Academic literature on the topic 'Coagulation; Antibodies; Complement system'
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Journal articles on the topic "Coagulation; Antibodies; Complement system"
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Shibeko, A. M., A. N. Balandina, and M. A. Panteleev. "New approaches to the diagnosis and treatment of coagulation disorders." Pediatric Hematology/Oncology and Immunopathology 19, no. 4 (December 22, 2020): 243–50. http://dx.doi.org/10.24287/1726-1708-2020-19-4-243-250.
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With the advent of new approaches in coagulation studies capable of identifying regulatory mechanisms involved in transport processes, the spatial localization of processes and interaction between the coagulation system and the immune system, the complement system, and fibrinolysis, the existing diagnostic and treatment approaches used in clinical and laboratory practice are changing as well. This review describes modern diagnostic methods for hemostasis disorders that are based on an integrative approach and are used to assess many aspects of the coagulation system at once. The reviewed methods are sensitive not only to bleeding but also to prothrombotic states, and enable monitoring of treatment with various medications including both oral anticoagulants and antihemophilic agents. We will also cover new approaches to the treatment of hemostasis disorders made possible by the understanding of the involved control mechanisms, such as the use of bispecific antibodies as an alternative to coagulation cofactors, the inhibition of inhibitors and the development of new drug delivery techniques.
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Arnout, J. "Mechanism of action of Lupus anticoagulants." Hämostaseologie 21, no. 02 (2001): 44–49. http://dx.doi.org/10.1055/s-0037-1619504.
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SummaryThe antiphospholipid syndrome (APS) is defined as the association of antiphospholipid antibodies (aPL) with thrombosis, fetal loss or thrombocytopenia. Some aPL can be detected via coagulation assays where they present as an aspecific inhibitor termed the lupus anticoagulant (LA). Others can be measured via direct binding to cardiolipin and are termed anticardiolipin antibodies. aPL found in APS patients bind to a variety of PL-binding proteins such as beta-2-glycoprotein I (β2GPI) and prothrombin bound to PL surfaces. LA retard coagulation reactions in vitro by forming stable bivalent immune complexes on coagulation active phospholipids. These complexes have increased affinity for PL and compete with coagulation factors for the same catalytic surface. Animal experimental work has provided evidence that aPL are pathogenic. Based on similarities with heparin induced thrombocytopenia, another thrombotic syndrome, the following mechanism might be proposed. As a consequence of an initial activation, anionic PL exposed on bloodcells, endothelium or trophoblasts may promote the formation of bivalent complexes of aPL and PL-binding proteins. In this way, aPL concentrate on the cell surface, activate cellular FcγRII receptors or the complement system and induce thrombosis.
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Krychtiuk, K. A., S. P. Kastl, J. Wojta, and W. S. Speidl. "Inflammation and coagulation in atherosclerosis." Hämostaseologie 33, no. 04 (2013): 269–82. http://dx.doi.org/10.5482/hamo-13-07-0039.
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SummaryCardiovascular diseases remain to be the leading cause of death in Western societies. Despite major findings in vascular biology that lead to a better understanding of the pathomechanisms involved in atherosclerosis, treatment of the disease has only changed slightly within the last years. A big body of evidence suggests that atherosclerosis is a chronic inflammatory disease of the vessel wall. Accumulation and peroxidation of LDL-particles within the vessel wall trigger a strong inflammatory response, causing macrophage and T-cell accumulation within the vessel wall. Additionally, B-cells and specific antibodies against LDL-particles, as well as the complement system are implicated in atherogenesis. Besides data from clinical trials and autopsy studies it was the implementation of mouse models of atherosclerosis and the emerging field of direct genmodification that lead to a thorough description of the pathophysiological mechanisms involved in the disease and created overwhelming evidence for a participation of the immune system. Recently, the cross-talk between coagulation and inflammation in atherogenesis has gained attention. Serious limitations and disparities in the pathophysiology of atherosclerosis in mice and men complicated the translation of experimental data into clinical practice. Despite these limitations, new anti-inflammatory medical therapies in cardiovascular disease are currently being tested in clinical trials.
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Ruf, Wolfram. "Links Between Complement Activation and Thrombosis." Blood 134, Supplement_1 (November 13, 2019): SCI—40—SCI—40. http://dx.doi.org/10.1182/blood-2019-121113.
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The coagulation and complement systems are central mediators of innate immune defense and aide the peri- and intravascular elimination of invading microorganisms in a process termed immuno-thrombosis. Complement and coagulation proteases are engaged in reciprocal amplifications at different levels of these enzymatic cascades. In addition, activated complement factor (C) 3 specifically stimulates platelets through C3a receptor signaling and thereby amplifies thrombus formation. A non-enzymatic function of complement activation emerged as a crucial mechanism that rapidly alters the function of the extrinsic coagulation activator tissue factor (TF) on monocytes. Activation of the classical complement pathway by therapeutic anti-thymocyte globulin preparations rapidly enhances monocyte TF procoagulant activity. On the one hand, complement activation-associated thiol-disulfide exchange supports protein disulfide isomerase-dependent conformational changes in TF. Insertion of the C5b-C7 complex supports these conformational changes in TF by exposing procoagulant phosphatidylserine (PS). Furthermore, these dual roles of complement activation play a central role in venous thrombosis. C3, but not C5-deficient mice are protected from platelet deposition. In contrast, C5 knock-out mice show diminished PS exposure on leukocytes and lack TF-dependent coagulation activation and fibrin deposition at the flow restricted venous vessel wall. Antiphospholipid antibodies (aPL) also cause TF- and complement-dependent thrombosis. Whereas C3-dependent thiol-disulfide exchange is again required for converting TF to a procoagulant form, aPL do not rely on downstream complement components for the exposure of PS and induce pathological thrombosis in C5-deficient mice. Our recent data show that aPL dissociate a cell surface-localized, inhibited complex with monocyte-expressed TF pathway inhibitor (TFPI). In addition to promoting TF procoagulant activation, complement-dependent thiol-disulfide exchange emerged as an additional central mechanism that allows for aPL internalization and endosomal signaling involving integrin- and TF cytoplasmic domain-dependent translocation of the NADPH oxidase to the endosome. A monoclonal antibody that traps TF with low procoagulant activity on the surface prevents TF endosomal trafficking, aPL signaling and aPL-induced pregnancy loss. These complement-dependent effects require assistance by thrombin-PAR1/PAR2 heterodimer signaling initiated by FXa dissociated from the inhibited TF complex. Monocyte TFPI-dysfunctional mice are protected from aPL pathogenic signaling in vitro and from aPL-induced thrombosis, but form thrombi normally in other experimental thrombosis models. These data show that formation of an inhibited TF cell surface complex specifically primes monocytes for thrombosis and pathogenic aPL signaling. Thus, the evolutionary conserved crosstalk of complement and coagulation cascades not only plays crucial roles in thrombosis, but also regulates thrombo-inflammatory signaling in autoimmune disease. Disclosures Ruf: MeruVasimmune: Equity Ownership; Iconic Therapeutics: Consultancy.
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Bavli, Yaelle, Bing-Mae Chen, Steve R. Roffler, Marina A. Dobrovolskaia, Eldad Elnekave, Shifra Ash, Yechezkel Barenholz, and Keren Turjeman. "PEGylated Liposomal Methyl Prednisolone Succinate does not Induce Infusion Reactions in Patients: A Correlation Between in Vitro Immunological and in Vivo Clinical Studies." Molecules 25, no. 3 (January 28, 2020): 558. http://dx.doi.org/10.3390/molecules25030558.
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PEGylated nanomedicines are known to induce infusion reactions (IRs) that in some cases can be life-threatening. Herein, we report a case study in which a patient with rare mediastinal and intracardiac IgG4-related sclerosing disease received 8 treatments of intravenously administered PEGylated liposomal methylprednisolone-succinate (NSSL-MPS). Due to the ethical requirements to reduce IRs, the patient received a cocktail of premedication including low dose of steroids, acetaminophen and H2 blockers before each infusion. The treatment was well-tolerated in that IRs, complement activation, anti-PEG antibodies and accelerated blood clearance of the PEGylated drug were not detected. Prior to the clinical study, an in vitro panel of assays utilizing blood of healthy donors was used to determine the potential of a PEGylated drug to activate complement system, elicit pro-inflammatory cytokines, damage erythrocytes and affect various components of the blood coagulation system. The overall findings of the in vitro panel were negative and correlated with the results observed in the clinical phase.
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Klimova, E. M., Yu V. Kalashnikova, T. I. Kordon, E. V. Lavinskaya, A. N. Agarkova, R. R. Osmanov, and O. V. Ryabinskaya. "PREDICTORS OF HEMORRHAGIC AND THROMBOTIC COMPLICATIONS OF HEPATOSPLENOMEGALY SYNDROME." Kharkiv Surgical School, no. 1 (February 20, 2020): 148–54. http://dx.doi.org/10.37699/2308-7005.1.2020.25.
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Summary. Goal. Investigation of the interactions of coagulation, anticoagulant and fibrinolytic systems with factors of immunoresistance in hepatosplenomegaly syndrome (SHSM).
Materials and methods. Materials — сells and blood serum of 58 patients with SHSM against the background of liver cirrhosis complicated by portal hypertension, with the etiological factor — HCV / HBV virus infection (group I, 22 people) and the etiological factor — CMV / VEB virus infection (group II, 36 people), who were admitted to the hospital for bleeding from esophageal varicose veins. Methods - photometric on a biochemical analyzer Stat Fax 1904 Plus (USA). (C3 and C4 components of complement, antithrombin III and plasminogen, concentration of circulating immune complexes (CIC), determination of the coagulation time of venous blood Lee-White, calculation of the prothrombin index, fibrinogen content by the Rutberg gravimetric method. Protein C activity (PrS) by the clotting method on a coagulometer K 3002 Spectramed (Poland). Peripheral blood platelet counts were performed using immersion microscopy according to the Fonio method.
Results. Multidirectional changes in the functions of the hemostasis system were revealed: a decrease in antithrombin III activity, protein C content, fibrinogen concentration, a decrease in plasminogen activity, a decrease in platelet counts, an increase in platelet antibodies, an increase in the concentration of the C3 component and a decrease in the C4 component of complement.
Conclusions. Hemorrhagic and thrombotic complications of HCV, life-threatening and affecting the tactics and results of surgical and minimally invasive treatment, can occur both in the HCV group on the background of HBV/HCV viral hepatitis, and in the HCV group on the background of herpes virus CMV/VEB infection, but in group I both hemorrhagic and thrombotic complications were dominated by plasma risk factors for and in group II - platelet and immunological (complement component C3) risk factors for hemorrhagic complications, plasma factors of thrombotic complications.
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Gerlofs-Nijland, Miriam E., Karel J. M. Assmann, Henry B. P. M. Dijkman, Jürgen W. C. Dieker, Jacco P. H. F. van Son, Stef Mentzel, Jorge P. van Kats, et al. "Albuminuria in Mice after Injection of Antibodies against Aminopeptidase A: Role of Angiotensin II." Journal of the American Society of Nephrology 12, no. 12 (December 2001): 2711–20. http://dx.doi.org/10.1681/asn.v12122711.
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ABSTRACT. It has been shown that injection of combinations of anti-aminopeptidase A (APA) monoclonal antibodies (mAb) that inhibit the enzyme activity induces an acute albuminuria in mice. This albuminuria is not dependent on inflammatory cells, complement, or the coagulation system. APA is an important regulator of the renin-angiotensin system because it is involved in the degradation of angiotensin II (Ang II). This study examined the potential role of glomerular Ang II in the induction of albuminuria. The relation among renal Ang II, glomerular APAX enzyme activity, and albuminuria was examined first. Injection of the nephritogenic combinations ASD-3/37 and ASD-37/41 in BALB/c mice induced albuminuria, whereas the non-nephritogenic combination ASD-3/41 had no effect. There was no clear relation between the inhibition of glomerular APA activity and albuminuria, yet it was evident that intrarenal Ang II levels were significantly increased in albuminuric mice and not in nonalbuminuric mice. As a next step, anti-APA mAb were administered to angiotensinogen-deficient mice that do not produce Ang II, and kidney morphology and albuminuria were determined. Angiotensinogen-deficient mice also developed albuminuria upon ASD-37/41 administration. Altogether, these findings clearly demonstrate that Ang II is not required for the induction of albuminuria upon injection of enzyme-inhibiting anti-APA mAb.
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Doszpoly, Andor, Fernando de la Cuesta, Estrella Lopez-Gordo, Cécile Bénézech, Stuart A. Nicklin, and Andrew H. Baker. "Human Adenovirus Serotype 5 Is Sensitive to IgM-Independent Neutralization In Vitro and In Vivo." Viruses 11, no. 7 (July 5, 2019): 616. http://dx.doi.org/10.3390/v11070616.
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Human adenovirus 5 (HAdV-5) is used as a vector in gene therapy clinical trials, hence its interactions with the host immune system have been widely studied. Previous studies have demonstrated that HAdV-5 binds specifically to murine coagulation factor X (mFX), inhibiting IgM and complement-mediated neutralization. Here, we examined the physical binding of immune components to HAdV-5 by nanoparticle tracking analysis, neutralization assays, mass spectrometry analysis and in vivo experiments. We observed that purified mouse Immunoglobulin M (IgM) antibodies bound to HAdV-5 only in the presence of complement components. Active serum components were demonstrated to bind to HAdV-5 in the presence or absence of mFX, indicating that immune molecules and mFX might bind to different sites. Since binding of mFX to HAdV-5 blocks the neutralization cascade, these findings suggested that not all complement-binding sites may be involved in virion neutralization. Furthermore, the data obtained from serum neutralization experiments suggested that immune molecules other than IgM and IgG may trigger activation of the complement cascade in vitro. In vivo experiments were conducted in immunocompetent C57BL/6 or immuno-deficient Rag2-/- mice. HAdV-5T* (a mutant HAdV-5 unable to bind to human or mFX) was neutralized to some extent in both mouse models, suggesting that murine immunoglobulins were not required for neutralization of HAdV-5 in vivo. Liquid Chromatography-Mass Spectrometry (LC-MS/MS) analysis of HAdV-5 and HAdV-5T* after exposure to murine sera showed stable binding of C3 and C4b in the absence of mFX. In summary, these results suggest that HAdV-5 neutralization can be mediated by both the classical and alternative pathways and that, in the absence of immunoglobulins, the complement cascade can be activated by direct binding of C3 to the virion.
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Nasonov, E. L., T. V. Beketova, T. M. Reshetnyak, A. M. Lila, L. P. Ananieva, T. A. Lisitsyna, and S. K. Soloviev. "Coronavirus disease 2019 (COVID-19) and immune-mediated inflammatory rheumatic diseases: at the crossroads of thromboinflammation and autoimmunity." Rheumatology Science and Practice 58, no. 4 (September 4, 2020): 353–67. http://dx.doi.org/10.47360/1995-4484-2020-353-367.
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Inflammation and coagulation are key basic mechanism of protection against all potentially pathogenic mechanical and biological factors targeting human organism from inner and outer environment. On the other hand, uncontrolled inflammation results in hypercoagulation, inhibition of anticoagulation and alteration of mechanisms responsible for resolution of inflammation, while production of “procoagulant” mediators (thrombin, tissue factor and others), activation of platelets and of vascular endothelial cells maintains inflammation. All factors taken together serve as the basis for a pathological process called thromboinflammation or immunothrombosis. Currently thromboinflammation is considered in the broad sense as a universal pathogenetic mechanism of numerous widespread acute and chronic conditions, including immune-mediated (autoimmune) inflammatory rheumatic diseases, oftentimes complicated by severe irreversible damage to vital organs. Thromboinflammation gained specific attention during СОVID-19 (coronavirus disease 2019) pandemic, caused by SARS-Cov-2 (severe acute respiratory syndrome Coronavirus-2). COVID-19 is considered currently as systemic thromboinflammation syndrome, manifesting via generalized thrombosis of arterial and venous macro- and microvasculature, termed as COVID-19-coagulopathy. The paper discusses common pathogenetic coagulopathy mechanisms in COVID-19 and immune-mediated (autoimmune) inflammatory rheumatic diseases (IMRDs), associated with overproduction of antiphospholipid antibodies, activation of the complement system, and dis-regulated synthesis of proinflammatory cytokines, etc. Delineating the autoimmune subtype of thromboinflammation, identification of genetic (i.e., genes encoding the complement system and others) and molecular-biologic biomarkers associated with higher occurrence of COVID-19-coagulopathy are the most relevant undertakings for the current practice. Gaining insights into mechanisms of thromboinflammation and converting them into potential pharmacotherapies of IMDs would facilitate and accelerate the drafting of effective therapeutic strategies for COVID-19.
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Arvieux, Josiane, Gilles Pernod, Véronique Regnault, Luc Darnige, and Jérôme Garin. "Some Anticardiolipin Antibodies Recognize a Combination of Phospholipids With Thrombin-Modified Antithrombin, Complement C4b-Binding Protein, and Lipopolysaccharide Binding Protein." Blood 93, no. 12 (June 15, 1999): 4248–55. http://dx.doi.org/10.1182/blood.v93.12.4248.
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Abstract The standard enzyme-linked immunosorbent assay (ELISA) for anticardiolipin antibodies (ACA) detects a heterogenous group of antibodies against cardiolipin on its own, β2-glycoprotein I (β2GPI), and, potentially, other phospholipid-binding plasma proteins from bovine or human origin. In an attempt to identify new proteic targets of ACA, we selected 6 patients who possessed cofactor-dependent ACA but no antibody to human or bovine β2GPI detectable in the β2GPI-ELISA. Three of these samples proved to recognize β2GPI in combination with cardiolipin, but not β2GPI directly immobilized on γ-irradiated polystyrene or agarose beads. In the other cases, the component required for ACA binding was purified from adult bovine serum or plasma by means of ammonium sulfate precipitation and chromatography on Phenyl-Sepharose, diethyl aminoethyl (DEAE)-cellulose, heparin-Ultrogel, and Sephacryl S-300 columns. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis coupled to N-terminal amino acid microsequencing identified the cofactors of patients no. 4, 5, and 6 ACA as lipopolysaccharide binding protein (LBP), complement C4b-binding protein (C4BP), and the thrombin-antithrombin (AT) complex, respectively. Adsorption of each of these cofactor preparations with cardiolipin liposomes led to suppression of ACA reactivity, concomitant with the loss of bands from SDS gels corresponding to sequenced material. Bacterial lipopolysaccharide (which forms high-affinity complexes with LBP) specifically neutralized the cofactor activity of the LBP preparation in a concentration-dependent manner. Bovine serum and plasma, as well as the C4BP preparation, optimally supported the binding of a rabbit anti-C4BP antiserum to immobilized cardiolipin. The binding of a rabbit anti-AT antiserum to solid-phase cardiolipin was sustained by the thrombin-AT preparation and bovine serum, but neither by bovine plasma nor by native AT, thus reproducing the behavior of patient no. 6 ACA. Taking advantage of the restricted recognition by the latter ACA of a cofactor from bovine origin appearing upon clotting, we studied the generation of such activity in human plasma supplemented with bovine AT or bovine prothrombin before clotting. In these conditions, patient no. 6 antibody binding to cardiolipin required the addition of bovine AT, whereas addition of bovine prothrombin alone was ineffective. We therefore concluded that those ACA targeted bovine AT once it has been modified/cleaved by thrombin. These findings underline the wide heterogeneity of ACA and the links that may exist between various coagulation pathways, inflammation and the complement system.
Dissertations / Theses on the topic "Coagulation; Antibodies; Complement system"
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Yu, Bing Bin. "Comparison of the functional and antigenic properties of apoliprotein H (APOH)#beta#â†21 and its homologue, factor H." Thesis, University of Oxford, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.299418.
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Krarup, Anders. "The lectin pathway of complement activation." Thesis, University of Oxford, 2007. http://ora.ox.ac.uk/objects/uuid:46255854-bfba-4d57-9185-3e6ed970a2db.
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The complement system is an important immune system mechanism involved in both the recognition and elimination of invading pathogens. It is activated by three different pathways: The classical pathway, which relies on binding of C1, and results in the cleavage of C4 and C2 through activation of C1r and C1s; the alternative pathway that relies on the spontaneous hydrolysis of C3 and the lectin pathway. The lectin pathway is activated by binding of Mannan-binding lectin (MBL) or the ficolins (L-ficolin, H-ficolin and M-ficolin) to microbial binding motifs, and the subsequent activation of the MBL-associated serine proteases (MASP) 1/ 2/ 3. Of these MASP2 has been identified as the enzyme responsible for the activation of complement by C4 and C2 cleavage. The work presented here will focus on four different aspects of the lectin pathway: specificity and stoichiometry of the L-ficolin protein complex, expression of H-ficolin, substrate characterization for MASP1 and investigation of the prothrombin activation potential of MASP2. L-ficolin binding specificity was investigated using glycan array technology, and it was found that L-ficolin, instead of recognizing single monosaccharides like MBL, instead binds to extended oligosaccharide structures. The binding to these was dependent not only on the presence of acetyl groups, but also on their orientation in space. It was also found that L-ficolin in serum is found as a multimeric protein complex composed of 18 polypeptide chains and associated with one MASP dimer. The expression of H-ficolin resulted in the generation of a stable mammalian cell line producing oligomerized and biologically functional H-ficolin. MASP1 substrate specificity was investigated by two different procedures. Firstly fractionated plasma was subjected to MASP1 treatment in an attempt to identify a plasma protein substrate. This did not yield any substrate candidates, since only cleavage of the protease inhibitor α-2-macroglobulin could be detected. Additionally the thrombin-like activity of MASP1 was investigated through cleavage experiments done with factor XIII and fibrinogen. These experiments showed that the factor XIII cleavage site for MASP1 and thrombin is identical. This was also found for the fibrinogen β-chain but not for the α-chain showing that MASP1 interaction with fibrinogen is distinct from that of thrombin. An earlier observation that MASP2 was capable of activating prothrombin and generating thrombin was further characterized. Here it was shown that the activation of prothrombin by MASP2 is identical to that by factor Xa, which is the enzyme undertaking this role in the coagulation system, and that the activation can result in deposition of fibrin on the surface upon which MASP2 is bound. The prothrombin activation potential of MASP2 was also utilized to develop a new MASP2 activity assay, which was shown to be capable of measuring MASP2 activity, when MASP2 is bound, via MBL (or L-ficolin) to appropriate surfaces.
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Hamer, Rizwan. "Donor specific antibodies and the complement system in HLA-antibody incompatible renal transplantation." Thesis, University of Warwick, 2012. http://wrap.warwick.ac.uk/51636/.
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Despite advances in medical science, dialysis treatment for end stage renal disease remains fraught with complications and severely limits the quality and longevity of life in these patients. Renal transplantation allows for an enhanced length and quality of life. Unfortunately the demand for kidneys outstrips the supply and nephrologists have taken to performing transplantation in conditions that were previously thought impossible. Human leucocyte antigen (HLA) antibody incompatible transplantation, a process of transplanting kidneys into recipients who have antibodies against HLA antigen on the donor kidney, has recently become an acceptable mode of transplanting patients who would have previously died whilst on dialysis. Although increasingly successful, the Achilles’ heel of this form of transplantation remains acute antibody mediated rejection (AMR), a particularly severe form of rejection. It is generally accepted that the complement system is intricately involved in the process of acute AMR and, indeed, C4d, a split product of complement factor C4, when detected on renal biopsies in the correct context, is considered by the BANFF classification (an internationally accepted method of classifying renal transplant rejection) to be a hallmark feature of acute AMR. The sensitivity and specificity of this test, however, is increasingly debated and requires an interventional diagnostic test that is not without risk. A “blood” test to detect or predict the onset of acute AMR is not available. In addition, although the complement system is known to be involved in acute AMR, characterisation of the three complement pathways and the degree of their systemic activation has not been fully described. Although the liver is the main source of complement factors in the body, other organs such as the kidney, are capable of synthesizing complement. It is unknown whether the complement factors involved in acute AMR following renal transplantation are of systemic or local origin. It is also not known which renal cell, if any, is responsible for this. Importantly, the first cells to encounter antibodies against antigen on their surfaces, the renal microvascular endothelial cells, have not so far been shown to be able to produce complement factors. This thesis briefly examines changes in antibody levels during the process of HLA antibody incompatible transplantation, histological features associated with subsequent graft dysfunction and possible serum markers (soluble CD27 and Cd30) that could indicate onset of AMR. Whilst anti-HLA antibody monitoring was found to be useful in the management of patients it was not possible to use levels to predict rejection or accommodation of the graft. No correlation was found between soluble factors CD27 and CD30 and AMR. The thesis then examines the effect of HLA antibody incompatible renal transplantation on the complement pathways and on the levels of complement factors C3a and C4a. There was no systemic pathway activation in the presence of rejection. Systemic levels of C3a and C4a did not rise with a simultaneous increased level of HLA antibodies or with rejection episodes. Indeed, in patients who did not have an episode of rejection and in those with rejection but no evidence of C4d on renal biopsy, mean C4a levels were significantly lower at 4-6 weeks when compared to those who did have C4d-postive AMR. This points to a role for inhibitory mechanisms in these patients. The thesis also demonstrates the ability of microvascular endothelial cells (including of glomerular origin for the first time) to produce complement C4 on stimulation with gamma interferon and with antibodies against the cell HLA type. Finally, the thesis briefly examines the possible use of a complement inhibitor in the treatment of AMR.
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Dutta, Ray Tathagat. "Novel Complement Blocking Antibodies Against Serogroup B N. meningitidis: A Dissertation." eScholarship@UMMS, 2010. https://escholarship.umassmed.edu/gsbs_diss/495.
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N. meningitidis is a common commensal of the human upper respiratory tract and a leading cause of bacterial meningitis and septicemia worldwide. The classical pathway of complement (C) is essential for both naturally acquired and vaccine induced immunity against N. meningitidis. Qualitative and/or quantitative differences in anti-meningococcal antibodies (Abs) in serum is one reason for variations in C-dependent bactericidal Ab activity among individuals. I showed that IgG isolated from select individuals could block killing of group B meningococci by Abs that were otherwise bactericidal. Ligand overlay immunoblots revealed that these blocking IgG Abs were directed against a meningococcal antigen called H.8, Killing of meningococci in reactions containing bactericidal mAbs and human blocking Abs was restored when blocking Ab binding to meningococci was inhibited (or competed for) using either synthetic peptides corresponding to H.8 or a non-blocking mAb against H.8. Further, genetic deletion of H.8 from target organisms abrogated blocking. The Fc region of the blocking IgG was required for blocking because F(ab)2 fragments alone generated by pepsin treatment were ineffective. Blocking required IgG glycosylation; deglycosylation of blocking IgG with peptide:N-glycanase (PNGase) eliminated blocking. C4 deposition mediated by a bactericidal mAb directed against a meningococcal vaccine candidate, called factor H-binding protein (fHbp), was reduced by blocking Ab. Anti-fHbp-mediated C4 deposition was unaffected, however, by deglycosylated blocking IgG. Although preliminary, our data suggests blocking of serum bactericidal activity by human anti-H.8 blocking antibody may require mannan-binding lectin (MBL), which itself is a complement activator. Also, whether MBL recruits a complement inhibitor(s) that facilitates blocking remains to be determined. In conclusion, we have identified H.8 as a meningococcal target for novel blocking antibodies that are commonly found in human serum. Blocking Ab may reduce the efficacy of meningococcal vaccines. We propose that outer membrane vesicle-containing meningococcal vaccines may be more efficacious if purged of subversive immunogens such as H.8.
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Etheridge, W. "Production of soluble recombinant complement receptor (CR1) antigens to detect or inhibit antibodies to Knops (KN) blood group system antigens." Thesis, University of the West of England, Bristol, 2015. http://eprints.uwe.ac.uk/26375/.
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The purpose of this study was to produce a reagent to use in investigation of antibodies directed against the Knops blood group system antigens. A novel reagent based on sr-proteins was produced and used in a new test to inhibit these antibodies. Current investigation of patients with alloantibodies directed against Knops blood group system antigens can be a difficult, time-consuming process and the provision of blood for transfusion of these patients can often be delayed. This is because these antibodies are hard to identify and the most commonly found anti-Knops antibodies react with most reagent or donor cells that they are tested with because the corresponding Knops antigens are found at high frequency in most populations. The presence of Knops related antibodies can mask underlying antibodies that are clinically significant. The Knops antigens are carried on Complement Receptor 1 (CR1) located on the red blood cell membrane. Two DNA constructs encoding different parts of CR1 termed long homologous repeat (LHR) C and D were used to transfect human embryonic kidney (HEK293) cells. The cells were grown in different culture systems. Cell culture supernatant containing soluble recombinant (sr)-LHRC or sr-LHR-D was harvested and purified by affinity gel chromatography. The production and purification processes were optimised in terms of protein yield and cost. The resulting purified sr-LHR-C and sr-LHR-D proteins were used to create a novel reagent containing both proteins. This reagent was used in a new inhibition test based on an indirect antiglobulin technique using commercial gel cards. Using the reagent all examples of previously identified Knops antibodies were inhibited. In addition once these antibodies had been inhibited, underlying antibodies were then detected and identified in some samples. For the first time Knops specific antibodies can be detected and identified using one unique test. Any underlying clinically significant antibodies will be rapidly identified if present due to inhibition of the KN antibodies. Introduction of the inhibition test into nine NHSBT patient testing laboratories will reduce the time taken for investigation of these patients and make provision of blood for patients a safer, faster process.
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Rivillas, Carolina Salcedo. "Desenvolvimento de vacinas proteicas contra Streptococcus pneumoniae: caracterização dos componetes adjuvantes da vacina celular pertussis e análise de novas combinações vacinais." Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/87/87131/tde-04122015-181138/.
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Em trabalhos anteriores o nosso grupo mostrou que a vacina celular pertussis (wP) apresenta atividade adjuvante quando combinada a proteína A da superfície de Streptococcus pneumoniae (pneumococo), PspA, A formulação PspA5-wP induz altos níveis de anticorpos e proteção em camundongos após desafio com pneumococo. Neste trabalho foram avaliados os mecanismos da ação adjuvante e os componentes de B. pertussis responsáveis por este efeito. A imunização de camundongos com PspA em combinação a mutantes de B. pertussis ou componentes desta bactéria purificados mostrou que a presença da toxina pertussis (PT) capaz é essencial para induzir altos níveis de anticorpos anti-PspA e proteção significativa contra o desafio letal com pneumococo. Este efeito não foi dependente da atividade enzimática. Anticorpos anti-PspA e as proteínas do sistema complemento foram essenciais para a proteção conferida por PspA-wP. As vacinas celulares BCG e DTP combinadas a PspA, também apresentaram atividade adjuvante, induzindo anticorpos anti-PspA e proteção contra o desafio invasivo por pneumococo.Previously our group showed that the pneumococcal surface protein A from Streptococcus pneumoniae (pneumococcus), PspA, when combined with cellular pertussis vaccine (wP) as adjuvant, induce high levels of antibodies and mice protection on pneumococcal challenge. In this work were used mutants and purified components derived from B. pertussis for investigate the components responsible for this adjuvant effect, through of mice immunizations in combination with the PspA5 (Clade 5 PspA) antigen. Pertussis toxin (PT) was able to inducing the higher levels of PspA5 specific antibodies and significative protection against the pneumococcal lethal challenge, independently of its enzymatic effect. Was observed that in the protection conferred by the PspA5-wP formulation thus as the anti-PspA5 antibodies, the complements proteins are essentials. Lastly, prime-boost experiments showed that the cellular vaccines BCG and DTP when combined to PspA5, induced high levels of anti-PspA5 antibodies and protection against invasive challenge with pneumococcus.
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Lahtinen, Mika. "NO Effect on Inflammatory Reaction in Extracorporeal Circulation : Ex vivo Studies." Doctoral thesis, Uppsala University, Department of Medical Sciences, 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-5908.
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Nitric oxide (NO) is expressed in inflammatory tissues. However, NO effects are controversial in inflammation; NO is described as acting in a dose dependent manner and possess both pro-inflammatory and anti-inflammatory properties.
The present thesis explored the role of NO in relation to white blood cell (WBC) and protein system activation by foreign surfaces in simulated extracorporeal circulation (SECC) using human whole blood from volunteer donors. Three doses of NO, 40 ppm, 80 ppm and 500 ppm, were administered and an array of markers of WBC and protein activation were studied. Neutrophil degranulation was detected with myeloperoxidase (MPO), human neutrophil lipocalin (HNL) and lactoferrin (LF); eosinophil degranulation with eosinophil cationic protein (ECP) and eosinophil peroxidase (EPO); and basophil degranulation with histamine. Furthermore, whole blood and WBC capacity to produce reactive oxygen species (ROS) were studied and cytokine release was measured with IL-1 and IL-10. Complement activation was measured with C3a and C5b-9 complex and contact system activation with FXIIa-C1INH, FXIIa-AT, FXIa-C1INH and FXIa-AT.
NO increased neutrophil degranulation at all dose levels and 80 ppm NO increased basophil degranulation; whereas, NO exerted no effect on eosinophil degranulation, WBC subset counts, cytokine release or capacity to produce ROS. In addition, while increasing both specific and azurophil degranulation with 40 ppm, 80 ppm and 500 ppm, NO reversed the classical degranulation hierarchy with 500 ppm and azurophil degranulation became predominant. Furthermore, NO effect was greater with 500 ppm than with 80 ppm, indicating a dose response effect. The lack of iNOS mRNA expression in WBC and lack of L-NAME effect on degranulation and nitrite/nitrate production, together with absent increase in nitrite/nitrate in controls, excluded autocrine or paracrine regulation of degranulation. FXIIa-AT and FXIa-AT complexes increased and became predominant during early recirculation, whereas FXIIa-C1INH and FXIa-C1INH complexes were predominant at baseline but remained unaltered, suggesting contact system inhibition predominantly via AT. C3a and C5b-C9 increased. NO had no effect on either contact or complement system activation; however, 500 ppm NO shortened active clotting time.
In conclusion, the present data suggest that NO has a direct effect on neutrophil and basophil degranulation. Recognition of NO as an enhancer of degranulation may give access to new therapeutic tools for local and systemic inflammatory therapies; whereas, the identification of increased AT mediated inhibition of FXIIa and unchanged C1INH complexes presents new possibilities for therapeutic intervention in conditions such as hereditary angioedema and heart surgery.
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Och, Daniela. "Etablierung eines Messverfahrens für die Komplementkomponente FHR-3 und seine Anwendung auf die Bestimmung von FHR-3 Plasmakonzentrationen bei Patienten mit altersabhängiger Makuladegeneration." Doctoral thesis, 2012. http://hdl.handle.net/11858/00-1735-0000-000D-EFE6-C.
Full textBooks on the topic "Coagulation; Antibodies; Complement system"
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Mechanisms in blood coagulation fibrinolysis and the complement system. Cambridge: Cambridge University Press, 1991.
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Hvas, Anne-Mette, Erik L. Grove, and Steen Dalby Kristensen. Biomarkers of coagulation and thrombosis. Oxford University Press, 2015. http://dx.doi.org/10.1093/med/9780199687039.003.0038.
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Coagulation is evaluated by conventional coagulation analyses, often supplemented by point-of-care tests. Recently, a number of point-of-care tests for evaluation of platelet function and the efficacy of antiplatelet therapy has been investigated. Thrombophilia contributes to the risk of thrombosis, and a battery of complex assays is required to identify all thrombophilias. Disseminated intravascular coagulation is characterized by microthrombosis and clinical bleeding. A scoring system for overt disseminated intravascular coagulation provides a five-step diagnostic algorithm. The cornerstone of the management of disseminated intravascular coagulation is treatment of the underlying triggering condition. Heparin-induced thrombocytopenia is an adverse immunological effect of heparin therapy. Besides thrombocytopenia, the major clinical consequence of heparin-induced thrombocytopenia is an increased risk of thrombosis. The diagnosis is based on clinical symptoms and detection of platelet-activating heparin-induced thrombocytopenia antibodies. When heparin-induced thrombocytopenia is strongly suspected, it is recommended to stop heparin treatment, investigate for heparin-induced thrombocytopenia antibodies, and initiate non-heparin anticoagulant treatment.
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Hvas, Anne-Mette, Erik L. Grove, and Steen Dalby Kristensen. Biomarkers of coagulation and thrombosis. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780199687039.003.0038_update_001.
Full textAbstract:
Coagulation is evaluated by conventional coagulation analyses, often supplemented by point-of-care tests. Recently, a number of point-of-care tests for evaluation of platelet function and the efficacy of antiplatelet therapy has been investigated. Thrombophilia contributes to the risk of thrombosis, and a battery of complex assays is required to identify all thrombophilias. Disseminated intravascular coagulation is characterized by microthrombosis and clinical bleeding. A scoring system for overt disseminated intravascular coagulation provides a five-step diagnostic algorithm. The cornerstone of the management of disseminated intravascular coagulation is treatment of the underlying triggering condition. Heparin-induced thrombocytopenia is an adverse immunological effect of heparin therapy. Besides thrombocytopenia, the major clinical consequence of heparin-induced thrombocytopenia is an increased risk of thrombosis. The diagnosis is based on clinical symptoms and detection of platelet-activating heparin-induced thrombocytopenia antibodies. When heparin-induced thrombocytopenia is strongly suspected, it is recommended to stop heparin treatment, investigate for heparin-induced thrombocytopenia antibodies, and initiate non-heparin anticoagulant treatment.
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Shrivastava, Seema, Beverley J. Hunt, and Anthony Dorling. Coagulopathies in chronic kidney disease. Edited by David J. Goldsmith. Oxford University Press, 2015. http://dx.doi.org/10.1093/med/9780199592548.003.0135.
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Coagulation abnormalities are common in chronic kidney disease (CKD). Both haemorrhage and thrombosis are more common than in the general population. Haemorrhage, when it occurs, is associated with increased morbidity and mortality compared to that seen in non-uraemic patients. It is more likely spontaneously, but particularly in association with anti-platelet agents or anticoagulants. The increased risk of both arterial and venous thrombosis occurs in part because of the increase prevalence of traditional risk factors for thrombosis in CKD, in part because of the specific problems associated with nephrotic syndrome, and also because of specific putative prothrombotic factors associated with CKD, such as increased levels of coagulation factors and altered platelet function associated with uraemia. Two syndromes, both characterized by intravascular thrombosis can contribute to the development of CKD. The first is antiphospholipid syndrome, due to the presence of antibodies against negatively charged phospholipids, in which thrombosis of the renal vasculature is relatively common. The second is a group of conditions, the thrombotic microangiopathies, in which inherited or acquired deficiencies of ADAMTS13, antiphospholipid antibodies, or pathological endothelial cell activation in renal vessels, sometimes due to functional deficiencies of one or more proteins regulating coagulation or complement activation, leads to acute renal dysfunction associated with anaemia.
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Noris, Marina, and Tim Goodship. The patient with haemolytic uraemic syndrome/thrombotic thrombocytopenic purpura. Edited by Giuseppe Remuzzi. Oxford University Press, 2015. http://dx.doi.org/10.1093/med/9780199592548.003.0174.
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The patient who presents with microangiopathic haemolytic anaemia, thrombocytopenia, and evidence of acute kidney injury presents a diagnostic and management challenge. Haemolytic uraemic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) are two of the conditions that frequently present with this triad. They are characterized by low platelet count with normal or near-normal coagulation tests, anaemia, and signs of intravascular red cell fragmentation on blood films, and high LDH levels.HUS associated with shiga-like toxins produced usually by E.coli (typically O157 strains) may occur in outbreaks or sporadically, with geographical variations in incidence. It is predominantly a disease of young children in which painful blood diarrhoea in a minority of infected patients is succeeded by microangiopathy and acute kidney injury. Management is supportive and recovery is usual, although permanent renal damage may lead to later deterioration. Older patients may be affected and tend to have worse outcomes. Neuraminidase-producing Streptococcus pneumoniae infections (usually pneumonia) very rarely cause a similar HUS.Atypical HUS occurs sporadically and is increasingly associated with defects in the regulation of the complement pathway, either genetic or autoimmune-caused. It may respond to plasma exchange for fresh frozen plasma. Recurrences are common, including after transplantation.TTP is associated with more neurological disease and less renal involvement, but HUS and TTP overlap substantially in their manifestations. The underlying problem is in von Willebrand factor (vWF) cleavage. The plasma metalloprotease ADAMTS13 is responsible for cleaving vWF multimers, a process that is important to prevent thrombosis in the microvasculature. Autoantibodies or rarely genetic deficiency may impair this process. Plasma exchange may remove antibodies and replenish the protease.
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Alchi, Bassam, and David Jayne. The patient with antiphospholipid syndrome with or without lupus. Edited by Giuseppe Remuzzi. Oxford University Press, 2015. http://dx.doi.org/10.1093/med/9780199592548.003.0164.
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Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by recurrent arterial or venous thrombosis and/or pregnancy loss, accompanied by laboratory evidence of antiphospholipid antibodies (aPL), namely anticardiolipin antibodies (aCL), lupus anticoagulant (LA), and antibodies directed against beta-2 glycoprotein 1 (β2GP1). APS may occur as a ‘primary’ form, ‘antiphospholipid syndrome,’ without any known systemic disease or may occur in the context of systemic lupus erythematosus (SLE), ‘SLE-related APS’. APS may affect any organ system and displays a broad spectrum of thrombotic manifestations, ranging from isolated lower extremity deep vein thrombosis to the ‘thrombotic storm’ observed in catastrophic antiphospholipid syndrome. Less frequently, patients present with non-thrombotic manifestations (e.g. thrombocytopaenia, livedo reticularis, pulmonary hypertension, valvular heart disease, chorea, and recurrent fetal loss).The kidney is a major target organ in both primary and SLE-related APS. Renal involvement is typically caused by thrombosis occurring at any location within the renal vasculature, leading to diverse effects, depending on the size, type, and site of vessel involved. The renal manifestations of APS include renal artery stenosis and/or renovascular hypertension, renal infarction, APS nephropathy (APSN), renal vein thrombosis, allograft vasculopathy and vascular thrombosis, and thrombosis of dialysis access.Typical vascular lesions of APSN may be acute, the so-called thrombotic microangiopathy, and/or chronic, such as arteriosclerosis, fibrous intimal hyperplasia, tubular thyroidization, and focal cortical atrophy. The spectrum of renal lesions includes non-thrombotic conditions, such as glomerulonephritis. Furthermore, renal manifestations of APS may coexist with other pathologies, especially proliferative lupus nephritis.Early diagnosis of APS requires a high degree of clinical suspicion. The diagnosis requires one clinical (vascular thrombosis or pregnancy morbidity) and at least one laboratory (LA, aCL, and/or anti-β2GP1) criterion, positive on repeated testing.The aetiology of APS is not known. Although aPL are diagnostic of, and pathogenic in, APS, a ‘second hit’ (usually an inflammatory event) may trigger thrombosis in APS. The pathogenesis of the thrombotic tendency in APS remains to be elucidated, but may involve a combination of autoantibody-mediated dysregulation of coagulation, platelet activation, and endothelial injury.Treatment of APS remains centred on anticoagulation; however, it has also included the use of corticosteroids and other immunosuppressive therapy. The prognosis of patients with primary APS is variable and unpredictable. The presence of APS increases morbidity (renal and cerebral) and mortality of SLE patients.
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Barros, Rodrigo José Saraiva de, Tereza Cristina de Brito Azevedo, Carla de Castro Sant’Anna, Marianne Rodrigues Fernandes, Leticia Martins Lamarão, and Rommel Mario Rodríguez Burbano. Grupos sanguíneos e anticorpos anti-eritrocitários de importância transfusional. Brazil Publishing, 2020. http://dx.doi.org/10.31012/978-65-5861-112-7.
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Immunohematology is an area dedicated to the study of the interactions of the immune system and blood cells in transfusion practice. Blood transfusion is a therapeutic technique that has been widely used since the 17th century. The transfusion medicine aims to repair the pathological needs of blood components in the living organism, be it red blood cells, plasma, platelets, clotting factors, among others. Despite being a therapeutic means, transfusion of blood components can be considered at risk because it is a biological material and due to the transfusion immunological reactions that can be caused during or after the moment of transfusion. In the surface structure of red blood cells, numerous molecules of a protein, glycoprotein or glycolipid nature are found, which are also called membrane antigens that make up structures and perform transport functions, as receptors, as adhesion, enzymatic and / or complement regulatory molecules. The formation of these antigens occurs by an approximate amount of 39 genes involved in their production, of which 282 different antigens are organized in more than 30 blood group systems. This antigenic diversity is a major cause of the formation of irregular anti-erythrocyte antibodies. Therefore, with the increase in blood transfusions in surgeries, transplants and clinical treatment of cancer and other chronic diseases, a significant increase in the occurrence of alloimmunizations in polytransfused patients began to be observed. Such biological phenomena motivated us to carry out this study and the antigenic diversity motivated us to elaborate this small compendium where we also describe the main blood groups.
Book chapters on the topic "Coagulation; Antibodies; Complement system"
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Popescu, Narcis I., and Florea Lupu. "The Complement System and Coagulation." In Trauma Induced Coagulopathy, 173–93. Cham: Springer International Publishing, 2016. http://dx.doi.org/10.1007/978-3-319-28308-1_12.
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Amara, Umme, Daniel Rittirsch, Michael Flierl, Uwe Bruckner, Andreas Klos, Florian Gebhard, John D. Lambris, and Markus Huber-Lang. "Interaction Between the Coagulation and Complement System." In Advances in Experimental Medicine and Biology, 68–76. New York, NY: Springer US, 2008. http://dx.doi.org/10.1007/978-0-387-78952-1_6.
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Karsten, Christian M., and Jörg Köhl. "Cross-Talk Between Antibodies, IgG Fc Receptors, and the Complement System." In Molecular and Cellular Mechanisms of Antibody Activity, 159–87. New York, NY: Springer New York, 2013. http://dx.doi.org/10.1007/978-1-4614-7107-3_7.
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Staerz, Uwe D., Leo Lefrancois, and Michael J. Bevan. "Targeting for T-Lymphocyte-Mediated Lysis by Hybrid Antibodies." In Cytolytic Lymphocytes and Complement: Effectors of the Immune System, 205–18. CRC Press, 2018. http://dx.doi.org/10.1201/9781351071291-15.
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Hvas, Anne-Mette, Erik L. Grove, and Steen Dalby Kristensen. "Biomarkers of coagulation and thrombosis." In The ESC Textbook of Intensive and Acute Cardiovascular Care, edited by Marco Tubaro, Pascal Vranckx, Eric Bonnefoy-Cudraz, Susanna Price, and Christiaan Vrints, 425–33. Oxford University Press, 2021. http://dx.doi.org/10.1093/med/9780198849346.003.0035.
Full textAbstract:
Coagulation is evaluated by conventional coagulation analyses, often supplemented by point-of-care tests. A number of point-of-care tests for evaluation of platelet function and the efficacy of antiplatelet therapy have been investigated. Thrombophilia contributes to the risk of thrombosis, and a battery of complex assays is required to identify thrombophilias. Disseminated intravascular coagulation is characterized by microthrombosis and clinical bleeding. A scoring system for overt disseminated intravascular coagulation provides a five-step diagnostic algorithm. The cornerstone of the managing disseminated intravascular coagulation is treatment of the underlying triggering condition. Heparin-induced thrombocytopenia is an adverse immunological effect of heparin therapy. Besides thrombocytopenia, the major clinical consequence of heparin-induced thrombocytopenia is an increased risk of thrombosis. The diagnosis is based on clinical symptoms and detection of platelet-activating heparin-induced thrombocytopenia antibodies. When heparin-induced thrombocytopenia is strongly suspected, it is recommended to stop heparin treatment, investigate for heparin-induced thrombocytopenia antibodies, and initiate non-heparin anticoagulant treatment.
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Powers, Amy, Leslie Silberstein, and Frank J. Strobl. "Haemolytic anaemia—congenital and acquired." In Oxford Textbook of Medicine, 4450–60. Oxford University Press, 2010. http://dx.doi.org/10.1093/med/9780199204854.003.220509.
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Premature destruction of red cells occurs through two primary mechanisms: (1) decreased erythrocyte deformability that leads to red-cell sequestration and extravascular haemolysis in the spleen and other components of the reticuloendothelial system—may be caused by membrane defects, metabolic abnormalities, exogenous oxidizing agents, or pathological antibodies; (2) red-cell membrane damage and intravascular haemolysis—may be caused by exposure to pathological antibodies, activated complement, mechanical forces, chemicals, and infectious agents....
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Powers, Amy, and Leslie Silberstein. "Acquired haemolytic anaemia." In Oxford Textbook of Medicine, edited by Chris Hatton and Deborah Hay, 5479–89. Oxford University Press, 2020. http://dx.doi.org/10.1093/med/9780198746690.003.0542.
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Premature destruction of red cells occurs through two primary mechanisms: (1) decreased erythrocyte deformability that leads to red cell sequestration and extravascular haemolysis in the spleen and other components of the reticuloendothelial system—may be caused by membrane defects, metabolic abnormalities, exogenous oxidizing agents, or pathological antibodies; and (2) red cell membrane damage and intravascular haemolysis—may be caused by exposure to pathological antibodies, activated complement, mechanical forces, chemicals, and infectious agents. Congenital haemolytic anaemias—congenital disorders resulting in a haemolytic anaemia include (1) disorders of the red cell membrane such as hereditary spherocytosis and hereditary elliptocytosis; (2) disorders of red cell enzymes such as glucose-6-phosphate dehydrogenase deficiency and pyruvate kinase deficiency; and (3) disorders of globin structure. Acquired immune haemolytic anaemias—immune haemolysis may occur when IgG, IgM, or IgA antibodies and/or complement bind to the erythrocyte surface. Autoimmune haemolytic anaemias—these are best classified according to the temperature at which the antibody optimally binds to the erythrocyte: warm autoimmune haemolytic anaemia, cold agglutinin-mediated autoimmune haemolytic anaemia, paroxysmal cold haemoglobinuria, and mixed type autoimmune haemolytic anaemia. Drug-induced haemolytic anaemia—haemolysis can be caused by drugs that induce a positive DAT. Drug-induced antibodies may be drug dependent or drug independent depending on whether the presence of the drug is required for their detection. Alloimmune haemolytic anaemias—these include acute haemolytic transfusion reactions and other conditions such as delayed haemolytic transfusion reactions, passenger lymphocyte haemolysis, and haemolytic disease of the newborn. Acquired nonimmune haemolytic anaemias and microangiopathic haemolytic anaemia are also discussed in this chapter.
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Davies, Jamie A. "7. Defence." In Human Physiology: A Very Short Introduction, 104–14. Oxford University Press, 2021. http://dx.doi.org/10.1093/actrade/9780198869887.003.0007.
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This chapter describes how the human body protects its internal conditions against micro-organisms and the environment. The body’s first line of defence is the mechanical barrier provided by the skin, a part of the integumentary system. When the integument is breached, the body’s immediate priority is to seal the hole by coagulation of the leaking blood. The next line of defence is chemical: the secretions that cover the surfaces of eyes and the inside of the nose contain a variety of proteins that attack bacteria. Within the blood and fluids that bathe internal tissues are proteins of the complement system. The chapter then considers the innate and the adaptive immune systems.
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Tsikouras, Panagiotis, Christina Tsiggalou, Anastasia Bothou, Aggeliki Gerede, Ifigenia Apostolou, Fotini Gaitatzi, Anna Chalkidou, et al. "Antiphospholipid Syndrome and Pregnancy-Diagnosis, Complications and Management: An Overview." In Inflammation [Working Title]. IntechOpen, 2021. http://dx.doi.org/10.5772/intechopen.99283.
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Antiphospholipid syndrome which is also known as APS is an autoimmune disease which represents an acquired form of thrombophilia. The etiology of APS remains unknown. This disorder occurs when the immune system mistakenly attacks some of the normal human proteins and manifests itself as recurrent arterial or venous thrombosis and it could emerge after abortions or in recurrent pregnancy loss. In APS, the body produces the wrong antibodies against phospholipid-binding proteins, that is present in the blood and plays an important role in coagulation. Antibodies are specific proteins that usually target and neutralize the body’s invaders, such as viruses and bacteria. When antibodies attack phospholipid-binding proteins, blood clots abnormally. Specifically, it could cause blood clots in veins or arteries leading to stroke and various pregnancy complications such as: endometrial death, miscarriage, preeclampsia, intrauterine growth restriction and prematurity. APS is divided into primary and secondary, which is associated with autoimmune diseases and more often with systemic lupus erythematosus (SLE), while antibodies against cardiolipin are detected in many other conditions (infections, malignancies, drugs, etc.). The symptoms of APS, in addition to arterial and/or venous thrombosis and pregnancy complications, are multisystemic and the differential diagnosis of the primary APS from the secondary, in the context of SLE, is of particular clinical interest and is subject of this literature review.
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Puerta-Guardo, Henry, Scott B. Biering, Eva Harris, Norma Pavia-Ruz, Gonzalo Vázquez-Prokopec, Guadalupe Ayora-Talavera, and Pablo Manrique-Saide. "Dengue Immunopathogenesis: A Crosstalk between Host and Viral Factors Leading to Disease: PART II - DENV Infection, Adaptive Immune Responses, and NS1 Pathogenesis." In Dengue Fever in a One Health Perspective. IntechOpen, 2020. http://dx.doi.org/10.5772/intechopen.93551.
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Severe disease is associated with serial infection with DENV of different serotypes. Thus, primary DENV infections normally cause asymptomatic infections, and secondary heterotypic infections with a new DENV serotype potentially increase the risks of developing severe disease. Despite many proposed hypotheses trying to explain it, the exact immunological mechanism leading to severe dengue disease is unknown. In turn, severe manifestations are believed to be a consequence of the combinations of many immunopathogenic mechanisms involving viral and host factors leading to increased pathogenesis and disease. Of these mechanisms, the adaptive immune response has been proposed to play a critical role in the development of severe dengue manifestations. This includes the effect of non-neutralizing but enhancing antibodies produced during primary infections, which results in enhanced-DENV infection of Fc-γ-receptor-expressing cells (e.g. monocytes and macrophages) during DENV heterotypic exposure in a phenomenon called antibody-dependent enhancement (ADE); the increased activation of memory T cells during secondary infections, which has low affinity for the current infecting serotype and high affinity for a past infection with a different serotype known as the original antigenic sin; the unbalanced production of pro-inflammatory cytokines that have a direct effect on vascular endothelial cells resulting in plasma leak in a phenomenon known as cytokine storm; and the excessive activation of the complement system that causes exacerbated inflammatory responses, increasing disease severity. In addition to the adaptive immune responses, a secreted viral factor known as the nonstructural protein 1 (NS1) has been recently proposed as the missing corner piece of the DENV pathogenesis influencing disease. This Part II of the chapter will discuss the interplay between the distinct host adaptive immune responses and viral factors that together contribute to the development of DENV pathogenesis and severe disease.
Conference papers on the topic "Coagulation; Antibodies; Complement system"
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Imamura, K., R. Sato, S. Sakata, T. Ikeda, Y. Horio, S. Iyama, K. Akaike, et al. "Disorder of Coagulation-Fibrinolysis System: An Emerging Toxicity of Anti-PD-1/PD-L1 Monoclonal Antibodies." In American Thoracic Society 2020 International Conference, May 15-20, 2020 - Philadelphia, PA. American Thoracic Society, 2020. http://dx.doi.org/10.1164/ajrccm-conference.2020.201.1_meetingabstracts.a2456.
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Tanaka, I., A. Yoshioka, T. Fujiwara, H. Nakai, and H. Fukui. "THE CHANGES OF FACTOR VIII ANTIGEN DURING THE COAGULATION PROCESS." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644038.
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The changes of factor VIII (F. VIII) during blood coagulation process is still controversial. We analyzed the F. VIII antigen (F. VIII:Ag) at various intervals of in vitro blood clotting by immunoassays using polyclonal and different kinds of monoclonal antibodies to F. VIII.We used two immunoassays, an immunoradiometric assay (IRMA) and an enzyme-linked immunosorbent assay (ELISA). The IRMA was performed by the method of Peake et al. using high-titer allo-antibodies to F. VIII. The ELISA was performed by two-site solid phase system consisting of alloantibodies as the first and one of three kinds of monoclonal antibodies (NMC-VIII/1, -VIII/2 or C5*) as the second antibody. Using the immunoblotting technique, it had been shown that NMC-VIII/1 recognized the 80/79 kDa derived from C-terminus and both NMC-VIII/2 and C5 recognized 54 kDa derived from N-terminus.The mean levels of F. VIII:Ag in 20 normal plasmas and sera were 0.97±0.23 U/ml and 0.68±0.21 U/ml, respectively using the polyclonal IRMA. The mean levels of F. VIII:Ag in normal sera were 0.14±0.05 U/ml (NMC-VIII/1), 0.71±0.21 U/ml (NMC-VIII/2), and 0.012±0.02 U/ml (C5) using the monoclonal ELISAs. In the initial phase of whole blood coagulation in vitro, the increase of F. VIII: Ag was observed by the polyclonal IRMA as F. VIII:C assayed by a one-stage clotting method increased. On the other hand, the F. VIII:Ag assayed by NMC-VIII/1 or C5 monoclonal ELISA progressively decreased to the serum level within 30 min. The F. VIII:Ag by NMC-VIII/2 declined to the serum level at a slow rate. In order to study the influence of thrombin on F. VIIIrAg during blood clotting, a synthesized selective thrombin inhibitor (MD-805, Mitsubishi Chemical Ind.) was previously added to the whole blood tested. The changes of F. VIII:Ag with MD-805 by the monoclonal ELISAs were almost the same as those without MD-805.It is suggested that in the whole blood coagulation process the antigenicity of F. VIII molecule changes in the initial phase (within 30 min.), but that thrombin does not play the main role of the phenomenon in physiological concentration.*C5 was kindly supplied from Dr. C. Fulcher (Scripps Clinic and Research Foundation, USA)
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Leyte, A., R. F. Evers, and M. Ph Verbeet. "EPITOPE MAPPING OF HUMAN COAGULATION FACTOR VIII WITH IN VITRO SYNTHESIZED FRAGMENTS OF THE PROTEIN." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644043.
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We have used recombinant DNA techniques to map the epitopes of the coagulation Factor VIII for several monoclonal antibodies, raised against this protein. For this purpose, we cloned full- length- and partial Factor VIII cDNA sequences in the vector pSP64. Corresponding RNA fragments were synthesized in vitro with SP6 RNA polymerase and translated in a rabbit reticulocyte lysate system. The resulting Factor VII. I polypeptide fragments were immunoprecipitated. We have located the binding sites of a panel of monoclonal anti-Factor VIII antibodies. Two examples are shown in the figure below. The epitopes for anti-Factor VIII CLB-9 and CLB-65 have been confined to areas of 29 (711-740) and 142 (1635-1777) amino acids, respectively. The results of these studies will be useful in determining structure-function relationships of Factor VIII
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Scheefers-Borchel, U., and G. Muller-Berghaus. "A NEW FIBRIN-SPECIFIC ANTIBODY DISCRIMINATING BETWEEN FIBRIN AND FIBRINOGEN IS DIRECTED AGAINST THE SYNTHETIC PEPTIDE LEU-ILE-ASP-GLY-LYS-MET." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643771.
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To determine soluble fibrin in blood of patients with coagulation disorders we produced monoclonal antibodies which distinct fibrin from fibrinogen and other blood constituents. Fibrin-specific monoclonal antibodies were obtained by immunizing mice with the synthetic hexapeptide Leu-Ile-Asp-Gly-Lys-Met which was covalently linked to KLH via its C-terminus. Several of the monoclonal antibodies which reacted with the hexapeptide also reacted with batroxobin-induced desAA-fibrin and thrombin-induced desAABB-fibrin, but not with fibrinogen. No reaction was observed with plasmin-induced fibrinogenolytic and fibrinolytic degradation products, respectively. The epitope recognized by these fibrin-specific antibodies is located on the αchain of fibrin and is not accessible for an antibody in native fibrinogen. One monoclonal antibody (B/H11) was used to quantify the amount of soluble fibrin in plasma of patients with a variety of coagulation disorders. This antibody could also be used to develop an ELISA based on two different fibrin-specific monoclonal antibodies. For this assay anti-fbn 17 (Scheefers- Borchel et al., Proc. Natl. Acad. Sci. USA 82: 7091, 1985) was coated onto ELISA plates. After adding plasma which contained soluble fibrin, the fibrin bound was detected by the second fibrin-specific antibody B/H^ to which biotin was covalently linked. The second antibody was probed by the addition of peroxydase conjugated streptavidin and the substrate ABTS for peroxydase. This test can be used to detect fibrin at concentrations as low as 70 ng/ml. With this assay system, it is possible to measure the amount of soluble fibrin present in plasma samples without the interference of fibrinogen which is associated with soluble fibrin.
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Dahiback, Bjorn, Ake Lundwall, Andreas Hillarp, Johan Malm, and Johan Stenflo. "STRUCTURE AND FUNCTION OF VITAMIN K-DEPENDENT PROTEIN S, a cofactor to activated protein C which also interacts with the complement protein C4b-binding protein." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1642960.
Full textAbstract:
Protein S is a single chain (Mr 75.000) plasma protein. It is a cofactor to activated protein C (APC) in the regulation of coagulation factors Va and Villa. It has high affinity for negatively charged phospolipids and it forms a 1:1 complex with APC on phospholipid surfaces, platelets and on endothelial cells. Patients with heterozygous protein S deficiency have a high incidence of thrombosis. Protein S is cleaved by thrombin, which leads to a loss of calcium binding sites and of APC cofactor activity. Protein S has two to three high affinity (KD 20uM) calcium binding sites - unrelated to the Gla-region - that are unaffected by the thrombin cleavage. In human plasma protein S (25 mg/liter) circulates in two forms; free (approx. 40%) and in a 1:1 noncovalent complex (KD 1× 10-7M) with the complement protein C4b-binding protein (C4BP). C4BP (Mr 570.000) is composed of seven identical 70 kDa subunits that are linked by disulfide bonds. When visualized by electron microscopy, C4BP has a spiderlike structure with the single protein S binding site located close to the central core and one C4b-binding site on each of the seven tentacles. When bound to C4BP, protein S looses its APC cofactor activity, whereas the function-of C4BP is not directly affected by the protein S binding. Chymotrypsin cleaves each of the seven C4BP subunits close to the central core which results in the liberation of multiple 48 kDa “tentacte” fragments and the formation of a 160 kDa central core fragment. We have successfully isolated a 160 kDa central core fragment with essentially intact protein S binding ability.The primary structure of both bovine and human protein S has been determined and found to contain 635 and 634 amino acids, respectively, with 82 % homology to each other. Four different regions were distinguished; the N-terminal Gla-domain (position 1-45) was followed by a region which has two thrombin-sensitive bonds positioned within a disulfide loop. Position 76 to 244 was occupied by four repeats homologous to the epidermal growth factor (EGF) precursor. In the first EGF-domain a modified aspartic acid was identified at position 95, B-hydroxaspartic acid (Hya), and in corresponding positions in the three following EGF-domains (positions 136,178 and 217) we found B-hydroxyasparagine (Hyn). Hyn has not previously been identified in proteins. The C-terminal half of protein S (from position 245) shows no homology to the serine proteases but instead to human Sexual Hormon Binding Globulin (SHBG)(see separate abstract). To study the structure-function relationship we made eighteen monoclonal antibodies to human protein S. The effects of the monoclonals on the C4BP-protein S interaction and on the APC cofactor activity were analysed. Eight of the antibodies were calciumdependent, four of these were against the Gla-domain, two against the thrombin sensitive portion and two against the region bearing the high affinity calcium binding sites. Three of the monoclonals were dependent on the presence of chelating agents, EDTA or EGTA, and were probably directed against the high affinity calcium binding region. Three other monoclonals inhibited the protein S-C4BP interaction. At present, efforts are made to localize the epitopes to gain information about functionally important regions of protein S.
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Hessing, Martin, Joost C. M. Meijers, Jan A. van Mourik, and Bonno N. Bouma. "MONOCLONAL ANTIBODIES TO HUMAN PROTEIN S AND C4b-BINDING PROTEIN." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644291.
Full textAbstract:
Protein S (PS) circulates in plasma both free and in reversible association with the complement component C4b-binding protein (C4bp). Only free PS is functional as a cofactor for activated protein C (APC). Cleavage of PS by thrombin at a site near the r-carboxyglutamic acid domain is associated with a loss of cofactor activity. This may be a control mechanism for the anticoagulant activity of APC. These observations led us to investigate the role of C4bp and thrombin in the regulation of PS. Complex formation between purified PS and C4bp was studied in plasma and in a system with purified components. 125I-labeled PS was first incubated with either C4bp or citrated plasma and then subjected to polyacrylamide gelelectrophoresis in the absence of SDS. The formation of the C4bp-PS complex in plasma and in the purified system was demonstrated by autoradiography. Crossed immuno-electrophoresis using an antiserum against PS was performed in the presence of 8 mM EDTA. Human citrated plasma showed two precipitin peaks. Free PS migrated rapidly in the first dimension, whereas the C4bp-PS complex was just anodal to the application slot. The addition of C4bp to either plasma or purified PS resulted in the disappearance of the free PS peak and an increase of the slower migrating peak. The effect of purified C4bp on the PS-cofactor function of APC was studied in citrated plasma. The prolongation of the APTT induced by the addition of APC could be inhibited by the addition of increasing amounts of C4bp. Monoclonal antibodies to PS and C4bp were prepared and characterized. The monoclonal antibodies to either PS or C4bp did not block the complex formation between and PS, as was demonstrated by dot blotting of C4bp with 125I-PS and agarose gelelectrophoresis followed by Western blotting. Three out of 7 monoclonal antibodies to PS did not detect PS after thrombin cleavage on an immunoblot after non-reduced SDS polyacrylamide gelelectrophoresis. These 3 antibodies gave a significant shortening of the prolonged APTT induced by the addition of APC to normal plasma, indicating that these monoclonals inhibited the cofactor function of PS. The other 4 monoclonals to PS that did detect PS after thrombin cleavage on an immunoblot, gave only a minor inhibition of the PS cofactor function.
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Krasnoshtanova, Alla, and Alesya Yudina. "PRODUCTION OF ANTIBODIES FROM POULTRY YOLK (IgY) AND INVESTIGATION OF THEIR IMMUNOCHEMICAL PROPERTIES." In GEOLINKS Conference Proceedings. Saima Consult Ltd, 2021. http://dx.doi.org/10.32008/geolinks2021/b1/v3/17.
Full textAbstract:
"A particularly important aspect of immunology is to develop non-invasive methods of obtaining antibodies which could be a great alternative to traditional ones that based on the harmful procedure of isolation of immunoglobulins from animal blood sera. That’s why the extraction of antibodies from poultry egg yolks (IgY) is the most promising. Due to the fact of variation of IgY structural features that determine the definite immunochemical properties, yolk antibodies in comparison with mammalian immunoglobulins (IgG) does not interact with rheumatoid factor (Rf), contribute to the activation of the complement system, bind to the Fc-receptor (FcR), and also has weak cross-reactivity, which confirms the possibility of their widespread use in medicine and food. Also the presence of phylogenetic distance between chickens and mammalians guarantees immune response against conservative mammalian protein molecules which is highly important for the creation of new generation test systems. The aim of this work is to develop a selective method of producing high-purity immunoglobulin Y preparations from the yolk of chicken eggs. There were adopted selective conditions of isolation of IgY under spontaneous thawing procedure at the room temperature of firstly frozen yolk solution in a sodium-phosphate buffer mixed with water (pH 5.0) in a ratio of 1:6, which leads to receiving a water-soluble fraction further precipitated with the sodium chloride at a concentration of 10% of the solution mass and subsequently concentrated using ultrafiltration with membrane UAM-10, that allows achieving the content of IgY not less than 95% per dry substance in immunoglobulin fraction. It is possible to produce a protein fraction with a protein content of at least 9 g/l. The purity of the immunoglobulin fraction was verified using polyacrylamide gel electrophoresis. The presence of a light chain in the IgY solution was proved to be a low-molecular compound using the method of gel-filtration-chromatography. The immunological activity of IgY was studied with respect to bovine serum albumin (BSA) as an antigen. The enzymatic resistance of IgY against proteolytic enzymes was tested in area of the gastrointestinal tract."
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Bom, V. J. J., V. W. M. van Hinsberqh, J. H. Reinalda-Poot, R. W. Mohanlal, and R. M. Bertina. "EXTRINSIC ACTIVATION OF HUMAN COAGULATION FACTORS IX AND X ON THE ENDOTHELIAL SURFACE." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644730.
Full textAbstract:
In previous studies using purified human tissue factor (TF) apoprotein reconstituted with PS/PC membranes, no dramatic differences between the kinetic parameters for extrinsic activation of factor X (FX)and factor IX (FIX)could be observed. In vivo however, TF is an integral part of a complex biological membrane. Therefore we studied the kinetics of extrinsic FX and FIX activation on endothelial cells.TF expression was stimulated by incubation of cultured human endothelial cells with endotoxin (4 hr). The cells were washed and incubated with FVII(a), FX and/or FIX n the presence of CaCl2. FXa and FIXa formation were measured with a sensitive spectrophotometric assay (S2337) and an immunoradiometric assay (IRMA-IXa), respectively. Unstimulated cells did not induce significant activation of FX or IX. Stimulation of the cells and recombination of exposed TF withFVIIa resulted in rapidactivation of both substrates.Rates of FXa formation reached a maximum after a lag of about 1 min. Upon prolonged incubation the rate of FXa formation progressively decreased, probably by inactivation of FVIIa by product Xa. At the other hand, FIXa formation was linear in time for at least 30 min. When added together, FIX was found to be a weak, competitive inhibitor of FX activation, while FIX activation was severely inhibited by FX. Both FX and FIX activation were dependent on the presence of TF (sensitive to µ-TF antibodies) and FVIIa. The calculated Km of FIX (∼0.09µM) and of FX (∼0.07µM) for extrinsic activation at the endothelial surface were both higher than those observed in a cell free system using purified TF apoprotein and the ratio of Km-FIX/Km-FX was about 6-fold increased. The ratios of Vmax-FIX activation/Vmax-FX activation for both systems were similar (−0.3). These data indicate that the microenvironment of TF in the biological membrane does not introduce important alterations in the kinetic parameters of TF-FVIIa dependent activation reactions in favour of extrinsic FIX activation.
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Schwarz, H. P., and W. Muntean. "LOW TOTAL PROTEIN S ANTIGEN BUT HIGH PROTEIN S ACTIVITY DUE TO DECREASED C4b-BINDING PROTEIN (C4b-BP) LEVELS IN NEWBORNS." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643610.
Full textAbstract:
Vitamin K-dependent coagulation proteins are known to be decreased in the neonatal period. So far no data have been published on protein S (PS), the vitamin K-dependent cofactor for the antithrombotic enzyme, activated protein C (APC) in this period. We determined, therefore, PS antigen, PS activity and C4b-BP,a regulatory protein of the classical complement pathway to which PS is complexed, in 36 neonates. Total PS antigen in newborns was below the range associated with thromboembolism in patients congenitally deficient in this protein (22±9.6%, mean±SD). None of these infants had clinical or laboratory evidence of thromboembolism or DIC. In contrast to the PS antigen level PS activity measured by the ability of APC to prolong the clotting time of a modified APTT assay using PS-immunodep1eted plasma was significantly higher (77.6±14%, mean±SD, p< 0,001), suggesting a shift in PS to the free form. In fact two dimensional immunoe1ectrophoresis studies revealed the absence of protein S-C4b-BP complexes and only one precipitation indicating free PS was seen in 15 out of the 36 infants. In these 15 neonates C4b-BP was below the limit of detection by sensitive quantitative immunob1otting techniques using monoclonal or polyclonal antibodies. In the remaining 21 infants PS-C4b-BP complexes were detected, but in contrast to adult normal plasma approximately 80% of PS was found in the free form. Mixing experiments with normal human plasma and newborn’s plasma indicate that PS in neonate deficient of C4b-BP can bind normally to C4bp. Absence of C4b-BP did not correlate to gestational age. If an equilibrium distribution of PS between bound and free form regulates the cofactor activity of PS for the anticoagulant and profibrino 1ytic properties of APC in normal adults, our study demonstrates that the absence of PS-C4b-BP complexes in newborns and the presence of free PS only may contribute to the increased bleeding risk of premature infants.
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Hauert, J., and F. Bachmann. "IN VITRO CLOT LYSIS INDUCED BY SINGLE-CHAIN UROKINASE (scu-PA) AND ACTIVATION OF THE CONTACT PHASE SYSTEM." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644418.
Full textAbstract:
Scu-PA was purified from ccaiditioned medium of cell lines (HT 1080, MG 118) by immunoaffinity chrcxnatography on anti-u-PA Sepharose and passage through benzamidine-Sepharose to remove traces of two-chain u-PA (tcu-PA). The amidolytic activity determined with S-2444 was 20'000 u-PA IU/mg before and undetectable ( <700 IU/mg) after the benzamidine-Sepharose step. Pretreatment of scu-PA by plasmin yielded a specific activity of 100'000 IU/mg. We have studied, in vitro, the lysis of plasma clots containing 125I-fibrin as tracer. To obtain 50% lysis in 90 min, 130 IU/ml of scu-PA had to be added to plasma before clotting; an equivalent rate of lysis was obtained with 45 IU/ml of tcu-PA. When, after the addition of scu-PA, the contact phase system of plasma was activated using ellagic acid and phospholipids, lysis was complete within minutes following clotting; 7 IU/ml of scu-PA induced 50% lysis in 90 min. An equivalent concentration of tcu-PA or plasmin-treated scu-PA did not bring about clot lysis after 7 h. Using plasmas deficient in prekalli-krein or in high molecular weight kininogen no lysis occured in the presence of 7 IU/ ml of scu-PA and contact phase activation; lysis reached 15% after 7 h with FXII deficient plasma and was normal with FXI deficient plasma. Clot digestion was totally abolished in the presence of a kallikrein inhibitor (SBTI 0.2 mg/ml) or antibodies directed against prekallikrein or u-PA. Hie addition of FXII inhibitor (LBTI 0.2 mg/ml) or of antibodies against FXII reduced the rate, but did not totally block the lysis. Contact dependent fibrinolysis in the presence of 7 IU/ml of scu-PA was furthermore modulated by plasminogen activator inhibitor 1 (PAI-1). A positive exponential correlation between the level of PAI-1 activity and 50% lysis time was observed (r2=0.83, n=12).We have previously reported that kallikrein efficiently converts scu-PA into tcu-PA. The present study shows that, in normal human plasma, the fibrinolytic effect of scu-PA is twenty fold potentiated through contact activation and suggests an important physiological role for scu-PA counteracting excessive clot formation in situations associated with contact activation of the coagulation system.