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\\n
IntechOpen 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.
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\n
Designed 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.
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After 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.
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Our innovative Book Series format brings you:
\n\n
\n\t
Topic Focused Publications - Each topic showcases high impact subject areas
\n\t
Renowned Editorial Expertise - Series Editors, Topic Editors, and a team of international Board Members that permanently support each Book Series
\n\t
Fast Publishing - quick turnaround which is unique for book publishing
\n\t
The benefit of ISSN and ISBN for increased citation and indexing possibilities
\n
\n\n\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\n
IntechOpen 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.
We invite you to explore our IntechOpen Book Series, find the right publishing program for you and reach your desired audience in record time.
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Note: 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:"21",leadTitle:null,fullTitle:"Ferroelectrics",title:"Ferroelectrics",subtitle:null,reviewType:"peer-reviewed",abstract:"Ferroelectric materials exhibit a wide spectrum of functional properties, including switchable polarization, piezoelectricity, high non-linear optical activity, pyroelectricity, and non-linear dielectric behaviour. These properties are crucial for application in electronic devices such as sensors, microactuators, infrared detectors, microwave phase filters and, non-volatile memories. This unique combination of properties of ferroelectric materials has attracted researchers and engineers for a long time. This book reviews a wide range of diverse topics related to the phenomenon of ferroelectricity (in the bulk as well as thin film form) and provides a forum for scientists, engineers, and students working in this field. The present book containing 24 chapters is a result of contributions of experts from international scientific community working in different aspects of ferroelectricity related to experimental and theoretical work aimed at the understanding of ferroelectricity and their utilization in devices. It provides an up-to-date insightful coverage to the recent advances in the synthesis, characterization, functional properties and potential device applications in specialized areas.",isbn:null,printIsbn:"978-953-307-439-9",pdfIsbn:"978-953-51-4917-0",doi:"10.5772/554",price:139,priceEur:155,priceUsd:179,slug:"ferroelectrics",numberOfPages:466,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:null,bookSignature:"Indrani Coondoo",publishedDate:"December 14th 2010",coverURL:"https://cdn.intechopen.com/books/images_new/21.jpg",numberOfDownloads:73215,numberOfWosCitations:120,numberOfCrossrefCitations:25,numberOfCrossrefCitationsByBook:4,numberOfDimensionsCitations:70,numberOfDimensionsCitationsByBook:5,hasAltmetrics:0,numberOfTotalCitations:215,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 13th 2010",dateEndSecondStepPublish:"May 11th 2010",dateEndThirdStepPublish:"September 15th 2010",dateEndFourthStepPublish:"October 15th 2010",dateEndFifthStepPublish:"December 14th 2010",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,7",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"289832",title:"Dr.",name:"Indrani",middleName:null,surname:"Coondoo",slug:"indrani-coondoo",fullName:"Indrani Coondoo",profilePictureURL:"https://mts.intechopen.com/storage/users/289832/images/system/289832.jpeg",biography:"Dr. Indrani Coondoo has been working as a research scientist at\nthe University of Aveiro, Portugal since 2019. She has worked\nas an FCT postdoctoral researcher at the same university (2010-\n2017). She was a visiting researcher at the University of Puerto\nRico, U.S.A. (2010). She obtained her Doctorate degree from\nthe Faculty of Applied Sciences, University of Delhi (2008). She\nserved as a CSIR Research Associate and Project Fellow at the\nNational Physical Laboratory, India (2008-2009). Her research interest lies in the\nstudy of lead-free piezoelectrics, layered ferroelectrics, and multiferroics. She has\npublished more than fifty research papers in journals of international repute. She\nhas one U.S.A. patent to her credit. She has edited a book entitled “Ferroelectrics”\nand written many book chapters, as well as review articles.",institutionString:"University of Aveiro",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"University of Aveiro",institutionURL:null,country:{name:"Portugal"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"505",title:"Electrochemistry",slug:"chemistry-physical-chemistry-electrochemistry"}],chapters:[{id:"12488",title:"Principle Operation of 3-D Memory Device based on Piezoacousto Properties of Ferroelectric Films",doi:"10.5772/13238",slug:"principle-operation-and-3-d-architectures-of-universal-memory-device-based-on-piezoacousto-propertie",totalDownloads:2911,totalCrossrefCites:1,totalDimensionsCites:2,hasAltmetrics:0,abstract:null,signatures:"Ju. H. 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\n\t\t\t
1. Introduction
\n\t\t\t
Group B streptococcus (GBS), also known as Streptococcus agalactiae is a Gram-positive, β-hemolytic, chain-forming bacterium and a commensal within the genital tract flora in approximately 25% of healthy adult women (Campbell et al., 2000). The organism is a leading cause of serious infection in newborns, pregnant women, and older persons with chronic medical illness (Baker et al., Edwards&Baker, 2005). In neonates GBS infection most commonly causes pneumonia, meningitis, and sepsis. In addition to maternal cervicovaginal colonization and neonatal infection that can result from vertical transmission of GBS from mothers to their infants, the bacterium can also cause urinary tract infection (UTI). The spectrum of GBS UTI includes asymptomatic bacteriuria (ABU), cystitis, pyelonephritis, urethritis, and urosepsis (Bronsema et al., 1993, Edwards&Baker, 2005, Farley et al., 1993, Lefevre et al., 1991, McKenna et al., 2003, Munoz et al., 1992, Ulett et al., 2009). GBS ABU is particularly common among pregnant women, although those most at risk for cystitis due to GBS appear to be elderly individuals (Edwards&Baker, 2005, Falagas et al., 2006, Muller et al., 2006). In addition to acute and asymptomatic UTI other invasive diseases caused by GBS infection include skin infections, bacteraemia, pneumonia, arthritis, and endocarditis (Liston et al., 1979, Patil & Martin, 2010, Tissi et al., 1997, Trivalle et al., 1998). Thus, GBS is considered unique in terms of its ability to cause a spectrum of diseases in newborns and adult humans and its ability to colonize the genital tract of healthy women in a commensal-type manner. In contrast to GBS disease conditions resulting from neonatal infection, the clinical and microbiological features of GBS UTI and asymptomatic genital tract colonization are not well characterized. Moreover, the risk factors for the various diseases caused by GBS including UTI and the pathogenesis of the different diseases caused as a result of GBS infection are not well defined.
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Recent advances in the awareness, diagnosis and treatment of GBS infections, particularly in relation to vertical transmission and neonatal infection, have significantly reduced mortality in the newborn population. Establishment of preventative and treatment guidelines by the Centres for Disease Control (CDC) beginning in the 1990s has resulted in a reduction in mortality rates due to acute GBS infection in newborns from approximately 30-50% to 4–5% (Dermer et al., 2004). Guidelines for the prevention of GBS infections in newborns first published in 1992 and revised in 1997 include surveillance programs and administration of antibiotics during labour (intrapartum antibiotic chemoprophylaxis) (1992, 1997). Since the mid-1990s, most pregnant women in the United States have been screened for infection by GBS and the success of intrapartum antibiotic chemoprophylaxis for the prevention of vertical transmission of GBS has been noted (Verani et al., 2010). However, preventive strategies to identify at-risk individuals are controversial and the rates of GBS-related stillbirths, prematurity, and late onset disease (LOD) have not decreased (Gibbs et al., 2004). The incidence of morbidities in newborn survivors of acute GBS infection ranges from 20–60% and includes neurological sequelae (Gibbs et al., 2004, Lukacs et al., 2004). The manner in which specific preventative strategies are implemented may also affect disease prevalence due to GBS in some areas (Krasnianin et al., 2009, Rausch et al., 2009). Thus, infections due to GBS and the ensuing diseases that result remain a significant cause of morbidity and mortality in newborns as well as healthy adults (Berner, 2004, van der Poll&Opal, 2008).
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In addition to representing a major infection risk for neonates and pregnant women GBS is also a prominent pathogen of the elderly, immunocompromised, and individuals with diabetes and malignancies. These populations are particularly at risk for invasive GBS infection (Edwards&Baker, 2005, Farley, 2001). The manifestations of GBS infection in these populations are highly varied; however, some of the most common clinical presentations include skin and soft tissue infections, bacteraemia, pneumonia, arthritis, UTI, and endocarditis (Baker, 1997, Farley, 2001, Lee et al., 2007, Trivalle et al., 1998). The case fatality rate for GBS infection in elderly adults was estimated to be approximately 15% in the United States between 2001 and 2005 (Edwards&Baker, 2005, Farley, 2001). Importantly, there is no vaccine currently available to prevent GBS disease in neonates or adults despite a substantial research effort in identifying potential immunogens as vaccine candidates in immunization strategies (Doro et al., 2009).
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The recent emergence of GBS strains that are resistant to multiple antibiotics represents a significant concern in the treatment of these infections in adults and children (Andrews et al., 2000, Bland et al., 2001, Dahesh et al., 2008, Heelan et al., 2004, Kimura et al., 2008, Nagano et al., 2008, Simoes et al., 2004). Penicillin-derived antibiotics remain the drugs of choice for treatment of GBS infections in infants and adults (Sendi et al., 2008, Verani&Schrag, 2010). These antibiotics inhibit cell wall synthesis during active growth of the bacteria. Vancomycin, cefezolin, clindamycin and telavancin are also used for the treatment of GBS infections. Trends of increasing antibiotic resistance (Edwards, 2006) may reflect clonal dissemination and horizontal transfer of resistance genes, which occurs among some GBS isolates (Puopolo et al., 2007). In addition, the identification of GBS strains resistant to penicillin, clindamycin and erythromycin represents a significant concern for the treatment of infections (Andrews et al., 2000, Bland et al., 2001, Dahesh et al., 2008, Heelan et al., 2004, Kimura et al., 2008, Nagano et al., 2008, Simoes et al., 2004). A large number of microbiological studies on GBS infection over the past two decades have underscored the importance of GBS as a major public health concern and a need for improvements in preventative and therapeutic strategies. An improved understanding of the mechanisms of GBS disease pathogenesis is vital for such strategies.
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1.1. Host range and GBS serotypes
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GBS was once seen only as a veterinary pathogen. The organism was originally isolated from cattle in the 1930s and prior to the 1980s was regarded as a prominent cause of bovine mastitis in dairy cows. Indeed, the species name, agalactiae, translates to "no milk" and reflects this history. Subsequently, epidemiology and prevalence studies indicated that GBS was associated with disease in neonates and the bacterium was increasingly recognized beginning in 1977 as a major cause of postpartum infection in human newborns (Ferrieri et al., 1977). GBS is now universally accepted as among the most common causes of neonatal sepsis and meningitis. Research in the mid-1980s demonstrated that GBS was carried in the genital tract and the gastrointestinal flora in up to 30% of healthy adult women, which reflected intermittent, transient, or persistent colonization (Boyer et al., 1983, Dillon et al., 1982). Over the last fifteen years studies have demonstrated that GBS is a significant cause of serious disease in non-pregnant adults including elderly people and immunocompromised individuals. Emerging trends in GBS disease incidence and prevalence strongly suggest that changes in the recognition and treatment of GBS infections are impacting the types of individuals affected by the bacterium and invasive disease in adults is now more common than in neonates (Baker, 2000., Falagas et al., 2006, Muller et al., 2006).
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There are ten different capsular serotypes of GBS, namely Ia, Ib, and II-IX. These are based on the structure of the surface polysaccharide capsule of the bacterium. Nontypeable GBS also exist and are associated with some infections in humans including UTI (Baker&Barrett, 1974, Mc Kenna et al., 2003, Persson et al., 1985). Capsular serotyping of GBS can be performed by latex agglutination using commercial antisera (Slotved et al., 2003), which differentiates the major Lancefield groups (Facklam, 2002) based on serotype-specific antibody-based binding. Molecular serotyping (MS) methods have gained popularity and can provide additional insight into serotype traits that are not able to be derived from antisera-based approaches, possibly as a result of limited antigen expression in some strains (Ferrieri et al., 2004, Kong et al., 2002, Manning et al., 2008, Ramaswamy et al., 2006, Wen et al., 2006). MS identification of all ten serotypes is possible (MS Ia, Ib, and II-IX) with the use of a multiplex PCR and reverse line blot hybridization assay targeting a GBS species-specific gene (cfb) and serotype-specific sequences in various other capsular loci genes (Kong et al., 2005). Among the ten different types, the serotypes most frequently associated with serious disease are serotypes Ia, II, III, and V (Edwards&Baker, 2005). There is some evidence to suggest that switching can occur between capsular types in GBS (Martins et al., 2010).
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1.2. GBS disease spectrum and Co-morbidities
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GBS is a frequent cause of puerperal infections including pneumonia, sepsis, meningitis, amnionitis and endometritis. These infections are common in newborns, pregnant women, and adults with underlying medical conditions (Nizet et al., 2000, Pass et al., 1982). Diabetes mellitus and malignancy are among the most common underlying conditions associated with these GBS infections (Huang et al., 2006). Other co-morbidities that have been associated with GBS disease in adults include cardiovascular abnormalities, genitourinary disorders, neurologic deficits, cirrhosis, steroid use, AIDS, renal dysfunction, and peripheral vascular disease. Relapse of GBS disease in affected individuals is not uncommon, with approximately 5% of non-pregnant adults experiencing a second episode of GBS disease after resolution of the primary infection (Sendi et al., 2008). The pathogenic basis of this recurrence is unknown but it is nonetheless an important consideration clinically.
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The nature of GBS as a frequent constituent of the resident vaginal bacterial microflora in healthy adult women means that the bacterium is regarded as a normal commensal under these circumstances. Colonized women often carry GBS for long periods of time and usually do not show clinical symptoms as a result of persistent genital tract infection. On the other hand, conditions during pregnancy may lead to increased GBS multiplication in the urogenital tract and GBS can grow to high numbers in human amniotic fluid. This may lead to serious consequences for both the colonized mother and the infant. Between 15%-45% of pregnant women harbour GBS in the gastrointestinal and or genitourinary tracts (Schuchat, 1998); neonates acquire the bacteria at birth from their asymptomatically colonized mothers in approximately 1% of all live births (Baker, 2000., Nandyal, 2008, Schuchat, 1998). The neonatal lung can receive a substantial inoculum from infected amniotic fluid at birth (Nizet et al., 2000). In addition, GBS may be acquired by the growing fetus prior to birth in utero, which can trigger adverse pregnancy outcomes. Thus, GBS continues to be an important perinatal pathogen but causes a wide spectrum of diseases that is associated with various co-morbidities.
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1.3. Detection and identification of GBS
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The majority of GBS infections can be diagnosed through routine laboratory testing of clinical samples such as blood, cerebrospinal fluid, or aspirates from sites of local suppuration. In the majority of cases isolates are rapidly identified by typical colony morphology on agar medium such as tryptic soy agar-5% sheep blood, and are tested for catalase, which streptococci do not express. Isolates are grouped into the Lancefield B group (Facklam, 2002) using commercial typing antisera for latex agglutination assays. GBS antigens can occasionally be detected in blood, cerebrospinal fluid, and urine but are not routinely tested for in any diagnostic assays. A Gram stain of a clinical specimen can be useful in the detection of infection but is not specific and therefore not definitive for identification. Polymerase chain reaction and optical immunoassay may, on the other hand, provide rapid and specific results for the detection of GBS infection; however, optimization and validation of these assays to ensure sensitivity and specificity has limited their widespread application in the clinical laboratory (Daniels et al., 2009, Schwope et al., 2010).
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1.4. GBS virulence factors and host cell responses
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A number of GBS virulence factors that contribute to disease and infection in the host have been discovered. The role of these GBS virulence factors in UTI remains unexplored. A number of exotoxigenic virulence factors are produced by GBS, including hyaluronate lyase, Christine Atkins Munch Peterson (CAMP) factor, superoxide dismutase, proteases, nucleases, platelet-activating factor, collagenase/oligopeptidase, protein c, RIB, R protein, and C5a peptidase (Lindahl et al., 2005, \n\t\t\t\t\t\tLiu&Nizet, 2004\n\t\t\t\t\t, Nizet et al., 2000). The functions and structures of several of these virulence factors are reviewed elsewhere (\n\t\t\t\t\t\tLiu&Nizet, 2004\n\t\t\t\t\t). One of the major GBS virulence factor is the sialic acid-rich capsular polysaccharide, which has been extensively studied as a virulence factor for many years (Slotved et al., 2007). Capsular polysaccharide is anti-phagocytic and influences the pathogenicity of GBS by mediating evasion of phagocytes (Adderson et al., 2000). GBS lipotechoic acid (LTA) is another key virulence factor that contributes to successful infection in the host. GBS LTA is cytotoxic to human monocytes and induces inflammation including the production of pro-inflammatory cytokines such as TNF-α (Berner, 2002). Cytotoxicity including the ability to induce programmed cell death (PCD) in host cells may contribute to disease by promoting adhesion, invasion, and host immune-evasion (Nizet et al., 2000). β-hemolysin is produced in varying amounts by virtually all clinical isolates of GBS and has several known roles in virulence including cytotoxicity (\n\t\t\t\t\t\tLiu&Nizet, 2004\n\t\t\t\t\t, Nizet et al., 2000). β-hemolysin is expressed on the surface of GBS and is responsible for the characteristic β-hemolytic activity on blood agar (Nizet, 2002, Nizet et al., 2000). β-hemolysin has a role in early but not late PCD and its expression is abolished by glucose (Fettucciari et al., 2000, Ulett et al., 2003).
Ten to forty percent of adult women will contract at least one UTI in their lifetime, and approximately 3% will experience more than one infection per year (Andriole&Patterson, 1991, Patton et al., 1991, Foxman, 2002). UTI are the second most common infectious diseases in humans after respiratory tract infections, and contribute to approximately 60 million hospital visits per year. The costs to health care systems have been estimated at over $2 billion annually (Andriole&Patterson, 1991, Barnett&Stephens, 1997, Hooton&Stamm, 1997, Patton et al., 1991). Chronic UTI are difficult to prevent and treat, and infections are often recurrent. Over 80% of UTI are caused by uropathogenic Escherichia coli (UPEC) (Ronald, 2002). Approximately 2% of UTI are caused by GBS. Among an estimated 40% of all adult women who will experience a UTI episode in their lifetime almost 1% will suffer UTI caused by GBS (Foxman, 2002). The urinary tract is a distinct mucosal surface of the body and bacterial colonization of the uroepithelium is unique compared to other mucosal surfaces. Colonizing bacteria must overcome the normal flushing actions of urine flow and the physical barrier of the uroepithelial lining. This lining embodies a tightly interlaced latticework of proteins called uroplakins (Apodaca, 2004). These are closely associated with a collection of lipids, sphingolipids, and cholesterol referred to as lipid rafts that cumulatively constitute a surface that is highly impregnable to urine, solutes, and potential pathogens such as UPEC and GBS (Apodaca, 2004).
While the overall prevalence of GBS UTI remains unclear, GBS bacteriuria during pregnancy occurs at rates of between 1 and 3.5% (Baker, 1997, Mc Kenna et al., 2003, Whitney et al., 2004). Approximately 2-7% of pregnant women exhibit ABU caused by GBS and GBS ABU during pregnancy is considered a surrogate marker for heavy maternal genital tract colonization (Liston et al., 1979, Mc Kenna et al., 2003, Moller et al., 1984, Persson et al., 1986a, Wood & Dillon, 1981) and is indicated for intrapartum antibiotic chemoprophylaxis (Mc Kenna et al., 2003, Schrag et al., 2002). In addition, up to 7% of pregnancies may be complicated by GBS UTI, and GBS reportedly accounts for approximately 10% of all cases of pyelonephritis during pregnancy (Muller et al., 2006, Persson et al., 1986a, Persson et al., 1986b). GBS UTI may also contribute to chorioamnionitis (Anderson et al., 2007), premature onset of labour (Moller et al., 1984), and an increased risk of vertical transmission of GBS (Persson et al., 1985, Wood&Dillon, 1981). Stemming from this, maternal GBS ABU (including pure and predominant growth of GBS in the urine) has been associated with vertical transmission and an increased risk for early-onset disease (EOD) in newborn infants (Heath et al., 2009, Liston et al., 1979, Moller et al., 1984, Persson et al., 1986a, Persson et al., 1985, Wood&Dillon, 1981). One study found an elevated risk for EOD among infants born to women with low colony-count GBS ABU compared with mothers who did not have GBS ABU (Weng et al., 2010). However, studies have also demonstrated that some women with GBS ABU during the first trimester of pregnancy may not exhibit vaginal-rectal colonization at 35-37 weeks gestation (McKenna et al., 2003) or at the time of delivery (Edwards et al., 2002). Thus, while maternal ABU does not necessarily lead to vertical transmission, ABU at any point during pregnancy may be a risk factor for neonatal EOD and has therefore been an indication for intrapartum antibiotic chemoprophylaxis since 1996 (Schrag et al., 2002, Yancey et al., 1996). ABU may also be an indicator of potential preterm labour (Schrag et al., 2002, Yancey et al., 1996). The American College of Obstetricians and Gynecologists (ACOG) and CDC guidelines recommend the evaluation of pregnant women at 35-37 weeks gestation and antibiotic therapy for women with positive cultures for GBS ABU. The 1996 ACOG and CDC guidelines do not specify a colony-count threshold for defining GBS ABU. However, the 2002 and more recent guidelines recommend reporting of GBS at any concentration in urine (Lin&Fajardo, 2008). Finally, although pregnant women may receive antibiotics to treat GBS ABU this therapy may not eliminate GBS from the genitourinary tract, and recolonization after a course of antibiotics can occur (Baecher&Grobman, 2008, Gardner et al., 1979, Hall et al., 1976).
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Most data on the risk for EOD among infants born to women with GBS ABU are derived from studies using thresholds >105 cfu/ml despite lower counts of 103 cfu/ml having been associated with acute GBS UTI (Persson et al., 1986b, Persson et al., 1985, Ulett et al., 2009, Wood&Dillon, 1981). Although low concentrations (103-104 cfu/ml) of GBS in urine can be associated with colonization (Centelles-Serrano et al., 2009) limited data support the risk for EOD among infants born to women with low colony-count GBS ABU (Persson et al., 1986a). The recommendation to report any colony count of GBS in urine represents increased workload for clinical laboratories, which generally do not report bacterial growth in urine of other pathogens at concentrations <104 cfu/ml (Mc Carter et al., 2009) and rarely know whether urine samples are from pregnant women. In the context of universal late antenatal GBS screening, it is unclear how much EOD is prevented by screening for low colony-count GBS ABU and whether identification of low colony-count bacteriuria is cost-effective.
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2.3. Diagnosis of GBS UTI
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Diagnostic strategies for UTI vary substantially between clinicians (Hay&Fahey, 2002, Kaufmann&Modest, 2002, Libbus, 2002); however, patients with a combination of symptoms have a high probability of UTI (Bent et al., 2002, Nicolle, 2008). Pyuria concurrently with bacteriuria constitutes diagnostic criteria in some settings (Shaikh et al., 2007), although what constitutes clinically significant bacteriuria is not strictly defined; colony counts >103 cfu/ml of a uropathogen is however, now widely accepted diagnostic criteria for cystitis (Nicolle, 2008, Rubin et al., 1992). Clinically, UTI due to GBS may be indistinguishable from UTI caused by other uropathogens (Muller et al., 2006). A recent study of multiple uropathogens highlighted unique frequencies of host characteristics in UTI groups defined by the causal organism (Tabibian et al., 2008). This suggests that the clinical and microbiological features of UTI may differ depending on the infecting pathogen and the most ideal diagnostic approaches may depend on the causal organism. In one study the investigators regarded single-organism GBS bacteriuria and at least one UTI symptom as being a probable case of UTI and used urinary leukocyte esterase with pyuria as confirmatory for diagnosis (Ulett et al., 2009). Here, a provisional diagnosis was defined by the presence of single-organism GBS bacteriuria (>104 cfu/ml) with at least one symptom that included dysuria, increased urinary frequency and/or urgency, fever of >38°C, flank pain, and/or lumbar tenderness. In cases where urinalysis (UA) was performed, UTI was confirmed on the basis of positive urinary leukocyte esterase and significant pyuria (≥107 white blood cells/high-power field; non-spun). These are the generally accepted criteria for the diagnosis of UTI (Hay&Fahey, 2002, Kaufmann&Modest, 2002, Libbus, 2002) although inclusion of bacteriuria counts of >103 cfu/ml may provide additional clinical relevance. In this study group, patients were grouped into probable GBS UTI where UA was not performed and confirmed cases where (positive) UA data were available. Individuals defined as having GBS isolated from urine incidentally were selected on the basis of low-grade GBS bacteriuria (<104 cfu/ml) in the absence of symptoms. In this study, multiple patients were identified who had symptoms of UTI and positive UA findings but had GBS bacteriuria counts between 103-105 cfu/ml, which is consistent with reports that up to 30% of women with cystitis present with bacteriuria of <105 cfu/ml. Thus, the level of bacteriuria in GBS UTI may not correlate well with acute disease. The serotypes of GBS associated with UTI have not been well defined; however it appears that most serotypes can cause acute UTI. MS and antisera-based serotyping was used in one study to identify the serotypes associated with UTI (Ulett et al., 2009), and demonstrated a predominance of serotypes Ia, II, III, and V in patients with acute UTI. Other studies demonstrated that nontypeable GBS also cause acute UTI (McKenna et al., 2003, Persson et al., 1985).
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2.4. How does GBS colonize the urogenital tract?
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GBS infection often begins with binding to epithelial cells at mucosal surfaces, such as those lining the respiratory or urogenital tracts. GBS are able bind to human vaginal epithelial cells under low pH conditions, which are characteristic of vaginal mucosa. These interactions occur via low avidity interactions of cell-wall-associated LTA and via higher-affinity interactions mediated by hydrophobic GBS surface proteins (Tamura et al., 1994). Many of these host-cell interactions involve attachment of GBS to extracellular matrix molecules such as fibronectin, fibrinogen and laminin, which in turn bind host-cell-surface proteins such as integrins (Maisey et al., 2008). For example, ScpB, which is a GBS cell-surface protein previously characterised for its ability to cleave the complement-derived chemoattractant C5a (Beckmann et al., 2002), can bind fibronectin (Cheng et al., 2002). ScpB can bind to integrins, which may promote both binding to host cells and complement proteolysis (Brown et al., 2005). Naturally occurring ScpB variants with a deletion that destroys peptidase function retain the capacity to bind fibronectin (Cleary et al., 2004, Tamura et al., 2006). GBS attachment to fibrinogen is mediated by the surface-anchored protein FbsA (Schubert et al., 2004), and adherence to laminin involves the adhesin Lmb (Spellerberg et al., 1999). The serine-rich repeat domain protein Srr-1 binds human keratin 4 (Samen et al., 2007) and the GBS surface protein LrrG, containing the leucine-rich-repeat motif found in many invasins, binds to epithelial cells, suggesting that it serves as an adhesin during GBS infection (Seepersaud et al., 2005). In each of these examples, these binding interactions probably promote GBS adherence to epithelial cells.
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GBS were also recently shown to express pili (Lauer et al., 2005), which typically facilitate Gram-negative bacterial attachment to host cells (Sauer et al., 2000). Among eight sequenced GBS genomes, two genetic loci encoding pili were identified, the second existing in one of two variants, although not all genomes contain both loci (Rosini et al., 2006). GBS pilus island 2’ includes the genes encoding PilB, an LP(x)TG-motif-containing protein that polymerises to form a pilus backbone, and accessory pilus proteins PilA and PilC (Dramsi et al., 2006, Maisey et al., 2007). Epithelial cell adherence is reduced in isogenic GBS mutants lacking PilA or PilC, but not those lacking PilB (Dramsi et al., 2006). The role of GBS pili in binding in the urogenital tract is unknown.
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2.5. Modeling GBS UTI from clinical studies
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Uropathogenic GBS (UPGBS) have been shown to bind to both murine and human bladder uroepithelium in in vivo (Figure 1) and in vitro (Figure 2) studies. These models were developed to study the pathogen-host interaction underlying GBS UTI. UPGBS bind more efficiently to bladder epithelial mucosa when compared with non-UPGBS (Ulett et al., 2010).
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Binding models of GBS UTI to study host cell interactions in vivo and in vitro have been derived from clinical studies conducted in the past five years. The largest of these clinical studies of GBS UTI to date was performed in the United States using a cohort of 387 patients with positive GBS cultures in urine. This study investigated the traits of UPGBS that cause acute UTI and ABU using detailed analysis of patients groups alongside serotyping comparisons, and risk factor analysis. The study also investigated the demographic data alongside standard diagnostic microbiological measures for the defined patient groups, which are summarized in Table 1. In this study, a total of 62 patients of the 387 patients with positive GBS urine culture had single-organism bacteriuria >104 cfu/ml concurrent with at least one UTI symptom and were defined as having probable GBS UTI. The most prevalent serotypes of GBS causing UTI in this study according to MS were serotypes V, Ia, and III, as shown in Table 2. Together, these serotypes accounted for 76% of GBS UTI cases. Serotype III GBS was the only serotype that was more frequently isolated from UTI case patients than from controls. Thus, in this study GBS UTI occurred mostly as uncomplicated cystitis in middle-aged women (>50 yrs) in the absence of chronic underlying disease but was associated with a prior history of UTI.
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Figure 1.
UPGBS bound to bladder uroepithelium in a murine model of GBS cystitis (A–C, flattened bladder; D, native conformation). The arrows in panel D show bound UPGBS between folds of bladder uroepithelium. Panel E illustrates better bind of UPGBS to bladder mucosa compared with non-UPGBS although binding is not as efficient as uropathogenic Escherichia coli (UPEC) and levels of bacteriuria are simiular (F). Reproduced, along with Figure 2, with permission from (Ulett et al., 2010) courtesy of Oxford Journals.
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Figure 2.
UPGBS (green) bound to human bladder cells (blue, nuclei; red F-actin) at multiplicities of infection of 50 (A) and 5 (B). Uninfected cells in (C). Measures of binding of UPGBS and non-UPGBS to T24 (D) and 5637 (E) cells shows higher binding of UPGBS.
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Table 1.
Patients who had GBS isolated from urine during routine assessement for UTI at University of Alabama Hospital between August 2007-2008. NOTE. Data are no. (%) of patients, unless otherwise indicated; a. Consecutive urine specimens sent for culture, from which GBS was isolated; b. Patients with ≥1 symptom(s) of UTI and pure growth of GBS >107 cfu/L; c. UA: +ve (consistent with UTI) positive leukocyte esterase and pyuria; ND not done; d. Subjects without symptoms from whose urine GBS was isolated in counts <107/L; e. Symptoms consistent with (C/W) cystitis: dysuria and/or frequency; f. Symptoms C/W pyelonephritis: dysuria and/or frequency plus flank pain and/or fever >38ºC; g. By Mann–Whitney U test; h. By Pearson χ2 analysis. Gender comparisons performed using population data (equal group sizes) from the US Census Bureau for Birmingham (male-female ratio 85.7); i. By Fisher’s exact test; j. By forward stepwise logistic regression subsequent to Pearson χ2 analysis; Reproduced, with Table 2, with permission from (Ulett et al., 2009) courtesy of The American Society for Microbiology.
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Table 2.
Molecular serotypes of GBS that cause UTI, from the largest study of 387 patients with positive urine cultures for GBS to date. NOTE. Data are no. (%) of GBS isolates, unless otherwise indicated; a. Consecutive urine specimens sent for culture, from which GBS was isolated; b. Patients with ≥1 symptom(s) of UTI and pure growth of GBS >107 cfu/L; c. UA: +ve (consistent with UTI) positive leukocyte esterase and pyuria; ND not done; d. Subjects without symptoms from whose urine GBS was isolated in counts <107/L; e. Difference between the prevalence of serotype III among all GBS UTI case patients and all other non-GBS UTI cases (n=325), significant by Pearson χ2 analysis (P=0.026); f. Isolates were identified using antisera as: NT (3), II (2), IV (1) and V (1).
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3. Conclusions
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In summary, GBS is an important pathogen that causes serious infections in newborns, pregnant women, and elderly people with chronic illness. While early diagnosis and management of GBS among pregnant women can reduce the incidence of neonatal infection the prevalence of GBS disease in adult populations emphasizes the need for additional preventative and therapeutic measures. Moreover, the emergence of antibiotic-resistant strains of GBS imposes a significant threat to the successful treatment of these infections. This is particularly relevant to GBS UTI, which is associated with relatively high rates of treatment failure and poor clinical outcomes (Munoz et al., 1992). Screening pregnant mothers for GBS ABU appears to be important in relation to the vertical transmission of GBS to infants however more research is needed to clarify this aspect of GBS UTI. An overarching and intriguing theme with GBS infection in humans is that GBS can efficiently colonize the genital tract of healthy adult women long-term without triggering apparent disease but, on the other hand, can also cause acute disease in some individuals. How this occurs is unknown.
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Research efforts to understand GBS pathogenesis should focus on the different strains of GBS that cause distinct clinical conditions of UTI such as ABU and cystitis in order to analyse the virulence traits that are associated with these infections. How these infections progress to disease in some individuals is completely unknown but acute inflammation in GBS UTI appears to differ mechanistically compared to that which occurs in other Gram-negative UTI. Further longer-term surveillance studies of GBS UTI and ABU will help to better define the clinical features and serotypes associated with these infections. The question of how GBS might adapt to the niche environment of the urinary tract is another intriguing and unanswered question. A better understanding of the molecular mechanisms used by GBS to colonise uroepithelium and persist in the bladder will be an important area for future investigation. Broader utilization of appropriate in vivo and in vitro models beyond those already characterized will help to answer these questions. One area for investigation, for example, would be to use human urine as a growth medium to study fitness traits of UPGBS as has been performed for other uropathogens to discover key elements of UTI disease pathogenesis and how some successful uropathogens persist within the urinary tract in the absence of direct binding to cellular targets. Such studies will pave the way to develop new preventive and perhaps therapeutic strategies for GBS UTI. While many of the current strategies have focused on the development of vaccines for prevention of GBS disease (Maione et al., 2005) their potential for reducing GBS disease burden due to UTI is unknown. Identification of alternate drug targets would also be a goal of future research. Elucidation of the mechanisms that underlie GBS disease pathogenesis is pivotal for the identification of such alternate drug targets and also in the development of novel vaccines. A better understanding of how GBS regulates expression of its virulence survival factors is imperative. Finally, the underlying phenotypic basis for UPGBS could be gained by comparing GBS isolated from asymptomatic infection to cystitis strains by comparative genome sequencing approaches. Discoveries from such research may challenge the existing paradigms and reveal surprising insights into the versatile nature of this important human pathogen.
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Acknowledgments
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This work was supported with grants from the Australian National Health and Medical Research Council (grant 569674) and a Griffith Health Institute Grant.
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\n',keywords:null,chapterPDFUrl:"https://cdn.intechopen.com/pdfs/19315.pdf",chapterXML:"https://mts.intechopen.com/source/xml/19315.xml",downloadPdfUrl:"/chapter/pdf-download/19315",previewPdfUrl:"/chapter/pdf-preview/19315",totalDownloads:28268,totalViews:4448,totalCrossrefCites:3,totalDimensionsCites:4,totalAltmetricsMentions:13,impactScore:3,impactScorePercentile:85,impactScoreQuartile:4,hasAltmetrics:1,dateSubmitted:"November 17th 2010",dateReviewed:"April 14th 2011",datePrePublished:null,datePublished:"September 6th 2011",dateFinished:null,readingETA:"0",abstract:null,reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/19315",risUrl:"/chapter/ris/19315",book:{id:"370",slug:"clinical-management-of-complicated-urinary-tract-infection"},signatures:"Chee Keong Tan, Alison J Carey, Deepak Ipe and Glen C Ulett",authors:[{id:"45849",title:"Dr.",name:"Glen",middleName:"C",surname:"Ulett",fullName:"Glen Ulett",slug:"glen-ulett",email:"g.ulett@griffith.edu.au",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"45860",title:"Mr.",name:"Chee Keong",middleName:null,surname:"Tan",fullName:"Chee Keong Tan",slug:"chee-keong-tan",email:"chee.tan@griffith.edu.au",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Griffith University",institutionURL:null,country:{name:"Australia"}}},{id:"45861",title:"Dr.",name:"Alison",middleName:"Jane",surname:"Carey",fullName:"Alison Carey",slug:"alison-carey",email:"a.carey@griffith.edu.au",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Griffith University",institutionURL:null,country:{name:"Australia"}}},{id:"91301",title:"Mr.",name:"Deepak",middleName:"Samuel",surname:"Ipe",fullName:"Deepak Ipe",slug:"deepak-ipe",email:"deepsam_deepipe@yahoo.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Griffith University",institutionURL:null,country:{name:"Australia"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_1_2",title:"1.1. Host range and GBS serotypes",level:"2"},{id:"sec_2_2",title:"1.2. GBS disease spectrum and Co-morbidities",level:"2"},{id:"sec_3_2",title:"1.3. Detection and identification of GBS",level:"2"},{id:"sec_4_2",title:"1.4. GBS virulence factors and host cell responses",level:"2"},{id:"sec_6",title:"2. Bacterial UTI: general aspects",level:"1"},{id:"sec_6_2",title:"2.1. Prevalence of GBS in the urinary tract",level:"2"},{id:"sec_7_2",title:"2.2. GBS ABU and UTI in pregnancy",level:"2"},{id:"sec_8_2",title:"2.3. Diagnosis of GBS UTI",level:"2"},{id:"sec_9_2",title:"2.4. How does GBS colonize the urogenital tract? ",level:"2"},{id:"sec_10_2",title:"2.5. Modeling GBS UTI from clinical studies ",level:"2"},{id:"sec_12",title:"3. 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Journal of Clinical Microbiology,\n\t\t\t\t\t47\n\t\t\t\t\t2055\n\t\t\t\t\t2060\n\t\t\t\t\n\t\t\t'},{id:"B133",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tValenti-Weigand\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t1996Entry and intracellular survival of group B streptococci in J774 macrophages. Infect Immun,\n\t\t\t\t\t64\n\t\t\t\t\t2467\n\t\t\t\t\t2473\n\t\t\t\t\n\t\t\t'},{id:"B134",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVan Der Poll\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOpal\n\t\t\t\t\t\t\tS. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008Host-pathogen interactions in sepsis. Lancet Infect Dis,\n\t\t\t\t\t8\n\t\t\t\t\t32\n\t\t\t\t\t43\n\t\t\t\t\n\t\t\t'},{id:"B135",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVerani\n\t\t\t\t\t\t\tJ. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2010Prevention of perinatal group B streptococcal disease--revised guidelines from CDC, 2010. MMWR Recomm Rep,\n\t\t\t\t\t59\n\t\t\t\t\t1\n\t\t\t\t\t36\n\t\t\t\t\n\t\t\t'},{id:"B136",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVerani\n\t\t\t\t\t\t\tJ. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\tS. C. H. R. A. G. S. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010Group B streptococcal disease in infants: progress in prevention and continued challenges. Clin Perinatol,\n\t\t\t\t\t37\n\t\t\t\t\t375\n\t\t\t\t\t392\n\t\t\t\t\n\t\t\t'},{id:"B137",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWen\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2006Use of a serotype-specific DNA microarray for identification of group B Streptococcus (Streptococcus agalactiae). 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R.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1981A prospective study of group B streptococcal bacteriuria in pregnancy. American Journal of Obstetrics & Gynecology,\n\t\t\t\t\t140\n\t\t\t\t\t515\n\t\t\t\t\t520\n\t\t\t\t\n\t\t\t'},{id:"B141",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYagupsky\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t1991The changing spectrum of group B streptococcal disease in infants: an eleven-year experience in a tertiary care hospital. Pediatr Infect Dis J,\n\t\t\t\t\t10\n\t\t\t\t\t801\n\t\t\t\t\t808\n\t\t\t\t\n\t\t\t'},{id:"B142",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYancey\n\t\t\t\t\t\t\tM. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t1996The accuracy of late antenatal screening cultures in predicting genital group B streptococcal colonization at delivery. Obstetrics & Gynecology,\n\t\t\t\t\t88\n\t\t\t\t\t811\n\t\t\t\t\t815\n\t\t\t\t\n\t\t\t'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Chee Keong Tan",address:"",affiliation:'
Griffith University, Australia
'},{corresp:null,contributorFullName:"Alison J. Carey",address:null,affiliation:'
'},{corresp:null,contributorFullName:"Glen C. Ulett",address:null,affiliation:'
Griffith University, Australia
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1. Introduction
There are a number of factors that influence patient outcome in trauma and orthopedic surgery in relation to hemorrhage. These can include patient factors, for example anticoagulant and antiplatelet medications, coagulopathies and other conditions, as well as surgical factors such as bony bleeding, large surgical incisions, diffuse venous bleeding and unseen sources of bleeding [1, 2].
Trauma still remains a leading worldwide cause of morbidity and mortality [3] and despite various developments over the years, hemorrhagic shock from trauma continues to form one part of the terrible triad contributing to mortality in both the military and civilian settings [4].
Effective hemostasis during surgery is advantageous to the surgeon as it prevents diffuse bleeding from capillaries and venules obscuring the surgical field and adding to operation time and infection risk [5, 6].
Significant blood loss has been associated with increased need for allogeneic and autologous blood transfusion [2, 7, 8]. These are associated with attendant risks including nosocomial infections [9], transfusion-related injury and fluid overload [10, 11]. In fact blood transfusion is an independent risk factor for infection, respiratory complications and the need for critical care support in traumatic injuries and resulted in a twofold increase in complications and critical care admissions, with more than two units of blood transfusion [7]. The risk of major perioperative complications is also increased with high intraoperative blood loss [2, 12, 13]. Therefore, patient outcome is optimal when the balance between bleeding and clotting is maintained during surgery such that tissue perfusion is adequate without excessive blood loss [5, 6].
2. The biology of hemostasis
Hemostasis in regard to trauma and surgery is a highly regulated process, maintaining flow through vessels at the same time as the thrombotic response to tissue damage is occurring [14], thereby ensuring tissue perfusion and limiting blood loss. The process is a complex interaction between vascular endothelium, platelets, the coagulation and fibrinolytic systems [15, 16].
Following injury, a temporary vascular smooth muscle contraction occurs in an attempt to stem blood flow. Endothelial disruption exposes the subendothelial layer and circulating Von Willebrand factor attaches to the site of injury. Surface glycoproteins also adhere to platelet surfaces. The subendothelial collagen activates adhering platelets and their surface receptors then bind circulating fibrinogen, forming a soft platelet plug comprising aggregated platelets and fibrinogen [14]. The adhering platelets secrete humoral factors including serotonin, prostaglandins and thromboxane that maintain a reduced blood flow, creating an environment that is conducive to clot formation at the site of bleeding. At the same time, circulating coagulating factors produced by the liver are activated in a series of precisely controlled sequential and dependant reactions [14, 17].
The final common pathway is the activation of thrombin that leads to conversion of soluble plasma fibrinogen to insoluble fibrin. The complex of activated factor XIII and fibrin results in cross-linking of fibrin monomers to form a stable clot [17].
3. Techniques for hemostasis in trauma and orthopedic surgery
Broadly speaking, there are mechanical, thermal, pharmacological and topical methods of hemorrhage control [2, 6, 8, 17, 18, 19, 20].
Mechanical methods include direct pressure, ligating clips and staples, sutures, fabric pads and gauze while hemostatic scalpels and lasers also reduce bleeding during surgery [6, 7, 17]. However, these methods have their drawbacks with respect to certain situations. The location of bleeding is particularly important with respect to orthopedics and in particular trauma. Bony surface bleeding and bleeding from the intramedullary canals are almost impossible to control with mechanical methods. Inflamed or friable tissues may contain a dense network of friable capillaries may prove a challenge [1, 2, 7]. Junctional bleeding in trauma may be potentially catastrophic and its control may not be amenable to the above methods.
The use of pharmacological methods can be a useful adjunct to other methods in these circumstances [7]. These may include epinephrine, desmopressin, tranexamic acid, vitamin K, aminocaproic acid and others.
In some situations though, even the above methods are ineffective or impractical [15] and hence the development of topical hemostatic agents. These are a diverse group of agents of varying composition and mechanisms of action. They can be versatile in the sense that when blood loss is minimal, they can be used sparingly and when there is severe blood loss then more liberal application could be an option [2]. They may be applied directly to the bleeding site and prevent or reduce continuous and unrelenting bleeding intraoperatively and postoperatively [2] and their topical nature broadly avoids the systemic adverse effects associated with systemic hemostatic medications including thrombosis [8].
4. Topical hemostasis
4.1 Concept of passive and active hemostasis
Topical hemostasis is defined as a process that acts locally to stop bleeding from damaged vessels [21]. Recent and continuing developments have focused on agents that can be used as adjuncts to control bleeding during surgical procedures and control residual problematic bleeding if conventional methods fail. Broadly speaking, topical hemostats can be divided into three types [17, 20].
Passive—where the mechanism of action is to provide a physical scaffold around which platelets can aggregate. These act through contact activation and promote platelet aggregation so a clot can form. Examples include collagen, cellulose and gelatins.
Active—these have biological activity and their mechanism of action is actively influencing the clotting cascade to promote clot formation [17, 20]. These usually contain thrombin in one form or another [14].
Combined—combination of passive product with thrombin.
4.2 Passive hemostasis
4.2.1 Collagen-based products
Contact activation occurs between receptors on platelets and collagen, promoting platelet aggregation [15, 17]. Preparation includes collagen sponges, pastes and powders [15, 17] and is obtained mainly from bovine sources [15], making it potentially immunogenic. In fact a 2–4% allergy in the total population to bovine collagen has been reported in the literature [22] (Table 1).
Hemostatic agent
Examples
Manufacturer
Collagen-based products
Avitene
Davol/BD BARD
Helistat/Helitene
Integra Lifesciences
Instat/Ultrafoam
Ethicon, Johnson & Johnson
Oxidized cellulose
Surgicel Fibrillar
Ethicon, Johnson & Johnson
Surgicel Nu-Knit
Ethicon, Johnson & Johnson
Gelatin-based products
Gelfoam
Pharmacia Corp, Pfizer
Surgifoam
Johnson & Johnson
Polysaccharide spheres
Arista AH
BD BARD
Table 1.
Passive hemostats.
4.2.2 Cellulose-based products
The active ingredient in this product is oxidized regenerated cellulose (ORC). Its exact mechanism of action is poorly understood but contact activation is thought to play a part [15]. Often at reoperation, previously used ORC is visible, indicating reduced absorption and poor biodegradability, although this may be related to the amount used and the site of implantation [8]. For this reason, only the minimum possible amount to be used is indicated and it is recommended that the product be removed once hemostasis is achieved and before definitive closure [6, 8].
4.2.3 Gelatin-based products
Their mechanism of action involves swelling while in contact with blood, providing a tamponade effect in confined spaces and restoring blood flow, and thereby producing a stable scaffold around which clots can form [17]. This does make it suitable for irregular wounds [6] and confined spaces [17]. However, it tends to stick to instruments when soaked with blood, making it difficult to handle and does not form a tight bond with the bleeding surface and can hence easily be dislodged [17].
4.3 Active hemostasis
Active agents have biological activity and actively participate in the coagulation cascade to induce clot formation at the site of bleeding [20]. They include thrombin, which comes into play in the last stages of the clotting cascade, converting circulating fibrinogen to a fibrin clot [17, 23]. Hence a significant advantage of thrombin is that its action is less susceptible to coagulopathies caused by clotting factor or platelet dysfunction [17]. Its activity constitutes the final steps in the clotting cascade and therefore it bypasses the initial steps in the cascade. Therefore, other aspects of the clotting cascade can be dysfunctional without significantly impairing the local hemostatic activity of thrombin [20].
Thrombin-based products are therefore excellent adjuncts in the presence of congenital and acquired coagulation and platelet disorders and in the presence of pharmacological and antiplatelet agents that are increasingly being used in the general population [5, 17]. Circulating fibrinogen is necessary for hemostasis to occur by active agents as thrombin converts it into insoluble fibrin that forms part of the clot. Therefore in rare cases of fibrinogen deficiency, clotting by thrombin-based products is impaired [17, 23].
5. Combination agents
5.1 Fibrin sealants
These accomplish their action by bypassing the coagulation cascade to the final steps and converting fibrinogen to fibrin [24]. A fibrin precursor and thrombin stored in two separate adjacent syringes (dual syringe kit) with a single lumen enables delivery and mixing of these agents in the lumen and onto the surgical site, causing thrombin to cleave the fibrin precursor, resulting in fibrin monomers that polymerize at the site into a soluble mesh stabilized into a stable clot by factor XIII at the tissue surface [25]. Previously, bovine thrombin was used, which has recently been replaced by human thrombin [26] and more recently autologous human thrombin. Autologous fibrin sealants overcome the risk of allogeneic blood products, for example one is a patient-derived fibrin sealant utilizing the patient’s own blood as a source of fibrinogen and prothrombin and mixing it with an alkaline buffer solution to lower the pH, activating endogenous prothrombin [24] (Table 2).
Biosurgical
Examples
Manufacturer
Liquid fibrin adhesives
Tiseel
Baxter
Evicel
Ethicon, Johnson & Johnson
Crosseal
Ethicon, Johnson & Johnson
Floseal
Baxter
Fibrin patches
Tachosil
Takeda
Platelet gels
Vitagel
Orthovita
Glutaraldehyde cross-linked albumin
BioGlue
Cryolife
Table 2.
Sealants and adhesives.
5.2 Platelet gels
These are a combination of thrombin, calcium and platelet-rich plasma, usually obtained from autologous sources using centrifugation systems that produce platelet-rich plasma. Platelets provide growth factors to stimulate wound healing and contribute to the strength of the clot [27].
These systems however rely on an intact coagulation system and may not be as effective in patients on antiplatelet or anticoagulant medications [27]. Also the extraction systems are expensive and there is a risk of contamination.
5.3 Advantages of active and combined products over passive hemostats
In addition to not requiring normal clotting mechanisms to work as mentioned before, active hemostats may offer other advantages. With many passive hemostatic agents, degeneration and reabsorption are a problem. This necessitates their removal from the surgical site prior to closure. With thrombin, this is not the case as degeneration and resorption of the resulting fibrin clot is achieved as part of wound healing [1, 8]. Thrombin and combination products also have a rapid onset of action with hemostasis being achieved within 10 min in most patients [7, 17, 28, 29]. Studies have shown that combining an active hemostat within a hemostatic product accelerates clotting. In a comparison of collagen-based products at different bleeding sites after surgical tumor resection, the combination of a collagen-thrombin product (n = 23) achieved complete hemostasis three times faster than the collagen sponge alone (n = 30). The median time to hemostasis was 78 seconds versus 243 seconds respectively (p < 0.001) [30]. Furthermore, approximately 80% achieved complete hemostasis within 2 min with an active topical hemostatic agent compared with only one-third of patients receiving a passive topical hemostatic agent [31]. Active hemostats are also very versatile and can come in various forms. These include sprays that can be advantageous in covering large bleeding surfaces quickly without the need for tamponade [31], and the concentration of thrombin in the formulation can also be varied depending on the severity and type of bleeding. Surgeons can use them in multiple ways during a single procedure due to their flexibility and range of delivery options [20]. Although bovine sources of thrombin may induce antibodies in hosts, this has not manifest itself as a major problem in the clinical setting [1, 32].
5.4 Hemostasis in the trauma setting
It has been shown that the terrible triad of hypothermia, coagulopathy and acidosis are associated with increased mortality in multiple trauma patients and that infection and multiple organ failure are other potential complications arising from severe blood loss [33, 34]. About a quarter of patients presenting to trauma centers have an established coagulopathy secondary to hemorrhage [35] with attendant risks of significant complications. Multiple defects in hemostasis can occur in combat injuries and as such, conventional methods of hemostasis may not be possible. Time is of the essence in these situations and non-transfusional approaches to hemostasis and the use of biosurgicals may be indicated [36, 37, 38, 39].
The combat setting has proved a challenging environment in many different ways in terms of management of hemorrhage. The tissue available for controlling life-threatening hemorrhage may be limited, the wound severity and the possibility of multiple injuries make the situation uniquely challenging [40]. Most combat injuries are penetrating in nature and a large proportion are limb wounds. Mortality from hemorrhage from these kinds of wounds is potentially preventable [36, 41, 42].
In the combat setting, the three principal sites of lethal hemorrhage are truncal (67%), junctional (19%) and extremity (14%). A report from the National Trauma Database suggests that the mortality from isolated lower limb extremity trauma with arterial injury is 2.8% with a 6.6% amputation rate [38]. Tourniquets can be used for these isolated injuries and their use in the military and civilian setting is supported by the Hartford consensus [39] and by the American College of Surgeons Committee on Trauma [38].
Junctional injuries (neck, axilla, groin and perineum) form a significant proportion of trauma in a combat setting and may damage the large vascular structures. These types of injuries are difficult to compress and are not amenable to tourniquet control [43, 44]. Topical hemostatic agents that have been developed in the last two decades [36, 45] can play a vital role in controlling severe bleeding in these situations and increase survival [33, 46] and have thus been listed as optional basic equipment for ambulances [39]. In addition, in a combat setting, more complex types of wound patterns are encountered than in a civilian setting, including blast injuries, which may be more amenable to topical hemostasis.
5.5 Characteristics of the ideal trauma hemostatic agent
In 2003, USAIR [47] introduced guidelines of what should constitute the perfect hemostatic agent for use in the prehospital and battlefield settings [33, 41, 47, 48, 49] that included the following: being able to stop large vessel and arterial bleeding within 2 min of application, ability to be delivered through a pool of blood when applied, ready to use with no need for on-site preparation, simple enough to use by the wounded victim or a paramedic with minimal training, light weight and durable with a minimum 2-year shelf life in extreme environmental conditions, safe to use with no risk of injury to tissues or transmission of infection and inexpensive [41, 45, 50, 51]. In addition, hemostatic dressings need to be conformable and flexible enough due to the irregular shape, depth and wound configurations caused by modern explosive devices [40, 48].
6. Types of hemostatic agents
6.1 Mechanical hemostats
These include gelatin [52], oxidized cellulose [53] and collagen and plant-derived polysaccharide spheres [54]. These agents are not biologically active and rely on the patients’ endogenous fibrin production for hemostasis. They provide a scaffold for platelet activation and aggregation, absorbing fluid several times their own weight to form a matrix at the site of hemorrhage, activating the extrinsic coagulation pathway and allowing clotting to occur. This makes them suitable only for patients in whom the coagulation system is intact [55, 56]. In fact in the absence of some coagulation factors, these agents may not be effective [53, 56]. They can be used as first line due to their ready availability and favorable cost-effectiveness, mostly as adjuncts with direct pressure at bleeding sites to control minimal residual hemorrhage [56].
6.1.1 Bovine collagen
These agents act by forming a physical matrix that stimulates platelet aggregation and degranulation to release factors that encourage clot formation [55].
6.1.2 Oxidized cellulose
Cellulose is a homopolysaccharide made by polymerization of glucopyranose molecules through glucosidic bonds. Surgical oxidized cellulose is either regenerated where organized fibers are formed prior to oxidation (regenerated ORC), or non-regenerated, with unorganized fibers prior to oxidation [55]. ORC conforms more rapidly to the surrounding environment. Surgical oxidized cellulose offers several favorable properties in hemostasis including bactericidal activity, good biocompatibility and ease of use [55]. It is usually resorbed but can take anywhere between 2 and 6 weeks depending on the amount used, the degree of saturation with blood and the tissue bed. The excess material may also cause foreign body reactions and granuloma formation without biodegradation and complicate radiological and clinical diagnoses of abscess, residual or recurrent tumor and granuloma [55, 57, 58]. For this reason, the minimal effective amount should be used and excess material removed prior to definitive closure. In addition, these products should not be used or left in place close to nerves, ureters, intestinal and vascular structures due to the risk of local inflammatory reactions and ischemia [55].
6.1.3 Gelatin-based products
These can be used in combination with active agents such as thrombin in adhesives, or in a stand-alone manner. They are usually of bovine or porcine origin and act at the terminal stages of clotting to facilitate fibrin clot formation and are highly absorptive, forming a mechanical matrix for the clot to adhere to [55, 59]. They are quite versatile and available as sponges, powders or granules and are usually completely resorbed in 4–6 weeks [59]. It is important to use the minimum amount necessary to achieve hemostasis and to remove excess because part of the mechanism of action is swelling to cause a tamponade effect and this could potentially cause compression and necrosis in surrounding tissues if packed in tight spaces. This is particularly important around neural tissue and in bony spaces [59]. They are also useful in irregular wounds and surgical cavities as they can expand and fill these irregular spaces.
6.1.4 Plant-based hemostatic agents
Mucoporous polysaccharide hemispheres are among a relatively new class of hemostatic agents derived from plant starch. Their mechanism of action includes absorbing water and the low-molecular weight components of blood, hence concentrating platelets and clotting factors in the vicinity, thereby enhancing local clotting processes [58, 60]. They have been used safely in cardiothoracic and neurospinal surgery.
6.2 Fibrin sealants/adhesives
These are active formulations containing mostly two agents—human purified fibrinogen and thrombin. They may also have added other compounds such as factor XIII, fibronectin and antifibrinolytics such as aprotinin used previously and tranexamic acid currently [61]. However, formulations without tranexamic acid or aprotinin are available to avoid hypersensitivity associated with aprotinin and neurotoxicity associated with tranexamic acid [62, 63] (Table 2).
These products are available in liquid or low-viscosity forms (fibrin glues) or as part of stiff collagen fleece (fibrin patches) [55]. Once applied, their mechanism of action is cleavage of fibrinogen to fibrin monomers by thrombin, which also activates factor XIII and the complex fibrin matrix forms the clot [55]. Calcium is required in both these steps and then the clot is eventually resorbed via the fibrinolytic pathway [25]. Generally, they connect atraumatically to tissues and form a barrier to leakage and bleeding through covalent polymerization between themselves and adjacent tissue [55]. Chiara et al. set out the properties of an sealant as being strong, rapid to adhere, flexible, sterile, without toxicity, biologically inert, biocompatible and able to be used in relatively wet environments with low thrombogenicity [55].
7. True sealants and bioglues
True sealants are of two types: synthetic (PEG-based or cyanoacrylates) [53, 60, 64, 65, 66, 67] or semisynthetic glutaraldehyde [68] (Table 2).
True sealants are cross-linking sealants that polymerize through nonenzymatic reactions, free of the need for the presence of blood or coagulation factors although some do have some coagulation factors within them. Both can be used to control residual ooze [53, 67].
PEG sealants are composed of polyethylene glycol and come in both flowing form as well as pads or fleeces. They should be avoided in kidney disease due to the renal clearance of polyethylene glycol and may contain allergenic components such as human albumin that can also lead to the theoretical risk of disease transmission [55].
Cyanoacrylates are products generally used for skin closure or lacerations in areas of low skin tension, for example scalp wounds. They are synthetic sealants that rapidly polymerize with water acting as the catalyst. There are two formulations: octyl-2-cyanocrylate and N-Butyl-2-cyanoacrylate. In a systematic review looking at octyl-2-cyanoacrylate, there were no differences in infections, wound dehiscence or cosmetic appearance when compared with other methods of closure [65]. Polymerization generates heat and therefore the amount used should be just enough and should certainly be avoided in delicate areas such as the spinal canal and neural tissue [55, 65]. Below the skin, a foreign body reaction may occur [65] and intravascular use is contraindicated due to the risk of systemic embolization [55].
Semisynthetic sealants otherwise known as bioglues are compounds of semisynthetic glutaraldehyde—bovine albumin-based sealant. Proteins on the surface of bleeding human tissue link with those of bovine albumin in the bioglue, causing a sealant effect [55]. Within synthetic graft materials, bioglue permeates interstices within the graft matrix [69], making it suitable for sealing anastomotic sites and decreasing postop bleeding [70].
7.1 Liquid fibrin adhesives
These can be used as an adjunct to surgical hemostasis to improve residual moderate bleeding [55]. They are usually applied by double syringe systems. Each component is located in a separate section of the syringe, which then combine in a single lumen. They subsequently are applied using a blunt needle or spray tips in cases of large bleeding surface areas to the bleeding surgical site [25, 61]. Since the components bypass the initial steps in the extrinsic coagulation pathway, they can be used in achieving hemostasis in patients with congenital or acquired bleeding disorders such as hemophilia and patients on anticoagulants or antiplatelet medications [25, 62, 71] (Table 2).
They do have some drawbacks including the risk of thrombosis if injected intravascularly, hypotension and death and the risk of air embolization with the use of gas-driven sprayers [55]. In addition, the cost of sealants is significant and hence they are not recommended for use except in particular situations where indicated, for example in those with coagulation disorders [61]. One cost-effectiveness analysis done in the United Kingdom in patients undergoing total knee replacement on Quixil, one of the commercial brands, in addition to conventional hemostatic agents estimated that the use of a 5-ml dose of Quixil in addition to conventional hemostatic methods was cost saving in comparison to conventional methods alone. But the use of a 10-ml dose increased the cost substantially and they recommended that liquid fibrin adhesives only be used in selected cases [25]. They have however been found to be effective. Echave et al. [59] carried out a systematic review of 27 studies on the effectiveness of human gelatin-thrombin matrix sealant in different surgical fields including orthopedics. All 27 studies demonstrated that this sealant was associated with a significantly higher rate of successful hemostasis, and a shorter time to achieve it (p < 0.001) in comparison to other alternatives when conventional methods failed.
7.2 Fibrin patches
These products are also available as patches, for example Tachosil. They may have slightly different components but all of them have essentially the same mechanism of action, offering mechanical support with either collagen, oxidized cellulose/polyglactin 910 matrix, binding coagulation factors, allowing better adherence to bleeding tissue even in the presence of brisk bleeding, preventing the so-called “streaming effect” observed with fluid adhesives [72, 73, 74]. Tachosil is a ready-to-use fixed combination of equine collagen patch on one side and coated with coagulation factors, human fibrinogen and human thrombin on the other side [55]. Fibrin-pad and PGA-felt are absorbable hemostats composed of polyglactin 910, oxidized regenerated cellulose, thrombin and fibrinogen shown to be effective in a variety of tissue types [25, 72] and can rapidly achieve hemostasis in brisk bleeding in the retroperitoneum and pelvis, compared with the standard of care [72, 73] (Table 2).
8. Hemostasis in major trauma
8.1 Hemostatic dressings
Junctional hemorrhage is a significant problem in major trauma especially on the battlefield and often conventional methods such as tourniquets are ineffective [55]. In this respect, science has led to the development of products that are effective options in these circumstances and they can be divided into factor concentrators [75], procoagulants [76] and mucoadhesives [77] (Table 3).
Biosurgical
Examples
Manufacturer
Zeolite dressings
QuikClot & QuikClot ACS
Z-Medica
Smectite dressings
WoundStat
TraumaCure Inc.
Kaolin dressings
QuikClot Combat Gauze
Z-Medica
Rapid Deployment Hemostat
Marine Polymer Technologies
Celox
Med Trade Products, UK
Trauma Stat
OreMedix
Fibrin dressings
Dry fibrin sealant dressing (DFSD)
American Red Cross
Table 3.
Hemostatic dressings.
8.1.1 Factor concentrators
These are compounds of either zeolite (microporous crystalline aluminum silicate) or smectite (a nonmetallic clay mineral sodium, calcium and aluminum silicate). Examples include QuikClot (Z-Medica LLC, CT,USA) and QuikClot ACS (advanced clotting sponge), Traumadex (Medafor Inc., MN, USA) and self-expanding hemostatic polymer (SEHP) [35]. As the group name suggests these agents rapidly absorb the fluid content of blood. The resulting effect is an increase in relative concentration of its cellular and protein content and therefore clot formation. Water molecules are held in its pores by hydrogen bonds and this results in a relative local increase in concentration of platelets and clotting factors [35]. The first generation of QuikClot was designed as granules that were poured onto the bleeding wound. A high efficiency rate of 92% was demonstrated in a series of 103 patients in the military and civilian setting. There were eight patients in which hemorrhage was not effectively controlled with QC in coagulopathic patients where it was used as a last resort [75]. There were also some side effects of QC including intense exothermic reaction and scar formation from foreign body reaction [75]. Animal and early human studies on QC revealed thermal injury, poor biodegradability and foreign body reactions as the main drawbacks of QC [78, 79, 80]. In fact temperature generated by QuikClot in contact with aqueous components of blood at bleeding wounds has been measured to reach and average of 61°C with a potential rise to 76°C [78].
QuikClot has been compared to other hemostatic agents including HemCon (HemCon Medical Technologies Inc., OR, USA) in a military setting in multiple patients injured after explosions and gunshot wounds [81]. In this study, QC was effective but thermal injury was an issue. This has also been investigated in other studies by McMannus et al. [82] in the combat setting and evidence suggests that the greater the amount of blood and the more the QC applied, the greater is the risk of thermal injury. Thus currently it is only recommended for external use and the minimum amount required to achieve effective hemostasis is recommended.
QuikClot ACS is a newer generation of product made by larger zeolite beads packaged into mesh bags. This makes it easier to pack into cavities and irregular wounds often found on the battlefield and at junctional sites of hemorrhage and in cavities [55] and is claimed to produce much less of an exothermic reaction [75, 78] although there is a lack of studies with sufficient numbers to confirm this unequivocally [41].
Self-expanding hemostatic polymer (SEHP) is a dual action factor concentrator. Its mechanism of action results from its extremely potent absorptive capacity following absorption of the fluid component of blood and its ability to expand to conform to large irregular cavities and spaces, exerting a tamponade effect [35]. The other action is the effect of the polymer absorbing the liquid phase of blood into its matrix, thereby leading to a relative increase in concentration of platelets and coagulation factors at the site of bleeding, thereby promoting clotting [83, 84].
Woundstat is a compound of smectite granules that come in granular form. Its mechanism of action is absorption of the aqueous phase of blood, forming a clay substance that adheres to bleeding tissue and acts as a sealant and also concentrates clotting factors and blood cells locally, contributing to hemostasis. Granules are negatively charged and activate the intrinsic pathway as well [85, 86, 87].
8.1.2 Mucoadhesive agents
These are products where the basic component is chitosan, which is a polymer derived from crustacean chitin. It is a complex biodegradable carbohydrate [55]. The mechanism of action appears to be related to highly positively charged chitosan interacting electronically with negatively charged cell membranes of erythrocytes. The product adheres strongly to tissues and seals bleeding wounds [77, 88, 89]. Examples include HemCon (HemCon Med Tech, Portland, OR) and Celox (Med. Trade Products, UK).
Celox is a chitosan-based adhesive, which is biodegradable and causes absorption of the aqueous phase and the advancement of red blood cell bonding. The positively charged Celox binds negatively charged red blood cells independently of the body’s clotting system, resulting in clot formation without the exothermic reaction associated with certain factor concentrators like QuikClot [35]. Its action is independent of the body’s clotting system, a property that makes it useful in patients requiring antiplatelet or anticoagulant medications or in the presence of coagulopathy and its local action means that it is not associated with distant clot formation. It is also reported to be very versatile, being available in granular and bandage forms and easy to remove from the wound after its clot formation activity is complete [49, 90, 91, 92]. HemCon, however, does have a hard consistency and is made in a square shape. Therefore, it works best on flat bleeding surfaces rather than deep irregular wounds [79, 83]. Wedmore et al. [77] looked at a series of patients with prehospital combative injuries where chitosan-based products had been used externally in chest, groin, buttock and abdominal wounds in 25 patients, 35 extremity wounds and neck and facial wounds in 4 cases. In about two-thirds of cases, the chitosan dressings were used following failure of hemostasis using only gauze with 100% success. In 97% of cases, bleeding stopped or hemostasis was improved, with failure only occurring in two cases attributed to blind stuffing of bandages into large cavitational injuries [77].
Trauma Stat is another chitosan-based derivative that was developed in collaboration with the United States Army, in which the mechanism of action involves positive charges in the amine groups on the chitosan molecule interacting with negative charges on the red blood cell membranes and in addition the adsorption of chitosan for fibrinogen and plasma proteins [79, 93].
Te Grotenhuis carried out a study of 66 patients in which conventional treatment with gauze and compression failed to control excessive bleeding or where conventional treatment was unlikely to achieve hemostasis. Complete cessation of hemorrhage including arterial hemorrhage occurred in 70% using the HemCon ChitoGauze, and reduction in hemorrhage occurred in 20% of patients despite 21 patients being on anticoagulants or having a clotting disorder and no adverse events occurred [88].
Due to the fact that chitosan is derived from crustaceans, there is a theoretical risk of allergenic reactions in patients allergic to shellfish. However in a study of 19 patients who had a positive IgE test to shellfish, none of the patients demonstrated a positive skin prick test to chitosan powder or expressed a reaction to HemCon bandage during serial bandage challenges, indicating favorable but not completely risk-free use of these products [94].
Chitosan-based dressings are also easy to remove after hemostasis has been achieved [41] and are known to have some antimicrobial properties [41, 95].
8.1.3 Procoagulants
Their mechanism of action is mainly to deliver factors that promote coagulation into the bleeding wound. Examples are dry fibrin sealant dressing (DFSD) and QuikClot Combat Gauze (QCG) [70, 96, 97]. QCG is a surgical gauze coated with kaolin. On contact with injured endothelium, kaolin activates the extrinsic pathway, enhancing coagulation and promoting hemostasis. It is not degradable and needs to be removed from the wound following achievement of hemostasis [76].
Kaolin-based products have been used in a military setting and have demonstrated good results in both junctional and non-junctional hemorrhage [76]. In the above study, Shina et al. retrospectively reviewed 133 kaolin-based dressings applied to 122 military patients. 27% were for junctional hemorrhage with a success rate of 88% while the rest were extremity trauma where the success rate was 92%.
8.2 Problems with hemostatic agents
In addition to problems specific to certain types of hemostatic agents, there are also general drawbacks.
The hemostats that contain biological agents, usually the active hemostats, can be associated with the risk of disease transmission. For example, DFSD has the theoretical risk of viral disease transmission and hence has not achieved FDA approval.
Some agents have handling characteristics that are beneficial in certain situations. For example agents that have a granular nature can be used for complex irregular wounds with multiple bleeding points. However, the handling characteristics are difficult and they are difficult to apply in combat situations [89]. In addition, many agents are nonabsorbable and need to be removed after hemostasis is achieved. This may be difficult with some agents and require multiple washouts. Granular agents also have the potential to enter the vascular system and occlude the distal parts of vessels, causing endothelial injury and intravascular coagulation [41]. This has been demonstrated by Kheirabadi et al. [89] in their study, and for these reasons a bandage/gauze form of hemostatic agent is preferable as being safer for hemorrhage control, avoiding intravascular complications [38].
8.3 Tranexamic acid in trauma
Any chapter on hemostasis in trauma and orthopedics is incomplete without the mention of tranexamic acid. This drug has been shown to be effective in reducing mortality due to bleeding in both the military and civilian setting.
The CRASH-2 (Clinical Randomization of an Antibrinolytic in Severe Hemorrhage-2) trial was a multicenter trial involving 40 centers looking at 20,211 adult trauma patients with significant bleeding who were randomized to two arms. One arm received TA within the first 3 hours of trauma and the other received placebo. The study demonstrated a reduction in mortality risk due to any cause from 14.5% compared with 16% in the placebo group (p < 0.001), with no increase in vasoocclusive events such as pulmonary embolism or myocardial infarction (0.3% versus 0.5% p-0.096) [98].
The MATTER (Military Application of Tranexamic Acid in Trauma) study looked at 896 patients with severe combat injuries and demonstrated a 6.5% absolute risk reduction in mortality in these patients with the use of tranexamic acid [99].
Both these studies have recommended incorporation of intravenous tranexamic acid into clinical practice [24].
8.4 Hemostasis in arthroplasty surgery
Joint replacements are major procedures in elective orthopedics and can be associated with significant blood loss and increased transfusion requirements if appropriate steps are not taken to mitigate against this. In addition to the conventional methods of blood management including preoperative optimization, tourniquets if appropriate, intraoperative techniques such as cell saver and cauterization, topical and pharmacological hemostats and biosurgicals may offer some excellent solutions to reduce the transfusion requirements and achieve hemostasis.
A few studies have looked at human-derived fibrin sealants in total knee replacement [100, 101, 102]. A multicenter randomized control trial looking at 58 patients who underwent total knee replacement demonstrated a reduced postoperative blood loss, reduced postoperative decrease in hemoglobin and calculated blood loss in patients in whom fibrin sealant was used compared with that in the standard group (20% compared with the standard 83% p = 0.004) [100]. Another study that showed benefit was done by Dhillon et al. [25]. Results from other studies have been equivocal and have not demonstrated any clear difference.
In total hip arthroplasty, the use of fibrin sealants has been associated with reducing blood loss but inconsistent results have been demonstrated with regard to reduction in postoperative transfusion requirements [24, 103, 104, 105].
Multiple studies have looked at platelet gels in arthroplasty surgery. The evidence has been inconsistent in many. One randomized control trial looking at 100 total knee replacements did demonstrate significantly lower transfusion requirements in patients in whom platelet gels were used [106].
Desmopressin is a synthetic analog of anti-diuretic hormone. Its mechanism of action is to increase the levels of factor VIII and Von Willebrand factor, thereby enhancing primary hemostasis and platelet aggregation and adherence. This makes it suitable as a blood management strategy in patients with platelet dysfunction or other clotting disorders such as Von Willebrand’s disease and hemophilia A [107, 108]. It has also been used in healthy individuals for reducing postoperative bleeding in total hip and knee replacement surgery [109]. Six randomized placebo-controlled trials addressing the use of desmopressin in total hip and knee arthroplasty have been undertaken [110, 111, 112, 113, 114, 115]; however, evidence suggests that desmopressin is not significantly effective in reducing blood loss or transfusion requirements in these patients [24].
There are a number of good-quality randomized control trials that support the use of tranexamic acid in reducing blood loss and transfusion requirements in both knee and hip arthroplasty surgery [24]. There is however considerable amount of heterogeneity between the trials with regard to methods of delivery including single intravenous bolus dose, repeated boluses, prolonged infusion or intraarticular injection [116], and also differing dosing regimes [117]. In total knee arthroplasty, it has been shown that one intraoperative dose is sufficiently effective in reducing transfusion requirements and postoperative bleeding [118]. With the theoretical risk of intravascular thrombosis, intraarticular injection of tranexamic acid was investigated and compared to placebo and the studies showed reduction in blood loss but no reduction in transfusion rates [101, 119, 120]. Only one RCT by Seo et al. [121] showed a reduction in transfusion requirements with intraarticular (20%) rather than intravenous (34%) or placebo (94%). The evidence in total hip replacement with regard to intraarticular tranexamic acid is less convincing than in knee arthroplasty and more studies are needed.
With regard to aminocaproic acid, three RCTs did demonstrate benefit in hip and knee replacement surgery in terms of reducing blood loss in comparison with placebo. However, with regard to reducing transfusion requirements the evidence is much less convincing [24, 122, 123, 124].
8.5 Hemostasis and biosurgicals in spine surgery
Spine surgery presents a few unique challenges that limit the products that can be used for hemostasis in these situations. One of them is the friability of neural tissue and secondly the fact that the spinal cord and nerve roots are enclosed in rigid bony spaces that limit the kinds of hemostats that can be used due to the potential of swelling and compression of neural tissue in a rigid space. In addition, there is the potential for neurotoxicity with certain agents.
Cerebrospinal fluid leaks are a common source of postoperative morbidity in patients who have undergone spinal surgery. The morbidity burden includes severe postural headaches, vomiting, dizziness, photophobia, tinnitus, pseudomeningoceles and the risk of meningitis. It is therefore important that when dural tears occur or when an iatrogenic durotomy is created a water tight repair is essential. PEG hydrogel sealant has been found to be a safe effective way to augment dural closure and prevent these complications. A prospective study by Kim et al. [66] demonstrated that augmentation of standard dural closure techniques with this sealant in patients had significantly higher rates of watertight closure than with controls (100% and 64.3% respectively), without statistical differences in cerebrospinal fluid leaks, infections or wound healing. Complications due to swelling of polyethylene glycol and nerve compression were not demonstrated in this study but this remains a possibility. This led to the development of low-swell PEG hydrogel sealant (Duraseal) [55] and has been found to be safe and effective in a 3-to-1 randomized single-blind multicenter trial in which 100% of patients who had this low-swell formulation achieved watertight dural closure. Another study has also shown that BioGlue (semisynthetic glutaraldehyde-bovine albumin sealant) is safe and cost-effective in proximity to neurological structures despite previous concerns. Miscusi et al. [125] demonstrated a watertight dural closure in 23 patients requiring dural repair, with no incidence of neurological or infection related complications.
Collagen and gelatin-based products can be used to achieve hemostasis in spinal surgery. Xu et al. [64] carried out a study on 92 patients undergoing spinal fusion surgery and concluded that collagen-based products are superior to gelatin-based products in achieving hemostasis in spine surgery, with lower blood loss and postoperative drain volume.
Oxidized regenerated cellulose has been used for hemostasis in spine surgery. However when used around or in foramina with rigid bony walls, the swelling of small portions of the cellulose material may lead to significant mass effect and neural compression 1 day after surgery as demonstrated by Menovsky et al. [126] and may lead to rapid neurological deterioration. Therefore this material should be removed after hemostasis has been achieved prior to closure.
As mentioned before, liquid fibrin sealants can be used in spine surgery for hemostasis, but those containing tranexamic acid may be associated with neurotoxicity and should not be used if CSF leak or dural tear is present [55].
9. Conclusions and future perspectives
Topical hemostats and biosurgicals are a diverse group of compounds that have been developed and can be used in different situations as part of a comprehensive blood management program to limit the amount of blood loss. Trauma and orthopedics as a specialty also presents some unique challenges, with operations having significant blood loss and in trauma, junctional injuries on the battlefield with hemorrhage that is hard to control by conventional means. In addition, patients may be complex and frequently have platelet or coagulation disorders that preclude the use of certain classes of hemostatic agents. As mentioned before, these compounds are diverse, with different mechanisms of actions and indications, both in an elective and an emergency trauma setting. A comprehensive knowledge of these products is essential in modern-day trauma and orthopedic practice.
Despite recent developments, the perfect hemostatic or biosurgical agent still remains elusive and each of these products has their own drawbacks, side effects and unique indications and future research will hopefully continue to improve on these.
\n',keywords:"hemostasis, coagulation, trauma",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/72519.pdf",chapterXML:"https://mts.intechopen.com/source/xml/72519.xml",downloadPdfUrl:"/chapter/pdf-download/72519",previewPdfUrl:"/chapter/pdf-preview/72519",totalDownloads:597,totalViews:0,totalCrossrefCites:0,dateSubmitted:"March 11th 2019",dateReviewed:"May 12th 2020",datePrePublished:"June 18th 2020",datePublished:null,dateFinished:"June 18th 2020",readingETA:"0",abstract:"Trauma and orthopedics is a specialty in which significant blood loss can be incurred both in terms of traumatic injuries and operative management. This chapter starts with a brief review of the biology of hemostasis followed by the importance of hemostasis in surgery. This is followed by a discussion on the ideal hemostatic agent. Various strategies of achieving hemostasis will be discussed including mechanical, thermal, pharmacological and topical agents in both elective orthopedic and spine surgery as well as in trauma. Specifically, we will look at synthetic agents such as cyanoacrylate, polyethylene glycol hydrogel and glutaraldehyde cross-linked albumin and absorbable agents such as gelatin foams and oxidized cellulose. We will also look at biological agents such as topical thrombin, sealants and platelet gels. Hemostatic dressings will be discussed in detail.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/72519",risUrl:"/chapter/ris/72519",signatures:"Saqeb Beig Mirza, Khaled Elawady, Syed Kashif Abbas, Shafat A. Gangoo and Sukhmeet S. Panesar",book:{id:"8206",type:"book",title:"Contemporary Applications of Biologic Hemostatic Agents across Surgical Specialties - Volume 1",subtitle:null,fullTitle:"Contemporary Applications of Biologic Hemostatic Agents across Surgical Specialties - Volume 1",slug:null,publishedDate:null,bookSignature:"Dr. Michael S. Firstenberg and Dr. Stanislaw P. Stawicki",coverURL:"https://cdn.intechopen.com/books/images_new/8206.jpg",licenceType:"CC BY 3.0",editedByType:null,isbn:"978-1-78984-441-2",printIsbn:"978-1-78984-440-5",pdfIsbn:null,isAvailableForWebshopOrdering:!0,editors:[{id:"64343",title:"Dr.",name:"Michael S.",middleName:null,surname:"Firstenberg",slug:"michael-s.-firstenberg",fullName:"Michael S. Firstenberg"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. The biology of hemostasis",level:"1"},{id:"sec_3",title:"3. Techniques for hemostasis in trauma and orthopedic surgery",level:"1"},{id:"sec_4",title:"4. Topical hemostasis",level:"1"},{id:"sec_4_2",title:"4.1 Concept of passive and active hemostasis",level:"2"},{id:"sec_5_2",title:"4.2 Passive hemostasis",level:"2"},{id:"sec_5_3",title:"Table 1.",level:"3"},{id:"sec_6_3",title:"4.2.2 Cellulose-based products",level:"3"},{id:"sec_7_3",title:"4.2.3 Gelatin-based products",level:"3"},{id:"sec_9_2",title:"4.3 Active hemostasis",level:"2"},{id:"sec_11",title:"5. Combination agents",level:"1"},{id:"sec_11_2",title:"5.1 Fibrin sealants",level:"2"},{id:"sec_12_2",title:"5.2 Platelet gels",level:"2"},{id:"sec_13_2",title:"5.3 Advantages of active and combined products over passive hemostats",level:"2"},{id:"sec_14_2",title:"5.4 Hemostasis in the trauma setting",level:"2"},{id:"sec_15_2",title:"5.5 Characteristics of the ideal trauma hemostatic agent",level:"2"},{id:"sec_17",title:"6. Types of hemostatic agents",level:"1"},{id:"sec_17_2",title:"6.1 Mechanical hemostats",level:"2"},{id:"sec_17_3",title:"6.1.1 Bovine collagen",level:"3"},{id:"sec_18_3",title:"6.1.2 Oxidized cellulose",level:"3"},{id:"sec_19_3",title:"6.1.3 Gelatin-based products",level:"3"},{id:"sec_20_3",title:"6.1.4 Plant-based hemostatic agents",level:"3"},{id:"sec_22_2",title:"6.2 Fibrin sealants/adhesives",level:"2"},{id:"sec_24",title:"7. True sealants and bioglues",level:"1"},{id:"sec_24_2",title:"7.1 Liquid fibrin adhesives",level:"2"},{id:"sec_25_2",title:"7.2 Fibrin patches",level:"2"},{id:"sec_27",title:"8. Hemostasis in major trauma",level:"1"},{id:"sec_27_2",title:"8.1 Hemostatic dressings",level:"2"},{id:"sec_27_3",title:"8.1.1 Factor concentrators",level:"3"},{id:"sec_28_3",title:"8.1.2 Mucoadhesive agents",level:"3"},{id:"sec_29_3",title:"8.1.3 Procoagulants",level:"3"},{id:"sec_31_2",title:"8.2 Problems with hemostatic agents",level:"2"},{id:"sec_32_2",title:"8.3 Tranexamic acid in trauma",level:"2"},{id:"sec_33_2",title:"8.4 Hemostasis in arthroplasty surgery",level:"2"},{id:"sec_34_2",title:"8.5 Hemostasis and biosurgicals in spine surgery",level:"2"},{id:"sec_36",title:"9. Conclusions and future perspectives",level:"1"}],chapterReferences:[{id:"B1",body:'Morikawa T. Tissue sealing. American Journal of Surgery. 2001;182(2 Suppl):29S-35S'},{id:"B2",body:'Block JE. Severe blood loss during spinal reconstructive procedures: The potential usefulness of topical hemostatic agents. Medical Hypotheses. 2005;65(3):617-621'},{id:"B3",body:'Morrison CA. 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Acta Anaesthesiologica Scandinavica. 1995;39(5):592-598'},{id:"B113",body:'Leino KA et al. The effect of desmopressin on blood loss in patients with rheumatoid arthritis undergoing hip arthroplasty. Acta Anaesthesiologica Scandinavica. 2010;54(7):863-870'},{id:"B114",body:'Ellis MH et al. The effect of tourniquet application, tranexamic acid, and desmopressin on the procoagulant and fibrinolytic systems during total knee replacement. Journal of Clinical Anesthesia. 2001;13(7):509-513'},{id:"B115",body:'Zohar E et al. A comparative study of the postoperative allogeneic blood-sparing effects of tranexamic acid and of desmopressin after total knee replacement. Transfusion. 2001;41(10):1285-1289'},{id:"B116",body:'Sukeik M et al. Systematic review and meta-analysis of the use of tranexamic acid in total hip replacement. Journal of Bone and Joint Surgery. British Volume (London). 2011;93(1):39-46'},{id:"B117",body:'Yang ZG, Chen WP, Wu LD. Effectiveness and safety of tranexamic acid in reducing blood loss in total knee arthroplasty: A meta-analysis. The Journal of Bone and Joint Surgery. American Volume. 2012;94(13):1153-1159'},{id:"B118",body:'Lin PC et al. The blood-saving effect of tranexamic acid in minimally invasive total knee replacement: Is an additional pre-operative injection effective? Journal of Bone and Joint Surgery. British Volume (London). 2012;94(7):932-936'},{id:"B119",body:'Ishida K et al. Intra-articular injection of tranexamic acid reduces not only blood loss but also knee joint swelling after total knee arthroplasty. International Orthopaedics. 2011;35(11):1639-1645'},{id:"B120",body:'Roy SP et al. Efficacy of intra-articular tranexamic acid in blood loss reduction following primary unilateral total knee arthroplasty. Knee Surgery, Sports Traumatology, Arthroscopy. 2012;20(12):2494-2501'},{id:"B121",body:'Seo JG et al. The comparative efficacies of intra-articular and IV tranexamic acid for reducing blood loss during total knee arthroplasty. Knee Surgery, Sports Traumatology, Arthroscopy. 2013;21(8):1869-1874'},{id:"B122",body:'Harley BJ et al. The effect of epsilon aminocaproic acid on blood loss in patients who undergo primary total hip replacement: A pilot study. Canadian Journal of Surgery. 2002;45(3):185-190'},{id:"B123",body:'Ray M et al. Aprotinin and epsilon aminocaproic acid are effective in reducing blood loss after primary total hip arthroplasty—A prospective randomized double-blind placebo-controlled study. Journal of Thrombosis and Haemostasis. 2005;3(7):1421-1427'},{id:"B124",body:'Camarasa MA et al. Efficacy of aminocaproic, tranexamic acids in the control of bleeding during total knee replacement: A randomized clinical trial. British Journal of Anaesthesia. 2006;96(5):576-582'},{id:"B125",body:'Miscusi M et al. The use of surgical sealants in the repair of dural tears during non-instrumented spinal surgery. European Spine Journal. 2014;23(8):1761-1766'},{id:"B126",body:'Menovsky T et al. Massive swelling of Surgicel(R) Fibrillar hemostat after spinal surgery. Case report and a review of the literature. Minimally Invasive Neurosurgery. 2011;54(5-6):257-259'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Saqeb Beig Mirza",address:"saqebmirza@yahoo.com",affiliation:'
'},{corresp:null,contributorFullName:"Shafat A. Gangoo",address:null,affiliation:'
James Paget University Hospital, United Kingdom
'},{corresp:null,contributorFullName:"Sukhmeet S. Panesar",address:null,affiliation:'
NHS England and NHS Improvement, United Kingdom
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Our journals are currently in their launching issue. They will be applied to all relevant indexes as soon as they are eligible. These include (but are not limited to): Web of Science, Scopus, PubMed, MEDLINE, Database of Open Access Journals (DOAJ), Google Scholar and Inspec.
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IntechOpen books are indexed by the following abstracting and indexing services:
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BKCI is a part of Web of Science Core Collection (WoSCC) and the world’s leading citation index with multidisciplinary content from the top tier international and regional journals, conference proceedings, and books. The Book Citation Index includes over 104,500 editorially selected books, with 10,000 new books added each year. Containing more than 53.2 million cited references, coverage dates back from 2005 to present. The Book Citation Index is multidisciplinary, covering disciplines across the sciences, social sciences, and arts & humanities.
Produced by the Web Of Science group, BIOSIS Previews research database provides researchers with the most current sources of life sciences information, including journals, conferences, patents, books, review articles, and more. Researchers can also access multidisciplinary coverage via specialized indexing such as MeSH disease terms, CAS registry numbers, Sequence Databank Numbers and Major Concepts.
Produced by the Web Of Science group, Zoological Record is the world’s oldest continuing database of animal biology. It is considered the world’s leading taxonomic reference, and with coverage back to 1864, has long acted as the world’s unofficial register of animal names. The broad scope of coverage ranges from biodiversity and the environment to taxonomy and veterinary sciences.
Provides a simple way to search broadly for scholarly literature. Includes peer-reviewed papers, theses, books, abstracts and articles, from academic publishers, professsional societies, preprint repositories, universities and other scholarly organizations. Google Scholar sorts articles by weighing the full text of each article, the author, the publication in which the article appears, and how often the article has been cited in other scholarly literature, so that the most relevant results are returned on the first page.
Microsoft Academic is a project exploring how to assist human conducting scientific research by leveraging machine’s cognitive power in memory, computation, sensing, attention, and endurance. Re-launched in 2016, the tool features an entirely new data structure and search engine using semantic search technologies. The Academic Knowledge API offers information retrieval from the underlying database using REST endpoints for advanced research purposes.
The national library of the United Kingdom includes 150 million manuscripts, maps, newspapers, magazines, prints and drawings, music scores, and patents. Online catalogues, information and exhibitions can be found on its website. The library operates the world's largest document delivery service, providing millions of items a year to national and international customers.
The digital NSK portal is the central gathering place for the digital collections of the National and University Library (NSK) in Croatia. It was established in 2016 to provide access to the Library’s digital and digitized material collections regardless of storage location. The digital NSK portal enables a unified search of digitized material from the NSK Special Collections - books, visual material, maps and music material. From the end of 2019, all thematic portals are available independently: Digital Books, Digitized Manuscripts, Digitized Visual Materials, Digital Music Materials and Digitized Cartographic Materials (established in 2017). Currently available only in Croatian.
The official DOI (digital object identifier) link registration agency for scholarly and professional publications. Crossref operates a cross-publisher citation linking system that allows a researcher to click on a reference citation on one publisher’s platform and link directly to the cited content on another publisher’s platform, subject to the target publisher’s access control practices. This citation-linking network covers millions of articles and other content items from several hundred scholarly and professional publishers.
Dimensions is a next-generation linked research information system that makes it easier to find and access the most relevant information, analyze the academic and broader outcomes of research, and gather insights to inform future strategy. Dimensions delivers an array of search and discovery, analytical, and research management tools, all in a single platform. Developed in collaboration with over 100 leading research organizations around the world, it brings together over 128 million publications, grants, policy, data and metrics for the first time, enabling users to explore over 4 billion connections between them.
The primary aim of DOAB (Directory of Open Access Books) is to increase discoverability of Open Access books. Metadata will be harvestable in order to maximize dissemination, visibility and impact. Aggregators can integrate the records in their commercial services and libraries can integrate the directory into their online catalogues, helping scholars and students to discover the books.
OAPEN is dedicated to open access, peer-reviewed books. OAPEN operates two platforms, the OAPEN Library (www.oapen.org), a central repository for hosting and disseminating OA books, and the Directory of Open Access Books (DOAB, www.doabooks.org), a discovery service for OA books.
OpenAIRE aims at promoting and implementing the directives of the European Commission (EC) and the European Research Council on the promotion and funding of science and research. OpenAIRE supports the Open Access Mandate and the Open Research Data Pilot developed as part of the Horizon 2020 projects.
An integrated information service combining reference databases, subscription management, online journals, books and linking services. Widely used by libraries, schools, government institutions, medical institutions, corporations and others.
SFX® link resolver gives patrons and librarians a wealth of features that optimize management of and access to resources. It provides patrons with a direct route to electronic full-text records through OpenURL linking, delivers alternative links for further resource discovery, access to journals, and more. Released in 2001 as the first OpenURL resolver, SFX is continuously enhanced to support the newest industry developments and meet the evolving needs of customers. The records include a mix of scholarly material – primarily articles and e-books – but also conference proceedings, newspaper articles, and more.
A non-profit, membership, computer library service and research organization dedicated to the public purposes of furthering access to the world's information and reducing information costs. More than 41,555 libraries in 112 countries and territories around the world use OCLC services to locate, acquire, catalogue, lend and preserve library materials.
The world’s largest collection of open access research papers. CORE's mission is to aggregate all open access research outputs from repositories and journals worldwide and make them available to the public. In this way CORE facilitates free unrestricted access to research for all.
Since 2002, Research4Life has provided researchers at more than 10,500 institutions in over 125 lower and middle-income countries with free or low-cost online access to up 151,000 leading journals and books in the fields of health, agriculture, environment, applied sciences and legal information. There are five programs through which users can access content: Research for Health (Hinari), Research in Agriculture (AGORA), Research in the Environment (OARE), Research for Development and Innovation (ARDI) and Research for Global Justice (GOALI).
Perlego is a digital online library focusing on the delivery of academic, professional and non-fiction eBooks. It is a subscription-based service that offers users unlimited access to these texts for the duration of their subscription, however IntechOpen content integrated on the platform will always be available for free. They have been billed as “the Spotify for Textbooks” by the Evening Standard. Perlego is based in London but is available to users worldwide.
MyScienceWork provides a suite of data-driven solutions for research institutions, scientific publishers and private-sector R&D companies. MyScienceWork's comprehensive database includes more than 90 million scientific publications and 12 million patents.
CNKI (China National Knowledge Infrastructure) is a key national information construction project under the lead of Tsinghua University, and supported by PRC Ministry of Education, PRC Ministry of Science, Propaganda Department of the Communist Party of China and PRC General Administration of Press and Publication. CNKI has built a comprehensive China Integrated Knowledge Resources System, including journals, doctoral dissertations, masters' theses, proceedings, newspapers, yearbooks, statistical yearbooks, ebooks, patents, standards and so on. CNKI keeps integrating new contents and developing new products in 2 aspects: full-text academic resources, software on digitization and knowledge management. Began with academic journals, CNKI has become the largest and mostly-used academic online library in China.
As one of the largest digital content platform in China,independently developed by CNPIEC, CNPeReading positions herself as “One Platform,Vast Content, Global Services”. Through their new cooperation model and service philosophy, CNPeReading provides integrated promotion and marketing solutionsfor upstream publishers, one-stop, triune, recommendation, online reading and management servicesfor downstream institutions & libraries.
ERIC (Education Resources Information Center), sponsored by the Institute of Education Sciences (IES) of the U.S. Department of Education, provides access to education literature to support the use of educational research and information to improve practice in learning, teaching, educational decision-making, and research. The ERIC website is available to the public for searching more than one million citations going back to 1966.
The ACM Digital Library is a research, discovery and networking platform containing: The Full-Text Collection of all ACM publications, including journals, conference proceedings, technical magazines, newsletters and books. A collection of curated and hosted full-text publications from select publishers.
BASE (Bielefeld Academic Search Engine) is one of the world's most voluminous search sengines especially for academic web resources, e.g. journal articles, preprints, digital collections, images / videos or research data. BASE facilitates effective and targeted searches and retrieves high quality, academically relevant results. Other than search engines like Google or Bing BASE searches the deep web as well. The sources which are included in BASE are intellectually selected (by people from the BASE team) and reviewed. That's why data garbage and spam do not occur.
Zentralblatt MATH (zbMATH) is the world’s most comprehensive and longest-running abstracting and reviewing service in pure and applied mathematics. It is edited by the European Mathematical Society (EMS), the Heidelberg Academy of Sciences and Humanities and FIZ Karlsruhe. zbMATH provides easy access to bibliographic data, reviews and abstracts from all areas of pure mathematics as well as applications, in particular to natural sciences, computer science, economics and engineering. It also covers history and philosophy of mathematics and university education. All entries are classified according to the Mathematics Subject Classification Scheme (MSC 2020) and are equipped with keywords in order to characterize their particular content.
IDEAS is the largest bibliographic database dedicated to Economics and available freely on the Internet. Based on RePEc, it indexes over 3,100,000 items of research, including over 2,900,000 that can be downloaded in full text. RePEc (Research Papers in Economics) is a large volunteer effort to enhance the free dissemination of research in Economics which includes bibliographic metadata from over 2,000 participating archives, including all the major publishers and research outlets. IDEAS is just one of several services that use RePEc data.
As the authoritative source for chemical names, structures and CAS Registry Numbers®, the CAS substance collection, CAS REGISTRY®, serves as a universal standard for chemists worldwide. Covering advances in chemistry and related sciences over the last 150 years, the CAS content collection empowers researchers, business leaders, and information professionals around the world with immediate access to the reliable information they need to fuel innovation.
BKCI is a part of Web of Science Core Collection (WoSCC) and the world’s leading citation index with multidisciplinary content from the top tier international and regional journals, conference proceedings, and books. The Book Citation Index includes over 104,500 editorially selected books, with 10,000 new books added each year. Containing more than 53.2 million cited references, coverage dates back from 2005 to present. The Book Citation Index is multidisciplinary, covering disciplines across the sciences, social sciences, and arts & humanities.
Produced by the Web Of Science group, BIOSIS Previews research database provides researchers with the most current sources of life sciences information, including journals, conferences, patents, books, review articles, and more. Researchers can also access multidisciplinary coverage via specialized indexing such as MeSH disease terms, CAS registry numbers, Sequence Databank Numbers and Major Concepts.
Produced by the Web Of Science group, Zoological Record is the world’s oldest continuing database of animal biology. It is considered the world’s leading taxonomic reference, and with coverage back to 1864, has long acted as the world’s unofficial register of animal names. The broad scope of coverage ranges from biodiversity and the environment to taxonomy and veterinary sciences.
Provides a simple way to search broadly for scholarly literature. Includes peer-reviewed papers, theses, books, abstracts and articles, from academic publishers, professsional societies, preprint repositories, universities and other scholarly organizations. Google Scholar sorts articles by weighing the full text of each article, the author, the publication in which the article appears, and how often the article has been cited in other scholarly literature, so that the most relevant results are returned on the first page.
Microsoft Academic is a project exploring how to assist human conducting scientific research by leveraging machine’s cognitive power in memory, computation, sensing, attention, and endurance. Re-launched in 2016, the tool features an entirely new data structure and search engine using semantic search technologies. The Academic Knowledge API offers information retrieval from the underlying database using REST endpoints for advanced research purposes.
The national library of the United Kingdom includes 150 million manuscripts, maps, newspapers, magazines, prints and drawings, music scores, and patents. Online catalogues, information and exhibitions can be found on its website. The library operates the world's largest document delivery service, providing millions of items a year to national and international customers.
The digital NSK portal is the central gathering place for the digital collections of the National and University Library (NSK) in Croatia. It was established in 2016 to provide access to the Library’s digital and digitized material collections regardless of storage location. The digital NSK portal enables a unified search of digitized material from the NSK Special Collections - books, visual material, maps and music material. From the end of 2019, all thematic portals are available independently: Digital Books, Digitized Manuscripts, Digitized Visual Materials, Digital Music Materials and Digitized Cartographic Materials (established in 2017). Currently available only in Croatian.
The official DOI (digital object identifier) link registration agency for scholarly and professional publications. Crossref operates a cross-publisher citation linking system that allows a researcher to click on a reference citation on one publisher’s platform and link directly to the cited content on another publisher’s platform, subject to the target publisher’s access control practices. This citation-linking network covers millions of articles and other content items from several hundred scholarly and professional publishers.
Dimensions is a next-generation linked research information system that makes it easier to find and access the most relevant information, analyze the academic and broader outcomes of research, and gather insights to inform future strategy. Dimensions delivers an array of search and discovery, analytical, and research management tools, all in a single platform. Developed in collaboration with over 100 leading research organizations around the world, it brings together over 128 million publications, grants, policy, data and metrics for the first time, enabling users to explore over 4 billion connections between them.
The primary aim of DOAB (Directory of Open Access Books) is to increase discoverability of Open Access books. Metadata will be harvestable in order to maximize dissemination, visibility and impact. Aggregators can integrate the records in their commercial services and libraries can integrate the directory into their online catalogues, helping scholars and students to discover the books.
OAPEN is dedicated to open access, peer-reviewed books. OAPEN operates two platforms, the OAPEN Library (www.oapen.org), a central repository for hosting and disseminating OA books, and the Directory of Open Access Books (DOAB, www.doabooks.org), a discovery service for OA books.
OpenAIRE aims at promoting and implementing the directives of the European Commission (EC) and the European Research Council on the promotion and funding of science and research. OpenAIRE supports the Open Access Mandate and the Open Research Data Pilot developed as part of the Horizon 2020 projects.
An integrated information service combining reference databases, subscription management, online journals, books and linking services. Widely used by libraries, schools, government institutions, medical institutions, corporations and others.
SFX® link resolver gives patrons and librarians a wealth of features that optimize management of and access to resources. It provides patrons with a direct route to electronic full-text records through OpenURL linking, delivers alternative links for further resource discovery, access to journals, and more. Released in 2001 as the first OpenURL resolver, SFX is continuously enhanced to support the newest industry developments and meet the evolving needs of customers. The records include a mix of scholarly material – primarily articles and e-books – but also conference proceedings, newspaper articles, and more.
A non-profit, membership, computer library service and research organization dedicated to the public purposes of furthering access to the world's information and reducing information costs. More than 41,555 libraries in 112 countries and territories around the world use OCLC services to locate, acquire, catalogue, lend and preserve library materials.
The world’s largest collection of open access research papers. CORE's mission is to aggregate all open access research outputs from repositories and journals worldwide and make them available to the public. In this way CORE facilitates free unrestricted access to research for all.
Since 2002, Research4Life has provided researchers at more than 10,500 institutions in over 125 lower and middle-income countries with free or low-cost online access to up 151,000 leading journals and books in the fields of health, agriculture, environment, applied sciences and legal information. There are five programs through which users can access content: Research for Health (Hinari), Research in Agriculture (AGORA), Research in the Environment (OARE), Research for Development and Innovation (ARDI) and Research for Global Justice (GOALI).
Perlego is a digital online library focusing on the delivery of academic, professional and non-fiction eBooks. It is a subscription-based service that offers users unlimited access to these texts for the duration of their subscription, however IntechOpen content integrated on the platform will always be available for free. They have been billed as “the Spotify for Textbooks” by the Evening Standard. Perlego is based in London but is available to users worldwide.
MyScienceWork provides a suite of data-driven solutions for research institutions, scientific publishers and private-sector R&D companies. MyScienceWork's comprehensive database includes more than 90 million scientific publications and 12 million patents.
CNKI (China National Knowledge Infrastructure) is a key national information construction project under the lead of Tsinghua University, and supported by PRC Ministry of Education, PRC Ministry of Science, Propaganda Department of the Communist Party of China and PRC General Administration of Press and Publication. CNKI has built a comprehensive China Integrated Knowledge Resources System, including journals, doctoral dissertations, masters' theses, proceedings, newspapers, yearbooks, statistical yearbooks, ebooks, patents, standards and so on. CNKI keeps integrating new contents and developing new products in 2 aspects: full-text academic resources, software on digitization and knowledge management. Began with academic journals, CNKI has become the largest and mostly-used academic online library in China.
As one of the largest digital content platform in China,independently developed by CNPIEC, CNPeReading positions herself as “One Platform,Vast Content, Global Services”. Through their new cooperation model and service philosophy, CNPeReading provides integrated promotion and marketing solutionsfor upstream publishers, one-stop, triune, recommendation, online reading and management servicesfor downstream institutions & libraries.
ERIC (Education Resources Information Center), sponsored by the Institute of Education Sciences (IES) of the U.S. Department of Education, provides access to education literature to support the use of educational research and information to improve practice in learning, teaching, educational decision-making, and research. The ERIC website is available to the public for searching more than one million citations going back to 1966.
The ACM Digital Library is a research, discovery and networking platform containing: The Full-Text Collection of all ACM publications, including journals, conference proceedings, technical magazines, newsletters and books. A collection of curated and hosted full-text publications from select publishers.
BASE (Bielefeld Academic Search Engine) is one of the world's most voluminous search sengines especially for academic web resources, e.g. journal articles, preprints, digital collections, images / videos or research data. BASE facilitates effective and targeted searches and retrieves high quality, academically relevant results. Other than search engines like Google or Bing BASE searches the deep web as well. The sources which are included in BASE are intellectually selected (by people from the BASE team) and reviewed. That's why data garbage and spam do not occur.
Zentralblatt MATH (zbMATH) is the world’s most comprehensive and longest-running abstracting and reviewing service in pure and applied mathematics. It is edited by the European Mathematical Society (EMS), the Heidelberg Academy of Sciences and Humanities and FIZ Karlsruhe. zbMATH provides easy access to bibliographic data, reviews and abstracts from all areas of pure mathematics as well as applications, in particular to natural sciences, computer science, economics and engineering. It also covers history and philosophy of mathematics and university education. All entries are classified according to the Mathematics Subject Classification Scheme (MSC 2020) and are equipped with keywords in order to characterize their particular content.
IDEAS is the largest bibliographic database dedicated to Economics and available freely on the Internet. Based on RePEc, it indexes over 3,100,000 items of research, including over 2,900,000 that can be downloaded in full text. RePEc (Research Papers in Economics) is a large volunteer effort to enhance the free dissemination of research in Economics which includes bibliographic metadata from over 2,000 participating archives, including all the major publishers and research outlets. IDEAS is just one of several services that use RePEc data.
As the authoritative source for chemical names, structures and CAS Registry Numbers®, the CAS substance collection, CAS REGISTRY®, serves as a universal standard for chemists worldwide. Covering advances in chemistry and related sciences over the last 150 years, the CAS content collection empowers researchers, business leaders, and information professionals around the world with immediate access to the reliable information they need to fuel innovation.
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