Cp and Cpk values as a function of the specification limit (USL-LSL). The process capability is based on the critical values (Co) according to Pearn et al. [26].
\\n\\n
IntechOpen Book Series will also publish a program of research-driven Thematic Edited Volumes that focus on specific areas and allow for a more in-depth overview of a particular subject.
\\n\\nIntechOpen Book Series will be launching regularly to offer our authors and editors exciting opportunities to publish their research Open Access. We will begin by relaunching some of our existing Book Series in this innovative book format, and will expand in 2022 into rapidly growing research fields that are driving and advancing society.
\\n\\nLaunching 2021
\\n\\nArtificial Intelligence, ISSN 2633-1403
\\n\\nVeterinary Medicine and Science, ISSN 2632-0517
\\n\\nBiochemistry, ISSN 2632-0983
\\n\\nBiomedical Engineering, ISSN 2631-5343
\\n\\nInfectious Diseases, ISSN 2631-6188
\\n\\nPhysiology (Coming Soon)
\\n\\nDentistry (Coming Soon)
\\n\\nWe invite you to explore our IntechOpen Book Series, find the right publishing program for you and reach your desired audience in record time.
\\n\\nNote: Edited in October 2021
\\n"}]',published:!0,mainMedia:{caption:"",originalUrl:"/media/original/132"}},components:[{type:"htmlEditorComponent",content:'With the desire to make book publishing more relevant for the digital age and offer innovative Open Access publishing options, we are thrilled to announce the launch of our new publishing format: IntechOpen Book Series.
\n\nDesigned to cover fast-moving research fields in rapidly expanding areas, our Book Series feature a Topic structure allowing us to present the most relevant sub-disciplines. Book Series are headed by Series Editors, and a team of Topic Editors supported by international Editorial Board members. Topics are always open for submissions, with an Annual Volume published each calendar year.
\n\nAfter a robust peer-review process, accepted works are published quickly, thanks to Online First, ensuring research is made available to the scientific community without delay.
\n\nOur innovative Book Series format brings you:
\n\nIntechOpen Book Series will also publish a program of research-driven Thematic Edited Volumes that focus on specific areas and allow for a more in-depth overview of a particular subject.
\n\nIntechOpen Book Series will be launching regularly to offer our authors and editors exciting opportunities to publish their research Open Access. We will begin by relaunching some of our existing Book Series in this innovative book format, and will expand in 2022 into rapidly growing research fields that are driving and advancing society.
\n\nLaunching 2021
\n\nArtificial Intelligence, ISSN 2633-1403
\n\nVeterinary Medicine and Science, ISSN 2632-0517
\n\nBiochemistry, ISSN 2632-0983
\n\nBiomedical Engineering, ISSN 2631-5343
\n\nInfectious Diseases, ISSN 2631-6188
\n\nPhysiology (Coming Soon)
\n\nDentistry (Coming Soon)
\n\nWe invite you to explore our IntechOpen Book Series, find the right publishing program for you and reach your desired audience in record time.
\n\nNote: Edited in October 2021
\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"6373",leadTitle:null,fullTitle:"Myocardial Infarction",title:"Myocardial Infarction",subtitle:null,reviewType:"peer-reviewed",abstract:"Atherosclerotic cardiovascular disease is still the most common cause of death among adults. Its prevalence is increasing in developing countries and despite all advances in both diagnostic tools and treatment modalities, it is still very common in the developed world. Obesity, diabetes mellitus, hypercholesterolemia and overuse of dietary salt play a pivotal role in increased cardiovascular morbidity and mortality worldwide. Current clinical efforts are mainly focused on the diagnosis and treatment of myocardial infarction. In this book, we provide epidemiological data on myocardial infarction and atherosclerotic cardiovascular disease, current diagnostic biochemical tests and management strategies. A specific patient group, children, experiencing myocardial infarction are also addressed. Current advances in the management of myocardial infarction have decreased the morbidity and mortality from atherosclerotic cardiovascular disease and especially myocardial infarction; however, more can be achieved by the prevention of atherosclerotic processes via focusing on the early stages of the disease.",isbn:"978-1-78984-869-4",printIsbn:"978-1-78984-868-7",pdfIsbn:"978-1-83881-437-3",doi:"10.5772/intechopen.69907",price:119,priceEur:129,priceUsd:155,slug:"myocardial-infarction",numberOfPages:138,isOpenForSubmission:!1,isInWos:1,isInBkci:!1,hash:"10bca0bf18d68ec3c1641dbc3a1ae899",bookSignature:"Burak Pamukçu",publishedDate:"January 3rd 2019",coverURL:"https://cdn.intechopen.com/books/images_new/6373.jpg",numberOfDownloads:12543,numberOfWosCitations:23,numberOfCrossrefCitations:15,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:29,numberOfDimensionsCitationsByBook:0,hasAltmetrics:1,numberOfTotalCitations:67,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 30th 2017",dateEndSecondStepPublish:"June 20th 2017",dateEndThirdStepPublish:"October 29th 2017",dateEndFourthStepPublish:"December 29th 2017",dateEndFifthStepPublish:"February 28th 2018",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"70686",title:"Dr.",name:"Burak",middleName:null,surname:"Pamukçu",slug:"burak-pamukcu",fullName:"Burak Pamukçu",profilePictureURL:"https://mts.intechopen.com/storage/users/70686/images/system/70686.jpeg",biography:"Burak Pamukçu (M.D.) obtained a doctorate degree in Cardiology from Istanbul University Faculty of Medicine, Istanbul, Turkey. Dr. Pamukçu finalized his post doctorate fellowship (European Society of Cardiology Atherothrombosis Research Fellowship) at the University Department of Medicine, Centre for Cardiovascular Sciences, City Hospital, Birmingham, England, UK. He is mainly interested in atherothrombosis, atherosclerotic heart vessel disease, antithrombotic therapy and interventional cardiology. Currently Dr. Pamukçu is working as a Consultant Cardiologist and Associate Professor of Cardiology in Acıbadem Healthcare Group. He has published 99 scientific publications and served as reviewer for thirty different medical journals. He is also serving as associate editor and editorial board member at peer reviewed medical scientific journals.",institutionString:"Acibadem Mehmet Ali Aydinlar University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"Istanbul University",institutionURL:null,country:{name:"Turkey"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"170",title:"Cardiology and Cardiovascular Medicine",slug:"cardiology-and-cardiovascular-medicine"}],chapters:[{id:"64090",title:"Introductory Chapter: Atherosclerotic Cardiovascular Disease",doi:"10.5772/intechopen.81697",slug:"introductory-chapter-atherosclerotic-cardiovascular-disease",totalDownloads:963,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:null,signatures:"Burak Pamukcu",downloadPdfUrl:"/chapter/pdf-download/64090",previewPdfUrl:"/chapter/pdf-preview/64090",authors:[{id:"70686",title:"Dr.",name:"Burak",surname:"Pamukçu",slug:"burak-pamukcu",fullName:"Burak Pamukçu"}],corrections:null},{id:"59778",title:"Epidemiology of Myocardial Infarction",doi:"10.5772/intechopen.74768",slug:"epidemiology-of-myocardial-infarction",totalDownloads:4453,totalCrossrefCites:11,totalDimensionsCites:22,hasAltmetrics:1,abstract:"Coronary heart disease (CHD) is the leading cause of morbidity and mortality throughout the world. The most common form of CHD is the myocardial infarction. It is responsible for over 15% of mortality each year, among the vast majority of people suffering from non-ST-segment elevation myocardial infarction (NSTEMI) than ST-segment elevation myocardial infarction (STEMI). The prevalence of myocardial infarction (MI) is higher in men in all age-specific groups than women. Although the incidence of MI is decreased in the industrialized nations partly because of improved health systems and implementation of effective public health strategies, nevertheless the rates are surging in the developing countries such as South Asia, parts of Latin America, and Eastern Europe. The modifiable risk factors represent over 90% of the risk for acute MI. The risk factors such as dyslipidemia, smoking, psychosocial stressors, diabetes mellitus, hypertension, obesity, alcohol consumption, physical inactivity, and a diet low in fruits and vegetables were strongly associated with acute MI.",signatures:"Joshua Chadwick Jayaraj, Karapet Davatyan, S.S. Subramanian and Jemmi Priya",downloadPdfUrl:"/chapter/pdf-download/59778",previewPdfUrl:"/chapter/pdf-preview/59778",authors:[{id:"223196",title:"Dr.",name:"Joshua",surname:"Chadwick",slug:"joshua-chadwick",fullName:"Joshua Chadwick"},{id:"231054",title:"Dr.",name:"Karapet",surname:"Davatyan",slug:"karapet-davatyan",fullName:"Karapet Davatyan"},{id:"231055",title:"Ms.",name:"Jemmi",surname:"Priya",slug:"jemmi-priya",fullName:"Jemmi Priya"},{id:"244487",title:"Dr.",name:"S.S.",surname:"Subramanian",slug:"s.s.-subramanian",fullName:"S.S. Subramanian"}],corrections:null},{id:"62951",title:"The Diagnostic Value of Biochemical Cardiac Markers in Acute Myocardial Infarction",doi:"10.5772/intechopen.76150",slug:"the-diagnostic-value-of-biochemical-cardiac-markers-in-acute-myocardial-infarction",totalDownloads:2027,totalCrossrefCites:1,totalDimensionsCites:3,hasAltmetrics:0,abstract:"Cardiovascular disease is the leading cause of death worldwide. The role of cardiac markers in the diagnosis, risk stratification, and treatment of patients with chest pain is vital. Patients with elevated cardiac troponin levels but negative CK-MB who were formerly diagnosed with unstable angina or minor myocardial injury are now reclassified as non–ST-segment elevation MI (NSTEMI) even in the absence of diagnostic ECG changes. CK-MB is both a sensitive and specific marker for myocardial infarction. Cardiac troponin T is a cardio-specific, highly sensitive marker for myocardial damage. Cardiac troponin I is a contractile protein exclusively present in the cardiac muscle. The absolute cardiospecificity of cTnI allows the diagnosis of myocardial infarction distinct from muscle lesions and non-cardiac surgery. In 2000, the European Society of Cardiology and the American College of Cardiology redefined AMI with a particular advocacy on troponin. The 2002/2007 American College of Cardiology (ACC) and the American Heart Association (AHA) Guideline Update for the management of these patients strongly recommend to include cTnI. Specifically, with rare exception, the diagnosis cannot be made in the absence of elevated biomarkers of cardiac injury.",signatures:"Shazia Rashid, Arif Malik, Rukhshan Khurshid, Uzma Faryal and\nSumera Qazi",downloadPdfUrl:"/chapter/pdf-download/62951",previewPdfUrl:"/chapter/pdf-preview/62951",authors:[{id:"222194",title:"Associate Prof.",name:"Shazia",surname:"Rashid",slug:"shazia-rashid",fullName:"Shazia Rashid"},{id:"222621",title:"Prof.",name:"Arif",surname:"Malik",slug:"arif-malik",fullName:"Arif Malik"},{id:"238058",title:"Dr.",name:"Rakhshan",surname:"Khurshid",slug:"rakhshan-khurshid",fullName:"Rakhshan Khurshid"},{id:"238060",title:"Dr.",name:"Uzma",surname:"Faryal",slug:"uzma-faryal",fullName:"Uzma Faryal"},{id:"238062",title:"Dr.",name:"Sumera",surname:"Qazi",slug:"sumera-qazi",fullName:"Sumera Qazi"}],corrections:null},{id:"60334",title:"Interventional Therapies for Post-Cardiac Arrest Patients Suffering from Coronary Artery Disease",doi:"10.5772/intechopen.75045",slug:"interventional-therapies-for-post-cardiac-arrest-patients-suffering-from-coronary-artery-disease",totalDownloads:1040,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Acute myocardial infarction and coronary artery disease (CAD) are the most common causes for the development of malignant arrhythmia often leading to cardiogenic shock and cardiac arrest. Structural heart disease represents the main pathology in older patients, whereas young adults mostly suffer from cardiomyopathies and channelopathies. This book chapter delineates modern interventional therapies for patients with cardiogenic shock or aborted cardiac arrest. Epidemiological data on the incidence of malignant arrhythmia depending causing cardiac arrest depending on the presence or absence of CAD and myocardial infarction are presented. Realistic difficulties within clinical decision-making are counterbalanced for and against an early, aggressive and invasive therapeutic approach including early coronary angiography with percutaneous coronary intervention (PCI), targeted temperature management and mechanical cardiac assist devices, depending on the individual clinical presentation and underlying cardiac arrhythmia.",signatures:"Michael Behnes, Philipp Kuche, Ibrahim Akin and Kambis Mashayekhi",downloadPdfUrl:"/chapter/pdf-download/60334",previewPdfUrl:"/chapter/pdf-preview/60334",authors:[{id:"189154",title:"Prof.",name:"Ibrahim",surname:"Akin",slug:"ibrahim-akin",fullName:"Ibrahim Akin"},{id:"204569",title:"Dr.",name:"Michael",surname:"Behnes",slug:"michael-behnes",fullName:"Michael Behnes"},{id:"213288",title:"Dr.",name:"Kambis",surname:"Mashayekhi",slug:"kambis-mashayekhi",fullName:"Kambis Mashayekhi"},{id:"240764",title:"Dr.",name:"Philipp",surname:"Kuche",slug:"philipp-kuche",fullName:"Philipp Kuche"}],corrections:null},{id:"61346",title:"Non-ST Elevation Myocardial Infarction: Diagnosis and Management",doi:"10.5772/intechopen.76241",slug:"non-st-elevation-myocardial-infarction-diagnosis-and-management",totalDownloads:2454,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Cardiovascular disease is expected to be the main cause of death globally due to the rapidly increasing prevalence of obesity, hypertension and diabetes mellitus. Atherosclerotic lesions and plaque rupture are the most common cause of myocardial infarction. Resting 12-lead ECG is the first diagnostic test for patients with chest pain and should be performed and interpreted within the first 10 min of the patient’s admission to the emergency department. Cardiac biomarkers preferably, high-sensitivity cardiac troponin, is mandatory in all patients with suspected NSTEMI for the diagnosis, risk stratification and treatment. Rapid, efficient diagnosis and risk stratification of patients with chest pain will help to administer the appropriate medication and plan for the timing of invasive strategy and the choice of revascularization. This chapter helps to simply but elaborately discuss the diagnosis, risk stratification and the management of patients with non-ST elevation of myocardial infarction.",signatures:"Yaser Al Ahmad and Mohammed T. Ali",downloadPdfUrl:"/chapter/pdf-download/61346",previewPdfUrl:"/chapter/pdf-preview/61346",authors:[{id:"218369",title:"Dr.",name:"Mohammed",surname:"Ali",slug:"mohammed-ali",fullName:"Mohammed Ali"},{id:"248884",title:"Dr.",name:"Yaser",surname:"Alahamd",slug:"yaser-alahamd",fullName:"Yaser Alahamd"}],corrections:null},{id:"60068",title:"Myocardial Infarction in Children",doi:"10.5772/intechopen.74793",slug:"myocardial-infarction-in-children",totalDownloads:1610,totalCrossrefCites:2,totalDimensionsCites:3,hasAltmetrics:1,abstract:"Myocardial infarction (MI) is a clinical condition that develops associated with a sudden reduction or interruption of the blood flow of the vessels supplying the heart for various reasons. The electrocardiographic, echocardiographic and enzymatic diagnostic criteria of MI have been well defined in adults, in children there are some difficulties. Although seen more often in the presence of congenital heart disease (CHD), MI may also be seen in patients without CHD. Unlike atherosclerotic coronary artery disease in adult patients, ischaemia and infarct in children are often associated with coronary artery anomalies and CHD. In addition, congenital prothrombotic diseases, vasculitis, surgical or interventional procedures may also cause ischaemia and infarct. Subendocardial ischaemia, especially aortic stenosis characterised by hypertrophy in the left ventricle is often seen in hypertrophic cardiomyopathy or hypertensive patients. The most important risk factors in neonates and infants are the presence of CHD, coronary artery anomalies and perinatal asfixia. The most frequently seen causes of pediatric myocardial infarction (PMI) are abnormal left coronary artery originating from the pulmonary artery (ALCAPA) and Kawasaki disease. Another often seen cause of PMI is patients who underwent arterial switch operations.",signatures:"Meki Bilici, Mehmet Ture and Hasan Balik",downloadPdfUrl:"/chapter/pdf-download/60068",previewPdfUrl:"/chapter/pdf-preview/60068",authors:[{id:"219534",title:"Associate Prof.",name:"Meki",surname:"Bilici",slug:"meki-bilici",fullName:"Meki Bilici"},{id:"239944",title:"Dr.",name:"Mehmet",surname:"Ture",slug:"mehmet-ture",fullName:"Mehmet Ture"},{id:"239945",title:"Dr.",name:"Hasan",surname:"Balik",slug:"hasan-balik",fullName:"Hasan Balik"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"7055",title:"Angiography",subtitle:null,isOpenForSubmission:!1,hash:"20638a6ce5e042484cc33b5b510cdca6",slug:"angiography",bookSignature:"Burak Pamukçu",coverURL:"https://cdn.intechopen.com/books/images_new/7055.jpg",editedByType:"Edited by",editors:[{id:"70686",title:"Dr.",name:"Burak",surname:"Pamukçu",slug:"burak-pamukcu",fullName:"Burak Pamukçu"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6209",title:"Endothelial Dysfunction",subtitle:"Old Concepts and New Challenges",isOpenForSubmission:!1,hash:"f6e76bbf7858977527679a6e6ad6a173",slug:"endothelial-dysfunction-old-concepts-and-new-challenges",bookSignature:"Helena Lenasi",coverURL:"https://cdn.intechopen.com/books/images_new/6209.jpg",editedByType:"Edited by",editors:[{id:"68746",title:"Dr.",name:"Helena",surname:"Lenasi",slug:"helena-lenasi",fullName:"Helena Lenasi"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7220",title:"Congenital Heart Disease",subtitle:null,isOpenForSubmission:!1,hash:"f59bacfffcccc636ec3082869d10a82e",slug:"congenital-heart-disease",bookSignature:"David C. 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Blood transfusion has become more performable in small and large animal practice. By donor selection and the availability of blood component substitutes, usage of the blood products improved. The use of blood component therapy safely needed knowledge of blood groups, antibody prevalence and the impact of blood groups on veterinary transfusion medicine. Animal blood transfusions antibodies against blood group antigens also play a role. In addition knowledge of the means to decrease the risk of adverse reactions by using proper donors and screening assays that simplify detection of serological incompatibility is important. The clinical significance of blood group antigens in veterinary medicine is generally in the areas of transfusion reactions and neonatal isoerythrolysis (NI). This chapter includes an update on canine and feline, horse, donkey, cattle, sheep, gaot, pig, llama and alpaca blood groups and known blood incompatibilities, donor selection and blood collection, storage of blood components, available equine blood products and indications for transfusion, whole blood (WB) and blood product transfusion in ruminants and camelids, blood component and blood substitute therapy, administration, and adverse reactions in small and large animal blood transfusion.
Blood types are classified according to specific antigens on the surface of erythrocytes. Platelets, leukocytes, and body tissues and fluids may also consists of erytrocyte antigens. [1]. In immunogenicity and clinical significance these antigens can differ. They can serve as markers of disease in some cases and taking part in recognition of self. The clinical significance of blood group antigens is generally noted in transfusion reactions and neonatal isoerythrolysis (NI) in veterinary medicine [2]. These antigens can characteristically trigger a reaction caused by circulating anti-erythrocyte antibodies in the opposite host or donor. These antibodies can occur naturally. Also they can be induced by a previous transfusion. Interaction leads to the destruction by hemolysis of red blood cells (RBCs). This is one of the severe and potentially life-threatening situation. [3].
The dog erytrocyte antigen types or blood types are categorized by the DEA (Dog Erythrocyte Antigen) system. DEA 1.1, 1.2, and 1.3 are termed A system. There are also DEA 3, DEA 4, DEA 5, DEA 6, DEA 7 and DEA 8. [2]. In the United States the incidence of DEA 1.1 is approximately 45% and DEA 1.2 is 20% [4]. DEA 1.3 is common in German shepherd dogs and has been reported only in Australia [5]. Frequency of DEA 1.1 in Kangal Dog was found as 61.1% in Turkey [6]. In Croatia where the closest data studied the rate was 66.7% [7]. The rate was also 56.9% in Portugal [8] and 55% in Japan [9]. Approximately 60 % of the canine population is in DEAs 1.1 and 1.2 group. DEA 1.1 is the strongest antigen in the dog. Two membrane proteins of 50 and 200 kD has been identified by a monoclonal antibody to DEA 1.1 using immunoprecipitation techniques. [10]. Presenting in a single band DEA 1.2 has been found to be an 85-kD protein [11].
DEA 1.1 is the most antigenic group in respect to transfusion medicine. Little is investigated about DEA 3, 4, 5 and 7 in comparison to DEA 1.1. In literature, the frequency of DEA 3 is lower in comparison to DEA 1.1 blood type. In the United States it is determined that approximately 6% of the general dog population is DEA 3 positive [12]. This rate is reported as 13% in Brazil [13]. In Turkey, DEA 3 is most found blood type in the Kangal Dog [6]. In the canine blood groups DEA 4 is the most common type. In USA, it is indicated that overall 98% of the general dog population have DEA 4 blood [12]. In Brazil, all dogs blood type were positive for DEA 4 [13]. The molecular weight of DEA 4 present in a single band has been found to be 32 to 40 kD using immunoprecipitation techniques [11].
In the United States typing sera can be commercially obtained only for DEA 1.1, 1.2, 3, 4, 5, and 7 [4]. In Brazil a report studied on German shepherd dogs determined that 14% of the dogs were positive for DEA 5 and 8% were positive for DEA 7 [13]. The frequency of DEA 5 and 7 positive dogs was 55.5% and 71.7% respectively in Turkey [6]. Also, DEA 7 may cause an antibody response in dogs that lack it. A system of nomenclature about antigen Tr has described. The Tr antigen system is a 3-phenotype, 6-genotype system [14]. The molecular weight of DEA 7 present in 3 distinct bands has been found to be 53, 58, and 63 kD by using immunoprecipitation techniques [11].
An exact definition of a canine universal donor is not agreed among veterinary transfusion experts. Well excepted description of the universal donor is that a dog negative for DEA 1.1, 1.2, DEA 3, DEA 5, DEA 7, and positive for DEA 4. It is difficult to find DEA 4 negative dog because 98% of all dogs are positive for DEA 4. Thus there is a very little chance to influence donor selection. If the dog is DEA 7 positive, some other experts do not exclude it from the donor pool [15]. In most populations the incidence of DEA 4 blood type is more than 98% [16]. Because of this in transfusion medicine these dogs are the best candidate for being a donor. If other donors are known to be compatible with the recipient they can also be utilized [17]. DEA 3, 5 and 7 negative dogs have naturally occurring antibodies to DEA 3, 5 and 7 positive red cells. However during the first transfusion these blood groups do not possess a major transfusion reaction [4]. In Turkey, the most common blood types were DEA 1.1, 4 and 7. Because all Kangal dogs have DEA 4 positivity it does not seem to be important in respect to transfusion medicine. The prevalence and antigenic properties of DEA 1.1 and 7 are significantly important. If unmatched transfusion is performed in Turkish Kangal dogs they can constitute acute hemolytic transfusion reactions [6]. Dogs with DEA 1.1 or 1.2 are called group A positive. Adversely, dogs do not have DEA 1.1 or 1.2 are called group A negative [1].
A blood group system described as N-acetylneuraminic acid and N-glycolylneuraminic acid present on gangliosides (hematosides) of the RBC membrane in Japan [18]. It is referred as the D system. This system is consist of two antigens, D1 and D2, with phenotypes, D1, D2, and D1D2. The D1 and D2 antigens are codominanat factors. Anti-D1 is identical to anti-DEA3. The importance of this system in transfusion medicine pointed out by transfusion of D2 type blood into a D1 type patient, or of D1 type blood into a D2 type patient consistently cause severe acute transfusion reactions [19, 20]. RBCs of some dogs designated as type C at titre sup to 128 are aglutinated rather than lectin extracted from seeds of Clerodendron tricotomum. Type C is completely negative for other dogs. C system was compared to the DEA system and determined to be different [10, 19, 21]. Specific IgG alloantibodies in previously sensitized Dalmatian dog by blood transfusion is described as the Dal blood type. The frequency is not known. Typing sera for this antigen also is commercially not available [2, 22, 23].
Three blood types are described in the feline AB blood group system and mik group system. In cats a new blood group defined as Mik. It is named after the alloantibody identified in the first blood donor cat, Mike. In three cats that had not previously received transfusions Mik antibodies were detected. They are defined as a cause of incompatibilities between donor and recipient blood that are not related to the AB blood group system [24].
The phenotypes type A, type B, and type AB are occured. A null phenotype is not exist. The most common blood type is Type A. Type B is less common. Type AB is rare [2, 25]. Type B is indicated in Australia (26.3%), and Greece (20.3%) ([26], [27] ). In large studies of both pedigree and non-pedigree cats in the USA distribution of type AB cats is demonstrated to be rare (0.14%) ([28] ). Type AB were 0.4% in Australia (([26]). In Scotland the incidence of AB cats is 4.4% ([29] ).
Type B is indicated in Australia (26.3%), and Greece (20.3%) ([26, 27]. In large studies of both pedigree and non-pedigree cats in the USA distribution of type AB cats is demonstrated to be rare (0.14%) [28]. Type AB were 0.4% in Australia [26]. In Scotland the incidence of AB cats is 4.4% [29].
In Turkey, 60 % of Van cats and 46.4 % of Angora cats are type B [30]. And 220 (73.1%) nonpedigree domestic cats had type A blood, 74 (24.6%) had type B and seven (2.3%) had type AB [31] in Turkey. Except type AB group, cats have naturally occurring alloantibodies. It is known that cats have naturally occurring alloantibodies (isoantibodies) against the blood type they are lacking. Because of this to prevent blood incompatibility reactions in cats feline blood typing is important in clinical practice. Blood type incompatibility can especially result in two fatal reactions. The first is acute haemolytic transfusion reactions, occur particularly in cat transfused with type A blood [32]. Feline neonatal isoerythrolysis (NI) is the second incompatibility reaction. It occurs when type A or AB kittens born to type B queens are nursing. Naturally occurring anti-A alloantibodies result in blood incompatibility reaction in the type B queen’s colostrum and milk [25, 30].
Cats constitute non-self antibodies in contrast to dogs. As a result of this non-self antibodies potentially fatal antibody-mediated reactions can occur towards non-self red blood cells. Nearly 20% of type A cats have anti-B antibodies. These antibodies are usually weak. All type B cats have strong anti-A antibodies. In contrast AB cats do not have alloantibodies [32]. In previously unsensitized cats naturally occuring isoantibodies are responsible for transfusion reactions. Nearly all type B cats have highly titered anti-A agglutinins and hemolysins. RBCs can be destructed rapidly in type B cats taking type A blood. In type B cats the high titres of naturally occurring anti-A antibodies cause rapid intravascular destruction of transfused type A red blood cells [33]. This can be mediated by IgM, complement fixation and the release of potent vasoactive compounds. As a result of this shock can develop usually due to possessed antibodies towards the transfused RBCs [3, 34]. This can cause severe transfusion reaction and death even if as little as 1 ml of type A blood is administered to a type B-cat [2, 35]. Because of their endotheliochorial placenta newborn kittens have no alloantibodies. Nevertheless colostral transfer of immunoglobulin (Ig) G and a small amount of IgM occurs. Neonatal isoerythrolysis develops in cats. It is one of the cause of the fading kitten syndrome. Kittens that are type A or AB and those that are born to type B queens are at risk. In affected kittens Clinical sings can range from unapparent, to severe hemolytic anemia with hemoglobinuria, icterus, and death [1, 36, 37, 38].
Packed red blood cells (pRBCs) and fresh frozen plasma (FFP) are components generally provided for canine transfusions. If processed at once, 1-4 each unit (450 mL) of whole blood can be seperated into 1 unit of pRBCs and 1 unit of FFP. It is difficult to prepare components from a small volume of blood. Because of this cat blood transfusions are usually administered as fresh or stored whole blood. If patients requires specific components like pRBCs and FFP, in this case whole blood can be separated into them [39].
In veterinary medicine, red blood cell transfusions are used more frequent recently. They are the integral part of lifesaving. They are used in critically ill as advanced treatment. Situations required transfusions include life-threatening anemia from acute hemorrhage or surgical blood loss, hemolysis from drugs or toxins, immune-mediated diseases, severe nonregenerative conditions, and neonatal isoerythrolysis [40].
Indications of red blood cell transfusions are in the treatment of anemia caused by hemorrhage, hemolysis, or ineffective erythropoiesis. Oxygen is poorly soluble in plasma. Because of this oxygen in blood is mostly carried by hemoglobin (Hgb). In anemic patient, RBC transfusions increase the oxygen-carrying capacity. Therefore inadequate delivery of oxygen to tissues with consequent tissue hypoxia are prevented or treated [41].
The treatment of severe anemia caused by hemorrhage, hemolysis, ineffective erythropoiesis, auto-immune hemolytic anemia, or neoplasia is primary indication for blood transfusion. Lethargy and altered mentation, increased respiratory effort, pale mucous membranes and tachycardia are the clinical signs of anaemia. The body carry out a number of adaptive responses physiologically, to maintain carrying of oxygen to the tissues [42, 43]. The solution of oxygen in plasma is weak. Because of this hemoglobin (Hgb) carries approximately whole oxygen in blood [41]. The decision to conduct a RBC transfusion is generally based on a measurement of the patient\'s packed cell volume (PCV), hematocrit (Hct) or Hgb concentration (Hgb) and especially on clinical evaluation of the patient [41]. Clinically animals should be evaluated individually. Generally when the hematocrit is less than 10%, the treatment of anemia is transfusion. However, animals with acute-onset anemia usually require transfusion before their hematocrit decreases to 15%. This contrasts with the situation in animals with chronic anemia. Other indications for transfusion are hypovolemia, thrombocytopenia, clotting factor deficiency, and hypoproteinemia [1]. Electrocardiographic signs of myocardial ischaemia are similar to those identified in human patients with myocardial infarction. It can ocur with anemia [44].
The usage of administration of FFP are for the treatment of a single or multiple clotting factor deficiency, vitamin K deficiency or antagonism, surgical bleeding or where a massive transfusion is required [45]. Hypoalbuminaemia and coagulopathies especially due to liver disease are the main reported indications for FFP transfusions in cats [46].
Stored blood is more than 8 hours old. The length of storage depends on the anticoagulant/preservative solution used. It varies from 48 hours for 3.8% sodium citrate (no preservative) to 4 weeks for CPD-A1 (citrate, phosphate, dextrose, and adenine). Acid citrate dextrose (ACD), citrate phosphate dextrose (CPD and CP2D), and citrate phosphatedextrose-adenine (CPDA-1) are mostly used as preservatives. The viability of RBCs is provided by the added dextrose, phosphate, and adenine. Due to the preservative used, the storage can extend up to 3 to 5 week ([3, 41, 47].
In patients that are hypothermic or receiving large volumes of blood, refrigerated RBC products should be prewarmed to temperatures between 22 C and 37 C immediately before transfusion. In the routine practice of RBC products to normovolemic anemic patients, refrigerated blood components do not need warming before transfusion. Warming may accelerate the deterioration of stored RBCs and may cause rapid growth of contaminating microorganisms [48].
In clinical practice advances in safety of blood transfusion is important in preventing transfusion-transmitted infections (TTI). The most frequent severe infectious outcome of transfusion has been known as bacterial contamination of platelets, with resultant sepsis in the recipient recently. Using automated or semi-automated blood culture devices, apheresis platelets and prestorage pooled platelets are most often tested [49].
Generally, before a blood transfusion is given to animals, blood typing and/or cross-matching of the recipent and donor should be done to avoid the likelihood of a transfusion reaction. Also, ineffective therapy is caused by shortened survival of transfused mismatched red cells. In order to prevent primary sensitization and risk of developing hemolytic disease in breeding females, cross-matching and/or blood typing is important. In general veterinary practise, blood typing for canine DEA 1.1 and for feline types A and B is applied [1].
To decrease adverse reactions one sould pay attention to blood typing and crossmatching procedures as much as monitoring. There is always risk in blood transfusions. For this reason, they should be performed only when warranted. When taking history, previous transfusion therapy should be asked and in a history of previous transfusion therapy cross-matching is necessary [1, 50].
Depending on availability and indication for transfusion, whole-blood or blood-component therapy may be administered. RBCs, white blood cells (WBCs), platelets, all the coagulation factors, albumin and immunoglobulins constitute whole blood (WB) [51].
In cats, fresh whole blood is the most common product used recently. Stored whole blood, packed red blood cells and fresh frozen plasma (FFP) are also given as transfusions [45].
The heavier cellular elements from the supernatant plasma are sedimented by centrifugation of whole blood sediments. Due to separation of blood collection within 8 hours all protein activity and concentration are maintained in the plasma. The obtained supernatant usually frozen. For subsequent transfusion, it is stored as fresh frozen plasma (FFP). In addition it can also processed to provide cryoprecipitate and cryosupernatant. It can also be transfused immediately as fresh plasma [52, 53]. Fresh frozen plasma have to be stored frozen at -30 C before used. Also it should be identified with the donor blood type, name and collection date. Samples thawed and not used sould discarded or stored in a fridge and used within 12-24 h and should not be refrozen [43].
Recently an ultra-purified polymerised bovine haemoglobin solution is the only commercially available alternative to red cell transfusion (Oxyglobin). It is not licensed in cats but it has been used in treatment of anaemia in cats and also in therapy of carbon monoxide poisoning [54, 55].
Hemostatic protein deficiencies lead to hemorrhagic disorders and the treatment is done principally by plasma components [56]. In animals with von Willebrand disease (vWD) and hereditary coagulation factor deficiencies active hemorrhage is controlled by plasma components. Plasma components are also used for preoperative prophylaxis in these diseases [53].
For preparation of plasma components sterile plastic bags are used. After that they are stored and transferred as frozen in individual boxes. Products have to be stored at -20 C or lower. Just before transfusion they warmed to 37 C in a water bath or incubator. Preferred route of administration is the intravenous transfusion of plasma components. If attempts at vascular access have failed, intraosseous transfusion can be used in emergency situations. When acut allergic reactions occur transfusion is stopped and antihistamines and/or short-acting steroids are given [53, 57].
Cats have antibodies to non-self blood types within the plasma. Because of this only type-specific plasma should be administered to cats in contrast to dogs. Using one of the commercially available systems whole blood can be separated into FFP and packed red cells if it is taken aseptically. The blood spun at 3800 rpm at 10˚C in a refrigerated centrifuge for 12 mins. Using a plasma extractor the plasma is extracted and stored at –20 C [57].
In hypoalbuminemic dogs and cats, human serum albumin has been used for therapeutic use [58].
Correction of coagulation by fresh platelets are shown by in vitro coagulation studies. Freshly collected platelets correct thrombocytopenia, control associated hemorrhage, and prevent death from bleeding. Hemorrhagic diathesis are prevented by platelet replacement for thrombocytopenia [59].
Severe thrombocytopenia or thrombopathia result in bleeding. Platelet transfusion is used for the control of this bleeding. In veterinary medicine platelet transfusion has been used rarely compared to red blood cell (RBC) and plasma transfusion. In dogs, reports related to platelet transfusion are generally associated with experimental hematopoietic stem cell transplantation. Platelet-rich blood products consist of fresh whole blood (FWB), platelet-rich plasma (PRP) and platelet concentrate (PC). They are used for aggressive anticancer therapy and treating complex hematologic disorders. Centrifugation of whole blood constitute platelet-rich plasma (PRP) and centrifugation of platelet-rich plasma constitude platelet concentrates (PC). Platelet activation is induced by centrifugation so that the resuspension of the platelet pellet during PC preparation from dogs is difficult. The preparation efficiency of PC from dogs can be improved by addition of PGE1 in PRP before the centrifugation of PRP. Also therapeutic efficacy of the platelets are maintained. In 10-28 kg body weight dogs plateletpheresis has been used successfully. On the canine donor thrombocytopenia and hypocalcemia are the main adverse effects of plateletpheresis [60-62].
At room temperature (RT) (20-24 C), PRP and PC can be stored for 5-7 days with continuous or intermittent agitation. At RT FWB can be stored for up to 8 hours. The interest in freezed (4 C) storage of platelets is increasing because of the increased risk of bacterial proliferation at RT storage. Storage of human PRP and PC are limited to 5 days because of prevention of bacterial proliferation at room temperature [60- 63].
Platelet transfusions as with RBC and plasma components should be performed with 170 µm filters standard blood administration sets. Transfusion sets which can bind platelets should be exempt from latex [60].
The most common reaction to PC are febrile reactions. The frequency is decreased by pre-storage leukoreduction. In immunocompetent dogs receiving multiple transfusions, alloimmunization to platelet antigens occurs. Leukocyte reduction and ultraviolet B irradiation are recently accepted methods for preventing the development of platelet alloimmunization [64-66].
Recently platelet cryopreservation are used to provide long-term storage and immediate availability of platelet products for transfusion. When fresh platelets are unavailable cryopreserved platelets can be activated in vitro and provide therapeutic benefit [63].
Granulocyte transfusion can be used as supportive therapy. It is used in patients with life-threatening neutropenia caused by bone marrow failure or in patients with neutrophil dysfunction. Granulocyte transfusions is shown to be useful in treatment of infections in patients after treatment with high-dose chemotherapy. It is helpful especially in the chemotherapy associated with conditioning for hematopoietic stem cell transplant. By using granulocyte colony-stimulated factors higher doses of granulocytes for transfusion are produced. Thus recently the use of therapeutic granulocyte transfusion has been increased. The outcome of transfusion are effected by the type of infection being treated, the likelihood of recipient marrow recovery, and recipient alloimmunization [67].
In small animals therapeutic granulocyte transfusions have been used especially in experimental models of myelosuppression and neonatal sepsis. In clinical veterinary medicine they have been used rarely. Granulocytes can be used to identify the site of inflammation. Beside leukapheresis, centrifugation of FWB, with or without colloid-facilitated sedimentation, may be used to isolate canine and feline buffy coats. Only sedimentation may also be used in the cat. At RT granulocytes are stored immobil for 24 hours. The dose for beginning is 1 x 1011 granulocytes/kg in a volume of 15mL/kg. It is used once to twice in a day [68-70].
To select permanent blood donors, blood typing have to be performed. Donors should be healthy young adults. They undergo routine physical check up and hematology and clinical chemistry evaluations are done. They should never taken a blood transfusion and should be free of blood parasites and other infectious diseases [1].
Nulliparous and spayed female dog and cat donors have to be chosen. Blood have be collected via jugular venipuncture aseptically. Acepromazine interferes with platelet function. Because of this donors should not be sedated with it [1].
Every 3 to 4 weeks, dogs can donate between 13 and 17 ml of blood per kilogram of body weight. Features of donors sould include well nourished, supplemented with oral iron, bled less than once per month to prevent iron deficiency, greater than 25 kg, and negative for antigens for DEAs 1.1, 1.2, 3, 5, and 7. Donors should not have heartworm disease, babesiosis, brucellosis, ehrlichiosis, and Rocky Mountain spotted fever. Donors have appropriate neck skin that allows easy entrance to the jugular vein, have a packed cell volume that is at least 0.40 L/L, have demonstrated a good temperament and be in good physical condition, have no past time history of transfusion or pregnancy, and have got sufficient levels of von Willebrand factor (vWF) [1, 3].
The ideal feline blood donors should be healthy, indoor-only cats with an agreeable temperament for easy handling and restraint. Owned pet cats should be donate maximum once every 2 months [43]. The features of feline donor sould be as follows; weigh more than 4.5 kg, have a packed cell volume that is at least 0.35 L/L, have demonstrated a good temperament, and be in good physical condition [3]. Donor cats can donate between 10 and 12 ml/kg. Adult healthy cats can donate 50 ml every weeks. Donors have to be type A. Type B donors may be demanded depending on breed prevalence and geography. Feline leukemia virus, feline immunodeficiency virus (FIV), feline infectious peritonitis, heartworm disease, and Hemobartonella sp have to be excluded in donor cats [1].
For appropriate care of donors some processes needed. These are current vaccinations, if there is contact with new animals every 6 mo fecal floatation, monitorization of hemogram every year, analysing clinical chemistry, screening for infectious diseases and in the dog preventative heartworm therapy in areas where it is necessary. When blood collection is taken the donor\'s weight, temperature, and packed cell volume have to be analysed [3, 71]. PCV or Hb are measured by taking a blood sample. Preferentially cats with a PCV of 30–35% are used but cats with low–normal PCVs should not be used [43].
In the cat, blood can be taken by using a 19- to 20 gauge needle or butterfly into a syringe via jugular vein venipuncture. The region over the jugular vein is clipped and prepared aseptically and sedation is administered. It is prefered to use a 1:1 combination of ketamine 100 mg/ml and midazolam 5 mg/ml. It is made up in a small syringe and given intravenously up to a maximum dose of 5 mg/kg ketamine (0.1 ml/kg of combination). Syringe consists of either ACD, CPD, or CPDA- 1 (1 mL/9 mL of blood), or heparin (5 units/mL of blood). Before a preservative solution is used it can be placed in a small blood bag. To access the jugular vein a 19-21G butterfly needle is used. The blood is collected over a total of 10 15 mins. At once a maximum of 10-12 ml/kg blood can be donated. Isotonic crystalloid fluid therapy post-donation at a rate of 60 ml/h for 3 h is given to the cat [3, 43].
Precaution is necessary to prevent damage of the blood product and harm to recipient. Blood typing or crossmatching have to be carried out to provide compatibility before RBC transfusion [41].
Transfusions of red blood cell should be administered through a filter. The filter is arranged to remove clots and particles which are potentially harmful to the patient. Blood infusion sets have in-line filters. These filters trap large cells, cellular debris, and coagulated proteins. The pore size range from 170µm to 260µm. A filter may be used to administer 2-4 units of blood to a patient or for a maximum time limit of 4 hours according to human blood banking standards. High protein concentration at the filter surface and room temperature conditions promote proliferation of any contaminating microorganisms. The rate of flow slowed down by accumulated material. After 5 days or more of refrigerated storage constituted microaggregates composed of degenerating platelets, white blood cells (WBCs), and fibrin strands in blood. They are removed by other blood filters with a pore size of 20-40 Jim. For transfusions of RBCs primarily microaggregate filters are designed. In administering small volumes of blood (<50 mL WB or <25mL pRBCs) to cats and small dogs a pediatric micro-aggregate blood filter (18 um pore size, priming space <lmL) is especially helpful. Because of a progressive decrease in pore size due to increased blood filtered larger volumes of blood administration can result in hemolysis [41].
If plasma is taken from blood preservative solutions can be put in. Blood preservative solutions are dextrose, adenine, mannitol, and the sodium chloride. They are necessary for RBCs to carry on their energy metabolism and viability during storage [3]. Canine pRBCs stored in a RBC preservative can be applied directly. Other pRBC products have to be diluted by putting 10mL of saline feline pRBCs or 100mL of saline to the blood bag so that the viscosity of the donor blood decreased [41].
In the dog, if sedation is needed, butorphanol (0.1 mg/kg BW, IV) is generally used for sedation. But acepromazine should not be used because it may cause platelet function disturbance [72]. In the cat, ketamin may be used 2 to 4 mg/kg BW, IV for sedation. In addition to ketamin is very successful when it is used together with 0.1 to 0.2 mg/kg BW diazepam [3]. Also combinations of ketamine hydrochloride, midazolam and butorphanol tartrate, or mask administration of sevoflurane can be used [73, 74].
Generally, intravenous administration is used for RBC transfusions. In addition intraosseous administration is a perfect alternative. Peripheral veins may be preferred to central veins because of an increased bleeding predisposition [41].
Blood is administered through administration sets containing 0.9% saline intravenously. Contraindications include hypotonic saline, 5% dextrose in water and lactated Ringer\'s solution. Cardiac arrest may be caused by injection of undiluted citrate containing anticoagulants [1].
Using a syringe driver or by hand the transfusion should begin slowly at 0.25 ml/kg/h. If no adverse affects are encountered after the first 30–60 mins of administration the rate can be increased. Due to the urgency of the requirement for whole blood and any underlying concurrent disease the rate of administration can vary [75].
With a PCV of 20%, dogs and cats with chronic anemia can be cardiovascularly stable [76]. Conversely in patients with an acute onset of anemia and continuing blood loss or hemolysis, transfusion to a higher PCV is necessary for stabilization. Generally administration of 2mL/kg of WB or lmL/ kg of pRBCs will increase the patient\'s PCV by 1% if there is no continuing hemorrhage or hemolysis [41].
Patient\'s overall condition determine the rate of blood administration. The maximum rate of transfusion is 10-20mL/ kg/h in normovolemic anemic patients, to avoid circulatory overload [41].
To provide blood volume again fluid therapy with crystalloids or colloids is necessary. If the patient\'s total blood volume do not decrease under 20% this is usually enough for losses. If losses are more than 20% whole blood or packed red cell transfusion is used. Between 20% and 50% of blood volume losses are treated by crystalloids and packed RBCs [3, 77].
Blood components like cryoprecipitate and platelet-rich plasma are used infrequently. Cryoprecipitate contains vWF, factors VIII, XIII, fibrinogen, and fibronectin. In vWF-deficient patients cryoprecipitate is recommended particularly when surgery is planned or patient affected by blood loss. Bleeding hemophilia A patients, or patients having hypo or dysfibrinogenemia are the other indications for choosing it [3, 78].
Sometimes platelet-rich plasma is used in veterinary practice. In small-sized animals it is more useful because in larger dogs it is difficult to gain enough volume and management of platelet count. An alternative to platelet-rich plasma are frozen platelet concentrates [79].
For expansion of plasma volume, different types of colloids as dextrans and hetastarch are used as alternatives to blood products. Altering hemostasis is one of the problems of dextrans and hetastarch. Oxyglobin is a hemoglobin-based oxygen carrier. It is approved for use in the dog in 1998. In emergency situations it is used instead of blood products when there is limited time for preparing it or performing compatibility testing [3, 80].
In clinical signs of anaemia and as a therapy for carbon monoxide poisoning oxyglobin is used in cats. Because it is a potent colloid (colloid osmotic pressure 43 mmHg), the main risk associated with administration is volume overload. In patients with normovolaemic anaemia conservative administration rates are needed such as as low as 0.2-0.4 ml/kg/h and to a maximum of 1 ml/kg/h. Careful monitorization of patients with paying particular attention to their heart and respiratory rate is recommended [81, 82].
A recent study described the clinical outcome in dogs experiencing massive transfusion. Also this study documented predictable changes in electrolytes and coagulation status. Massive transfusion is different from usual transfusions in terms of volume and rate of blood transfusion and blood components administered. Transfusion of a volume of whole blood or blood components has been described as massive transfusion. The administrated blood is greater than the patient\'s predicted blood volume within a 24-hour period or arranged as replacement of half the patient\'s predicted blood volume in 3 hours. In a study, massive transfusion receiving dogs were investigated and in this study the mean volumes of pRBCs was 66.5mL/kg and FFP was 22.2mL/kg. As a result of this mean plasma, RBC ratio was 1:3. After transfusion clinicopathologic changes consists of electrolytes disturbances, dilutional coagulopathy, ionized hypocalcemia and hypomagnesemia and progressive thrombocytopenia and prolongation of prothrombin and activated partial thromboplastin times [41, 83].
The gold standard approach is that the donor and recipient are cross-matched before administration. Administration is maintained mainly intravascular with the use of peripheral or centrally placed catheter. Also intraosseous catheters can be used to administer all blood products. It is useful in collapsed neonatal patients where vascular access is difficult [43, 75, 84].
In acute hemorrhage, anemia, decreased red cell mass, severe methaemoglobinaemia, paracetamol toxicity, chronic non-regenerative anaemia, coagulation disorders, and thrombocytopenia fresh whole blood is used [1, 45].
The reason of anaemia in cats requiring transfusion are haemorrhage and primary immune-mediated haemolytic anaemia. Hemorrhage is caused as a result of peri- or postoperative bleeding, trauma, gastrointestinal bleeding, abdominal neoplasia, primary immune-mediated thrombocytopenia and coagulopathies [85, 86, 87]. Also in a number of infectious diseases anaemia is reported such as especially feline immuno-deficiency virus (FIV) and feline leukaemia virus (FeLV) infections, and feline infectious peritonitis [88, 89]. Other infectious diseases which cause anemia are Ehrlichia species, Bartonella species, Haemoplasmas (Mycoplasma haemofelis, ‘Candidatus Mycoplasma haemominutum’ and ‘Candidatus Mycoplasma turicensis’), Anaplasma phagocytophilum, Neorickettsia risticii, Cytauxzoon felis and Rickettsia felis have additionally been associated with anaemia [43, 90].
The indication of whole blood is in a patient whom needed several blood components or has acutely lost more than 50% of its total blood volume. When 50% of total blood volume is lost oxygen carrying capacity and oncotic activity should be recovered. In anemia, stored whole blood is used. For anemic animals packed erythrocytes especially those with volume overload are prefered. For tissue reoxygenation the transfusion of packed RBCs are used. They are also useful for normovolemic, anemic patient. Before administration, to dilute any potentially damaging antibodies these erythrocytes can be washed with saline. Refrigerated whole blood should be warmed to room temperature. Before administration it sould be gently agitated to resuspend the red blood cells. Infusion rate is limited by colder blood which has a higher viscosity [3, 41, 91].
The usage of transfusion of fresh-frozen or stored-frozen plasma (FFP) are as follows; lack of coagulation factors associated with hepatic insufficiency, disseminated intravascular coagulation (DIC), vitamin K deficiency, rodenticide toxicosis, liver insufficiency, biliary tract obstruction, sepsis/multiple organ dysfunction syndrome, pancreatitis, hypoalbuminemia, and DIC without associated laboratoryproven coagulopathy, malassimilation syndrome, chronic antibiotic use, a need for plasma volume expansion, or a massive blood loss within a few hours. Other It is also used in congenital or a hereditary deficiency in coagulation factors (i.e hemophilia A, B, or von Willebrand\'s disease and hypoproteinemia), [1, 3, 39]. Plasma (FP or FFP) is used especially in the emergency conditions like excessive protein loss such as enteropathy, nephropathy, exudative dermatitis or inadequate intake. It is not appropriate for using as long-term source of protein in these patients [3, 92]. In cats, reactions have not been reported following transfusions of FFP [46].
The collection and re-transfusion of the cat’s own blood is called autotransfusion. It is a useful technique in an emergency situation. It can be obtained when animals bleed into body cavities. It should not be used if the blood is contaminated with urine, bacteria or bile. Blood is collected from the body cavity in a sterile manner. After that it re-transfused into the patient through an appropriate fitler. To prevent clotting anticoagulant like acid citrate dextrose should be included at a ratio of 1:7 [39, 43].
The indication of transfusion reactions can be immunologic or nonimmunologic. They can be immediate or delayed. Antibodies to surface antigens of transfused erythrocytes cause immune-mediated hemolytic reactions. According to surface antigens canine blood is grouped. For six of these antigens typing is available. Except DEA 4, canine universal donor is negative for all dog erythrocyte antigens (DEAs). Universal donors should be examined. If other donors are known to be compatible with the recipient they can be also used. Acute hypersensitivities mediated by IgE antibodies are one of the possible immunologic reaction. The other can be leukocyte or platelet sensitivity caused by recipient antibodies to the donor\'s white cells or platelets. The mechanisms of nonimmunologic reactions are various. According to the specific reaction the type and severity of clinical signs vary [17] Adverse reaction occurs in 2 types. First one is immediate reaction and following transfusion it occurs within 1 to 2 h. Second is delayed reaction and it may begin within days, months, or years later [17]. Adverse reaction varies from mild (fever) to severe (death). Transfusion reactions can be acute or delayed. In animals receiving incompatible transfusions, acute intravascular hemolysis with hemoglobinemia and hemoglobinuria may be seen. Acute hemolytic reaction is the most serious transfusion reaction that can be prevented. It is an immunological reaction and it happens when circulating natural or acquired antibodies towards donor erythrocytic antigens are given. Hemoglobinuria, vasoconstriction, renal ischemia occur due to intravascular hemolysis. Intravascular hemolysis determine clinical signs. Disseminated intravascular coagulopathy (DIC) can be caused by release of thromboplastic substances. Secondary to the release of vasoactive substances, hypotension and shock can ocur. Also acute renal failure and death can develop. After transfusion a decrease in hematocrit between 2 days and 2 weeks resulted in suspicion of delayed hemolysis. As a result of extravascular hemolysis, hyperbilirubinemia and bilirubinuria may occur. In dogs clinical signs are as follows: fever, tachycardia or bradycardia, hypotension, dyspnea, cyanosis, excessive salivation, tearing, urination, defecation, vomiting, collapse, opisthotonos, cardiac arrest, hemoglobinemia, and hemoglobinuria. When an acute hemolytic reaction occured transfusion sould be interrupted at once and shock should be treated. Also blood product being used sould be checked out and the steps that led to the transfusion sould be examined [1, 3, 17, 93].
To detect transfusion reactions earlier requires careful evaluation of patient\'s behavior, vital signs, and perfusion before, during, and after a RBC transfusion. Pre- and post-transfusion measurement of PCV and total solids for example instantly and at 24 hours are needed. Also evaluation of the plasma and urine for the presence of Hgb is done [41].
In the dog the acute hemolytic reaction is rare because in this species naturally occurring anti-erythrocytic antibodies prevalence is low [3]. Alloantibodies against the common canine erythrocyte antigens 1.1 and 1.2 do not exist in dogs. As a result of this generally first transfusion can be safely given without regard for donor blood type. Thus the recipient can be sensitized to immunogenic antigens (i.e 1.1, 1.2, 7, and others). On first transfusion it can cause shortened survival times of the transfused cells. Subsequent predisposition to severe transfusion reaction can develop. DEA 1.1 which is the strongest antigen in dogs, leads to the most severe transfusion reaction [1]. In the second transfusion especially when DEA-1 type blood is applied twice to a DEA- 1-negative dog there is more risk [3].
In cats receiving typed or crossmatched transfusions low rates of transfusion reactions have been indicated. Transfusions with whole blood or packed red blood cells transfusion reactions were reported [45]. But transfusions with FFP no reactions have been reported in cats [46].
Initial or subsequent AB-mismatched transfusions in cats can cause acute hemolytic incompatibility reactions. Erythrocytes are destroyed immediately in cats because of alloantibodies. On the contrary in dogs, delayed transfusion reactions are more often occur. A type B transfusion to type A cat causes mild signs. In this situation shortened erythrocyte survival can occur. This causes ineffective therapy. Acute hemolytic transfusion reaction with massive intravascular hemolysis with serious clinical signs occurs in type A transfusion to a type B cat. These symptoms may occur even if it is the first transfusion. Type AB or A blood can be received by type AB cats safely [1, 94].
The transfusion should be stopped immediately if a transfusion reaction is suspected. The recipient sould be monitored continually for follow up. The most severe is acute haemolytic transfusion reactions developing as a result of naturally occurring alloantibodies [32].
Clinical signs are restlessness, vocalisation, tachypnoea, bradycardia, tachycardia, hypotension and hypertension. Pyrexia is seen frequently as a result of reactions to donor leukocytes, platelets and plasma proteins. As a result of binding by citrate, there is potential for hypocalcaemia when administering large volumes of blood products. Thus, if the patient is showing clinical signs of hypocalcaemia calcium should be measured [38, 43].
The next hour after transfusion nonhemolytic fever can ocur as adverse reactions. If contaminated blood products applied by mistake, fever may occur in an acute hemolytic reaction in association with septicemia. Vomiting or diarrhea can be seen after plasma administration. Rarely urticaria may cause trouble to patient. It can be treated with antihistamines, with or without glucocorticosteroids. If whole blood is administered with rapid administration of a large volume of blood component to normovolemic cats or small-sized dogs hypervolemia can be observed. Hypervolemia can result in pulmonary edema. Cough, tachypnea, dyspnea, or cyanosis can occur due to hypervolemia. Treatment can be done by stopping the transfusion, administering diuretics (furosemide) to reduce pulmonary edema, and providing oxygen support [3,72, 93].
The recipient should be carefully examined before the procedure. Its heart rate, respiratory rate, mucous membrane colour, capillary refill time and temperature sould be recorded. Also the PCV and total plasma protein should be recorded [43, 51].
Delayed adverse transfusion reactions are consist of delayed hemolytic reaction, transmission of infectious disease, and posttransfusion purpura. Posttransfusion purpura has been reported in the dog. It is characterized by the appearance of severe thrombocytopenia in the week following a second transfusion. [3, 95, 96].
Anemia, regardless of underlying cause, is troublesome for clinicians in respect to stabilising and supporting the patient. The survival rate of all reasons for a transfusion is 84% in the first 24 h. It is 75% for blood loss anaemia and 49.6% for ineffective erythropoeisis at 10 days [43, 97].
The incompatibilities between the donor’s red blood cells and recipient’s plasma are identified by major cross-match. The incompatibilities between the donor’s plasma and recipient’s red blood cells is identified by a minor cross-match [43].
Cross-Matching usually is identified as either ‘‘major’’ or ‘‘minor’’ cross-matches. A major cross-match include putting patient serum into donor cells and determine the presence of agglutinating and/or hemolytic antibodies in the patient aganist the donor antigens. The principle of this test is hemolytic or agglutinating reaction. In this test the reagent or antibody reacts with the RBCs. Serological discordance between a candidate donor and the patient is identified by the crossmatching. It does not determine the blood group [3]. A positive in vitro reaction is caused by the presence of antibodies. In patients that had no antibodies at the time of transfusion, a mild reaction can be seen in 4 to 14 days after mismatched transfusions. When blood is transfused to a patient in which antibodies are already present, a severe reaction occurs. This antibody can be developed by either naturally occurring or as a result of a previous mismatched transfusion. Furthermore, high concentrations of antibodies can be caused by isosensitization from transplacental immunization. In dogs that have received transfusions before, a crossmatch should always be performed. A minor cross-match include putting donor serum into patient erythrocytes. This step is not necessary for the donor whom previously tested negative for antibodies. Transfusing packed or washed erythrocytes rather than whole blood can prevent administration of antibodies in donor blood against patient erythrocytes [1].
Before transfusion the reason of analysis with these methods are to prevent acute hemolytic reaction due to transfusion, to provide optimal lifetime of the transfused RBCs, to prevent next discordant blood transfusions and to prevent neonatal isoerythrolysis [3].
Because there are blood types that have not been described and it is not possible to type for Mik it is recommended that cross-matching is performed before any transfusion. If the recipient has received a transfusion before more than 4 days cross-matching should be performed [98].
Horses have eight RBC groups or systems: A, C, D, K, P, Q, U, and T. The first seven systems are recognized by the International Society of Animal Blood Grouping Research. Blood-typing antiserum is not readily available for horses. Because of this to identify suitable donors equine blood-group testing can be performed by only few diagnostic laboratories. Over 30 different factors have been identified within these seven equine systems. Experimentally many more systems have been identified [99, 100]. Red cell antigens Ca, Aa, and Qa are play an important role in transfusion reactions and neonatal isoerythrolysis. There is no universal equine blood donor. Because of this to prevent inadvertent sensitization of brood mares against the two most common alloantigens (Aa and Qa) involved in neonatal isoerythrolysis, the preferred donor should be negative for factors Aa, Qa, and Ca [100, 101]. Aa and Qa alloantigens are most immunogenic, and most neonatal isoerythrolysis cases are associated with anti-Aa or Qa antibodies. The horse is clinically relevant for blood group incompatibilities. It is the only livestock species for this situation. Blood group antibodies can laed to transfusion reactions or NI and can be found in horses either ‘‘naturally’’ or as a result of a blood group incompatible pregnancy [2]. A donkey RBC antigen that has not been found in the horse has been identified, it is unique to the donkey and the mule [1].
In horses, requirement of blood transfusion include correction of anemia arising from acute blood loss secondary to trauma, surgical complications, ruptured uterine artery, guttural pouch mycosis, and neonatal isoerythrolysis [99, 102].
Generally, whole blood transfusions are applied to horses that have acute blood loss caused by trauma, surgery, or some other conditions like splenic rupture or uterine artery hemorrhage. The transfusion recovers blood volume and oxygen-carrying capacity in cases of blood loss. There is no certain indicative variables for the beginning of transfusion so that physical examination and clinicopathologic parameters should be used to make the transfusion decision. In cases of acute hemorrhage one sould remember that the packed cell volume (PCV) may be normal for up to 12 hours because of the time required for fluid redistribution and the effects of splenic contraction. As the horse is rehydrated with intravenous fluids, serial monitoring of PCV and total protein (TP) can estimate the amount of blood loss. The transfusion decision is made by suspection of large volume blood loss, together with tachycardia, tachypnea, pale mucous membranes, lethargy, and decreasing TP. During an acute bleeding episode when the PCV fall under 20%, blood transfusion is probably required. In acute severe cases, transfusion may be required before there is a significant fall in PCV. PVC shows the need for beginning of transfusion in chronic anemia better whereas in acute hemorrhage, with transfusions proposed for horses with demonstration of tissue hypoxia and a PCV less than 10-12% [103, 104].
Blood is collected and stored in glass bottles containing acid–citrate–dextrose (ACD). The method traditionally used for collecting blood from donor horses. Glass bottles containing ACD are easy and suitable for rapid vacuum blood draw. Because of this they are recommended for equine whole-blood collection. For equine whole blood the optimal storage method is commercial citrate–phosphate–dextrose with adenine (CPDA-1) bags [105, 106].
Packed RBCs (pRBCs) are specified for normovolemic anemia (i.e neonatal isoerythrolysis, erythropoietic failure, and chronic blood loss). Markers of tissue oxygenation, for example lactate and oxygen extraction are useful in chronic or hemolytic anemia cases. In horses, disseminated intravascular coagulation, clotting factor deficiency, hypoalbuminemia, decreased colloid oncotic pressure, and failure of transfer of passive immunity (FPT) are treated by plasma [104].
Colloid is usually used in patients with a total protein less than 4.0g/dL or serum albumin concentration less than 2.0g/dL. When there is oncotic pressure less than 14 mmHg, clinical symptoms like ventral edema, and conditions which increase microvascular permeability like sepsis are other indications for colloid usage [104].
According to plasma obtained by plasmapheresis and centrifugation preparations, plasma prepared by gravity sedimentation contains greater numbers of erythrocytes and leucocytes. The risk of a transfusion reaction can be increased by these cells. During storage leukocytes can degranulate and fragment and release pyrogens and proinflammatory substances [107, 108, 112].
Multiple hyperimmune plasma products are avaible with bacterial or viral specific antibodies. For the treatment of equine endotoxemia, the efficacy of E. coli (J5) and Salmonella tiyphiimiriuni hyperimmune plasma has proved to be useful in some reports; in contrast, there are some reports which disapprove the utility of such products. For the protection of R. equi, the use of Rhodococcus equi hyperimmune plasma has also been controversial. For treatment of specific disease additional plasma products like botulism antitoxin, West Nile virus antibody, and Streptococcus equi antibody are usable. In general equine practice plasma is administered to neonates to provide protective immunoglobulins. Protective immunoglobulins are used for treatment of failure of transfer of passive immunity or prophylaxis against Rhodococcus equi. Also, the albumin content of the plasma used as a colloid for circulatory volume support and in the treatment of protein-losing enteropathies. In horses heritable and acquired coagulopathies can occur. Specific coagulation factors are not available for supplementation. Also indications include coagulopathies, protein-losing nephropathy and protein loss through third spacing into a body cavity (occurring with peritonitis or pleuritis) [104, 109-113].
Fresh frozen plasma must be separated and frozen within 8 hours of blood collection. Then it can be colder at -18 C and stored for up to 1 year. Frozen plasma is considered as plasma separated any time after 8 hours of blood storage [112, 114, 115].
Healthy, young gelding weighing at least 500 kg is the ideal equine blood donor. Donor horses should be performed current vaccinations. To prevent from equine infectious anemia donors should be tested each year. RBC antigens Aa and Qa are the most immunogenic antigens. Because of this in the ideal donor, the Aa and Qa alloantigens should be absent. There are breed-specific blood factor frequencies. Thus a donor of the same breed as the recipient, particularly when blood typing is absent may be preferable. Horses that have taken blood or plasma transfusions and mares that have had foals are not appropriate as donors. Because they have a higher risk of carrying RBC alloantibodies. Donkeys have a RBC antigen known as "donkey factor". Horses do not have this antigen. Thus donkeys or mules should not be used as donors for horses because horses can develop anti-donkey factor antibodies if transfusion takes place [1, 104, 116].
An immediate blood transfusion can be applied for the first time in an emergency situation with a very minor risk of serious transfusion reaction. Horses can develop alloantibodies within 1 week of transfusion. Thus blood typing and crossmatching are recommended before a second transfusion is given. A second blood transfusion may be given confidently without a blood crossmatch within 2-3 days of the first transfusion. Blood typing and alloantibody screening can be used for the transfusion needed patient to find the most suitable donor horse. Blood typing and antibody screening before initial transfusion are more important for horses. Because subsequent blood transfusions are anticipated and if sensitized to other blood group factors broodmares may produce foals with neonatal isoerythrolysis (NI). For detection of equine RBC antigens Ca and Aa, a rapid agglutination method has been developed. It can be more suitable for pretransfusion testing [99, 103, 104].
Blood is collected from the jugular vein of the donor horse. For this purpose two way used; direct needle cannulation or catheteri-zation. When a large volume of blood is required, a 10 or 12 gauge catheter is recommended. A 14 gauge catheter is also sufficient. Plastic bags and vacum-collection glass bottles in sizes ranging from 450 mL to 2 L are suitable for blood accumulation. Anticoagulation with 3.2% sodium citrate is enough when blood is received for immediate transfusion. In saline-adenine-glucose-mannitol solution red blood cell concentrates stored and they can be used for transfusion for up to 35 days after blood accumulation. Equine blood storage condition resemble to canine and human blood storage condition. According to both in vitro tests and human parameters after 35 days of storage equine erythrocytes remain appropriate for transfusion. Fresh frozen plasma is obtained by separation of erythrocytes and plasma. Both of them can be used alone. RBC survival evaluation sould be doen in vivo [104, 117].
To allow separation of red blood cells by gravity sedimentation the blood is stored in a refrigerator at 5 C for 48 hours in an upright position. Then the plasma is decanted into a sterile 3-L bag with sterile plastic connecting tubing using gravity. 3-L bags containes a constant weight of plasma (3.4 kg). The red cell fraction is thrown out. The plasma bags are sealed, labeled with the horse’s name and the date of decantation. They are stored at -20 C until needed for plasma transfusion [112, 118].
In acute blood loss cases, PCV is usually impractical for estimation of volume to be transfused because it does not exactly indicate blood loss. Instead of this the volume of blood needed are predicted by estimation of blood loss and evaluation of clinical parameters. Fluid shifts will replace much of the circulating volume so between 25% and 50% of the total blood lost should be replaced by transfusion. Pay attention sould be give to that up to 75% of RBCs lost into a body cavity like hemoperitoneum are within 24-72 hours autotransfused back into circulation. Thus in cases of intracavitary hemorrhage lower percentages of blood volume replacement can be needed. To remove small clots and fibrin blood and plasma products should be given with an in-line filter [104, 119].
Blood should be given at a rate of approximately 0.3mL/ kg over the first 10-20 minutes for monitoring the transfusion reactions. Heart rate, body temperature, and respiratory rate sould be monitored. Additionally horses have to be monitored for signs of muscle fasciculation, piloerection, and urticaria. Urticaria, hemolysis, pruritis, edema, tachycardia, tachypnea, pyrexia, colic, changes in mentation and acute anaphylactic reactions are adverse reactions indicated in horses taking blood transfusions. The rate of adverse reaction to WB transfusion has been reported as 16% which are mild urticarial reactions and worsening hemolysis. Also 1 of 44 horses (2%) exhibit a fatal anaphylactic reaction [103, 113].
Transfusion reactions may vary from mild urticarial reactions to anaphylaxis. They are divided into immunogenic and nonimmunogenic reactions. Immunogenic reactions include anaphylaxis, hemolysis, fever, hives, acute lung injury, posttransfusion purpura, immunosuppression, and neonatal isoerythrolysis. Nonimmunogenic reactions include circulatory overload, bacterial contamination, citrate toxicity, coagulopathy, hyperammonemia, and transmission of disease. In horses that have received fresh frozen plasma serum hepatitis has been observed [52, 93, 112, 120].
In a second plasma or blood transfusion there exists risk for severe adverse reactions in dogs. Also there is a risk of development of neonatal isoerythrolysis in gravid mares. The risk is much more in whole blood transfusions [26, 33, 112].
In horses suffered from normovolemic anemia polymerized ultrapurified bovine hemoglobin (PUBH) improves hemodynamics and oxygen transport parameters. During infusion to be informed about any adverse reactions patients should be monitored closely. Intense pruritus, tachycardia, and tachypnea can be resolved shortly after stopping the infusion [121].
Eleven blood groups have been classified in cattle. The greatest clinical relevance is in groups B and J. The B group is extremely complex, thus closely matched transfusions are very difficult. Newborn calves do not have the J antigen. During the first six months of life they generally acquire it. Cows can be sensitized to erythrocyte antigens by vaccinations of blood origin like some anaplasmosis and babesiosis vaccines. As a result of this neonatal isoerythrolysis in subsequent calves occur. [1].
Seven blood groups have been classified in sheep. The B group in these animals is resemble to the B group in cattle, and the R group is resemble to the J group in cattle. For example, antigens are soluble and soluble antigens passively absorbed to erythrocytes. In the goat, five blood groups are identified which resemble to those of sheep [1].
Blood group A–O expression is affected by 16 porcine blood groups and the S gene. Carbohydrate antigens like AO blood group antigens and minor histocompatibility antigens can be important targets for the immune response to transplanted organs or tissues. These antigens remain an unknown and untested variable in many transplant studies using pigs. Depending, on work performed in some Europian country pig blood groups developed and expanded largely. The source of blood typing reagents is especially from isoimmune sera. Most antibodies behave as agglutinins and a few as hemolysins. Internationally sixteen genetic systems are recognized [2, 122-124].
In two domestic South American camelids, Ilama and alpaca, our knowledge is little about group variation. Six blood groups factors were identified (e.g A, B, C, D, E and F). from iso- and heteroimmune sera constituted for these animals [2].
In ruminants and camelids indications for WB and plasma transfusion are similar to horses. Chronic anemia may be a more common problem in ruminants. Gastrointestinal parasites, particularly Haemonchus contains, and ectoparasites (e.g. Haematopinus spp. and Linognathus spp.) are causes of chronic blood loss anemia, and iron-deficiency anemia. These can affect neonatal calves [104, 121, 125].
Studies with camelids and bovines has showed that the neonatal intestine can only successfully absorb colostral immunoglobulins for 12–24 hours postpartum. Passive transfer (FPT) is failed in 19% to 24% of neonatal camelids. A common indication for plasma transfusion in neonatal calves and crias is failure of transfer of passive immunity. Hyperimmune serum products are existing for subcutaneous and intramuscular dosing in ruminants. These are products with antibodies against E. coli, Pasturella, Aercanobacter pyogenes, Salmonella typhimurium and Clostridium [104, 126-129].
An integral component of neonatal camelid care is IV plasma transfusion. It is used for the purpose of antibody supplementation and fluid resuscitation in critical illness. Neonates are immunocompetent at birth but due to initial postpartum absorption of colostrum for passive acquisition of immunoglobulins (especially IgG) they are severely hypogammaglobulinemic [130, 131].
In cattle, the first blood transfusion should usually be safe, regardless of the donor. J-negative donor is ideal. Because agglutination reactions do not develop, routine crossmatching is not useful in ruminants. First transfusions are usually safe to apply without a blood cross-match but crossmatching is recommended when more than 48-72 hours have passed away since the first blood transfusion. Blood donors should not have disease like bovine leukosis virus, anaplasmosis, and bovine viral diarrhea virus [104].
Total blood volume estimated in cattle is 80 mL/kg. From the donor animal up to 20-25% of total blood volume can be removed. Usually needle cannulation or jugular catheterization used in this situation. Blood can be collected into bottles or bags using citrate anticoagulant (e.g CPDA-1) in equine transfusions [104].
Blood samples can be taken from the jugular vein in sheep. A 500 ml transfer bag system including a needle can use for the storage. These bags include 70 ml of CPDA-1-stabiliser. Then the blood should be put into four 150 ml transfer bags. These bags can be stored on a horizontal shaker. It shows the best preservation of platelet function. Also it can be used for the storage experiment consecutively [132].
Platelet count and aggregability of CPDA-1-stabilised ovine blood is kept most covenient at room temperature. It provides adequate haemostatic function for ex vivo experiments for one working day. In ovine blood functional loss and high percentage of platelets within aggregates can be observed at refrigerator temperature. This should be considered in blood transfusion in sheep [132].
In order to monitor transfusion reactions blood should first be transported slowly. Ruminant blood type discordance result in primarily complement-mediated hemolysis. Volume overload should not be given. Also in neonates and small ruminants volume should carefully be given [104].
Intestinal absorption of antibodies declines sharply within the first 24 hours postpartum. For treatment of crias with failure of passive transfer (FPT) IV or intraperitoneal administration of 20–40 mL/kg of camelid plasma is recommended. In compromised neonates requiring fluid resuscitation IV administration of plasma is generally preferred. It is used for the correction of FPT and colloid support. In foals during extensive plasma volume expansion careful monitoring is needed to prevent cardiopulmonary complications. Following IV plasma administration the cardiovascular and pulmonary effects of plasma volume expansion have not been specifically worked out in camelids. But in several species (i.e sheep and cat) plasma volume overexpansion depending on excessive IV fluid administration has been associated with reduced lung function and pulmonary edema formation in clinical and experimental settings. In addition according to measures in presumed hypovolemic human patients administration of colloids can induce a greater reduction in lung function than crystalloids [130, 133-137].
Measurable plasma volume expansion and a concurrent reduction in pulmonary functional residual capacity (FRC) is caused by IV administration of 30 mL/kg camelid plasma to neonatal crias. In healthy neonatal crias administration of this quantity of plasma seems to be safe. But with underlying cardiopulmonary or systemic disease changes in lung volume associated with plasma administration could create risks for crias (131).
Adverse effects of transfusing blood stored for prolonged periods in lamps is encountered more often in patients with reduced vascular nitric oxide levels because of endothelial dysfunction. These patients can benefit from transfusion of fresh PRBC if available. Also inhaled nitric oxide supplementation can prevent pulmonary hypertension associated with transfusion of stored PRBC [138].
In previously untransfused pigs, hemolytic transfusion reactions do not appear to develop. But there have been two reports about adverse reactions in pigs undergoing liver transplants by the use of A–O incompatible transfusions. Pulmonary hypertension and decreased fibrinogen with an associated increase in fibrin degradation products occured in pigs that received A–O incompatible transfusions [139]. In a study, two pigs that administered A–O incompatible blood transfusions during liver transplants died because of disseminated intravascular coagulation (DIC), bleeding and progressive hypotension [140].
Vital part of veterinary emergency and critical care medicine is transfusion medicine. It is also therapy of some disease of patient. Blood and blood products can be obtained through the purchase of blood products or donors. Potentially fatal adverse transfusion reactions risk is higher in cats than in dogs. Also, adverse transfusion reactions are very important for large animals. By using known donors and screening assays that permit detection of incompatibility of blood typing or crossmatching, the risk can be decreased in both species.
At first, it is impossible to determine the quality of a product. However, it is necessary that the manufacturing processes are in control and stable as well as all the involved unitary processes in order to reduce the process variability. When an analytical procedure is performed on a sample, this is itself a process just as the manufacturing operation is a procedure. By analogy, we can apply the same rules and principles.
\nControl charts, as online statistical process control procedure, represent the first option for achieving this objective. Statistical process control allows to analyze the process stability and to estimate the process capability, knowing the level of variability. The Shewhart control chart is the most used technique to detect statistical changes in process quality. Walter A. Shewhart of the Bell Telephone Laboratories developed it in 1924. The control chart can be used as an estimating device, for example, process parameters such as the mean, standard deviation, fraction nonconforming, and so on may be estimated from a control chart. In addition, these estimates may be used to determine the capability of the process to produce acceptable results [1]. Shewhart control charts are effective when the in-control process data are stationary (i.e., the process data vary around a fixed mean in a stable manner) and uncorrelated. Under these conditions, their performance is predictable, allowing out-of-control situations to be reliably detected. In this type of control chart, the first step is as follows: a set of process data are collected and analyzed all at once in a retrospective analysis, constructing different control limits (such as warning and action control limits) in order to verify if the process is in control over the time during the collection of data. Second is to check if these limits can help to monitor future productions or samples. Alternatively, chart based on standard values allows specifying standard values for the process mean and standard deviation without analysis of the past data. A limitation of Shewhart control charts is that it uses only the information about the process contained in the last analyzed sample, ignoring any information provided by the set of collected data. This fact makes the Shewhart control chart relatively insensitive to small process shifts, about 1.5 standard deviations or less. The exponentially weighted moving average (EWMA) and the cumulative sum (Cusum) control charts are two good options in those situations where it is important to control small process shifts. Roberts [2] and later Crowder [3] and Lucas and Saccucci [4] introduced the EWMA control chart which analyzed different aspects of interest in detecting small changes in the process. Other authors, such as Lucas [5], Hawkins and Olwell [6], indicate that the Cusum control is more effective than the traditional Shewhart control chart in this type of situations.
\nIn industrial activities or in the laboratory, it is necessary to obtain information about the performance of the process or analytical method when it is operating under statistical control. For this, the process or analytical method is in control and stable. Process capability indices (PCIs) give an indication of the capability of a process or analytical method [7]. They are designed to quantify the relation between the desired specifications and the actual performance of the process or analytical method. In addition, the capability indices are calculated, to evaluate whether the process under study is able to provide sufficient conforming units. The capability indices could be used to evaluate whether the analytical method is only able to provide enough conforming results to check if a method is fitted for its intended purpose [8]. Various examples of the usefulness of capability indices in the framework of analytical method validation can be found in the literature [9, 10, 11]. At first, the methodology described earlier can be applied to any process or analytical method in statistical control.
\nThe main objective of this work was to evaluate the use of control charts in combination with the process capability indices as key elements in determining whether the process or analytical method is fitted for its purpose. The process capability indices, Cp, Cpk, and Cpm, were computed. The level of variability (i.e., method or process performance) was evaluated through the control chart, whereas the method or process specifications (i.e., analyst/customer requirements) were analyzed under different criteria based on the specification limit range. Finally, to determine whether the process or method meets the present capability requirement and runs under the desired quality conditions, the Pearn and Shu [24] method was used. All these aspects were analyzed using two examples: (1) the upper punch compaction force data obtained in a tablet manufacture process and (2) the RP-HPLC method data used for insulin quantitation in pharmaceutical preparations [12].
\nThe stability of a process is an important property, since if it is stable in the current time frame, it is also likely to be so in the future, assuming that no major changes occur [13]. This means that the process variation is due only to random causes and all assignable or special causes have been removed. If this is fulfilled, one can draw conclusions about the process capability and use the result for predicting it in future or other conditions. Usually, the process mean is monitored using location charts such as the x-chart, and the process dispersion is monitored using dispersion charts such as the R- or S-chart [1]. These control charts are based on samples (or subgroups) of n observations taken at regular sampling intervals. There are, however, many applications in which the control charts are based on individual observations (n = 1) rather than samples of n > 1. In such cases the R-chart cannot be used, as it is impossible to calculate the within-sample variation when the sample size equals 1.
\nThe control charts discussed above are designed under the assumption that a process being monitored will produce measurements that are independent and identically distributed over time, when only the inherent sources of variability are present in the process. For this, it is necessary to check the normality of the data, which is assessed through Q-Q plots and using statistical tests (e.g., Anderson-Darling, Shapiro-Wilk, or chi-square). Figure 1 shows the Q-Q plots for tablet manufacturing process. Shapiro-Wilk test confirmed that data follow a normal distribution at 5% significance level.
\nNormal Q-Q probability plot for compaction process data (left) and HPLC analytical method data used for the insulin quantification (right).
\nFigure 2 shows the two control charts, one for monitoring the process center (x-bar chart) and the other for monitoring the process variation (MR-chart), when a separate observation is made at each sampling point [1].
\nControl charts for compaction process: (upper) x-bar control chart and (lower) MR-chart (UCL = upper control limit; LCL = lower control limit; CL = mean or average range for the MR-chart). The red line corresponds to the warning limits using a RSD of 6%.
For the x-bar control chart based on individual observations, the central lines (CL) and control limits (UCL and LCL) are:
\nwhere x-bar is the sample mean and MR2 is the mean moving range of length two.
\nIn this case, the traditional choice is to use the moving range chart (MR-chart), which is the range of successive individual observations, to detect changes in the process variation [1].
\nFor the moving range charts, the following equations with n = 2 are used to establish the CL and control limits, respectively:
\nIn formulating the control limits of x-bar and MR-control charts, several factors, d2, D3, and D4, are constant, dependent on n, and assuming normal data distribution [14]. These values are tabulated and can be found in the bibliography [1]. In our case, d2 = 1.128 and D4 = 3.268, respectively.
\nIn this first example, we used the upper punch compaction force as variable. The data used in this example were generated using a compress machine (model Korsch AG XP-1) for 10 min with a sample frequency of 20 samples/min. The collected data corresponds to the acetaminophen tablet batch to laboratory scale (data not published).
\nThe data analysis was performed using the R-program (version 3.6.1) and plotted using the “qcc” package [15].
\nGiven the approximate normality of the data, we can use the x-chart to estimate the process mean, obtaining a value of 10.0 kN, whereas the MR-chart provides the process standard deviation, obtaining a value of 0.31 kN.
\n\nFigure 2 shows the x-bar control chart for the compression force variable. All plotted values fall within the control limits (9.16, 10.85), and therefore, the process is in statistical control. In addition, there is no evidence of cyclical or periodic behavior. However, there is a located zone between samples 148 and 152 indicating the nonrandom patterns present. This situation is related with the presence of “eight consecutive points plot on one side of the center line” [1] according to the application of decision rules for detecting this type of variation.
\nIn the compaction process, it is usually to fix the warning limits at ±6% of the mean value (RSD = 6%). In such situation, there are six points beyond these limits, indicating the existence of a problem during the process. The MR-control charts exhibit two points above the upper control limits (UCL = 1.013), and therefore the process should be considered out of control (Figure 2). However, a point above the upper control limit followed immediately by a point below control limit would not signal an out-of-control alarm. A similar situation was observed when the warning limits were fixed at ±6% of the mean value. In addition, the control charts show other forms of nonrandom variation; all of them are due to the presence of “eight consecutive values on one side of the centerline.” It is true that, when a point is plotted outside of the action limits, a search for an assignable cause is made and corrective action is taken if necessary. We have no explanation for this. The causes could be various: particle size and shape distribution, flow properties of the bulk material, mix process, tablet weight, etc. In this last case, we weighted some tablet during the manufacture process, the mean value being 700 ± 5 mg (n = 40), but this tablet batch does not satisfy the proposed fragility test by the USP [16]. Therefore, the process may not be operating properly. In this case, the sensitivity of the control chart should improve, changing the sampling frequency and/or the sample size in order to obtain more information about the process.
\nThis strategy may increase the risk of false alarms and be confusing to the operating personnel. In such situation, the average rung length (ARL) of the control chart is a good alternative. The ARL is the average number of points that must be plotted before a point indicates an out-of-control condition. If the process observations are uncorrelated, then in any Shewhart control chart, the ARL can be calculated as:
\nwhere p is the probability that any point exceeds the control limits. For the control at three sigma limits, p = 0.0027, and therefore, an out-of-control signal will be generated every 370 samples, on the average, even if the process remains in control. Some analysts like to report percentiles of the run length distribution instead of just the ARL [1]. The 10th and 50th percentiles are used more. In our example, around 10% of the time, the in-control run length will be less than 38 samples, and 50% of the time, it will be less than 256 samples.
\nFor the MR-control chart, the probability that any point exceeds the upper control limit (1.013) is 0.0052, and therefore, ARL is 190; this supposes that an out-of-control sample will be generated every 190 samples on the average. The second point outsider of control limits (sample #98) is too far from this value (see Figure 2).
\nCumulative sum and exponentially weighted moving average control charts efficiently complement the x-bar and MR-control charts when there is interest in detecting small changes in the process, around ±1.5 SD, and the sample consists of an individual unit. However, many researchers have discussed which of them is better in accordance with the level of variability that must be detected [17]. In practice, the EWMA control chart worked well with the parameters λ = 0.4 (smoothing constant) and L = 3.054 (control limit width fixed at three standard deviations), a value recommended by Montgomery [1]. Under this scenario, the sample number 112 was out of the control limits (see Figure 3), whereas the sample number 153 is very close to this limit. Using a value of λ = 0.2, the change was clearer, since the samples closest were also affected (data not shown). The values of λ = 0.2 and 0.05 with the respective width of control limits L = 2.814 and 2.614 are the best option to detect the average changes at order of one standard deviation.
\nEWMA control chart for the compaction process with the parameters λ = 0.2 and L = 3.054. Under these conditions, two points were beyond limits (#110 and #153, in red), whereas the number of points beyond limits was zero for λ = 0.4.
Cusum control charts directly incorporate all the information into the sequence of sample values by plotting the cumulative sums of their deviations from a value objective [18]. Moreover, when a tendency up or down appears, it indicates the process average changes, which requires a search to determine the causes. Oliva and Llabrés described a similar situation [19]. The Cusum control chart showed a similar situation to those observed in the EWMA control chart for the sample number 112; it was out of the limits. When we fixed the shift detection at ±1 SD, the situation is totally different; 17 points were beyond boundaries, approximately 8.4%, especially located at the beginning and at the end of the process (data not shown); for a shift detection equal to ±1.5 SD, a unique value was out of this limit. However, the data seems to describe a random way with an average of zero. There is no zone with an upward (C+) or downward (C−) tendency, perfectly defined, typical behavior of the Cusum control charts when the average process changes.
\nAt first, the Cusum control chart performed better for detecting shifts lower than 1.5 SD. However, EWMA provided the forecast of where the average will be in the next period, which makes it easier to apply in the process control (Figure 4).
\nCusum control chart for the compaction process. The number of points beyond boundaries was one (#110, in red) for shift detection fixed at ±1.5 SD, whereas the number of points was 8.4% for detection fixed at ±1 SD.
Details about PCIs and their statistical properties can be found in the literature [20, 21]. A capability index is generally a function of the process parameters, such as the mean μ, standard deviation σ, target value T, lower specification limit (LSL), and upper specification limit (USL) of x variable.
\nThe Cpm index is the best option to drive the process (or method) to the target value since this is intended to account for variability from the process (or method) mean and deviation from the target value T [7]. For a normally distributed process that is demonstrably stable (under statistical control), Boyles [22] considered the maximum likelihood estimator of Cpm as:
\nwhere USL and LSL are the upper and lower specification limits, respectively. Their difference provides a measure of allowable process (or method) spread (i.e., customer/analyst requirements), whereas σ2 and (μ − T)2 are a measure of precision and accuracy, respectively (i.e., process or method performance requirements). The mean of the process (or method) μ is estimated through the sample mean x-bar, whereas the following estimator for the standard deviation σ can be used:
\nwhere sj is the standard deviation of each subgroup and m is the number of subgroups. If the process is monitored using the MR-control chart, the following estimator can be used:
\nwhere \n
The Cpk index is defined as the ratio of the minimal distance of the specification limits to the method average to three times the standard deviation of the method (if the average is in between the specification limits) [23].
\nCpk is more commonly used because it is not dependent on the process or method being centered. However, Cpm is more sensitive to departure from the method target than Cpk is [24]. For example, when μ is within the interval of the specification limits, Cpk depends inversely on the method standard deviation σ (i.e., systematic error, σ2) and becomes large as σ gets closer to zero. Cpk also depends on the distance of the mean from the specification limits (i.e., method centering).
\nIf the method precision is improved, the Cpm will increase. If the method drifts from its target value (i.e., if μ moves away from T), then Cpm decreases. When both the method precision and the mean are modified, the Cpm index reflects these changes as well. This is also true for the Cpk index.
\nPearn and Shu [24] proposed the lower confidence bounds “C” on Cpm to measure the minimum capability of the process, based on the sample data. In this case, the critical values (Co) are used for making decisions in method capability testing with a designated type-I error, α, which is the risk of misjudging an incapable method (Ho: Cpm ≤ C) as a capable one (H1: Cpm > C), where C is the required process capability. This supposes that the decision-making procedure ensures that the risk of making a wrong decision will be no greater than the preset type-I error α. The algorithm proposed by Pearn and Shu [24] was used to compute the lower confidence bounds C. For this, the sample of size n, the confidence level γ (0.95), the estimated value Cpm, and the parameter ξ must be provided. In practice, the parameter ξ = (μ − T)/σ is unknown, but it can be calculated from the sample data as \n
Pearn and Chen [25] and Pearn et al. [26] have developed a procedure to obtain the lower confidence bounds and critical values of Cp and Cpk to determine whether a process or method meets the capability requirement or not.
\nTo calculate the PCIs, it is necessary to know the inherent variability in a process (using the control chart) and the customer requirements in terms of specification limits [27]. Control limits are set by the process and formulas; they are the voice of the process. The specification limits (LSL, USL) may be flexible, not rigorous, based on different criteria, since they represent the voice of the customer [7, 28]. The focus is to set some specification limits and compare them with the control limits of the process since they are the voice of the performance of the process (Figure 5).
\nThe black-dashed line shows the specified limits (USL and LSL) established at ±10% of mean value, whereas the red-dashed line corresponds to limits at ±6% of the mean value. The black line is the process mean.
Bouabidi et al. [8] proposed fixing the specification limits at ±5% around the true or nominal value, although Oliva and Llabrés [29] have proposed a lower variation level. The true value can be calculated using different procedures depending on variable characteristics. Other criteria could be to fix the specification limits equal to the control limits, which are just μ ± 3σ if a normal distribution is assumed.
\nSince the method is in control, capability indices can be computed, in this case, the indices Cp and Cpk (Table 1). To calculate the Cpm, the method mean and variability must be estimated relative to the method target and specification limits [25]. In this case, the T value is unknown given the process characteristic; no independent approach is available to calculate it since this response depends on working conditions. If the fixed T value is equal to the process mean, this implies that Cpm is equal to the Cp index.
\nUSL-LSL | \nCp\n | \nCo | \nCpk\n | \nCo | \nProcess capability | \n
---|---|---|---|---|---|
±3SD | \n1.02 | \n1.081 | \n1.03 | \n1.095 | \nInadequate | \n
±6% of x-bar | \n0.73 | \n1.081 | \n0.73 | \n1.095 | \nInadequate | \n
±10% of x-bar | \n1.21 | \n1.081 | \n1.21 | \n1.095 | \nCapable | \n
Cp and Cpk values as a function of the specification limit (USL-LSL). The process capability is based on the critical values (Co) according to Pearn et al. [26].
With respect to specification limits, we cannot apply Bouabidi et al.’s [8] proposed criteria, based on variations around the target value T. Other criteria could be to fix the specification limits equal to the control limits. In this case, the Cpk index was 1.03. To determine if the process meets the capability requirement, we must calculate the critical value Co for Cpk based on α risk, sample size, and C value (i.e., the required process capability) [25]. We find the critical value Co =1.095, based on C = 1.0, α = 0.05, and sample size n = 200, demonstrating that the process fails to meet the capability requirements (Table 1).
\nA similar result was obtained for the Cp index. A value of 1.02 was obtained, whereas the critical value Co with α risk of 0.05 was 1.081 [26], and therefore, the process does not satisfy the minimum process capability requirements.
\nAn alternative way to increase the process capability is to improve the process performance (modifying the allowable process spread through specification limits) or reduce the process systematic error (i.e., process standard deviation). In this last case, the quality improvement effort should focus on reducing the process variation, for example, changing the sampling frequency could solve the problem.
\nThe process performance may modify the function of the specification limit width. In the compaction process, it is usually to fix the warning limits at ±6% of the mean value (RSD = 6%). If the specification limits are fixed at this level, the estimated Cpk is lower than the critical value (0.73 < 1.095), and therefore, the process is not capable. If the specification limits are fixed at ±10% of the process mean value, the estimated Cpk value is 1.23 and exceeds the critical value of 1.095, indicating that the process is capable. This option does not suppose a real improvement in the process capability since the process conditions are maintained. The control limits are driven by the natural variability of the process, whereas the specification limits are determined externally by the manufacturing engineering, the customer, etc. We should know the process variability when setting specification limits. In our opinion, it is necessary to establish a compromise between the specification limit width and process variability.
\nThe main objective of any validation process is to check the maintenance of validation conditions in the laboratory over a long time period. In this second example, we used the insulin peak area expressed as concentration (U/mL) as control parameters [12]. For this, a standard solution with a nominal concentration of 100 U/mL was analyzed each working day (n = 144). The predicted concentration for the standard solution was obtained from the method calibration. This value is not independent due to the measurement errors which depend on various factors related to the method and its validation but not on the analyst [29].
\nHistogram and normal probability plots show that the collected data follow the normal distribution (Figure 1). The Shapiro-Wilk test confirmed this assumption. Therefore, control charts can be used to obtain the method requirements.
\nThe method mean was estimated to be 100.227 U/mL from the x-bar control chart (Figure 6), while the method standard deviation was estimated to be 0.60 U/mL from the MR-chart. The control limits were estimated using the “qcc” package from the R-program [15].
\nControl charts for HPLC method used for the insulin quantification in pharmaceutical preparations: (upper) x-bar control chart and (lower) MR-chart. (UCL = upper control limit; LCL = lower control limit; CL = mean or average range for the MR-chart).
The x-bar control chart shows that all plotted values fall within the control limits (98.40, 102.06), and therefore, the method is in statistical control. In addition, there is no evidence of cyclical or periodic behavior. However, the sample (#74) was outside of the control limits, but the cause of this was attributable to introducing a new column, whereas the sample #86 was related with the presence of “eight consecutive points plot on one side of the center line” [1]. The application of decision rules for detecting nonrandom patterns on control charts indicates that, in this situation, the method is out of control. However, the use of these rules allows enhancing the sensitivity of control charts against only criterion of control limit violation.
\nThe ARL was 370 since the probability that any point exceeds the control limits is 0.0027.
\nThe MR-control charts exhibit one point above the upper control limits (UCL = 2.214) as well as other forms of nonrandom variation, around the sample #40, and therefore the method should be considered out of control (Figure 6). In such situation, it is necessary to search the cause and take corrective action. In the first case, the cause was assignable with a column change, whereas the second one was due to the presence of “more eight consecutive point plots on one side of the centerline.”
\nIn this case, the obtained ARL value for MR-control was 189 since the probability that any value exceeds the upper control limit was 0.0053.
\nThe data were analyzed using the Cusum and EWMA control charts.
\nThe EWMA control chart shows that all plotted values fall within the control limits (Figure 7) using a smoothing constant of 0.2 (λ = 0.2) and control limit width fixed at three standard deviations (L = 3.054).
\nEWMA control chart for HPLC method. All points fall within control limit for λ = 0.2 and L = 3.054.
Cusum control chart, with a shift detection fixed at ±1 SD, shows four points beyond boundaries, all of them greater than the upper control limit. The first alteration is located around the samples #84–85, whereas the second one appears close to the end of the process (#130–131). In addition, if both alterations presented an upward tendency, it indicates the process average changes, which requires a search to determine the causes. When we fixed the shift detection at ±1.5 SD, the situation is totally different, all points fall within control limits (data not shown), and the data describe a random way with an average of zero, since the points show no evidence of an upward or downward tendency (Figure 8).
\nCusum control chart for HPLC method. The number of samples beyond limits was four for shift detection fixed at ±1 SD with an upward tendency. The cause of this alteration is unknown.
Since the analytical method is in control and stable, capability indices can be computed. Table 2 shows the estimated Cpk and Cpm indices to analyze the capability of our analytical method. The index Cpm, sometimes called the Taguchi index, adequately reveals the ability of the method to cluster around the target. This reflects the degree of method targeting (centering). For this, Cpm incorporates the variation in the method with respect to the target value and the specification limits preset by the analyst/customer [26]. This index conveys critical information regarding whether a method (or process) is capable of reproducing items satisfying a requirement that would be preset by the analyst [30]. If the prescribed minimum capability fails to be met, the method is considered incapable.
\nUSL-LSL | \nCpm\n | \nCo | \nCpk\n | \nCo | \nMethod capability | \n
---|---|---|---|---|---|
±3SD | \n0.95 | \n1.08 | \n0.79 | \n1.095 | \nInadequate | \n
±2.5% | \n1.30 | \n1.08 | \n1.26 | \n1.095 | \nCapable | \n
±3% | \n1.56 | \n1.44 | \n1.54 | \n1.45 | \nSatisfactory | \n
±5% | \n2.60 | \n2.16 | \n2.65 | \n2.18 | \nSuper | \n
Cpk and Cpm values as a function of the specification limit (USL-LSL). The method capability is based on the critical values (Co).
To calculate the Cpm, the method mean and variability must be estimated relative to the method target and specification limits [27]. In our case, the target value T corresponds to standard solution concentration (T = 100 U/mL). The analysis of the measurements during this period shows the accuracy; the average error between the mean and target concentration (μ − T)2 was 0.052 U/mL, whereas the precision calculated from the MR-chart was 0.36 U/mL. The overall uncertainty, calculated as the sum of the uncertainty of each component’s contribution (precision and accuracy), was 0.41 U/mL. The expanded uncertainty was 0.82 U/mL, using a coverage factor of 2. The calculated concentration is thus 100 ± 0.82 U/mL.
\nIf the specification limits are set at ±5% of the T value, according to Bouabidi et al. [8] criteria, the Cpm index was 2.60 (n = 100) with a lower confidence bound C on Cpm (i.e., the value used to measure method capability) of 2.48 (Figure 9). We therefore conclude that the true value of the method capability Cpm is no less than 2.48 with a 95% level of confidence. This result indicates that the method is “super” (Cpm > 2.0), and no further stringent precision control is required.
\nThe black-dashed line shows the specified limits (USL and LSL) established at ±5% of T value, whereas the blue-dashed line corresponds to ±3%. The red line is the T value.
If the specification limits are reduced to ±3% of T value, the Cpm was 1.56 with a lower 95% confidence limit of 1.47. This result implies that the method is considered “satisfactory” (1.33 < Cpm < 1.50). The method is inadequate for specification limits lower than ±2% of the T value, since the lower 95% confidence limit for the Cpm is less than 1. A similar result was obtained when the specification limits and the control limits were of equal width. Thus, the number of observations out of specification in the method was zero when the specification limits are greater than ±3% of the T value, and the proportion of nonconforming results was less than 1, giving a process yield of 100%. When the reference limits and the specification limits are of equal width, only 0.27% of the expected observations will be out of specification in the long term, and the process yield is 100%.
\nThe results obtained showed that we cannot use the control limits as specification limits, since the method is considered “inadequate” according to the criteria proposed by Pearn and Shu [24]. However, the control limits can be used in the development of the specification limits. In this example, a level of variability ±2.5% of T can be enough to declare the method capable (1.0 < Cpm < 1.33), as seen in Table 2.
\nAll these aspects were also analyzed using the Cpk index. The results are summarized in Table 2. To determine if the method meets the capability requirement, we must calculate the critical value Co for Cpk based on α risk, sample size, and C value (i.e., the required method capability) [25]. We find the critical value Co = 1.081, based on C = 1.0, α = 0.05, and sample size n = 200. When the specification limits are set at ±2.5% of T value, the estimated Cpk value is 1.30 and exceeds the critical value of 1.081, demonstrating that the method meets the capability requirements. Furthermore, if the limits are increased to ±5% of the T value, the Cpk increases to 2.65 with a critical value of 2.18 (based on C = 2.00; α = 0.05; n = 200), indicating that the capability is “super.” The obtained quality requirements were similar in both cases.
\nThe use of Cpk is clearly preferable when the limits are not equidistant, whereas the Cpm index can be overly conservative in this scenario. In our case, the target is at the center of the specification range, and if the aim of our method is to achieve a measure close to the target value with minimum variation, then Cpm is the most sensitive capability index. Given two analytical methods with different performances (i.e., precision and accuracy) and the same method departure, a simple comparison between both Cpm is sufficient to select the better, although similar results were obtained with the Cpk index. This fact was analyzed by Oliva and Llabrés [29].
\nThe traditional x-chart and moving range chart represent the first option to monitor the analytical method or process over a long time. The EWAMA and Cusum are two good alternatives in those situations where it is important to detect small process shifts. The capability indices are calculated to evaluate whether the process or analytical method under study is able to provide sufficient conforming results when it is operating under statistical control. To calculate the PCIs, it is necessary to know the actual performance of the process or analytical method (using the control chart) and the customer requirements in terms of specification limits. The specification limits should be determined externally from previous knowledge of inherent process variability. However, different criteria have been proposed to fix these limits. The Cpm and Cpk indices were used as part of the control strategy. Cpk is the best option because it is not dependent on the process or method being centered. However, Cpm is more sensitive to departure from the method target than Cpk is. Independent of the criteria used to establish the specification limits, computation of the capability indices depends on the analyzed response, and their application is limited to each particular situation and is not general.
\nThe authors wish to thank Dr. José B. Fariña from University of La Laguna, Tenerife, Spain, for providing the compaction process data. This research was financed by Instituto de Salud Carlos III, Ministerio de Ciencia, and Innovación y Universidades y FEDER as part of Project PI18/01380.
\nThe authors declare no conflict of interest.
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He has developed automation equipment for machine tools, spooling\nmachines, high-power ultrasound processes, and more.",institutionString:"Polytechnic University of Timişoara",institution:{name:"Polytechnic University of Timişoara",institutionURL:null,country:{name:"Romania"}}}]},{type:"book",id:"9963",title:"Advances and Applications in Deep Learning",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/9963.jpg",slug:"advances-and-applications-in-deep-learning",publishedDate:"December 9th 2020",editedByType:"Edited by",bookSignature:"Marco Antonio Aceves-Fernandez",hash:"0d51ba46f22e55cb89140f60d86a071e",volumeInSeries:4,fullTitle:"Advances and Applications in Deep Learning",editors:[{id:"24555",title:"Dr.",name:"Marco Antonio",middleName:null,surname:"Aceves Fernandez",slug:"marco-antonio-aceves-fernandez",fullName:"Marco Antonio Aceves Fernandez",profilePictureURL:"https://mts.intechopen.com/storage/users/24555/images/system/24555.jpg",biography:"Dr. Marco Antonio Aceves Fernandez obtained his B.Sc. (Eng.) in Telematics from the Universidad de Colima, Mexico. He obtained both his M.Sc. and Ph.D. from the University of Liverpool, England, in the field of Intelligent Systems. He is a full professor at the Universidad Autonoma de Queretaro, Mexico, and a member of the National System of Researchers (SNI) since 2009. Dr. Aceves Fernandez has published more than 80 research papers as well as a number of book chapters and congress papers. He has contributed in more than 20 funded research projects, both academic and industrial, in the area of artificial intelligence, ranging from environmental, biomedical, automotive, aviation, consumer, and robotics to other applications. He is also a honorary president at the National Association of Embedded Systems (AMESE), a senior member of the IEEE, and a board member of many institutions. His research interests include intelligent and embedded systems.",institutionString:"Universidad Autonoma de Queretaro",institution:{name:"Autonomous University of Queretaro",institutionURL:null,country:{name:"Mexico"}}}]}]},openForSubmissionBooks:{paginationCount:7,paginationItems:[{id:"11667",title:"Marine Pollution - Recent Developments",coverURL:"https://cdn.intechopen.com/books/images_new/11667.jpg",hash:"e524cd97843b075a724e151256773631",secondStepPassed:!0,currentStepOfPublishingProcess:3,submissionDeadline:"April 20th 2022",isOpenForSubmission:!0,editors:[{id:"318562",title:"Dr.",name:"Monique",surname:"Mancuso",slug:"monique-mancuso",fullName:"Monique Mancuso"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{id:"11664",title:"Recent Advances in Sensing Technologies for Environmental Control and Monitoring",coverURL:"https://cdn.intechopen.com/books/images_new/11664.jpg",hash:"cf1ee76443e393bc7597723c3ee3e26f",secondStepPassed:!0,currentStepOfPublishingProcess:3,submissionDeadline:"May 4th 2022",isOpenForSubmission:!0,editors:[{id:"24687",title:"Dr.",name:"Toonika",surname:"Rinken",slug:"toonika-rinken",fullName:"Toonika Rinken"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{id:"11662",title:"Limnology - The Importance of Monitoring and Correlations of Lentic and Lotic Waters",coverURL:"https://cdn.intechopen.com/books/images_new/11662.jpg",hash:"f1043cf6b1daae7a7b527e1d162ca4a8",secondStepPassed:!0,currentStepOfPublishingProcess:3,submissionDeadline:"May 10th 2022",isOpenForSubmission:!0,editors:[{id:"315689",title:"Dr.",name:"Carmine",surname:"Massarelli",slug:"carmine-massarelli",fullName:"Carmine Massarelli"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{id:"10845",title:"Marine Ecosystems - Biodiversity, Ecosystem Services and Human Impacts",coverURL:"https://cdn.intechopen.com/books/images_new/10845.jpg",hash:"727e7eb3d4ba529ec5eb4f150e078523",secondStepPassed:!0,currentStepOfPublishingProcess:3,submissionDeadline:"May 12th 2022",isOpenForSubmission:!0,editors:[{id:"320124",title:"Dr.",name:"Ana M.M.",surname:"Gonçalves",slug:"ana-m.m.-goncalves",fullName:"Ana M.M. 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He is also a faculty member in the Molecular Oncology Program. He obtained his MSc and Ph.D. at Oregon State University and Texas Tech University, respectively. He pursued his postdoctoral studies at Rutgers University Medical School and the National Institutes of Health (NIH/NIDDK), USA. His research focuses on biochemistry, biophysics, genetics, molecular biology, and molecular medicine with specialization in the fields of drug design, protein structure-function, protein folding, prions, microRNA, pseudogenes, molecular cancer, epigenetics, metabolites, proteomics, genomics, protein expression, and characterization by spectroscopic and calorimetric methods.",institutionString:"University of Health Sciences",institution:null},{id:"180528",title:"Dr.",name:"Hiroyuki",middleName:null,surname:"Kagechika",slug:"hiroyuki-kagechika",fullName:"Hiroyuki Kagechika",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/180528/images/system/180528.jpg",biography:"Hiroyuki Kagechika received his bachelor’s degree and Ph.D. in Pharmaceutical Sciences from the University of Tokyo, Japan, where he served as an associate professor until 2004. He is currently a professor at the Institute of Biomaterials and Bioengineering (IBB), Tokyo Medical and Dental University (TMDU). From 2010 to 2012, he was the dean of the Graduate School of Biomedical Science. Since 2012, he has served as the vice dean of the Graduate School of Medical and Dental Sciences. He has been the director of the IBB since 2020. Dr. Kagechika’s major research interests are the medicinal chemistry of retinoids, vitamins D/K, and nuclear receptors. He has developed various compounds including a drug for acute promyelocytic leukemia.",institutionString:"Tokyo Medical and Dental University",institution:{name:"Tokyo Medical and Dental University",country:{name:"Japan"}}},{id:"40482",title:null,name:"Rizwan",middleName:null,surname:"Ahmad",slug:"rizwan-ahmad",fullName:"Rizwan Ahmad",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/40482/images/system/40482.jpeg",biography:"Dr. Rizwan Ahmad is a University Professor and Coordinator, Quality and Development, College of Medicine, Imam Abdulrahman bin Faisal University, Saudi Arabia. Previously, he was Associate Professor of Human Function, Oman Medical College, Oman, and SBS University, Dehradun. Dr. Ahmad completed his education at Aligarh Muslim University, Aligarh. He has published several articles in peer-reviewed journals, chapters, and edited books. His area of specialization is free radical biochemistry and autoimmune diseases.",institutionString:"Imam Abdulrahman Bin Faisal University",institution:{name:"Imam Abdulrahman Bin Faisal University",country:{name:"Saudi Arabia"}}},{id:"41865",title:"Prof.",name:"Farid A.",middleName:null,surname:"Badria",slug:"farid-a.-badria",fullName:"Farid A. Badria",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/41865/images/system/41865.jpg",biography:"Farid A. Badria, Ph.D., is the recipient of several awards, including The World Academy of Sciences (TWAS) Prize for Public Understanding of Science; the World Intellectual Property Organization (WIPO) Gold Medal for best invention; Outstanding Arab Scholar, Kuwait; and the Khwarizmi International Award, Iran. He has 250 publications, 12 books, 20 patents, and several marketed pharmaceutical products to his credit. He continues to lead research projects on developing new therapies for liver, skin disorders, and cancer. Dr. Badria was listed among the world’s top 2% of scientists in medicinal and biomolecular chemistry in 2019 and 2020. He is a member of the Arab Development Fund, Kuwait; International Cell Research Organization–United Nations Educational, Scientific and Cultural Organization (ICRO–UNESCO), Chile; and UNESCO Biotechnology France",institutionString:"Mansoura University",institution:{name:"Mansoura University",country:{name:"Egypt"}}},{id:"329385",title:"Dr.",name:"Rajesh K.",middleName:"Kumar",surname:"Singh",slug:"rajesh-k.-singh",fullName:"Rajesh K. Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329385/images/system/329385.png",biography:"Dr. Singh received a BPharm (2003) and MPharm (2005) from Panjab University, Chandigarh, India, and a Ph.D. (2013) from Punjab Technical University (PTU), Jalandhar, India. He has more than sixteen years of teaching experience and has supervised numerous postgraduate and Ph.D. students. He has to his credit more than seventy papers in SCI- and SCOPUS-indexed journals, fifty-five conference proceedings, four books, six Best Paper Awards, and five projects from different government agencies. He is currently an editorial board member of eight international journals and a reviewer for more than fifty scientific journals. He received Top Reviewer and Excellent Peer Reviewer Awards from Publons in 2016 and 2017, respectively. He is also on the panel of The International Reviewer for reviewing research proposals for grants from the Royal Society. He also serves as a Publons Academy mentor and Bentham brand ambassador.",institutionString:"Punjab Technical University",institution:{name:"Punjab Technical University",country:{name:"India"}}},{id:"142388",title:"Dr.",name:"Thiago",middleName:"Gomes",surname:"Gomes Heck",slug:"thiago-gomes-heck",fullName:"Thiago Gomes Heck",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/142388/images/7259_n.jpg",biography:null,institutionString:null,institution:{name:"Universidade Regional do Noroeste do Estado do Rio Grande do Sul",country:{name:"Brazil"}}},{id:"336273",title:"Assistant Prof.",name:"Janja",middleName:null,surname:"Zupan",slug:"janja-zupan",fullName:"Janja Zupan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/336273/images/14853_n.jpeg",biography:"Janja Zupan graduated in 2005 at the Department of Clinical Biochemistry (superviser prof. dr. Janja Marc) in the field of genetics of osteoporosis. Since November 2009 she is working as a Teaching Assistant at the Faculty of Pharmacy, Department of Clinical Biochemistry. In 2011 she completed part of her research and PhD work at Institute of Genetics and Molecular Medicine, University of Edinburgh. She finished her PhD entitled The influence of the proinflammatory cytokines on the RANK/RANKL/OPG in bone tissue of osteoporotic and osteoarthritic patients in 2012. From 2014-2016 she worked at the Institute of Biomedical Sciences, University of Aberdeen as a postdoctoral research fellow on UK Arthritis research project where she gained knowledge in mesenchymal stem cells and regenerative medicine. She returned back to University of Ljubljana, Faculty of Pharmacy in 2016. She is currently leading project entitled Mesenchymal stem cells-the keepers of tissue endogenous regenerative capacity facing up to aging of the musculoskeletal system funded by Slovenian Research Agency.",institutionString:null,institution:{name:"University of Ljubljana",country:{name:"Slovenia"}}},{id:"357453",title:"Dr.",name:"Radheshyam",middleName:null,surname:"Maurya",slug:"radheshyam-maurya",fullName:"Radheshyam Maurya",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/357453/images/16535_n.jpg",biography:null,institutionString:null,institution:{name:"University of Hyderabad",country:{name:"India"}}},{id:"311457",title:"Dr.",name:"Júlia",middleName:null,surname:"Scherer Santos",slug:"julia-scherer-santos",fullName:"Júlia Scherer Santos",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/311457/images/system/311457.jpg",biography:"Dr. Júlia Scherer Santos works in the areas of cosmetology, nanotechnology, pharmaceutical technology, beauty, and aesthetics. Dr. Santos also has experience as a professor of graduate courses. Graduated in Pharmacy, specialization in Cosmetology and Cosmeceuticals applied to aesthetics, specialization in Aesthetic and Cosmetic Health, and a doctorate in Pharmaceutical Nanotechnology. Teaching experience in Pharmacy and Aesthetics and Cosmetics courses. She works mainly on the following subjects: nanotechnology, cosmetology, pharmaceutical technology, aesthetics.",institutionString:"Universidade Federal de Juiz de Fora",institution:{name:"Universidade Federal de Juiz de Fora",country:{name:"Brazil"}}},{id:"219081",title:"Dr.",name:"Abdulsamed",middleName:null,surname:"Kükürt",slug:"abdulsamed-kukurt",fullName:"Abdulsamed Kükürt",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRNVJQA4/Profile_Picture_2022-03-07T13:23:04.png",biography:"Dr. Kükürt graduated from Uludağ University in Turkey. He started his academic career as a Research Assistant in the Department of Biochemistry at Kafkas University. In 2019, he completed his Ph.D. program in the Department of Biochemistry at the Institute of Health Sciences. He is currently working at the Department of Biochemistry, Kafkas University. He has 27 published research articles in academic journals, 11 book chapters, and 37 papers. He took part in 10 academic projects. He served as a reviewer for many articles. He still serves as a member of the review board in many academic journals. His research interests include biochemistry, oxidative stress, reactive species, antioxidants, lipid peroxidation, inflammation, reproductive hormones, phenolic compounds, female infertility.",institutionString:"Kafkas University",institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"178366",title:"Associate Prof.",name:"Volkan",middleName:null,surname:"Gelen",slug:"volkan-gelen",fullName:"Volkan Gelen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178366/images/system/178366.jpg",biography:"Volkan Gelen is a Physiology specialist who received his veterinary degree from Kafkas University in 2011. Between 2011-2015, he worked as an assistant at Atatürk University, Faculty of Veterinary Medicine, Department of Physiology. In 2016, he joined Kafkas University, Faculty of Veterinary Medicine, Department of Physiology as an assistant professor. Dr. Gelen has been engaged in various academic activities at Kafkas University since 2016. There he completed 5 projects and has 3 ongoing projects. He has 60 articles published in scientific journals and 20 poster presentations in scientific congresses. His research interests include physiology, endocrine system, cancer, diabetes, cardiovascular system diseases, and isolated organ bath system studies.",institutionString:"Kafkas University",institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"418963",title:"Dr.",name:"Augustine Ododo",middleName:"Augustine",surname:"Osagie",slug:"augustine-ododo-osagie",fullName:"Augustine Ododo Osagie",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/418963/images/16900_n.jpg",biography:"Born into the family of Osagie, a prince of the Benin Kingdom. I am currently an academic in the Department of Medical Biochemistry, University of Benin. Part of the duties are to teach undergraduate students and conduct academic research.",institutionString:null,institution:{name:"University of Benin",country:{name:"Nigeria"}}},{id:"192992",title:"Prof.",name:"Shagufta",middleName:null,surname:"Perveen",slug:"shagufta-perveen",fullName:"Shagufta Perveen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192992/images/system/192992.png",biography:"Prof. Shagufta Perveen is a Distinguish Professor in the Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. Dr. Perveen has acted as the principal investigator of major research projects funded by the research unit of King Saud University. She has more than ninety original research papers in peer-reviewed journals of international repute to her credit. She is a fellow member of the Royal Society of Chemistry UK and the American Chemical Society of the United States.",institutionString:"King Saud University",institution:{name:"King Saud University",country:{name:"Saudi Arabia"}}},{id:"49848",title:"Dr.",name:"Wen-Long",middleName:null,surname:"Hu",slug:"wen-long-hu",fullName:"Wen-Long Hu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49848/images/system/49848.jpg",biography:"Wen-Long Hu is Chief of the Division of Acupuncture, Department of Chinese Medicine at Kaohsiung Chang Gung Memorial Hospital, as well as an adjunct associate professor at Fooyin University and Kaohsiung Medical University. Wen-Long is President of Taiwan Traditional Chinese Medicine Medical Association. He has 28 years of experience in clinical practice in laser acupuncture therapy and 34 years in acupuncture. He is an invited speaker for lectures and workshops in laser acupuncture at many symposiums held by medical associations. He owns the patent for herbal preparation and producing, and for the supercritical fluid-treated needle. Dr. Hu has published three books, 12 book chapters, and more than 30 papers in reputed journals, besides serving as an editorial board member of repute.",institutionString:"Kaohsiung Chang Gung Memorial Hospital",institution:{name:"Kaohsiung Chang Gung Memorial Hospital",country:{name:"Taiwan"}}},{id:"298472",title:"Prof.",name:"Andrey V.",middleName:null,surname:"Grechko",slug:"andrey-v.-grechko",fullName:"Andrey V. Grechko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/298472/images/system/298472.png",biography:"Andrey Vyacheslavovich Grechko, Ph.D., Professor, is a Corresponding Member of the Russian Academy of Sciences. He graduated from the Semashko Moscow Medical Institute (Semashko National Research Institute of Public Health) with a degree in Medicine (1998), the Clinical Department of Dermatovenerology (2000), and received a second higher education in Psychology (2009). Professor A.V. Grechko held the position of Сhief Physician of the Central Clinical Hospital in Moscow. He worked as a professor at the faculty and was engaged in scientific research at the Medical University. Starting in 2013, he has been the initiator of the creation of the Federal Scientific and Clinical Center for Intensive Care and Rehabilitology, Moscow, Russian Federation, where he also serves as Director since 2015. He has many years of experience in research and teaching in various fields of medicine, is an author/co-author of more than 200 scientific publications, 13 patents, 15 medical books/chapters, including Chapter in Book «Metabolomics», IntechOpen, 2020 «Metabolomic Discovery of Microbiota Dysfunction as the Cause of Pathology».",institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"199461",title:"Prof.",name:"Natalia V.",middleName:null,surname:"Beloborodova",slug:"natalia-v.-beloborodova",fullName:"Natalia V. Beloborodova",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/199461/images/system/199461.jpg",biography:'Natalia Vladimirovna Beloborodova was educated at the Pirogov Russian National Research Medical University, with a degree in pediatrics in 1980, a Ph.D. in 1987, and a specialization in Clinical Microbiology from First Moscow State Medical University in 2004. She has been a Professor since 1996. Currently, she is the Head of the Laboratory of Metabolism, a division of the Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, Moscow, Russian Federation. N.V. Beloborodova has many years of clinical experience in the field of intensive care and surgery. She studies infectious complications and sepsis. She initiated a series of interdisciplinary clinical and experimental studies based on the concept of integrating human metabolism and its microbiota. Her scientific achievements are widely known: she is the recipient of the Marie E. Coates Award \\"Best lecturer-scientist\\" Gustafsson Fund, Karolinska Institutes, Stockholm, Sweden, and the International Sepsis Forum Award, Pasteur Institute, Paris, France (2014), etc. Professor N.V. Beloborodova wrote 210 papers, five books, 10 chapters and has edited four books.',institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"354260",title:"Ph.D.",name:"Tércio Elyan",middleName:"Azevedo",surname:"Azevedo Martins",slug:"tercio-elyan-azevedo-martins",fullName:"Tércio Elyan Azevedo Martins",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/354260/images/16241_n.jpg",biography:"Graduated in Pharmacy from the Federal University of Ceará with the modality in Industrial Pharmacy, Specialist in Production and Control of Medicines from the University of São Paulo (USP), Master in Pharmaceuticals and Medicines from the University of São Paulo (USP) and Doctor of Science in the program of Pharmaceuticals and Medicines by the University of São Paulo. Professor at Universidade Paulista (UNIP) in the areas of chemistry, cosmetology and trichology. Assistant Coordinator of the Higher Course in Aesthetic and Cosmetic Technology at Universidade Paulista Campus Chácara Santo Antônio. Experience in the Pharmacy area, with emphasis on Pharmacotechnics, Pharmaceutical Technology, Research and Development of Cosmetics, acting mainly on topics such as cosmetology, antioxidant activity, aesthetics, photoprotection, cyclodextrin and thermal analysis.",institutionString:null,institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"334285",title:"Ph.D. Student",name:"Sameer",middleName:"Kumar",surname:"Jagirdar",slug:"sameer-jagirdar",fullName:"Sameer Jagirdar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334285/images/14691_n.jpg",biography:"I\\'m a graduate student at the center for biosystems science and engineering at the Indian Institute of Science, Bangalore, India. I am interested in studying host-pathogen interactions at the biomaterial interface.",institutionString:null,institution:{name:"Indian Institute of Science Bangalore",country:{name:"India"}}},{id:"329795",title:"Dr.",name:"Mohd Aftab",middleName:"Aftab",surname:"Siddiqui",slug:"mohd-aftab-siddiqui",fullName:"Mohd Aftab Siddiqui",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329795/images/15648_n.jpg",biography:"Dr. Mohd Aftab Siddiqui is currently working as Assistant Professor in the Faculty of Pharmacy, Integral University, Lucknow for the last 6 years. He has completed his Doctor in Philosophy (Pharmacology) in 2020 from Integral University, Lucknow. He completed his Bachelor in Pharmacy in 2013 and Master in Pharmacy (Pharmacology) in 2015 from Integral University, Lucknow. He is the gold medalist in Bachelor and Master degree. He qualified GPAT -2013, GPAT -2014, and GPAT 2015. His area of research is Pharmacological screening of herbal drugs/ natural products in liver and cardiac diseases. He has guided many M. Pharm. research projects. He has many national and international publications.",institutionString:"Integral University",institution:null},{id:"255360",title:"Dr.",name:"Usama",middleName:null,surname:"Ahmad",slug:"usama-ahmad",fullName:"Usama Ahmad",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255360/images/system/255360.png",biography:"Dr. Usama Ahmad holds a specialization in Pharmaceutics from Amity University, Lucknow, India. He received his Ph.D. degree from Integral University. Currently, he’s working as an Assistant Professor of Pharmaceutics in the Faculty of Pharmacy, Integral University. From 2013 to 2014 he worked on a research project funded by SERB-DST, Government of India. He has a rich publication record with more than 32 original articles published in reputed journals, 3 edited books, 5 book chapters, and a number of scientific articles published in ‘Ingredients South Asia Magazine’ and ‘QualPharma Magazine’. He is a member of the American Association for Cancer Research, International Association for the Study of Lung Cancer, and the British Society for Nanomedicine. Dr. Ahmad’s research focus is on the development of nanoformulations to facilitate the delivery of drugs that aim to provide practical solutions to current healthcare problems.",institutionString:"Integral University",institution:{name:"Integral University",country:{name:"India"}}},{id:"30568",title:"Prof.",name:"Madhu",middleName:null,surname:"Khullar",slug:"madhu-khullar",fullName:"Madhu Khullar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/30568/images/system/30568.jpg",biography:"Dr. Madhu Khullar is a Professor of Experimental Medicine and Biotechnology at the Post Graduate Institute of Medical Education and Research, Chandigarh, India. She completed her Post Doctorate in hypertension research at the Henry Ford Hospital, Detroit, USA in 1985. She is an editor and reviewer of several international journals, and a fellow and member of several cardiovascular research societies. Dr. Khullar has a keen research interest in genetics of hypertension, and is currently studying pharmacogenetics of hypertension.",institutionString:"Post Graduate Institute of Medical Education and Research",institution:{name:"Post Graduate Institute of Medical Education and Research",country:{name:"India"}}},{id:"223233",title:"Prof.",name:"Xianquan",middleName:null,surname:"Zhan",slug:"xianquan-zhan",fullName:"Xianquan Zhan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/223233/images/system/223233.png",biography:"Xianquan Zhan received his MD and Ph.D. in Preventive Medicine at West China University of Medical Sciences. He received his post-doctoral training in oncology and cancer proteomics at the Central South University, China, and the University of Tennessee Health Science Center (UTHSC), USA. He worked at UTHSC and the Cleveland Clinic in 2001–2012 and achieved the rank of associate professor at UTHSC. Currently, he is a full professor at Central South University and Shandong First Medical University, and an advisor to MS/PhD students and postdoctoral fellows. He is also a fellow of the Royal Society of Medicine and European Association for Predictive Preventive Personalized Medicine (EPMA), a national representative of EPMA, and a member of the American Society of Clinical Oncology (ASCO) and the American Association for the Advancement of Sciences (AAAS). He is also the editor in chief of International Journal of Chronic Diseases & Therapy, an associate editor of EPMA Journal, Frontiers in Endocrinology, and BMC Medical Genomics, and a guest editor of Mass Spectrometry Reviews, Frontiers in Endocrinology, EPMA Journal, and Oxidative Medicine and Cellular Longevity. He has published more than 148 articles, 28 book chapters, 6 books, and 2 US patents in the field of clinical proteomics and biomarkers.",institutionString:"Shandong First Medical University",institution:{name:"Affiliated Hospital of Shandong Academy of Medical Sciences",country:{name:"China"}}},{id:"297507",title:"Dr.",name:"Charles",middleName:"Elias",surname:"Assmann",slug:"charles-assmann",fullName:"Charles Assmann",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/297507/images/system/297507.jpg",biography:"Charles Elias Assmann is a biologist from Federal University of Santa Maria (UFSM, Brazil), who spent some time abroad at the Ludwig-Maximilians-Universität München (LMU, Germany). He has Masters Degree in Biochemistry (UFSM), and is currently a PhD student at Biochemistry at the Department of Biochemistry and Molecular Biology of the UFSM. His areas of expertise include: Biochemistry, Molecular Biology, Enzymology, Genetics and Toxicology. He is currently working on the following subjects: Aluminium toxicity, Neuroinflammation, Oxidative stress and Purinergic system. Since 2011 he has presented more than 80 abstracts in scientific proceedings of national and international meetings. Since 2014, he has published more than 20 peer reviewed papers (including 4 reviews, 3 in Portuguese) and 2 book chapters. He has also been a reviewer of international journals and ad hoc reviewer of scientific committees from Brazilian Universities.",institutionString:"Universidade Federal de Santa Maria",institution:{name:"Universidade Federal de Santa Maria",country:{name:"Brazil"}}},{id:"217850",title:"Dr.",name:"Margarete Dulce",middleName:null,surname:"Bagatini",slug:"margarete-dulce-bagatini",fullName:"Margarete Dulce Bagatini",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/217850/images/system/217850.jpeg",biography:"Dr. Margarete Dulce Bagatini is an associate professor at the Federal University of Fronteira Sul/Brazil. She has a degree in Pharmacy and a PhD in Biological Sciences: Toxicological Biochemistry. She is a member of the UFFS Research Advisory Committee\nand a member of the Biovitta Research Institute. She is currently:\nthe leader of the research group: Biological and Clinical Studies\nin Human Pathologies, professor of postgraduate program in\nBiochemistry at UFSC and postgraduate program in Science and Food Technology at\nUFFS. She has experience in the area of pharmacy and clinical analysis, acting mainly\non the following topics: oxidative stress, the purinergic system and human pathologies, being a reviewer of several international journals and books.",institutionString:"Universidade Federal da Fronteira Sul",institution:{name:"Universidade Federal da Fronteira Sul",country:{name:"Brazil"}}},{id:"226275",title:"Ph.D.",name:"Metin",middleName:null,surname:"Budak",slug:"metin-budak",fullName:"Metin Budak",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/226275/images/system/226275.jfif",biography:"Metin Budak, MSc, PhD is an Assistant Professor at Trakya University, Faculty of Medicine. He has been Head of the Molecular Research Lab at Prof. Mirko Tos Ear and Hearing Research Center since 2018. His specializations are biophysics, epigenetics, genetics, and methylation mechanisms. He has published around 25 peer-reviewed papers, 2 book chapters, and 28 abstracts. He is a member of the Clinical Research Ethics Committee and Quantification and Consideration Committee of Medicine Faculty. His research area is the role of methylation during gene transcription, chromatin packages DNA within the cell and DNA repair, replication, recombination, and gene transcription. His research focuses on how the cell overcomes chromatin structure and methylation to allow access to the underlying DNA and enable normal cellular function.",institutionString:"Trakya University",institution:{name:"Trakya University",country:{name:"Turkey"}}},{id:"243049",title:"Dr.",name:"Anca",middleName:null,surname:"Pantea Stoian",slug:"anca-pantea-stoian",fullName:"Anca Pantea Stoian",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243049/images/system/243049.jpg",biography:"Anca Pantea Stoian is a specialist in diabetes, nutrition, and metabolic diseases as well as health food hygiene. She also has competency in general ultrasonography.\n\nShe is an associate professor in the Diabetes, Nutrition and Metabolic Diseases Department, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania. She has been chief of the Hygiene Department, Faculty of Dentistry, at the same university since 2019. Her interests include micro and macrovascular complications in diabetes and new therapies. Her research activities focus on nutritional intervention in chronic pathology, as well as cardio-renal-metabolic risk assessment, and diabetes in cancer. She is currently engaged in developing new therapies and technological tools for screening, prevention, and patient education in diabetes. \n\nShe is a member of the European Association for the Study of Diabetes, Cardiometabolic Academy, CEDA, Romanian Society of Diabetes, Nutrition and Metabolic Diseases, Romanian Diabetes Federation, and Association for Renal Metabolic and Nutrition studies. She has authored or co-authored 160 papers in national and international peer-reviewed journals.",institutionString:null,institution:{name:"Carol Davila University of Medicine and Pharmacy",country:{name:"Romania"}}},{id:"279792",title:"Dr.",name:"João",middleName:null,surname:"Cotas",slug:"joao-cotas",fullName:"João Cotas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/279792/images/system/279792.jpg",biography:"Graduate and master in Biology from the University of Coimbra.\n\nI am a research fellow at the Macroalgae Laboratory Unit, in the MARE-UC – Marine and Environmental Sciences Centre of the University of Coimbra. My principal function is the collection, extraction and purification of macroalgae compounds, chemical and bioactive characterization of the compounds and algae extracts and development of new methodologies in marine biotechnology area. \nI am associated in two projects: one consists on discovery of natural compounds for oncobiology. The other project is the about the natural compounds/products for agricultural area.\n\nPublications:\nCotas, J.; Figueirinha, A.; Pereira, L.; Batista, T. 2018. An analysis of the effects of salinity on Fucus ceranoides (Ochrophyta, Phaeophyceae), in the Mondego River (Portugal). Journal of Oceanology and Limnology. in press. DOI: 10.1007/s00343-019-8111-3",institutionString:"Faculty of Sciences and Technology of University of Coimbra",institution:null},{id:"279788",title:"Dr.",name:"Leonel",middleName:null,surname:"Pereira",slug:"leonel-pereira",fullName:"Leonel Pereira",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/279788/images/system/279788.jpg",biography:"Leonel Pereira has an undergraduate degree in Biology, a Ph.D. in Biology (specialty in Cell Biology), and a Habilitation degree in Biosciences (specialization in Biotechnology) from the Faculty of Science and Technology, University of Coimbra, Portugal, where he is currently a professor. In addition to teaching at this university, he is an integrated researcher at the Marine and Environmental Sciences Center (MARE), Portugal. His interests include marine biodiversity (algae), marine biotechnology (algae bioactive compounds), and marine ecology (environmental assessment). Since 2008, he has been the author and editor of the electronic publication MACOI – Portuguese Seaweeds Website (www.seaweeds.uc.pt). He is also a member of the editorial boards of several scientific journals. Dr. Pereira has edited or authored more than 20 books, 100 journal articles, and 45 book chapters. He has given more than 100 lectures and oral communications at various national and international scientific events. He is the coordinator of several national and international research projects. In 1998, he received the Francisco de Holanda Award (Honorable Mention) and, more recently, the Mar Rei D. Carlos award (18th edition). He is also a winner of the 2016 CHOICE Award for an outstanding academic title for his book Edible Seaweeds of the World. In 2020, Dr. Pereira received an Honorable Mention for the Impact of International Publications from the Web of Science",institutionString:"University of Coimbra",institution:{name:"University of Coimbra",country:{name:"Portugal"}}},{id:"61946",title:"Dr.",name:"Carol",middleName:null,surname:"Bernstein",slug:"carol-bernstein",fullName:"Carol Bernstein",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/61946/images/system/61946.jpg",biography:"Carol Bernstein received her PhD in Genetics from the University of California (Davis). She was a faculty member at the University of Arizona College of Medicine for 43 years, retiring in 2011. Her research interests focus on DNA damage and its underlying role in sex, aging and in the early steps of initiation and progression to cancer. In her research, she had used organisms including bacteriophage T4, Neurospora crassa, Schizosaccharomyces pombe and mice, as well as human cells and tissues. She authored or co-authored more than 140 scientific publications, including articles in major peer reviewed journals, book chapters, invited reviews and one book.",institutionString:"University of Arizona",institution:{name:"University of Arizona",country:{name:"United States of America"}}},{id:"182258",title:"Dr.",name:"Ademar",middleName:"Pereira",surname:"Serra",slug:"ademar-serra",fullName:"Ademar Serra",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/182258/images/system/182258.jpeg",biography:"Dr. Serra studied Agronomy on Universidade Federal de Mato Grosso do Sul (UFMS) (2005). He received master degree in Agronomy, Crop Science (Soil fertility and plant nutrition) (2007) by Universidade Federal da Grande Dourados (UFGD), and PhD in agronomy (Soil fertility and plant nutrition) (2011) from Universidade Federal da Grande Dourados / Escola Superior de Agricultura Luiz de Queiroz (UFGD/ESALQ-USP). Dr. Serra is currently working at Brazilian Agricultural Research Corporation (EMBRAPA). His research focus is on mineral nutrition of plants, crop science and soil science. 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The applications of this research cover many related fields, such as biotechnology and medicine, where, for example, Bioinformatics contributes to faster drug design, DNA analysis in forensics, and DNA sequence analysis in the field of personalized medicine. Personalized medicine is a type of medical care in which treatment is customized individually for each patient. Personalized medicine enables more effective therapy, reduces the costs of therapy and clinical trials, and also minimizes the risk of side effects. Nevertheless, advances in personalized medicine would not have been possible without bioinformatics, which can analyze the human genome and other vast amounts of biomedical data, especially in genetics. The rapid growth of information technology enabled the development of new tools to decode human genomes, large-scale studies of genetic variations and medical informatics. 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