The main characteristics of hemostatic soluble plasma proteins (HSPPs)
\r\n\t
",isbn:"978-1-83969-642-8",printIsbn:"978-1-83969-641-1",pdfIsbn:"978-1-83969-643-5",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,hash:"5d7f2aa74874444bc6986e613ccebd7c",bookSignature:"Prof. Antonio Morata, Dr. Iris Loira and Prof. Carmen González",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10901.jpg",keywords:"Grape, Wine, Vine Biotechnology, Plant Disease, Vine Physiology, Wine Technology, Winemaking, Fungal Disease, Biological Control, Vigor Management, Aroma Compound, Polysaccharide",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 4th 2021",dateEndSecondStepPublish:"April 1st 2021",dateEndThirdStepPublish:"May 31st 2021",dateEndFourthStepPublish:"August 19th 2021",dateEndFifthStepPublish:"October 18th 2021",remainingDaysToSecondStep:"23 days",secondStepPassed:!1,currentStepOfPublishingProcess:2,editedByType:null,kuFlag:!1,biosketch:"Prof. Morata is the Spanish delegate at the group of experts in wine microbiology and wine technology of the International Organisation of Vine and Wine (OIV). His team won the international Enoforum award 2019 by the application of UHPH in wines and was among the 5 finalists in 2020 by using PL.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"180952",title:"Prof.",name:"Antonio",middleName:null,surname:"Morata",slug:"antonio-morata",fullName:"Antonio Morata",profilePictureURL:"https://mts.intechopen.com/storage/users/180952/images/system/180952.jpg",biography:"Antonio Morata is a professor of Food Science and Technology at the Universidad Politécnica de Madrid (UPM), Spain, specializing in wine technology. He is the coordinator of the Master in Food Engineering Program at UPM, and a professor of enology and wine technology in the European Master of Viticulture and Enology, Euromaster Vinifera-Erasmus+. He is the Spanish delegate at the group of experts in wine microbiology and wine technology of the International Organisation of Vine and Wine (OIV). He is the author of more than 70 research articles, 3 books, 4 edited books, 6 special issues and 16 book chapters.",institutionString:"Technical University of Madrid",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"6",totalChapterViews:"0",totalEditedBooks:"3",institution:{name:"Technical University of Madrid",institutionURL:null,country:{name:"Spain"}}}],coeditorOne:{id:"186423",title:"Dr.",name:"Iris",middleName:null,surname:"Loira",slug:"iris-loira",fullName:"Iris Loira",profilePictureURL:"https://mts.intechopen.com/storage/users/186423/images/system/186423.jpg",biography:"Iris Loira is an assistant professor of Food Science and Technology at the Universidad Politécnica de Madrid (UPM), Spain. 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Her research activity has focused on the field of oenological biotechnology and on the selection of microorganisms (yeasts and BAL) that are of special interest in wine making processes. She has extensive experience in the use of instrumental and sensory tests to assess the quality of alcoholic beverages (wine and beer) and meat products. She has participated in different educational innovation projects and coordinated three of them. These projects have made it possible to coordinate working groups for the implementation of degrees in the EEES, and apply new teaching methodologies that allow the acquisition of horizontal competences by students. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4816",title:"Face Recognition",subtitle:null,isOpenForSubmission:!1,hash:"146063b5359146b7718ea86bad47c8eb",slug:"face_recognition",bookSignature:"Kresimir Delac and Mislav Grgic",coverURL:"https://cdn.intechopen.com/books/images_new/4816.jpg",editedByType:"Edited by",editors:[{id:"528",title:"Dr.",name:"Kresimir",surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"21449",title:"Hemostatic Soluble Plasma Proteins During Acute-Phase Response and Chronic Inflammation",doi:"10.5772/20408",slug:"hemostatic-soluble-plasma-proteins-during-acute-phase-response-and-chronic-inflammation",body:'\n\t\tCoagulation and inflammation are the interdependent processes attributed to the host defence response to injuries. A synchronized activity of both pathways represents an essential prerequisite for restitution of host homeostasis after ultimate disturbances of the latter. Crosstalk between coagulation and inflammation is considered to inherit from primitive coagulation systems similar to invertebrates. For instance,in Horseshoe “crabs” (Limulus) coagulogen, a clotting protein with the bactericidal function, and coagulation-related serine proteases are both located in circulating hemolymph cells (hemocytes) and are capable ofsimultaneously protecting againstinjury, as well as to isolate pathogens within cysts (Tanaka et al., 2009). In humans, the complement system as a part of innate immunity remains closely related to the hemostasis system (Markiewski et al., 2007). The organizations of these two systems demonstrate several similarities of both structural and functional features. Both systems are organized into proteolytic cascades; serine proteases of the chymotrypsin family are the components of the latter. Proteases of each system are, in their molecular structure, glycoproteins, which have a highly conservative catalytic site composed of serine, histidine, and aspartic amino acidresidues. These proteases exist in the form of inactive zymogens and are subsequently activated by upstream, active proteases. Proteins of the complement and hemostasis systems are mostly synthesized in the liver by hepatocytes, besides being additionally produced during an acute-phase response stimulated by common inflammatory mediators. The biological role of the complement system is mentioned here in order to note that the above-mentioned similarities represent a forcible argument in favour of the common origin of both immunity and hemostasis phenomena. The complement system has been described in detail recently (Castellheim et al., 2009; Markiewski et al., 2007) and will not be further discussed here. Though, it is worthwhile to mention thatthe blood hemostasis system in humans, hypothetically, has been evolved progressively from the archaic innate immunity organization, diverging to certain narrow-specific pathways, which are responsible for the coagulation control.
\n\t\t\tHemostasis in humans is organized as closely interrelated enzyme cascade systems: (i) fibrin clotting system (coagulation); (ii) multilevel system for preventing uncontrolled fibrin formation (anticoagulation); and (iii) system for limiting the amount of cross-linked fibrin (fibrinolysis). Together, coagulation, anticoagulation and fibrinolysis are associated into a self-regulated and highly organized molecular machine that provides either acceleration or reduction of blood hemostasis process (Spronk et al., 2003). Accurateregulation of the coagulation rate is an effective mechanism, preventing circulatory disorders. This regulatory mechanism is known to be a part of the acute phase of the inflammatory reaction which provides rapid restoration of physiological homeostasis.
\n\t\t\tHemostasisis closely linked to innate immunity and inflammation through particular regulatory coupling like protein C system (Fig. 1). Cooperation between hemostasis and innate immunity facilitates injury recognition, vessel wall reparation, and preventionof excessive bleeding without causing thrombosis. These processes are mediated by a balance of cellular surface components, cell-derived factors, and soluble plasma proteins (SPPs). After interruption of the vascular integrity, concentrations of some hemostatic SPPs (HSPPs) change in a manner typical of those of acute-phase proteins (APPs). In agreement with definition of APPs (Kushner & Rzewnicki, 1994; Morley & Kushner, 1982), at least several HSPPs including fibrinogen, plasminogen, and PAI-1 should also be classified as APPs, since: (i) the intensity of synthesis of these HSPPs dramatically changes (by more than 50%) during pathological processes (ii) HSPPs synthesis in hepatocytes during the acute-phase response are regulated by inflammatory-associated cytokines; (iii) due to chronic stimulation by inflammatory mediators, HSPPs may persist in circulation and participate in the formation of a “semantically paradoxical chronic acute-phase response” (Gabay & Kushner, 2001). The above-indicated similarities between inflammation and hemostasis determine their unidirectional changes. These changes involve pro-coagulant activities of inflammatory processes, as well as the pro-inflammatory efficacy of the hemostatic molecular machine.
\n\t\t\tSchematic representation of the protein C-dependent cross-pointbetween hemostatic and inflammatory pathways. Diagram illustrates a putative regulatory mechanism, maintaining homeostasis within physiological limits. Both pathways are balanced by the PC/APC (protein C/activated protein C) system, directly by attenuation of production of thrombin as a pro-inflammatory and pro-coagulant agent, or indirectly, by controlling NF-kB-dependent anti-inflammatory pathways through EPCRs (endothelial protein C receptors) and PARs (protease-activated receptors) at the surface of the target cells. See the text for discussion in detail.
The capacity of inflammatory mediators to regulate hemostasis, as well as some aspects of the coagulation ability to affect inflammatory events have been extensively reviewed (Butenas et al., 2009; Danese et al., 2010; Esmon, 2005; Jennewein et al., 2011; Levi et al., 2004; Medcalf, 2007). Reciprocal regulation of gene expression is the most important mechanism, by which inflammatory and hemostatic pathways interact with each other. The role of cell surface receptors in providing APP-associated signalling has been recently elucidated (Busso et al., 2008; Guitton et al., 2011). The role of the increased HSPPs in the regulation of hemostasis and inflammation pathways under pathophysiological conditions, however, remains less clear. The molecular mechanisms, responsible for the influence of inflammation upon hemostasis and vice versa, remain largely unknown. We would like to review here the most important post-translational events, which might perturb HSPPs structure and functions, as well as those influencing measurable levels of HSPPs during inflammation.
\n\t\tIn normal conditions, HSPPs are presented by a soluble fibrous protein, fibrinogen, abundant serine protease zymogens (inactive enzymatic precursors), and minute amounts of active proteases, as well as by non-enzymatic cofactors and protease inhibitors (Table 1).
\n\t\t\tPrecursor conversion | \n\t\t\t\t\t\tHSPP identification | \n\t\t\t\t\t\tThe basic function in hemostasis | \n\t\t\t\t\t\tProteolytic activation | \n\t\t\t\t\t\tExpression during the acute-phase response | \n\t\t\t\t\t||
Clotting factors | \n\t\t\t\t\t\t\n\t\t\t\t\t | |||||
Fibrinogen (Fg) → fibrin (Fn) | \n\t\t\t\t\t\ta fibrous (structural) protein | \n\t\t\t\t\t\tsubstrate for polymerization to fibrin that is important in tissue repair | \n\t\t\t\t\t\tby thrombin \n\t\t\t\t\t\t | \n\t\t\t\t\t\tincrease, 1,5-4,0-fold | \n\t\t\t\t\t||
Prothrombin (II) → thrombin (IIa) | \n\t\t\t\t\t\ttrypsin-like serine protease (endopeptidase) | \n\t\t\t\t\t\tthe conversion of Fg to Fn leading to the formation of a fibrin clot | \n\t\t\t\t\t\tby prothrombinase | \n\t\t\t\t\t\tno change or weak increase | \n\t\t\t\t\t||
Factor V (V) → activated factor V (Va) | \n\t\t\t\t\t\tceruloplasmin-like binding protein | \n\t\t\t\t\t\tas a cofactor for Xa participates inthrombin activation, not enzymatically active | \n\t\t\t\t\t\tby thrombin \n\t\t\t\t\t\t | \n\t\t\t\t\t\tND | \n\t\t\t\t\t||
Factor VII (VII) → activated factor VIIa (VIIa) | \n\t\t\t\t\t\tserine protease (endopeptidase) | \n\t\t\t\t\t\tthe catalytic component of the extrinsic tenase, activatesIX to IXa and X to Xa | \n\t\t\t\t\t\tby thrombin, IXa, Xa, XIIa \n\t\t\t\t\t\t | \n\t\t\t\t\t\tND | \n\t\t\t\t\t||
Factor VIII (VIII) → activated factor VIIIa (VIIIa) | \n\t\t\t\t\t\tceruloplasmin-like binding protein | \n\t\t\t\t\t\tcofactor for IXa in conversion of X to Xa, receptor for IXa and X, not enzymatically active | \n\t\t\t\t\t\tbythrombin \n\t\t\t\t\t\t | \n\t\t\t\t\t\tincrease | \n\t\t\t\t\t||
Factor IX (IX) → activated factor IXa (IXa) | \n\t\t\t\t\t\tserine protease (endopeptidase) | \n\t\t\t\t\t\tthe enzyme component of the intrinsic tenase, activates X to Xa | \n\t\t\t\t\t\tby XIa or TF-VIIa/PL-Ca2+\n\t\t\t\t\t\t | \n\t\t\t\t\t\tND | \n\t\t\t\t\t||
Factor X (X) → activated factor Xa (Xa) | \n\t\t\t\t\t\tserine protease (endopeptidase) | \n\t\t\t\t\t\tthe enzyme component of the prothrombinase is responsible for rapid thrombin activation | \n\t\t\t\t\t\tby IXa-VIIIa/PL-Ca2+,\n\t\t\t\t\t\t\t TF-VIIa/PL-Ca2+\n\t\t\t\t\t\t | \n\t\t\t\t\t\tND | \n\t\t\t\t\t||
Factor XI (X) → activated factor XIa(XIa) | \n\t\t\t\t\t\tserine protease (endopeptidase) | \n\t\t\t\t\t\tthe conversion of IX to IXa within the intrinsic pathway | \n\t\t\t\t\t\tby surface bound α-XIIa | \n\t\t\t\t\t\tND | \n\t\t\t\t\t||
Factor XII (XII) → activated factor XII (α-XIIa) | \n\t\t\t\t\t\tserine protease (endopeptidase) | \n\t\t\t\t\t\tinitiation of the intrinsic coagulation pathway via conversion XI to XIa | \n\t\t\t\t\t\tby kallikrein \n\t\t\t\t\t\t | \n\t\t\t\t\t\tdecrease | \n\t\t\t\t\t||
Factor α-XIIa (α-XIIa)→factor β-XIIa (β-XIIa) | \n\t\t\t\t\t\tserine protease (endopeptidase) | \n\t\t\t\t\t\tsolution phase activation of kallikrein, factor VII and thecomplement cascade | \n\t\t\t\t\t\tby kallikrein \n\t\t\t\t\t\t | \n\t\t\t\t\t\tdecrease | \n\t\t\t\t\t||
Factor XIII (XIII) → activated factor XIIIa (XIIIa) | \n\t\t\t\t\t\ttransglutami-nase (transpeptidase) | \n\t\t\t\t\t\tstabilization of the fibrin clot via cross linking the α and γ-chains of Fn, α2-PI, V, vWF | \n\t\t\t\t\t\tby thrombin | \n\t\t\t\t\t\tND | \n\t\t\t\t\t||
Anticoagulants | \n\t\t\t\t\t\t\n\t\t\t\t\t | |||||
Tissue factor pathway inhibitor (TFPI) | \n\t\t\t\t\t\tKunitz-type protease inhibitor | \n\t\t\t\t\t\treverse inhibition of Xa and IIa, then TF-VIIa independently from Ca2+\n\t\t\t\t\t\t | \n\t\t\t\t\t\t- \n\t\t\t\t\t\t | \n\t\t\t\t\t\tdecrease | \n\t\t\t\t\t||
Antithrombin (AT) | \n\t\t\t\t\t\tserpin | \n\t\t\t\t\t\tInhibition of VIIa, IXa, Xa and XIa, kallikrein, plasmin, IIa | \n\t\t\t\t\t\t- | \n\t\t\t\t\t\tdecrease | \n\t\t\t\t\t||
Protein C (PC)→ Activated protein C (APC) | \n\t\t\t\t\t\ttrypsin-like serine protease (endopeptidase) | \n\t\t\t\t\t\tinactivation of Va and VIIIa, that inhibits the prothrombinase and tenase and, finally, IIa | \n\t\t\t\t\t\tby α-throm-bin/throm-bomodulin,by Xa or IIawithout Ca2+\n\t\t\t\t\t\t | \n\t\t\t\t\t\tno change or decrease | \n\t\t\t\t\t||
Protein S(PS) | \n\t\t\t\t\t\tbinding protein | \n\t\t\t\t\t\tas cofactor for APC | \n\t\t\t\t\t\t- | \n\t\t\t\t\t\tincrease | \n\t\t\t\t\t||
Fibrinolytic proteins | \n\t\t\t\t\t\t\n\t\t\t\t\t | |||||
Tissue-type plasminogen activator,single chain form (sc-tPA) → active two-chain form (tc-tPA) | \n\t\t\t\t\t\tserine protease (endopeptidase) | \n\t\t\t\t\t\tthe main endothelium- derived activator of the fibrinolytic system, converts Pg to Pm | \n\t\t\t\t\t\tby plasmin \n\t\t\t\t\t\t | \n\t\t\t\t\t\tdecrease or weak increase | \n\t\t\t\t\t||
Glu-plasminogen(Glu-Pg) →plasmin (Pm) | \n\t\t\t\t\t\tserine protease (endopeptidase) | \n\t\t\t\t\t\tresponsible for the fibrin clot digestion | \n\t\t\t\t\t\tby t-PA, u-PA, elastase, XIIa | \n\t\t\t\t\t\tincrease, 2-3- fold | \n\t\t\t\t\t||
Urokinase-type plasminogen activator, single chain(sc-uPA) | \n\t\t\t\t\t\tserine protease (endopeptidase) | \n\t\t\t\t\t\tactivator of the Pg conversion to Pm | \n\t\t\t\t\t\t- | \n\t\t\t\t\t\tincrease | \n\t\t\t\t\t||
Proteinase inhibitors | \n\t\t\t\t\t\t\n\t\t\t\t\t | |||||
α1-Antitrypsin or alpha 1-proteinase inhibitor (αl -PI) | \n\t\t\t\t\t\tserpin | \n\t\t\t\t\t\tprotects tissues from proteolytic enzymes, inhibits IIa and APC | \n\t\t\t\t\t\t- \n\t\t\t\t\t\t | \n\t\t\t\t\t\tincrease | \n\t\t\t\t\t||
α2-macroglobulin (α2-M) | \n\t\t\t\t\t\tbroad-range protease inhibitor | \n\t\t\t\t\t\tinhibits IIa, APC Pm, kallikrein, a remover of plasma enzymes | \n\t\t\t\t\t\t- \n\t\t\t\t\t\t | \n\t\t\t\t\t\tincrease, about 100-fold | \n\t\t\t\t\t||
α2-antiplasmin (α2 –plasmin inhibitor) (α2 -PI) | \n\t\t\t\t\t\tserpin | \n\t\t\t\t\t\tinhibitor of Pm, forms covalent complexesinterfered with the binding of Pg(Pm) to Fn | \n\t\t\t\t\t\t- | \n\t\t\t\t\t\tND | \n\t\t\t\t\t||
Thrombin activablefibrinolytic inhibitor (TAFI) → activated form (TAFIa) | \n\t\t\t\t\t\tcarboxypepti-dase | \n\t\t\t\t\t\tinhibitor of fibrinolysis, removes Pg-binding sites on Fn | \n\t\t\t\t\t\tby thrombin,plasmin, trypsin \n\t\t\t\t\t\t | \n\t\t\t\t\t\tND | \n\t\t\t\t\t||
Plasminogen activator inhibitor of type 1 (PAI-1) | \n\t\t\t\t\t\tserpin | \n\t\t\t\t\t\tthe major inhibitor of tPA that regulates the fibrinolysis by attenuation of Pmproduction | \n\t\t\t\t\t\t- \n\t\t\t\t\t\t | \n\t\t\t\t\t\tincrease | \n\t\t\t\t\t||
Plasminogen activator inhibitor of type2 (PAI-2) | \n\t\t\t\t\t\tserpin | \n\t\t\t\t\t\tinhibitor of urokinase as well as tPA | \n\t\t\t\t\t\t- | \n\t\t\t\t\t\tND | \n\t\t\t\t\t||
Plasminogen activator inhibitor of type3 (PAI-3 or PCI) | \n\t\t\t\t\t\tserpin | \n\t\t\t\t\t\tthe major inhibitor of APC as well as tPA and urokinase | \n\t\t\t\t\t\t- | \n\t\t\t\t\t\tND | \n\t\t\t\t\t
The main characteristics of hemostatic soluble plasma proteins (HSPPs)
Physiological anticoagulants are also available to suppress appropriate clotting factors. Some of the clotting factors (like thrombin or factor V) can promote both coagulation and anticoagulation; thus, these factors are called Janus-faced proteins.
\n\t\t\tA hemostatic response to the activating signal is manifested by a series of transformations of proenzymes to activated enzymes in a cascade-like manner.The formation of thrombin at the final stage of the coagulation cascade is aimed at conversion of soluble fibrinogen into insoluble fibrin, the non-cellular matrix of blood thrombus. The thrombus formation is considerably accelerated due to accumulation of tissue factor (TF) at the sites of vascular endothelial damage. Tissue factor, a membrane-bound glycoprotein, is considered the common physiologic trigger of both hemostasis and inflammation pathways.Under normal conditions, none cells, which contact with the bloodstream, express TF. An injury, as the initial triggering signal, starts up the TF expression and the externalization at the surface ofinflammatory cells (primarily, monocytes) and vascular wall cells (endothelial or smooth muscle cells). Immediately upon exposure to the bloodstream, TF contacts with activated coagulation factor VIIa (VIIa), whose trace amounts (about 1 % of total inactive enzyme precursor, coagulation factor VII) are conventionally present in circulation. The formation of macromolecular complex TF-VIIa is a crucial event that initiates the first stage of the coagulation process, initiation phase. Alongside with that TF initiates local inflammatory reaction.
\n\t\tTissue factor-VIIa complexes, newly appeared on the boundary between blood flow and the vessel wall, begin to bind plasma-derived coagulation factor VII to produce additionally factor VIIa. Thus, TF acts as a cofactor in the factor VII/VIIa autoactivation process (Fig. 2). Membrane-bound TF/VIIa complexes also interact with small amounts of coagulation factor X (X) and coagulation factor IX (IX). Activated factors X (Xa) and IX (IXa) start up prothrombin (coagulation factor II) conversion to thrombin (IIa). This first cycle of restricted thrombin production is limited by two plasma-derived inhibitors, tissue factor pathway inhibitor (TFPI) and antithrombin (AT). The former one neutralizes factor Xa when forms a quaternary structure with TF-VIIa-Xa. As well, AT upon binding to heparan sulphate/heparin, rapidly inactivates free factors Xa, IXa, and thrombin, initially accumulated at the site of vascular injury. So, TF-VIIa itself is incapable to generate substantial amounts of thrombin during the initiation phase. However, the TF-dependent cycle of thrombin production can overcome inhibition by TFPI and AT, when TF is maintained at a sufficiently high level (Tanaka et al., 2009). Blood-borne forms of TF (soluble sTF or TF-positive microparticles) shed from disrupted cell membranes of different origin presumably can be an additional driver of the increased TF-initiated thrombin production (Sommeijer et al., 2006). Apparently, cell-exposed and blood-borne TF can promote transduction of inflammatory signals via cellular protease-activated receptors (PARs). For example, sTF-mediated inflammation in animal models might develop via platelet PAR-4 signalling, while TF-proteases complexes (TF-VIIa and TF-VIIa-Xa ) induce the activity of signalling pathways in vascular cells via PAR-1 and PAR-2(Busso et al., 2008;\n\t\t\t\tRao & Pendurthi, 2005; Riewald & Ruf, 2001). Being a mediator of both inflammatory and hemostatic pathways, TF integrates different extra cellular signals and cellular responses, thus participating in the development of a host acute-phase response (Fig. 2). As an extremely potent triggering molecule, TF is capable of translating injury signals into activation of the coagulation cascade, sustaining thrombin initiation, and promoting its propagation.
\n\t\t\tTrace amounts of thrombin promote formation of a IXa-VIIIa-Ca2+-phospholipid assembly (tenase complex) ora Xa-Va-Ca2+-phospholipid assembly (prothrombinase complex) via feedback activation of non-enzymatic cofactors VIII (VIIIa) and V (Va) after their binding to negatively charged phospholipids (phosphatidylinositol and phosphatidylserine) on the surface of activated platelets in the presence of calcium ions. Thrombin also activates factor XI (XIa), which additionally stimulates the tenase complex. Tenase-produced prothrombinase complexes lead to the explosive generation of thrombin, which ultimately leads to generation of a fibrin clot. During an episode of TF-initiated coagulation, tenase and prothrombinase complexes are generated in concentrations that might be sufficient to maintain the TF-independent procoagulant response as long, as the reactants are available. From this moment, normal coagulation may become fully independent of TF (Butenas et al., 2009). The propagation phase can continue and prolong the acute-phase response, where driving of thrombin generation is a requisite for an adequate bleeding prevention via more fibrin deposition. By binding to PARs, thrombin activates platelets, endothelial cells, and immune cells. As a result, cytokines and chemokines are additionally expressed, as well as certain HSPP secretion is intensified, leukocyte and platelet recruitment to inflammatory foci increases, and fibrin deposition is accumulated. These events considerably enhance local
\n\t\t\t\tSchematic representation of the regulatory crosstalk between hemostasis and inflammation in response to exposed TF (coagulation factors and cytokines are all present in circulating plasma whereas TF is the only cell surface glycoprotein shown here). The interconnection of coagulation and inflammation pathways is an essential prerequisite for host homeostasis restitution after injury. Coagulation factors (as shown here with pink circles)and inflammatory mediators (blue circles) promote both coagulation and inflammation through complex and reciprocal interactions, thereby sustaining the acute phase response. At least, two clotting factors, factor VIIa and thrombin, contribute in pro-inflammatory action of coagulation system through positive feed-back autoactivation mechanism (closed-loop arrows). Red curved arrow represents propagation phase of coagulation, blue curved arrow represents amplification of inflammation. In proportion to increasing levels of clotting and inflammatory APP, anticoagulation and anti-inflammation processes are activated. The limiting action of the anticoagulant and fibrinolytic systems on coagulation as well as anti-inflammatory mechanism of inflammation attenuation is depicted by brick-built barrier. Abbreviations: IIa, VIIa, IXa, Xa and XIa indicate activated coagulation factors; Fg, fibrinogen; Fn, fibrin; TF, tissue factor; PARs, protease-activated receptors; IL, interleukin; CRP, C-reactive protein; ICAM, intercellular adhesion molecule-1; PC/APC, protein C/activated protein C; AT, antithrombin; TFPI, tissue factor pathway inhibitor; IL-1Ra, interleukin-1 receptor antagonist; TGF-ß, transforming growth factor beta.
inflammation and coagulation. Furthermore, the formation of thrombi in the microvasculature provides a mechanical barrier that blocks spreading of inflammatory/coagulation mediators into the circulation. Such limited clotting restricts thrombus propagation and prevents from acute local inflammation turning into systemic complications. An anti-clotting molecular process induced by several physiological anticoagulants and fibrinolytic agents is designated for regulation of an adequate clot size and formation of an effective thrombus. Two hemostatic pathways, anticoagulation and fibrinolysis, both are responsible for coagulation termination (Fig. 2).
\n\t\t\tAfter bleeding is arrested, and the injured vessel is repaired, coagulation attenuation begins to dominate over its propagation due to accumulation of inhibitors of blood clotting. Natural clotting inhibitors are orchestrated through successive induction of three major anticoagulant-dependent pathways: tissue factor pathway inhibitor-, heparin/antithrombin- and the protein C-dependent pathways. A tissue factor pathway inhibitor (TFPI), as was mentioned above, is a most effective inhibitor of coagulation at the initiation phase. This inhibitor specifically blocks the TF-VIIa-Xa complex after trace factor Xa has been formed (Spronk et al., 2003). Antithrombin (AT) is a direct protease inhibitor, which attenuates accumulation of coagulation factors IXa, Xa, and IIa during the propagation phase. Heparin-like glycosaminoglycans accelerate the rate of inactivation of these clotting factors by AT. The protein C system provides multi-directional attenuation of thrombin procoagulant activity and this terminates coagulation. Thrombomodulin (TM), a endothelial cell membrane-associated protein, is capable of to tackling excessive thrombin, thus changing its specific enzyme activity. Within the thrombin-thrombomodulin complex, thrombin looses its affinity to fibrinogen or cellular PARs. Instead this, it possesses an ability to convert precursor protein C (PC) into an anticoagulant enzyme, activated protein C (APC). Activated protein C interrupts thrombin propagation via limited proteolysis of cofactors Va and VIIIa. Cofactor protein S and platelet membrane phospholipids provide manifold acceleration of the APC activity. Endothelial protein C receptors (EPCR) enhance the thrombin-thrombomodulin affinity to PC. In such a way the protein C system down-regulates the coagulation cascade to moderate the explosive trend of thrombin production. Its anticoagulant competence enhances, due to the modulation of the thrombin activity through two mechanisms, inhibition of prothrombin converting into thrombin and promotion of thrombin inversion from a procoagulant enzyme into an anticoagulant one. Inhibition of thrombin formation can also reduce thrombin’s pro-inflammatory activities (Sarangi et al., 2010).
\n\t\t\tIn a complementary mode with respect to anticoagulation, the surplus clots are dissolved by proteases of the fibrinolytic system. Activation of intravascular fibrinolysis is controlled through enhancing synthesis and secretion of tissue plasminogen activator (tPA) by endothelial cells during fibrin clotting. Tissue plasminogen activator is released into the clot and binds in the clot volume with fibrin(ogen) and plasminogen (Pg). The formation of ternary Fn-tPA-Pg complex extremely effectively accelerates Pg converting into the serine protease plasmin (Pm). Plasmin cleaves fibrin into soluble fragments, the so called fibrin degradation products (FDPs). The rate and extent of local delivery of tPA during the clot formation is important for enhancing the process of fibrinolysis (Schrauwen et al., 1994). To avoid excessive clot digestion, which can affect bleeding, the activity of fibrinolytic system is down-regulated by numerous plasma- and cell-derived inhibitors (Meltzer et al., 2010). These are (i) plasminogen activator inhibitor of type 1 (PAI-1) that highly specifically inactivates tPA, (ii) α2-antiplasmin, primary Pm inhibitor that prevents Pm-dependent non-specific proteolysis due to effective neutralization of Pm, and (iii) thrombin activablefibrinolytic inhibitor (TAFI) that down-regulates the cofactor activity of fibrin during activation of plasminogen and, thereby, suppresses fibrinolysis.
\n\t\t\tThe activities of both coagulation and fibrinolytic cascades are normally latent but have the potential to be accelerated in an extremely acute manner during inflammation. The coagulation and fibrinolysis pathways have to follow each other, retaining a delicate physiological balance preventing thrombosis and bleeding. Activation of the coagulation cascade leads to increases in the plasma levels of coagulation factors VIIa, Xa, and thrombin, which are pro-inflammatory factors contributing to the acute-phase response (Fig. 2). In addition, fibrin deposition and fibrin degradation products, FDPs, enhance inflammation.Coagulation factors elicit inflammation via affecting a number of blood/vascular cells through protease-activated receptor (PAR)-mediated pathways up-regulating the expression of numerous APPs (tumour necrosis factor-alpha, interleukins, adhesion molecules, and growth factors) (Chua, 2005). At least fibrin, thrombin, and coagulation factor Xa, all are important cell-signalling effector molecules that are responsible for receptor triggering. When PARs are activated constantly (e.g., under the action of repeated stimuli), the acute-phase response can be inverted into a chronic one. Therefore, the inflammatory consequence caused by coagulation should be abolished within a necessary time intervals; otherwise it could be enormous. Resolution of the acute-phase response requires down-regulation of inflammatory/procoagulant APPs expression. In particular, IL-4, IL-10, TGF- ß are anti-inflammatory agents that inhibit the production of numerous inflammatory cytokines, including TNF-α, IL-1ß, IL-6, IL-8, and, finally, IL-10 itself(de Waal et al., 1991;Walley et al., 1996). In fact, human blood monocytes are known to produce both pro- and anti-inflammatory cytokines. During resolution, monocytes and macrophages considerably increase production of the latter above the former, thereby preventing prolongation or escalation of an early inflammatory response (Fig. 2). The concentration of cytokine-induced procoagulants is reciprocally decreased; thus, vascular homeostasis is restored.
\n\t\t\tA failure of the control of these processes causes incorrect inflammation termination or even its propagation. Such an inconsistency leads to deregulation of hemostasis, which, in turn, might force the further leap of inflammatory responses. Under pathological conditions, cytokines are released by immune regulatory cells in sites of the local inflammatory response. This process may be acute but limited in time (reverting to the normal homeostatic state) or persistent (resulting in chronic activation of coagulation and fibrinolysis). Initially acting within the frame of the adaptive defence system, inflammation and hemostasis might develop from a local response to a systemic host reaction. Escalation of inflammation can induce endothelial dysfunction subsequently activating the coagulation cascade, and vice versa — hypercoagulation follows amplification of inflammation (Levi et al., 2004)
\n\t\t\tUnder these conditions mutual activation of coagulation and fibrinolysis might follow to potentially exhausting consumptive coagulopathy and disseminated intravascular coagulation. A detrimental inflammatory response resulting from coupling of procoagulant and pro-inflammatory stimuli might cause thrombophilia, and, furthermore, provoke the thrombotic events. In such a way, inflammation/coagulation interaction drastically increases a risk of thrombus formation implicated in the pathogenesis of several diseases in humans. On the one hand, these are thrombophilias, atherosclerosis, and other cardio-vascular pathologies, as well as intercurrent illnesses (like trauma and cancer) or surgery. On the other hand, these are acute/chronic inflammatory diseases, including sepsis, inflammatory bowel disease, and lung and heart inflammation (Fig. 3).
\n\t\t\tA simplified hypothetic model of pathophysiological interactions between inflammatory and hemostatic APPs.Each spiral turn represents a potentially vicious cycle driven by excessive concentrations of some components (this is shown as arrows up) and/or insufficient concentrations of other components (as arrows down). Amplification of HSPP activation during an initiation phase is exerted through interaction with the components of the innate immune system, which, in turn, prolongs inflammation during the propagation phase. As a result, both processes, coagulation and inflammation, can come into perpetuation phase. These complex interactions can lead to life-threatening complications, such as thrombosis or sepsis. Refer to the text for discussion in detail.
Abbreviations: IIa, VIIa, IXa, Xa, and XIa indicate activated coagulation factors; Va and VIIIa – non enzymatic cofactors; Fn, fibrin; TF, tissue factor; sTF, blood-borne (soluble) forms of tissue factor; PARs, protease-activated receptors; IL, interleukin; CRP, C-reactive protein; TNF−α, tumour necrosis factor alpha; tPA, tissue activator of plasminogen; APC, activated protein C; AT, antithrombin; PAI-1, plasminogen activator inhibitor of type 1; TAFI, thrombin activable fibrinolytic inhibitor.
\n\t\tRecently, a clear association of high APP levels with a human procoagulant phenotype and impaired fibrinolysis were found in some studies. Indeed, a certain relationship is believed between the plasma levels of C-reactive protein (CRP) and some HSPPs. C-reactive protein is at present used as a sensitive biomarker of acute and chronic inflammation. This is the only APP that correctly displays the severity of vascular pathologies: from an endothelium-derived focal inflammatory response to a hard coronary lesion (Calabrò et al., 2009, Willerson & Ridker, 2004).CRP levels are now detected using a high-sensitivity assay (hsCRP); these indices are found to be an accurate predictor of cardiovascular disease (CVD) (de Ferranti & Rifai, 2007).
\n\t\t\tThe procoagulant function of the C-reactive protein is still debated (MacCallum, 2005), but there is some evidence proving that CRP is associated with the metabolism of HSPP. In ex vivo experiments on cell systems, CRP was found to induce expression of inflammatory cytokines or TF in monocytes(Cermak et al., 1993), of thrombomodulin and von Willebrand factor (vWF) in human umbilical vein endothelial cells (HUVECs)(Blann & Lip, 2003), and of PAI-1 in human arterial endothelial cells (HAECs) (Chen et al., 2008; Devaraj et al., 2003). Close correlation of the CRP amount with increasing fibrinogen levels was found in patients with acute ischemic stroke (Tamam et al., 2005). The CRP expression reflects not only to be a predictor but rather an active mediator of atherothrombotic events, as was reported for in vivo CRP-dependent induction of TF in blood monocytes (Sardo et al., 2008). Increased levels of hsCRP are associated with such CVD, as severe unstable angina, myocardial infarction, stroke, and peripheral arterial disease(de Ferranti & Rifai, 2007). The causative role of CRP in thrombogenesis is at present believed doubtful, but its active participation is supported by some results described earlier. One of the small group evaluation reports revealed that activation ofcoagulation and fibrinolysis inducedby recombinant CRP infusionprovoked increases in the levels of prothrombinF1+2 and D-dimer, as well as in the vWF and PAI-1 concentrations (Bisoendial et al.,2005). CRP also attenuated the fibrinolytic capacity, by inhibiting the tPA activity and stimulating PAI-1. An increased ECLT (euglobulin clot lysis time) and, hence, a decreased fibrinolytic capacity in the blood plasma obtained from volunteers with high CRP levels were found (Zouaoui Boudjeltia et al., 2004). These data confirm a conclusion on down-regulation of fibrinolysis during the enhanced inflammatory response indicated by CRP.
\n\t\t\tThe studies that elucidate the inhibitory role of cytokines in fibrinolysis are not limited to that of CRP.A multifunctional cytokine, IL-1, was shown to stimulate up-regulation of specific mRNA expression of urokinase-type plasminogen activator(u-PA) (Wojta et al., 1994). IL-1 also increased accumulation of PAI-1 in cardiac microvascular endothelial cells (Okada et al., 1998) and also controlled expression of PAI-1 and u-PA in human astrocytes (Kasza et al., 2002). Production of PAI-1 protein in human adult cardiac myocytes was found to be increased up to two times by interleukin-1α and tumour necrosis factor-α (TNF-α) and up to five times by transforming growth factor-ß (TGF- ß ) and oncostatin M. However, t-PA production in human cardiac myocytesdid not change after cytokine treatment (Macfelda et al., 2002). By contrast, IL-1 and tissue necrosis factor alpha inhibited t-PA in HUVEC (Bevilacqua et al., 1986).
\n\t\t\tDuring severe inflammation, the function offibrinolysis can be impaired. The same is true with respect to anticoagulant pathways. It was recently documented that an increase in serum CRP level in dogs was accompanied by lowering of the AT concentration (Cheng et al., 2009). Under inflammation conditions, the AT plasma level can decreased due to impaired synthesis (like other negative APPs) or due to protein degradation by elastase produced by activated neutrophils (Viles-Gonzalez et al., 2005).In addition, AT might be consumed proportionally to inhibition of the target proteases or removed from circulation after binding to fluid-phase complement attack complexes within the complement cascade (Esmon, 2005). Another natural anticoagulant, TFPI, seems to be incapable of regulating an enhanced thrombin amount during severe inflammation, since a low endogenous concentration of the anticoagulant does not increase (Bastarache et al., 2008). It would be noted that TFPI concentrations do not follow the development of disseminated intravascular coagulation and cannot prevent hypercoagulation (Wiinberg et al., 2008).TFPI is expressed primarily in the microvessels; thus, it might only nominally participate in hemostasis balancing in the larger vessels. Apparently, this pathway only slightly contributes to the coagulation/inflammation cross-over (DelGiudice & White, 2009). The PC anticoagulant system is more extensively present in the vascular network (Viles-Gonzalez et al., 2005). This system plays a pivotal role in hemostasis, shutting down coagulation and promoting fibrinolysis. These events might fail because of the presence of some vulnerable components. Down-regulation of membrane TM and EPCR by endotoxin, IL-1b, and TNF-α has been noted elsewhere (Esmon, 2005). The disappearance of TM from the endothelial cell surface impairs the process of activation of protein C. Not only the amount of APC but also its anticoagulant activity might be decreased under pathological conditions. Protein S, when forming an inactive complex with complement protein C4b (C4BP), thereby looses its ability to promote APC(Dahlback, 1991). Additionally, soluble forms of TM and EPCR can appear during inflammation in the blood flow. They may bind APC without potentiation of its activity or, moreover, even might inhibit APC anticoagulant function. sEPCRs have been found to block binding of protein C and APC to phospholipids and to alter the active site of APC (Liaw et al., 2000).
\n\t\t\tTissue factor, in addition to its procoagulant function, has been recently identified as a key secondary inflammatory mediator that markedly accelerates the feedback intensification of coagulation and inflammation pathways. Its concentration in circulation dramatically increases when the endothelium is disrupted and the blood begins to contact with extra vascular cells. In addition, inflammatory mediators many times increase the tissue factor protein amount and activity through stimulation of expression of this protein and through increasing the number of TF-positive microparticles as a consequence of paracrine and autocrine activity of the inflammatory cells (Esmon, 2005). It should be noted that TNF-α and IL-1ß are produced by lymphocytes and macrophages during vascular inflammation, and these events can also enhance the expression of the TF. The TF expression can be stimulated by several inflammatory mediators, namely TNF-α, IL-1, IL-6, activated complement, and immune complexes (DelGiudice & White, 2009).Activated T cells increase both TF expression and activity via paracrine stimulation of endothelial cells (Monaco et al., 2002). LPS-stimulated monocytes enhance intracellular transport of increased amounts of TF to the cell surface as well as the shedding of TF-containing microparticles(Egorina et al., 2005). Subsequently, soluble TF indirectly promotes inflammation by stimulation of thrombin production and by involvement of platelets via thrombin-activated PAR-dependent signalling. In PAR-4-deficient mice, recombinant sTF did not induce inflammation but was able to activate thrombin production, demonstrating, in such a way, the necessity of thrombin-sensitive platelets for sTF-mediated inflammation (Busso et al., 2008). Activation of platelets leads to release, from their α-granules, of a cocktail of chemokines and cytokines including IL-8, platelet factor–4 (PF4), and macrophage inflammatory protein–1a (MIP-1a) and to the expression of platelet surface adhesion molecules including P-selectin and CD40-ligand (CD40L). Platelet-derived CD40L is able to induce TF on the cell surface of endothelial cells and also of monocytes (Lindmark et al., 2000). Apparently, interaction between TF and flowing blood prolongs activation of the coagulation cascade through additional thrombin generation, which, in turn, might potentiate the formation of a platelet-rich thrombus. As was found recently, the inflammatory response involves activation not only of blood-borne cells (leukocytes and platelets), but also of the cells derived from the vascular wall (endothelial and smooth muscle cells, etc.). Binary TF-VIIa and ternary TF-VIIa-Xa complexes can also modulate inflammation via protease-activated receptor 2 (PAR 2) cleaving (Ahamed et al., 2006). Some vascular-bed specificities influence the TF-dependent mechanism of modulation of the acute response. In particular, vessel wall- derived TF forces mainly arterial thrombogenesis, since instable or ruptured atherosclerotic plaques are characterized by a high concentration of TF in both cellular and acellular regions. At the same time, soluble TF contributes mainly to venous thrombosis and microvascular thrombosis (Owens & Mackman, 2010). Nevertheless, circulating TF was found to be associated with the increased blood thrombogenicity in patients with unstable angina and chronic coronary artery disease (Corti et al., 2003). TF causes progression of coagulation within initial stages of disseminated intravascular coagulation (DIC)(Wiinberg et al., 2008). In animal models, TF was shown to participate in generalization of deep vein thrombosis(DVT) (Himber et al., 2003). Some reports indicate that myocardial inflammation and cardiomyocytes injuring enhance expression of TF, thereby increasing local formation of thrombin (Erlich et al., 2000;Luther et al., 2000).
\n\t\t\tCoagulation factor Xa was found to increase induction of endothelial TF and E-selectin by all the pro-inflammatory cytokines (e.g. TNF, IL-1ß, and CD40L). TF, in turn, initiates a new wave of factor Xa production after the formation of the TF-VIIa complex and activation of zymogens of factors IX and X. Binding of TF-VIIa to PAR-2 also results in up-regulation of the inflammatory responses in macrophages and neutrophils (Cunningham et al., 1999). A synergistic pattern of activity of factor Xa and inflammatory cytokines, resulting in both re-activation of coagulation cascade and augmentation of inflammatory mediators, is a good illustration of the apparent positive feedback mechanism, by which enhanced coagulation maintains pro-inflammatory environment and vice versa (Hezi-Yamit et al., 2005).
\n\t\tThe above-mentioned facts proved the capacity of the inflammatory factors to regulate coagulation and fibrinolysis. A converse molecular mechanism, by which hemostasis stimulates inflammation is at present less obvious but undergoes increasing investigations. Fibrinogen, the precursor of fibrin, is considered a rapid and sensitive marker of both coagulation and the acute-phase response, while its synthesis is enhanced during early inflammatory reactions. Fibrinogen contributes to coagulation being a terminal substrate in plasma clotting, which is cleaved specifically by thrombin. By splitting fibrinopeptide A and fibrinopeptide B from fibrinogen thrombin forms fibrin-monomers are spontaneously polymerized producing fibrin.Fibrin, in turn, provides plasma clotting, platelet aggregation and wound healing or thrombus formation. In addition, fibrin(ogen) participates in activation of vascular cells and regulation of the inflammatory response. Pro-inflammatory effects of fibrin(ogen) manifest itself after the abnormal fibrin deposition; this affects the vascular bed and enhances primarily local and, then, systemic inflammation through expression of the pro-inflammatory mediators. In fact, fibrin(ogen) increases the mRNA levels and induces synthesis of inflammatory cytokines IL-6 and TNF-alpha in human peripheral blood mononuclear cells (PBMCs) (Jensen et al.,2007), of IL-8 in HUVEC (Qi et al., 1997), and of transcription factor NF-kB in mononuclear phagocytes (Sitrin et al., 1998).Fg can manifest a pro-inflammatory action independently of its clotting function due to the existence of a high-affinity integrin binding site or multiple low-affinity binding sites, which interact with inflammatory competent cells. In particular, induction of cytokines IL-1β, IL-6, TNF-α has been found to be associated with fibrin binding to integrin receptors Mac-1 (CD11b/CD18) in monocytes (Trezzini et al., 1991). Cytokine secretion is suggested to be directly triggered by the process of Fg polymerization to Fn. The activity of thrombin that increases in Fg-deficient mice after LPS administration does not correlate with the levels of inflammatory mediators produced by bone marrow-derived macrophages and duration of their action. Both thrombin and Fg acting separately or in combination exert no effect on the cytokine production. It was concluded that up-regulation of secretion results in conformation changes of the Fg molecular structure during its conversion into Fn (Cruz-Topete et al., 2006). Some recently obtained data supported this conclusion. Molecular determinants of fibrin(ogen)-mediated pro-inflammatory activity were found to be localized in a γ-chain. These determinants can enhance the inflammatory cell recruitment and activation via interaction with integrin receptors Mac-1. Several specific sequences (all are attributed to the fibrinogen γ-chain) were found to participate in the interaction of fibrinogen with leucocytes. There are γ190-202, γ377-395, and γ383-395 sequences (the latter is localized within the γ-chain of the D nodule), which are capable of affecting leukocyte adhesion, their migration, or cytokine expression (Jennewein et al., 2011).In addition to Mac-1, leukocyte integrin receptorsαMß2 (but not platelet receptors αIIbß3) may be involved in the progression of inflammatory disease (Flick et al., 2004; Flick et al., 2007). The core recognition motif, γ-chain residues 383–395, was suggested to determine the affinity of Fg and Fn to αMß2.Obviously, soluble Fg has cryptic αMß2 binding sites, which are inaccessible for integrin αMß2 binding. Structural conformation changes during Fg immobilization or conversion of the latter into Fn permit Fg/Fn binding to integrin and provide local leukocyte activation. Being non-diffusible component fibrin deposition attaches to site of injury, marking spatial and temporal coverage for inflammatory cell targeting. Indeed, one might speculate that fibrin-mediated activation of αMß2 in macrophages and neutrophils represents a possible mechanism of the inflammatory response amplification during hypercoagulation. As a result, NF-kB-dependent intracellular signaling, which is triggered by fibrin interaction with αMß2, leads to a vicious cycle of cell recruitment, adhesion, degranulation, generalization of oxidative responses and release of inflammatory mediators (Flick et al., 2004; Flick et al., 2007).
\n\t\t\tThe involvement of fibrinogen in coagulation, as well as that of fibrin in the fibrinolytic process, is accompanied by generation of the various fibrin(ogen) degradation products, FDPs. These small and large fragments can exert an independent regulatory effect on the inflammatory process. In particular, fibrinopeptides A and B, the products of Fg conversion into Fn, are suggested to show a pro-inflammatory action on leucocytes functioning as chemoattractants. In contrast, the peptide Bβ15-42 which is generated by plasmin cleavage of fibrin, can mediate powerful anti-inflammatory effects. FDPs, which are formed after Fg(Fn) digestion by plasmin, also seem to modulate inflammation (Jennewein et al., 2011). Fg, Fn and FDPs were shown to induce intensification of CRP production in vascular smooth muscle cells.Herein, FDPs have the most prominent pro-inflammatory potency, as compared to that of fibrin(ogen) (Guo et al., 2009).
\n\t\t\tIt is interesting that plasmin(ogen) also generates degradation products during activation of fibrinolysis. These are either the first three, or the first four kringle domains (K1-3, K1-4) or only kringle domain 5 (K5). Angiostatin, a proteolytic fragment that contains K1-4, acts as a powerful anti-inflammatory modulator. In particular, angiostatin demonstrated a lowering adhesiveness of leukocytesto extracellular matrix proteins and the endothelium. Interaction of the angiostatin kringle domain K4 with integrin receptor Mac-1 down-regulates transcriptional factor NF-kB, whereby attenuates NF-kB-related expression of neutrophil-derived tissue factor (Chavakis et al., 2005).The kringle domain K5 has been found to restrict the neutrophil chemotactic activity (Perri et al., 2007). Obviously, impaired fibrinolysis looses this anti-inflammatory action.
\n\t\t\tThe formation of fibrin deposition is a direct consequence of increased thrombin production. A pro-inflammatory action of thrombin is realized by two interdependent ways: (i) by direct promotion of hypercoagulation accompanied by the pro-inflammatory effects described above; (ii) by stimulation of vascular and blood-borne cells and their further involvement in the inflammatory response. Being a powerful signal molecule, thrombin interacts specifically with PAR-1, PAR-2, or PAR-3 and activates the signaling pathways in endothelial cells, platelets, mononuclear cells, and fibroblasts. Thrombin-induced intracellular pathways up-regulate the expression of several cytokines and growth factors, as well as the secretion of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) (Levi & Poll, 2008). Thrombin is a key protease-agonist, which controls the platelet involvement in the formation of thrombi by stimulation of platelet aggregation, granule secretion, and additional recruitment in the inflammatory process. In an in vitro endothelial-cell-monolayer model, thrombin was shown to affect PAR-1-mediated signalling in a concentration-dependent manner. Low thrombin concentrations (20–40 pM) results in endothelial barrier protection, whereas high thrombin concentrations (> 80 pM) lead to disruption of this barrier (Feistritzer & Riewald, 2005). When activated protein C occupies PAR-1, thrombin can realise disruptive effects through activation of PAR-4; this effect requires a higher concentration of thrombin (Bae et al., 2007). Upon binding to thrombomodulin, thrombin inverts its coagulant and inflammatory functions into anticoagulant and anti-inflammatory ones. TM competes effectively with procoagulant substrates (fibrinogen, V, VIII, and PARs) for the same exosite-1 of thrombin but inhibits activation of the coagulation cascades. Moreover, a thrombin-TM complexationdown-regulates inflammation/coagulation-pathways via a feedback inhibition mechanism, while, at the same time, it initializes protein C-dependent anticoagulant pathway via PC activation (Bae et al., 2007). APC, in addition to its anticoagulant function, acts as a pleiotropic agent with anti-inflammatory, profibrinolytic, and cytoprotective effects. After its activation, APC dissociates from the thrombin-TM complex and comes into plasma, where it acts as anticoagulant and profibrinolytic agent, or binds to cell membrane EPCR and regulates intracellular inflammatory pathways. APC is now considered as a signaling molecule that possesses an ability to selectively regulate cytokine production during the inflammatory response. On the one hand, APC down-regulates the production of such pro-inflammatory cytokines, as TNF-α, IL-1ß, IL-6, and IL-8 in monocytes (Stephenson et al., 2006). On the other hand, APC up-regulates anti-inflammatory IL-10 that can reduce the protein concentration and activity of TF, as it was found after treatment of LPS-stimulated monocytes with recombinant APC, rAPC (Toltl et al., 2008). NF-kB-mediated signal transduction events aremodulated directly by APC interaction with EPCR on the plasma membrane of endothelial cells and mononuclears. APC-EPCR inhibits NF-kB nuclear translocation, which then results in inhibition of downstream NF-kB-regulated genes, e.g., ICAM-1, VCAM-1, and E-selectin in endothelial cells or TF in mononuclear cells (Joyce et al., 2001; White et al., 2000). APC has recently been reported to impair TNF signaling in vascular endothelial cells by preclusion of phosphorylation of NF-κB p65 and, thereby, by attenuating expression of cell adhesion molecules (including VCAM-1) (Guitton et al., 2011). At the same time, APC does not affect neutrophil respiratory bursts, phagocytic activity, and expression of monocyte adhesion molecules (Stephenson et al., 2006). In fact, APC does not seem to suppress the innate defensive mechanisms. As a consequence, the action of inflammatory cytokines and oxidative agents sharply reduce the efficiency of TM in PC activation and promote pro-inflammatory efficiency of thrombin.
\n\t\tAbnormal exposure of the procoagulant and pro-inflammatory agents contributes to sustaining of both local and systemic procoagulant/inflammatory potentials. Prolonged activation of inflammatory cells promotes the production of large amounts of inflammatory mediators by downstream-cells affecting not only via an autocrine mechanism, but also in a paracrine manner. The duration and amplitude of a cytokine-mediated systemic inflammation signal, upon reaching the liver, determine the probable pattern of HSPPs additionally produced during the acute inflammatory response. The HSPP level is known to be up-regulated by various pro-inflammatory cytokines similarly to other acute phase proteins, i.e., at the transcriptional and post-transcriptional levels. Genetic factors per se may contribute in different manners to a total variability of the HSPP systemic levels: cover about 50% variation in the fibrinogen level or 30% in factor VII plasma level, but exert a negligible effect on the plasma level of t-PA(neither that of antigen nor of its activity) (Voetsch &Loscalzo, 2004). Activated protein C, that breaks thrombus generation through regulation of both coagulation and fibrinolysis apparently is not additionally expressed during the acute-host response. There is some evidence that cytokine-dependent down-regulation of protein C synthesis occurs (Yamamoto et al., 1999);this allows one to classify this agent rather as a negative acute-phase protein. In case, lowering of the plasma protein C level is observed in some diseases, which are attended with inflammation (Danese et al., 2010). Another fact, which is a stronger proof, is that cytokines decrease the capacity of the endothelium to activate protein C precursor in activated protein C because they are able to down-regulate the amount of endothelial membrane-bound thrombomodulin (Esmon, 2004). Alternatively, some authors hypothesize that plasma pool of precursor PC can rapidly decline because of enhanced APC consumption after counteracting with plasma inhibitors (Danese et al., 2010; Patalakh et al., 2009). It is obvious, that in pathological states, the relative proportions of HSPPs significantly vary depending on either driving or suppression of their production by inflammation. Changes in the plasma protein ratio can lead to disproportion between procoagulant and anticoagulant patterns under different pathophysiological conditions. Activated proteases are rapidly cleared from circulation and this determines only a crude assessment of their production. That is why their plasma levels do not always respond “in unison” upon systemic inflammation.
\n\t\t\tUnlike CRP (type-1 acute phase protein) up-regulated by synergistic action of IL-6 and IL-1beta, most hemostatic proteases (type-2 acute phase proteins) require IL-6 alone for maximal induction of their synthesis (Trautwein et al., 1994). IL-6 is a key effector that effectively promotes the coagulation pathway, not only by up-regulation of expression ofsome procoagulant factors (such as TF, fibrinogen, and factor VIII) but also by down-regulation of synthesis of some anticoagulants (such as antithrombin and protein S) (Hou et al., 2008). Cytokine IL-6 is suggested to act as a common inductor for several vascular acute-phase proteins (CRP, α- and β- chains of Fg,Pg, α2-macroglobulin, and PAI-1). Under transcriptional control by the cytokine IL-6, their circulating levels increase via cooperative up-regulation of the corresponding gene promoter activity. The congruence of the HSPP gene responses to IL-6 is provided by an IL-6- responsive element (IL6-RE) that is required for maximal stimulation of the promoter activity by IL-6 (Bannach et al., 2004).Interestingly, IL-6-REs were identified in human CRP and α2-macroglobulin genes, as well as in two genes responsible for synthesis of fibrinogen α- and ß-chains. The same IL-6-REs is located in the region identified as a cytokine-response region of murine Pg and human PAI-1(Bannach et al., 2004; Loppnow & Libby, 1990). More than one IL-6-RE can exist in the promoter region required for the full responsiveness to IL- 6. Two macroglobulin promoters, e.g., have two functionally cooperated REs, which provide the full IL-6 response of the gene (Trautwein et al., 1994). It was assumed that any small differences in the amount or sequence homology of IL-6-REs in the HSPP genes can vary their inducibility by IL-6 (Hattory et al., 1990). Likewise, distinct transcription factors help to transduce the inflammation signal from cytokine to IL-6-RE in a cell- and/or tissue-specific manner.Such mechanisms might allow differential regulation of HSPPs gene expression induced by IL-6. IL-6-dependent regulatory machine is a good example for demonstration how the overall expression of a single plasma protease gene can be controlled by the inflammatory signal that begins in the extracellular milieu and terminates at separate sites on the promoter region of the gene.
\n\t\t\t\tNot only IL-6, but a number of cytokines, alone or in a combination, may also influence HSPP synthesis. TNF-α and other inflammatory agents are known to markedly suppress fibrinolysis, mainly via stimulation of PAI-1 and down-regulation of t-PA expression. The transcriptional and post-transcriptional regulation of the fibrinolytic system by inflammatory signals was recently reviewed in detail (Medcalf, 2007). Simultaneously acting cytokines can exert additive, inhibitory, or synergistic effects on the HSPP production. TNF-α and IL-1 provide mutual down-regulation of the mRNA for murine protein C. These cytokines are able to control gene expression independently or in combination with IL-6 (Yamamoto et al., 1999), whereas IL-6-mediated induction of Fg synthesis was partially inhibited by IL-1 or TNF-α (Mackiewicz et al., 1991).Various environmental factors and individual features of the patient (including age, body mass index, levels of plasma triglycerides and atherosclerotic transformation of the vessel wall) influence the cytokine-regulated levels of HSPP. For instance, shear stress can up-regulate cytokine-induced expression of t-PA, TGF-ß1, and ICAM-I genes at the transcriptional level (Kawai et al., 1996).These additional influences modify local or systemic inflammatory responses depending on the host phenotype (Lowry, 2009).
\n\t\t\tMarked alterations in the plasma HSPP levelsfollowing an acute-phase stimulus are determined not only by transcriptional regulation but also by post-transcriptional and post-translational mechanisms. The latter were found for such classic APPs, as serum amyloid A (SAA), complement factors B, and C3 (Jiang et al., 1995). It was reported that the α2-macroglobulin gene transcription ratemight increase (up to nine-fold)during the acute inflammatory response, while its protein plasma concentrations can rise much more significantly (to 100-fold) (Hattory et al., 1990). The other study demonstrated that aortic endothelial cells decreased production and secretion of t-PA after incubation with CRP without any alteration of the tPA mRNA level, thus underlying a suggestion that CRP-mediated tPA inhibition is a posttranscriptional event (Singh et al., 2005).In contrast, post-transcriptional regulation should not play a substantial role in monocyte-derived production of fibrinogen α-chain or α-1 protease inhibitor (α -PI) proteins (Jiang et al., 1995).
\n\t\t\t\tDespite the HSPPs are largely regulated by transcriptional control, they still strongly require the post-transcriptional regulation (including co-translational and post-translational modification) to confer their optimal functionality. They should form the disulfide bonds to get native conformation as well as should be carboxylated, hydroxylated, phosphorylated, sulfated or glycosylated to achieve a specific function. In particular, the main coagulation factors II, VII, IX, X and protein C (all are the vitamin K-dependent proteins) are processed through further post-translational modification to become biologically active. Prior to secretion into the blood they should be modified by a vitamin K-dependent gamma-glutamyl carboxylase, getting in such a way, an amount of negatively charged γ-carboxyglutamic acid (Gla) residues. Gla-residues have a chelating activity oriented to Ca2+-cations (Table 2). They are orchestrated in the "Gla domain" to participate in the Ca2+-dependent binding of parent protein to cell membrane or macromolecular complexes.
\n\t\t\t\tSimilarly to most secretory proteins, HSPPs are enriched by disulfide bonds (Table 2). Before secretion, they undergo oxidative maturation that leads to binding of the appropriate pairs of cystein residues. The disulfide bonds are formed in the rough endoplasmic reticulum, since this process requires an oxidative environment. These functional groups are well-known as playing an important role in protein folding (by stabilizing the tertiary and quaternary structure). Furthermore, disulfide bonds can be responsible for intra- and intermolecular reorganization or even proteins aggregation. In the few last years, a number of studies on functional disulfides have highlighted their two important functions, namely catalytic and allosteric (Chen & Hogg, 2006; Manukyan et al., 2008; Popescu et al., 2010).
\n\t\t\t\tIn addition to carboxylation and formation of disulfide bonds, a series of post-translational modifications occurs to attach N- or O-linked glycans to secreted proteins (Table 2). Several N-linked glycosylation sites are well-known to be an attributive feature of HSPPs, which are glycoproteins. N-glycosylation has been recently discovered to be a crucial event in the regulation of the glycoprotein structure and function. Viapromotion or inhibition of intra- and intermolecular binding, glycans can regulate protein folding, cell adhesion and aggregation. Glycosylation can also modulate the activity of plasma membrane receptors at the surface of the vascular endothelial cells, platelets, and leukocytes influencing in such a way intracellular signal transduction systems, which are responsible for homeostasis in circulation (Skropeta, 2009). Probably, a degree of initial core glycosylation might affect the efficiency of protein’s γ–carboxylation in endoplasmic reticulum before secretion (McClure et al., 1992).
\n\t\t\t\tThere are available data, suggesting that glycosylation is higher in proteins synthesized during the acute-phase responses. In vitro studies with isolated hepatocytes and hepatoma cell lines proved that inflammatory cytokines regulate changes in glycosylation independently of the rate of synthesis of the APP(Van Dijk & Mackiewicz, 1995). Variations
\n\t\t\t\tProtein | \n\t\t\t\t\t\t\tPercent carbo-hydrate (w/w) | \n\t\t\t\t\t\t\tnumber of modified residue | \n\t\t\t\t\t\t|||
Glycosylation \n\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\tDisulfide bond | \n\t\t\t\t\t\t\tHydroxylation, phosphorylationor sulfation | \n\t\t\t\t\t\t\tCarboxylation | \n\t\t\t\t\t\t||
fII | \n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t | 3 N-linked | \n\t\t\t\t\t\t\t10 (+2 predicted) | \n\t\t\t\t\t\t\tnone | \n\t\t\t\t\t\t\t10 Gla residues | \n\t\t\t\t\t\t
fV | \n\t\t\t\t\t\t\t~25% | \n\t\t\t\t\t\t\t5 N-linked (+21 predicted) | \n\t\t\t\t\t\t\t6 (+1 predicted) | \n\t\t\t\t\t\t\t1 phosphothreonine 1 phosphoserine 7 sulfotyrosine | \n\t\t\t\t\t\t\tnone | \n\t\t\t\t\t\t
fVII | \n\t\t\t\t\t\t\t13% | \n\t\t\t\t\t\t\t2 O-linked 2 N-linked | \n\t\t\t\t\t\t\t12 | \n\t\t\t\t\t\t\tone β-hydroxyaspartate | \n\t\t\t\t\t\t\t10 Gla residues | \n\t\t\t\t\t\t
fVIII | \n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t | 1 N-linked (+21predicted) | \n\t\t\t\t\t\t\t7 (+1 predicted) | \n\t\t\t\t\t\t\t6 sulfotyrosine | \n\t\t\t\t\t\t\tnone | \n\t\t\t\t\t\t
fIX | \n\t\t\t\t\t\t\t17% | \n\t\t\t\t\t\t\t4 O-linked 2 N-linked | \n\t\t\t\t\t\t\t11 | \n\t\t\t\t\t\t\tone β-hydroxyaspartate 2 phosphoserine 1 sulfotyrosine | \n\t\t\t\t\t\t\t12 Gla residues | \n\t\t\t\t\t\t
fX | \n\t\t\t\t\t\t\t15 % | \n\t\t\t\t\t\t\t2 O-linked 2 N-linked | \n\t\t\t\t\t\t\t12 | \n\t\t\t\t\t\t\tone β-hydroxyaspartate | \n\t\t\t\t\t\t\t11 Gla residues | \n\t\t\t\t\t\t
fXI | \n\t\t\t\t\t\t\t5% | \n\t\t\t\t\t\t\t5 N-linked | \n\t\t\t\t\t\t\t18 | \n\t\t\t\t\t\t\t2 phosphorilated | \n\t\t\t\t\t\t\tnone | \n\t\t\t\t\t\t
fXII | \n\t\t\t\t\t\t\t17% | \n\t\t\t\t\t\t\t7 O-linked 2 N-linked | \n\t\t\t\t\t\t\t20 | \n\t\t\t\t\t\t\tnone | \n\t\t\t\t\t\t\tnone | \n\t\t\t\t\t\t
Glu-Pg | \n\t\t\t\t\t\t\t~2% | \n\t\t\t\t\t\t\t2 O-linked 1 N-linked | \n\t\t\t\t\t\t\t24 | \n\t\t\t\t\t\t\t1 phosphoserine | \n\t\t\t\t\t\t\tnone | \n\t\t\t\t\t\t
tPA | \n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t | 1 O-linked 3 N-linked | \n\t\t\t\t\t\t\t17 | \n\t\t\t\t\t\t\tnone | \n\t\t\t\t\t\t\tnone | \n\t\t\t\t\t\t
TFPI | \n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t | 2 N-linked 3 O-linked | \n\t\t\t\t\t\t\t9 | \n\t\t\t\t\t\t\tnone | \n\t\t\t\t\t\t\tnone | \n\t\t\t\t\t\t
AT | \n\t\t\t\t\t\t\t9% | \n\t\t\t\t\t\t\t4 N-linked | \n\t\t\t\t\t\t\t3 | \n\t\t\t\t\t\t\t1 phosphoserine | \n\t\t\t\t\t\t\tnone | \n\t\t\t\t\t\t
PC | \n\t\t\t\t\t\t\t23 % | \n\t\t\t\t\t\t\t4 N-linked | \n\t\t\t\t\t\t\t12 | \n\t\t\t\t\t\t\tone β-hydroxyaspartate | \n\t\t\t\t\t\t\t9 Gla residues | \n\t\t\t\t\t\t
α2 -PI | \n\t\t\t\t\t\t\t14% | \n\t\t\t\t\t\t\t4 N-linked | \n\t\t\t\t\t\t\t1 | \n\t\t\t\t\t\t\t1 sulfotyrosine | \n\t\t\t\t\t\t\tnone | \n\t\t\t\t\t\t
PAI-1 | \n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t | 2 N-linked (+1 predicted) | \n\t\t\t\t\t\t\tnone | \n\t\t\t\t\t\t\tnone | \n\t\t\t\t\t\t\tnone | \n\t\t\t\t\t\t
TAFI | \n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t | 5 N-linked | \n\t\t\t\t\t\t\t3 | \n\t\t\t\t\t\t\tnone | \n\t\t\t\t\t\t\tnone | \n\t\t\t\t\t\t
Post-translational modifications of the major hemostasis soluble plasma proteins
\n\t\t\t\t\tTable 2.
\n\t\t\t\tin different glycoforms of APP in circulation most likely result from alterations in oligosaccharide branching, increased sialylation, and decreased galactosylation (Gabay & Kushner, 1999). The replacement of individual N-glycans by other ones exerts very specific and diverse effects on the protein structure and/or function. Human hemostatic proteins, coagulation factor IX and protein C, which both are the vitamin K-dependent proteins synthesized and secreted by hepatocytes, vary extensively in their glycosylation levels. Coagulant factor IX has two N-glycosylation sites and is characterised by significantly more heterogeneity of N-glycan structures than anticoagulant protein C.PC has four N-glycosylation sites, Q97, Q248, Q313, and Q329; the latter has an unusual consensus sequence, Asn-X-Cys. Desialylation of PC and factor IX was shown to result in a two-threefold increase in the anticoagulant activity of protein C and in a loss of the coagulant activity of factor IX (Gil et al., 2009; Grinnell et al., 1991). Alterations in the glycosylation pattern have been suggested to be specific in certain diseases (An et al., 2009; Ohtsubo&Marth,2006). Nevertheless, it remains unclear whether inflammation signals control processing of coagulation proenzymes or not. Well-documentedinflammation impact on glycosylation of classic APPs allows researchers to suggest such a control. The most important mechanism, through which the inflammatory environment is able to alter the enzyme activity and/or substrate specificity in local environments or in a systemic disease are modifications of the glycan moiety or heterogeneity.Experiments with glycoprotein deglycosylation showed that the removal of distinct glycan or total deglycosylation usually leads to remarkable reduction of the protein binding and enzymatic activity. However, at least two examples have been recently elucidated (Skropeta, 2009), wherethe enzyme activity increased upon deglycosylation of HSPPs. In particular, removal of the two of four existing glycosylation sites in the human protein C molecule resulted in a two–threefold increase in the anticoagulant activity of APC due to an enhanced affinity of thrombin, the natural activator of PC. Interestingly, two fibrinolytic proteins, tPA and its specific substrate, Pg, interact more or less effectively depending on the peculiarities of attached glycans. Indeed, tPA can exist as two glycoforms, type I with three N-glycosylated sites and type II with two N-glycans. Plasminogen also exists in two glycoforms; type 1 has both N- and O-linked glycans, while type 2 has only an O-linked glycan. The combination of type II tPA with type 2 plasminogen induced a twofold more intense conversion of plasminogen to plasmin compared to interaction of more heavily glycosylated type I tPA with type 1 Pg. Changes in the microheterogenity and unique structure of glycans are now known to be ensued from folding of the glycoprotein early form during post-translation processing in the secretory pathway. Glycosylation is an enzymatic process regulated by distinct glycosyltransferases in the endoplasmic reticulum, which modulate unfolded glycoproteins prior to trafficking to the Golgi apparatus. Unexpectedly, one experiment demonstrated that an alterated O-glycosylation pathway affects the N-glycosylated coagulation proteins in NAcT-1-deficient mice. In particular, the deficiency of a polypeptide GalNAc transferase (ppGalNAcT) contributed to shifting of O-glycan repertoire by other glycosyltransferases, as well as affected blood coagulation resulting in prolongation of the activated partial thromboplastin time, APTT, and bleeding time. These abnormalities were accompanied by mild or moderate decreases in the circulating levels of factors V, VII, VIII, IX, X, and XII, whereas the level of von Willebrand factor tendedto raise(Tenno et al., 2007). The reported results might be interpreted as a consequence of pleuotropic effects of O-glycosylation that contribute to regulation of HSPP expression and/or turnover (primarily secretion and clearance). Additionally, alterations in the degree of branching and of levels of sialylation, fucosylation, and mannosylation can dramatically change the glycoprotein turnover. Although our information about glycan-mediated pathophysiological mechanisms is still very limited, their impact on the enzyme secretion, stability, and activity and on molecular trafficking and clearance allows researchers to suggest that glycosylation plays a special role in the phenotypical variability of hemostatic and inflammatory proteins in circulation. Apparently, the acute-phase response generates a characteristic protein profile by alteration of synthesis, secretion, and clearance of protein reflected in their final concentrations. The actual level of plasma proteins under pathological conditions is also determined by changes in their stability, post-secretion proteolysis, functional activity, and accessibility for interaction.
\n\t\t\t\tMarked alterations in the plasma protein levels are probably paralleled by modifications of their disulphide bonds. The role of disulfides in regulation of the functional activity of HSPPs was subjected to intense research. A direct influence of inflammatory conditions on the structure or functions of plasma proteins is an intriguing question. Recently, we demonstrated that the concentration of DTNBA-active polypeptides produced in the course of the reaction of plasma and serum proteins with 5,5\'-dithiobis(2-nitrobenzoic acid), was noticeable increased in patients with stable angina pectoris compared to healthy subjects. In vitro blood coagulation was accompanied by a six-fold drop of the SS-containing components and 2,5-fold elevation of SH-containing polypeptides in patients, whereas mild changes were documented in control subjects. In addition, positive correlation of the plasma level of SH-containing polypeptides with concentrations of CRP and low-density lipoproteins was observed. Based on our findings, we can speculate that hypercoagulation in sclerotized vessels can enhance inflammation by promoting the development of oxidative stress. Activated, and thereby, partially degraded HSPPs, after their more open conformation has been obtained, can exhibit earlier buried disulphide bridges, which can serve as pro-oxidant derivates during thiol-disulfide exchange (Patalakh et al., 2008). Earlier, in the study of Procyk and colleagues (1992), it was found that thrombin looses its ability to cleave Fg in a calcium-free medium under non-denaturing conditions after reduction of several disulfide bonds in α- and γ-chains of fibrinogen. The loss of thrombin clottability was suggested to result from perturbation of carboxy-terminal polymerization sites in the fibrinogen γ-chain. It is interesting that tPA converted Pg into Pm more effectively on the surface of non-clottable (partially reduced) Fg rather than on untreated Fg (Procyk et al., 1992). These data confirm the statement on the ability of disrupted disulfide bonds to modulate the functional activity of major HSPPs via conformational changes. Newly obtained data suggest that particular SS-bonds are involved in regulation of HSPP functions via reduction or oxidation. Most hemostasis-related proteins probably contain these functionally active allosteric disulfide bonds;among them, there are TF, Fg, Pg(Pm), tPA, uPA, an uPA receptor, vitronectin, glycoprotein 1bα, ß3 subunit of αIIbß3 integrin, and thrombomodulin (Chen & Hogg, 2006). We hypothesized that at least one common sensitive element in the protein structures of the plasma pattern might facilitate the adequate integrated response of the hemostasis system to an inflammatory impact. Redox-mediated signals, which are generated in plasma during inflammation, might control hemostasis pathways via such a sensitive element in protein structures. And vice versa, exposed disulfide bonds through one-electron reduction can generate active intermediates transmitting pro-inflammatory or pro-oxidant extracellular signals to cell receptors and, thus, can induce production of more APPs and HSPPs, especially via the MAPK-mediated pathway (Forman et al., 2004; Rees et al., 2008).
\n\t\t\t\tAlthough HSPPs are synthesised and secreted principally in hepatocytes (Ruminy et al., 2001) other cell types can be additionally involved. For example, vascular endothelial cells represent an almost exclusive source of such a fibrinolytic component, as tPA produced by the endothelium in both physiological and pathophysiological states. Another fibrinolytic component, PAI-1, has additional sites of synthesis, such as vascular endothelial cells, leukocytes, adipocytes, and platelets, but this occurs predominantly after their activation at inflammatory foci. Synthesis of protein C, which mainly occurs in the liver, was also identified in the kidneys, lungs, brain, and male reproductive tissue. Therefore, a systemic or local inflammatory signal is able to recruit more than one cells source of HSPP. Aggregated platelets, activated leukocytes, and cells presented in the vascular wall release cytokines thereby altering local HSPP secretion. Impairment of total HSPP production because of disorders of the liver functions during systemic inflammation can be accompanied by increased protein consumption or by a decrease in the hepatic clearance for individual proteins. Perpetuation of inflammation in patients suffering from sepsis is known to depress the activity of Pg or α2-plasmin inhibitor (α2-PI) rather because of a low synthetic function of the liver but not consumption coagulopathy (Asakura et al., 2001). In contrast, increased consumption is the main reason for suppression of the plasma level of such enzymatically active proteases, as APC, thrombin, Pm, and tPA. In turn, depletion of the pool of proteases results in ineffective consumption and clearance of their substrates. Additionally to the protein expression, this mechanism can participate in elevation of such hemostatic APPs as factors VIIIa and Va, Fg, Fn, and Pg (Baklaja & Pešic, 2008). Finally, the rate of secretion and/or clearance processes of plasma proteins should be markedly distinct from the rate of their synthesis. Respectively, the half-life time of involved factors is shortened or prolonged.
\n\t\t\t\tIt is obvious that the plasma levels of naturally active (e.g., tPA) or in situ activated hemostatic proteases (e.g., thrombin or APC) fluctuate during inflammation rather due to stimulation of secretion, reactivity, and clearance than due to the respective gene expression in the cells. The above-mentioned regulatory mechanisms can affect significantly the HSPP kinetic profile with either a rise or a decline of their plasma levels. According to the study of Jern and colleagues (Jern et al., 1999), there is no correlation between the net release rate of total t-PA and plasma levels of either total or active tPA. These authors also suggested that the local endothelial release rate, rather than the systemic plasma level of t-PA, determines the plasma fibrinolytic potential destined to clot digestion in situ. The assay-measured plasma concentration of tPA insufficiently displays this local discrete increment. Moreover, while cytokine-induced PAI-I secretion increases, tPA secretion alternatively decreases (as after CRP-regulated secretion) or remains unchanged. Platelets have a large PAI-1 storage pool within secretory α-granules (about 90 % of the plasma level). After platelet activation, PAI-1 is released from α-granules along with other coagulation proteins, adhesion molecules, integrins, growth factors, and inflammatory modulators. Such a pro-inflammatory milieu facilitates the recruitment of additional platelet and inflammatory cells encouraging generate and amplify inflammation signals. Tissue plasminogen activator is secreted from the intracellular storage compartment after stimulation of PARs on the surface of endothelial cells. There are two pathways involved in tPA secretion from endothelial cells, constitutive and regulated secretion. Rates of the constitutive tPA release is differentiated markedly by the genotype; however, genetic variation most likely is not reflected in the circulating plasma t-PA levels. It was reported that CRP impaired the release of tPA via Fc-γ receptors but did not affect tPA mRNA (Devaraj et al., 2005). Stimulation of endothelial cells with IL-1ß or TNF-α did not change their ability to produce tPA(Jern et al., 1999). Shear stress can modulate the cytokine effects by enhancing t-PA secretion and attenuating the PAI-1 release (Kawai et al., 1996).
\n\t\t\t\tProbably, the recovery of the tPA plasma pool in proportion to excessive consumption by PAI-1 is rapid but transient, since the augmented local tPA secretion is limited by the rate of its synthesis. Because of the fact that the tPA-PAI-1 complex is usually cleared at a lower rate than free tPA, this can lead to the appearance of a disproportion between the antigen and activity values. Notably, activated protein C is suggested to compete with tPA for PAI-1 complexation. The importance of APC-PAI-1 in vivo association is still disputable because the PAI-1 reactivity with respect to APC is very low in a purified system. Nevertheless, it was demonstrated that vitronectin, a pro-inflammatory protein, enhances the reactivity of PAI-1 with APC about 300 times (Rezaie, 2001).
\n\t\t\t\tIn a study with patients suffering from chronic cardiac failure (CCF) and stable angina pectoris (SAP) we found an abnormality of the ratios between the plasma levels of t-PA, PC, and PAI-1 (Patalakh et al, 2009; Patalakh et al, 2007). An insufficiency of РС and t-PA proteins was accompanied by increase in the PAI-1 concentration and activity in the blood plasma of patients with high intravascular inflammation (hs-CRP levels were 12,951,81 and 6,831,48 mg/ml for SAP and CCF, respectively). We believe that these changes are a manifestation of reduction of the blood fibrinolytic potential. Using a regression analytical procedure, we simulated a potential profibrinolytic effect of endogenous PC as association of its plasma level with PAI-1 attenuation. The effect became apparent within a close-cut range of the PAI-1 concentrations and descended at low (<0,8 nM) or high (>3 nM) PAI concentrations. It was also predicted that the profibrinolytic function of APC during CCF duration might be realized under conditions where the precursor PC concentration did not decrease below 50-60 nМ.
\n\t\t\t\tSome evidence do exist that the plasma levels of PC are associated with the systemic inflammatory response to trauma, infection, resuscitated cardiac arrest, non-stable angina pectoris, etc. It seems that most cardio-vascular diseases during their severe inflammation stage are complicated by a transient PC deficiency. The nature of this failure is not completely clear. We suppose that the PAI-1 inhibitory activity is involved into PC plasma pool depletion during acute inflammation.It seems that phenotypic PC alterations reflect different aspects of the APC turnover, up-regulated by inflammation stimuli. It seems that conversion of PC into APC, forced by the increasing thrombin production, can lead to rapid consumption of PC since APC undergoes action of the abundant amount of serine protease inhibitors, accumulated in the blood during the acute-phase response. PAI-1 is the most up-regulated inhibitor of APC during acute inflammation. Activated platelets additionally produce PAI-1 during coagulation and thrombus formation. Particularly due to vitronectin activation PAI-1 should contribute significantly to the acquired protein C deficiency. Only when present in physiological concentrations, APC can deplete PAI-1 and, thus, promote the involvement of t-PA in fibrinolysis. Due to severe or prolonged conversion of PC into APC, the plasma pool of PC may be exhausted. As a result, further generation of activated protein C will be disturbed. The retarded turnover of protein C (t1/2~ 8 hours) and an extremely short clotting time (about 2-3 min) might cause depression of the protein C pathway and, consequently, uncontrolled promotion of the thrombin pathway. As a result APC loses its crucial role in the regulation of hemostasis and inflammation. While coagulation and inflammation are escalated, anticoagulant and fibrinolytic blood potentials are dropped. The described progression of events might provoke inflammatory and thrombogenic diseases in a manner we illustrate in figure 3.
\n\t\t\tRecent advances in our understanding of the nature of critical factors, linking hypercoagulation with both acute and chronic inflammation are rather promising. Nevertheless, we only can propose some speculations predicting the balance disruption between procoagulant and anticoagulant components under conditions of abnormal hemostasis, as well as consequences of their ratio abnormality on inflammation duration. The problem is complicated by the existence of poorly predictable mechanisms of most urgent thrombotic events that are happened rather “now” and “here”. A transient deficiency or acute inactivation of common hemostatic soluble plasma proteins, affecting hemostasis and inflammation by a mutual regulatory mechanism, was suggested as a key pathogenic factor of such life-threatening complications. Post-translational HSPPs modifications reviewed here could be considered as crucial phenomenon impacted by the inflammatory process. Apparently, inflammation-associated variations in the structure and function of hemostatic proteins can influence their catalytic efficiency and measurable plasma levels.These changes should be taken into account in indication of pathological hemostasis. The recent knowledge on regulatory crosstalk between hemostatic system components and the inflammatory system allows discovering new therapeutic targets to be developed. This new approach could not only change the traditional paradigm of clotting factor substitution therapy, but also anti-inflammatory therapies. Activated protein C is expected to be an attractive therapeutic target with prominent anticoagulant, profibrinolytic, and anti-inflammatory properties, which can simultaneously regulate both inflammation and coagulation. Nevertheless, the results of several clinical trials with recombinant APC or modified rAPC were found to be rather disappointing. Indeed, the peculiarities of the protein structure, attributed to regulatory components with pleiotropic action such as APC, may play a pivotal role in providing clinical benefit of designed protein variants. Hemostasis is a thorough “molecular machine”, which can not readily be improved. To understand and to reconstruct perturbed functions of this machinery should be a prominent goal for both basic and clinical research studies.
\n\t\tThe author is thankful to Professor Stanislaw A. Kudinov, Dept. of Enzyme Chemistry and Biochemistry (Palladin Institute of Biochemistry of the NAS of Ukraine) for initiating the idea of this review. The author would like also thank Professor Francisco Veas for advice and for critically reading the manuscript. We acknowledge the financial support from the Anisimov Property Management LTD (Ukraine) and from Sergey Davydov, businessman.
\n\t\tClays are inorganic, natural, earthy, and fine-grained materials that acquire plasticity when mixed with water [1]. For sedimentologists, a clay is a raw material whose grain size is less than 2 μm. Like clays, in turn, there are rocks made up of clay minerals and may contain other minerals such as quartz, feldspar, mica, calcite, hematite, and organic matter as accessories [2]. A clay, once ground and mixed with water, in addition to presenting excellent workability in the fresh state, after drying, becomes extremely rigid. After burning normally above 800°C, it acquires great resistance [3]. Clays are used worldwide in the ceramic industry, especially in bricks, coatings, and others. However, clays are formed from the weathering of explosion and can be contaminated with several minerals among them or carbonate, which can alter the shape that causes the following burns. Limestone may be present in colloidal form, or coarse particles. However, in all cases it is impossible to separate or calculate this. Some researchers have tried to reduce the size of the variations to improve the chemical changes. According to Barba et al. [4], calcium carbonate and magnesium carbonate are the main constituents of carbonate sedimentary rocks. Anionic carbonate groups are strongly activated units and share oxygen with each other. They are responsible for the properties of these minerals. The most important anhydrous carbonates belong to three isostructural groups: the calcite group, the aragonite group, and the dolomite group. Among these, the minerals most used in the ceramic industry are calcite and dolomite, as they are low-cost raw materials, in addition to having favorable physical and chemical properties and available deposits. Second, Padoa [5] adds that when CaCO3 is small, a decomposition can be complete and the calcium oxide reaches later with other mass components forming calcium silicates and silicon aluminates (wollastonite, anortite, gehlenite etc.) during sintering. Barba et al. [4] mentioned that the raw materials of clay when burned at high temperatures produce crystal phases that influence the properties of ceramic products. Calcite exerts a bleaching action on burnt products when added to a formulated mass of clays (in proportions above 5% and less than 30%) and at the same time decreases its expansion by legislation, as it forms crystalline and liquid phases, including cycles temperature and firing adopted. Calcite and dolomite are the most important representatives of carbonates in the ceramic industry. They are used as main components in the manufacture of ceramic tiles with high water absorption. These coatings include “porous coatings” or “tiles.” These products are designed or used on walls and are not suitable for application on floors, as they have undesirable technical characteristics, such as mechanical resistance, incompatibility with use. According to Amorós [6], properties of parts of a ceramic product are registered by crystalline phases formed based on calcium and magnesium as ghelenite (SiO2⋅Al2O3⋅2CaO) and anortite (2SiO2⋅Al2O3⋅CaO). To achieve these phases, use the dolomite calcium oxide and/or magnesium reaction with a remaining clay structure proven by its thermal decomposition.
The calculation in general can affect the ceramic product in two ways: low percentages (up to 3%) and high temperature (above 1180°C) result in flow agents, that is, materials that contribute to reduce water absorption and increase the resistance of ceramic products. Above 3%, they can act as a foundation at temperatures above 1170°C [7].
In this chapter, we will highlight properties of limestone clays and their application in the ceramic industry.
Clays are hydrated aluminum silicates with crystalline structure arranged in layers, consisting of continuous sheets of SiO4 tetrahedrons, ordered in a hexagonal shape, condensed with octahedral sheets of di and trivalent metal hydroxides, usually below 2 μm. They are materials that in contact with water become plastic, a fundamental characteristic for conformation of ceramic products because it provides mechanical resistance in the pressing, extrusion, or gluing process. Clays are mixtures of various clay minerals such as kaolinite, illite, and montmorillonite, which may or may not contain impurities [3, 8].
The kaolinite with structural formula Al2O3⋅2SiO2⋅2H2O has a dioctahedral structure, which consists of a tetrahedral layer linked by an octahedral layer. Pure kaolinites usually have low plasticity, see Figure 1.
Kaolinite structure. (a) Si▬O tetrahedra on the bottom half of the layer and Al▬O,OH octahedra on the top half. (b) Dioctahedral structure.
Montmorillonites are a set of family of clay minerals, composed of dioctahedral and trioctahedral silicate sheets, see Figure 2(a) and (b). The most outstanding feature of these minerals is their ability to absorb water molecules [8, 9]. It has 80% of exchangeable cations in the galleries and 20% on the lateral surfaces. The modification of montmorillonite clays has aroused scientific and technological interest for providing significant improvements when incorporated into pure polymeric materials and conventional composites. The clay modification process occurs preferably through the ionic exchange of the exchangeable cations of its crystalline structure.
Crystalline structure of a montmorillonite. (a) Montmorillonite structure, composed of Si, Al, and O. (b) Sheets of dioctahedral and trioctahedral silicates.
The basic structural unit of the illites is the same as that of the montmorillonites except that in illites, the silicon atoms in the silica layers are partially replaced by aluminum. Therefore, there are free valences in the boundary layers of the structural units, which are neutralized by K cations, arranged between the overlapping units. The structural scheme of the illites is shown in Figure 3. The K cation is the one that best adapts to the hexagonal meshes of the oxygen planes of the layers of silica tetrahedron and is not displaced by other cations. The water adsorption and cation exchange capacity is due only to the broken connections at the ends of the layers. The average diameter of the illites varies between 0.1 and 0.3 μm. When the replacement of silicon in the tetrahedron layers by aluminum in the illites is small, the connections between the structural units provided by the K cations may be deficient and will allow water to enter. When this occurs, the properties of the illites are close to the properties of montmorillonites [3].
Crystalline structure of an illite. (a) Silicon atoms in the silica layers partially replaced by aluminum in the illites. (b) Structural scheme of illites.
Chlorites are minerals made up of four hydrated aluminum and magnesium silicate layers, containing Fe (II) and Fe (III) as shown in Figure 4.
Crystalline structure of chlorite [9].
The most common clay minerals are interstratified, characteristic of mixtures of clay minerals, classified by subgroup and mineralogical species, see most common classification in Table 1. Clay minerals are divided into several classes. A large majority of clays do not have in just one crystalline phase. Two or more chemical species may be present.
Subgroup | Chemical species | Minerals |
---|---|---|
Kaolin Xn(Y2O5)(OH)4 | Kaolinites | Nacrite (Al2(Si2O5)(OH)4) Dikite (Al2(Si2O5)(OH)4) Livesite (Al2(Si2O5)(OH)4) Halloysite (Al2(Si2O5)(OH)4) |
Talc XB(Y2O5)(OH)2ZmH2O | Montmorillonites | Montmorillonites (Al1,51Fe0,07Mg0,60)(Al0,28Si3,72)O10(OH)2Na0,33 |
Beidellite (Al1,46Fe0,50Mg0,08)(Al0,36Si3,64)O10(OH)2Na0,4 | ||
Nontronite (Fe1,67Mg0,33)(Si4O10)(OH)2Na0,33 and Fe2,22(AlSi3O10)(OH)2Na0,33 | ||
Hectorite (Mg2,67Li0,33)(Si4O10)(F,OH)2Na0,33 | ||
Saponite Mg3(Al0,33Si3,67)O10(OH)2Na0,33 | ||
Illites | Wide variety of minerals | |
Chlorite | Chlorites | Chlorite |
X2n(Y2O5)2(OH)2 | [Mg2(Al,Fe(III))(OH)6][Mg3(AlSi3O10)(OH)2] |
The clays used in the ceramic manufacturing process can be classified into:
Carbonitic clays: they are formed by associations of illitic-chloritic and eventually illitic-kaolinite clay minerals. The amount of calcium carbonate present can be variable. These clays give the dough plasticity. Generally, after burning they have colors ranging from beige to orange [4].
Non-carbonitic clays: they are characterized by the almost total absence of carbonates. The clay minerals present are of the illitic-chloritic type. It has the function of giving plasticity to the dough, and generally after firing they give rise to well-sintered materials.
White plastic clays: the clay matrix is kaolinitic, with little illite. They give plasticity to the dough, and after burning they have a white color.
Kaolinitic clays: clays of low plasticity and normally free of fluxing oxides such as K2O and Na2O, therefore, with refractory characteristics.
According to Mackenzie [10], when a ceramic raw material is subjected to the action of heat, it experiences volumetric variations, usually permanent and irreversible, which can be classified as:
Oxidation of organic matter
Decomposition of compounds containing oxygen, such as sulfates, carbonates, etc.
Dehydroxylation of the clayey mineral
Crystallization by increasing the temperature
Vitreous phase formation
Solid solutions: adjacent crystals of two different materials but of similar structure can react with each other, forming a solid solution.
Kaolinitic clay: the scheme according to Figure 5 shows an endothermic peak between 560 and 590°C referring to the elimination of hydroxyls from the constitution water present in the clays, and an exothermic peak between 980 and 1000°C, due to the formation of mullite, which can be represented by the reactions 1 and 2 [8].
Differential thermal analysis of a kaolinitic clay [10].
Montmorillonite: montmorillonites have water that lodges in the mineral structure, that is, hydration water of adsorbed ions. The elimination of hydroxyl groups occurs at 700°C. At 850°C, a small endothermic peak may occur due to the loss of montmorillonite crystallinity. Illites can present loss of adsorbed water between 100 and 200°C and water loss in the constitution between 550 and 600°C, see Figure 6.
Differential thermal analysis of a montmorillonite clay [10].
Quartz: it appears in clays in colored or colorless round grains, whose percentage ranges from 0 to 60%. For high levels of quartz, the clay is called sandy and has low plasticity [11].
Hematite: iron can be present in the forms of hematite (α-Fe2O3), goethite (α-FeO⋅OH), and lemonade (a mixture of iron oxides and hydroxides of a weakly crystalline nature), or simply as Fe3+ ions in the clay structure. In the illite group, Fe3+ ions can replace Al3+ ions in the octahedral structure [11]. Fe2O3 is formed during sintering under oxidation conditions and from minerals in the clays, giving a reddish color to ceramic materials.
Feldspar: feldspars refer to a group of aluminum silicate minerals. The feldspar contained in the clays is a source of sodium and potassium oxides and plays an important role in ceramic materials with quality of flow agents, temperatures such as sintering temperatures, porosity after firing and facilitating phase formation [6]. The most representative are the orthoclase (KAlSi3O8) and albite (NaAlSi3O8).
Carbonates: calcium or magnesium carbonates can appear as coarse or small grains. If they are presented as large grains (>125 μm), they may not react completely and the resulting oxides may rehydrate causing expansion according to reactions [12, 13].
Ceramic enamels and frits: can be used in matte enamels as a source of CaO to form crystals such as wollastonite, anorthite, gehlenite or in transparent enamels giving shine.
Masses for ceramic coating: as a source of CaO up to the limit of 3%, CaCO3 assists in the formation of the vitreous phase. CaO levels that vary from 8 to 14% favor the formation of crystalline phases such as gehlenite, wollastonite, pseudo wollastonite, and anortite.
Putties for limestone porcelain: calcium carbonates provide the CaO that are used as a flux in limestone porcelain masses.
Ceramic pigments: the calcium carbonate provides calcium oxide, which together with SnO2 produces pink pigments.
Glasses: glasses based on NaOH and CaO use CaCO3 in their composition.
Obtaining settlement mortars: as a plasticizing agent for water retention and aggregate incorporation.
Steel: CaCO3 acts as a flux and pH regulator in water treatment and as lubricant for drawing steel rebars.
Sánchez et al. [14] defined some specification parameters for choosing raw materials for formulations of coating masses, as shown in Table 2 below.
Product | (%) of carbonates | Max. particle size of CaCO3 (μm) | Organic matter (%) | Sulfate content max. (%) | IP (%) |
---|---|---|---|---|---|
Stoned | ≤3 | ≤125 | ≤0.3 | 0.2 | 20–40 |
Porous | ≤40 | ≤125 | ≤0.3 | 0.2 | 20–40 |
Specifications for choosing raw materials.
IP: index of plasticity.
Calcium or magnesium carbonates can appear as coarse or small grains. If they are presented as large grains (>125 μm), they may not react completely, and the resulting oxides may rehydrate causing expansion.
In compositions of ceramic floor covering with low water absorption, CaCO3 acts as a flux until the limit of 3%; above this value, CaCO3 increases porosity and can be accepted up to 40% in porous coatings.
Enrique [15] recommends that the CaCO3 particle size should be less than 125 μm, because particles of larger sizes, the CaO resulting from the dissociation of carbonates when calcined at 900°C, do not react with the SiO2 present in the clays and feldspars that should form the pseudo-wollastonite and wollastonite phases, which can give rise to Ca(OH)2 formed by the hydration of CaO, when the part comes into contact with the humidity of the air, generating problems of expansion by humidity, with consequent cracking.
The ceramic tile and brick industry have grown enormously in recent years in Brazil. The clays must have sufficient plasticity to provide mechanical resistance when forming by pressing, in order to guarantee the integrity of the piece in the path between the press and the oven. The feldspar contained in the clays are sources of sodium and potassium oxides, acting as fluxes at temperatures above 800°C for bricks and above 1100°C for ceramic tiles, which facilitates the formation of a vitreous phase and reduces porosity [16, 17].
Quartz is mixed with clay during geological formation. If it is present in a smaller proportion, it helps in the formation of the vitreous phase, in the degassing of organic matter and water. However, large proportions of quartz lead to a drastic reduction in mechanical strength after firing [18]. Iron oxide is present in ceramic raw materials in the form of hematite or goethite, giving the finished product a red color.
Calcite, which appears in most clays used in the production process of ceramic tiles of type BIIb, is a mineral that needs special care in its use due to its high loss to fire. When present in a proportion equal to or less than 3%, this mineral acts as a flux. However, in higher proportions, calcite can cause an increase in the final porosity of the product. In addition, the size of the calcite particle for processing ceramics must be less than 125 μm. For larger sizes, it is observed that the CaO resulting from the dissociation of carbonates can hydrate after burning, promoting variations in the dimension of the piece. Therefore, the use of limestone clays is a challenge, requiring care in processing and control in the formulation and burning of coatings. To ensure the correct sintering of the product, proper grinding and pressing of the raw material are necessary, in addition to efficient, fast burning with the lowest possible energy consumption.
Table 3 shows the chemical compositions of a typical Brazilian limestone clay used in ceramics [19]. The chemical compositions of the raw materials were determined by X-ray fluorescence spectroscopy by wavelength dispersion (WDFRX), in a Bruker S8 Tiger equipment, in which the percentages of constituent oxides were estimated by the method semi-quantitatively. For these measurements, samples with a mass of 10.0 g were pressed as discs with 40.0 mm diameter and 4.0 mm thickness. During measurements, the samples were kept in a vacuum of 10−6 bar. A mixture of P-10 (90% argon and 10% methane) was used in the proportional counter.
Oxide (%) | C1 | C2 | C3 | C4 |
---|---|---|---|---|
SiO2 | 63.0 | 52.1 | 50.2 | 45.3 |
Al2O3 | 16.7 | 18.6 | 15.5 | 14.1 |
Fe2O3 | 4.7 | 6.8 | 6.2 | 7.1 |
CaO | 0.9 | 2.1 | 7.2 | 12.7 |
K2O | 3.8 | 4.7 | 3.2 | 3.2 |
Na2O | 0.6 | 0.4 | 0.5 | 0.7 |
MgO | 1.5 | 2.3 | 2.2 | 2.3 |
TiO2 | 0.6 | 0.8 | 0.7 | 0.8 |
L.O.I | 8.2 | 12.1 | 14.3 | 13.8 |
The results show that all clays are composed mainly of SiO2 and Al2O3. These elements are associated with clay minerals, quartz, and feldspar structures [17]. The highest amount of SiO2 was determined for sample C1. This component is important for the manufacture of ceramic tiles, as it improves workability and favors compaction. However, SiO2 can also cause low mechanical strength of sintered ceramic bodies, in addition to reducing shrinkage during firing.
The amount of Fe2O3 detected in the samples was between 4.7 and 7.1%. These values are acceptable for use in ceramic tiles, such as bricks and tiles, this element being responsible for the reddish color of the sintered pieces as well as being a powerful flux [20]. The high content of calcium oxide in C4 (12%) and C3 (7%) stands out, characterizing these clays as limestone [21]. C4 clay was previously studied in Alcântara [16], which reports the formation of stains on the ceramic bodies produced with this material, after sintering at 1120°C. This behavior was associated with a high content of CaO, estimated at 10%, which during the burning phase, the dissociation of CaCO3, promotes a high mass loss. C4 (13%) generates many pores, reducing water absorption and resistance of the final product. Thus, the higher the CaO content, the higher the CaCO3 content and in addition, the higher the mass loss.
Analyzing the levels of alkaline oxides, it is observed that the sample C2 has the highest concentration of K2O, while the concentration of Na2O is approximately the same in the four samples studied. Alkaline and alkaline earth compounds have a melting effect, which facilitates the formation of liquid phase and linear shrinkage during burning [13].
Table 4 was arranged according to the increasing amount of CaO present in the clays. Note that C1 and C2 have CaO content below 3%. According to Enrique [15], CaO acts as a flux until the limit of 3% in masses of ceramic coating. The percentage of alkali oxides (Na2O and K2O), also presented in Table 3, is another major factor for the densification process, due to the great tendency of liquid phase formation during burning. Considering the sum of the percentages of CaO and alkali oxides in samples C3 and C2, it can be concluded that C2 has a higher proportion of fluxing oxides, suggesting that this sample is the most promising. On the other hand, clays with a high limestone content, such as C3 and C4, tend to have greater porosity and less mechanical resistance after firing. Additionally, these two raw materials have lower alkaline oxide ratios than those observed for C3 and C2.
Clay | CaO (%) | Na2O + K2O (%) |
---|---|---|
C1 | 0.9 | 4.4 |
C2 | 2.1 | 5.1 |
C3 | 7.2 | 3.7 |
C4 | 12.7 | 3.9 |
The X-ray diffraction patterns of the clays are shown in Figure 7 and correlate positively with the results observed by X-ray fluorescence. The X-ray diffractometry (XRD) technique was used to determine the crystalline phases. The samples were dried in an oven at 110 °C for 24 h, ground, and passed through a 150-μm mesh sieve. The diffraction patterns were obtained in a Rigaku D-MAX 100 equipment, using Cu Kα1 radiation (λ = 1.5418 Å). All measurements were carried out in the continuous scanning mode with speed of 1°/min, in the range of 5 to 65° and in the range of 2 to 15° in samples saturated with ethylene glycol for 1 h to identify montmorillonite by displacing the diffraction peaks at smaller angles compared to dry sample testing. The crystalline phases were identified through Match! (Phase Identification by Powder Diffraction) in the demo version, according to the ICSD (Inorganic Crystal Structure Database).
X-ray diffraction patterns of the clays [19].
The main phases identified were quartz, kaolinite, muscovite, montmorillonite, calcite, feldspar, and hematite. Minerals from kaolinite and montmorillonite clay were identified in all analyzed clays. According to Celik [20], these clay minerals provide the necessary plasticity to guarantee conformation through the pressing process. The percentage of each crystalline phase present in the samples was estimated from the relative intensity of the main peaks in each phase. The values are shown in Table 5. The percentage of carbonates increases from 0.9% in C1 to 12.4% in C4.
Minerals (%) | C1 | C2 | C3 | C4 |
---|---|---|---|---|
Quartz | 55.7 | 51.8 | 65.1 | 57.1 |
Kaolinite | 6.3 | 10.7 | 7.4 | 5.5 |
Muscovite | 11.8 | 14.0 | 11.2 | 12.1 |
Montmorillonite | 5.6 | 4.9 | 4.6 | 6.7 |
Calcite | 8.6 | 2.8 | 1.1 | 13.7 |
Feldspar | 6.3 | 9.9 | 6.2 | 3.2 |
Hematite | 5.7 | 5.9 | 4.4 | 1.7 |
Mineralogical compositions of clays determined by XRD.
To verify the dimensional changes of expansion and thermal retraction of the samples, dilatometry tests were performed on a Netzsch dilatometer, model DIL 402PC, under synthetic air flow at 130 ml/min. For these analyses, the samples were compacted in a cylindrical shape, 12.0 mm in length and 6.0 mm in diameter. Under a constant heating rate of 10°C/min, the length of the compacted body is measured as a function of time and temperature, which varied from room temperature to 1150°C.
In Figure 8 we can observe a slight expansion in all curves up to approximately 850°C, and at 573°C, the expansion was more pronounced due to the transformation of α quartz to β [22, 23], except for C2, which presents a lower percentage of free quartz. From 573°C, there was a gradual reduction in the expansion rate, occurring or starting with sintering, followed by an exponential retraction [22].
Dilatometric curves of clays at a heating rate of 10°C/min [19].
The results shown in Table 5 with the percentages of CaO, Na2O, and K2O recommended by XRF measurements point out that sample C2 has a greater amount of funds (calcium carbonate up to a limit of 3% and alkaline oxides), or what is known as a greater linear shrinkage. Despite its advantages over the other samples, the C2 clay underwent deformation during firing up to 1150°C. This effect, known as pyroplastic deformation, may be due to the large proportion of funds in the sample, a high content of Fe2O3, and, even, the amount of organic matter [24]. One of the ways to control deformation during firing is to adjust the thermal cycle through the dilatometric curves, so that the plate remains within the required standards [25].
Clays containing limestone when subjected to burning, CaCO3 after heating, in the temperature range between 850 and 920°C, form CaO and release CO2. An intense endothermic peak of approximately 35–44% of the mass loss can be observed in differential thermal analysis. In ternary diagrams, it is observed that there is a eutectic point (above 1170°C), which reduces the dimensional stability in ceramic products, which can melt quickly (Figure 9).
Ternary diagram of CaO, SiO2, and Al2O3.
Clays when mixed with limestone can behave differently, as shown by Sánchez [25]. Figure 10 shows a standard clay with 5 and 10% of incorporated limestone. It was observed that as the limestone and temperature increase, respectively, the dimensional instability increases. In other words, the retraction increases constantly, when it undergoes an exponential increase, reaching the melting point.
Ceramic coating mass with incorporated calcite waste.
This phenomenon can be explained as follows: when exhibiting CaO up to the limit of 3%, this, associated with SiO2 and Al2O3 present in clays and feldspars, helps in the formation of eutectic systems at 1170°C, with consequent formation of liquid phase and contributing to obtain the desired mechanical strength and porosity. When introduced in percentages above 4%, CaCO3 levels are increased, and the composition moves from the eutectic line, forming crystalline phases such as CaSiO3 (pseudo-wollastonite) and 2CaO⋅Al2O3⋅SiO2 (gehlenite). So, a larger number of pores is left by the eliminated CO2. In this way, the porosity of the final product is increased, as shown in Figure 11. In Figure 12 is shown a photo of a clay mass with 10% calibration in which the porosity exerted can be observed.
Firing curve of a calcite clay.
Scanning electron microscopy of a ceramic with 10% of CaO.
Limestone is a contaminant for clay that above 125 μm can cause expansion and consequently cracks.
Rapid tests that mix clay with HCl can promote effervescence due to the release of CO2 and contribute to decrease the amount of limestone.
In the ceramic industry, wet grinding of components is carried out in ball mills and grinding will be more efficient if the sieves are 150 to 325 μm. In ceramic mass formulations, the amount of CaO up to 3% contributes to the formation of the vitreous phase, however, between 8 and 14%, it favors the formation of crystalline phases, reducing the absorption of water and increasing the mechanical resistance.
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