, the system described has proved useful for annual administrative quantitation of services performed. In fact, the Concordance Index serves as the annual report of the University of Missouri Veterinary Medical Diagnostic Laboratory. Having accurate detailed information on individual cases, as well as a variety of composite data, has been extremely helpful in the documentation necessary for attracting funding for study of specific disease states.