Siga este enlace para ver otros tipos de publicaciones sobre el tema: APS, Complement System, Coagulation Cascade.
Artículos de revistas sobre el tema "APS, Complement System, Coagulation Cascade"
Crea una cita precisa en los estilos APA, MLA, Chicago, Harvard y otros
Consulte los 50 mejores artículos de revistas para su investigación sobre el tema "APS, Complement System, Coagulation Cascade".
Junto a cada fuente en la lista de referencias hay un botón "Agregar a la bibliografía". Pulsa este botón, y generaremos automáticamente la referencia bibliográfica para la obra elegida en el estilo de cita que necesites: APA, MLA, Harvard, Vancouver, Chicago, etc.
También puede descargar el texto completo de la publicación académica en formato pdf y leer en línea su resumen siempre que esté disponible en los metadatos.
Explore artículos de revistas sobre una amplia variedad de disciplinas y organice su bibliografía correctamente.
1
Panebianco, Lauren M., and Teresa Gentile. "The Role of Monitoring Complement Levels in Catastrophic Antiphospholipid Syndrome: A Case Series of 4 Patients." Blood 134, Supplement_1 (2019): 4872. http://dx.doi.org/10.1182/blood-2019-128297.
Texto completoResumen
Introduction: Catastrophic antiphospholipid syndrome (CAPS) is characterized by multiple intravascular thrombotic events occurring over a short time period in the presence of persistently detectable antiphospholipid antibodies (APLA). Despite its clinical significance with mortality rate of 40-50%, the underlying pathophysiology remains somewhat enigmatic. More recent focus on the complement system as it interacts with the coagulation cascade has led to off-label use of eculizumab, a humanized monoclonal antibody against C5, in the treatment of CAPS. Consequently, monitoring of disease status with complement levels is an area of interest. We report complement levels in four patients with CAPS who had various clinical outcomes. Methods: Four patients admitted to SUNY Upstate Medical University with CAPS between February and May 2019 were included in this case series. All patients had APS with prior history of refractory CAPS (persistent disease despite standard therapy with steroids, rituximab, and therapeutic plasma exchange [TPEX]). Antiphospholipid antibodies (APLA) and complement (C3 and C4) levels were monitored during admission until discharge or death. Results: Patient characteristics are summarized in Table 1. Patient 1 was a 42-year-old female with antiphospholipid syndrome (APS) on warfarin, ischemic stroke, and aortic valve replacement admitted on March 2019 with shortness of breath, hemoptysis and menorrhagia. She was found to have elevated APLA, thrombocytopenia, and acute renal failure with renal biopsy confirming APS nephropathy. Despite therapy with ongoing anticoagulation, steroids, rituximab, IVIG, and TPEX her clinical course continued to deteriorate. Hypocomplementemia was present (both low C3 and C4), with lowest C3 level on admission at 31 (Graph 1A). Decision was made to pursue eculizumab on 4/16/19 with continued clinical decline and no improvement in complement levels. She ultimately died on 4/24/19. Patient 2 was a 35-year-old male with systemic lupus erythematosus (SLE), APS, end-stage renal disease, and Libman-Sacks endocarditis status post bioprosthetic aortic valve replacement admitted in February 2019 for worsening digital ischemia. Workup showed presence of lupus anticoagulant, thrombocytopenia, low C3 levels (Graph 1B), normal C4 levels, and arterial thrombi in the upper and lower extremities. Prior to initiation of treatment, respiratory status declined due to massive pulmonary embolus. He died after PEA arrest shortly thereafter. Patient 3 is a 63-year-old male with chronic ITP and APS on warfarin, maintenance rituximab and intermittent apheresis admitted with worsening renal dysfunction in April 2019. Workup demonstrated acute on chronic thrombocytopenia, elevated APLA, and normal C3 and C4 levels (Graph 1C). Renal replacement therapy was commenced and he was discharged to receive ongoing outpatient therapy. Patient 4 is a 35-year-old male with history of SLE and APS admitted in April 2019 with renal failure, anemia and thrombocytopenia. Workup showed presence of APLA. Despite therapy with steroids, IVIG, rituximab and TPEX he became anuric with renal biopsy showing thrombotic microangiopathy. He was also bacteremic with a mitral valve vegetation for which he underwent valve replacement. Hospital course was complicated by need respiratory failure necessitating intubation and ECMO. C3 levels were consistently low, but varied throughout his long admission (Graph 1D) and were not necessarily related to his clinical course (sepsis, ECMO, etc.). C4 levels were normal. Conclusions: Complement levels were variable among the patients in this case series. Three out of four patient had low C3, while only one patient had low C4. Further, complement levels did not improve in one patient after administration of eculizumab. Routine laboratory testing for C3 and C4 may not be optimal assays for monitoring disease status in CAPS. More specialized complement testing, such a C5 a/b, may be more appropriate especially in the setting of eculizumab use. While eculizumab is typically used in refractory disease, it may be pertinent to move this therapy into early line treatment to achieve better outcomes in certain clinical scenarios. Identification of a more specific biomarker to recognize cases in need of early therapy is warranted. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Eculizumab, a humanized monoclonal IgG antibody that binds to complement protein C5, is discussed for its off-label use in the treatment of catastrophic antiphospholipid antibody syndrome.
2
Liang, Yan, Shang-Bo Xie, Chang-Hao Wu, et al. "Coagulation cascade and complement system in systemic lupus erythematosus." Oncotarget 9, no. 19 (2017): 14862–81. http://dx.doi.org/10.18632/oncotarget.23206.
Texto completo
3
Fletcher-Sandersjöö, Alexander, Marc Maegele, and Bo-Michael Bellander. "Does Complement-Mediated Hemostatic Disturbance Occur in Traumatic Brain Injury? A Literature Review and Observational Study Protocol." International Journal of Molecular Sciences 21, no. 5 (2020): 1596. http://dx.doi.org/10.3390/ijms21051596.
Texto completoResumen
Despite improvements in medical triage and tertiary care, traumatic brain injury (TBI) remains associated with significant morbidity and mortality. Almost two-thirds of patients with severe TBI develop some form of hemostatic disturbance, which contributes to poor outcome. In addition, the complement system, which is abundant in the healthy brain, undergoes significant intra- and extracranial amplification following TBI. Previously considered to be structurally similar but separate systems, evidence of an interaction between the complement and coagulation systems in non-TBI cohorts has accumulated, with the activation of one system amplifying the activation of the other, independent of their established pathways. However, it is not known whether this interaction exists in TBI. In this review we summarize the available literature on complement activation following TBI, and the crosstalk between the complement and coagulation systems. We demonstrate how the complement system interacts with the coagulation cascade by activating the intrinsic coagulation pathway and by bypassing the initial cascade and directly producing thrombin as well. This crosstalk also effects platelets, where evidence points to a relationship with the complement system on multiple levels, with complement anaphylatoxins being able to induce disproportionate platelet activation and adhesion. The complement system also stimulates thrombosis by inhibiting fibrinolysis and stimulating endothelial cells to release prothrombotic microparticles. These interactions see clinical relevance in several disorders where a deficiency in complement regulation seems to result in a prothrombotic clinical presentation. Finally, based on these observations, we present the outline of an observational cohort study that is currently under preparation and aimed at assessing how complement influences coagulation in patients with isolated TBI.
4
Berkowitz, Shani, Joab Chapman, Amir Dori, Shany Guly Gofrit, Nicola Maggio, and Efrat Shavit-Stein. "Complement and Coagulation System Crosstalk in Synaptic and Neural Conduction in the Central and Peripheral Nervous Systems." Biomedicines 9, no. 12 (2021): 1950. http://dx.doi.org/10.3390/biomedicines9121950.
Texto completoResumen
Complement and coagulation are both key systems that defend the body from harm. They share multiple features and are similarly activated. They each play individual roles in the systemic circulation in physiology and pathophysiology, with significant crosstalk between them. Components from both systems are mapped to important structures in the central nervous system (CNS) and peripheral nervous system (PNS). Complement and coagulation participate in critical functions in neuronal development and synaptic plasticity. During pathophysiological states, complement and coagulation factors are upregulated and can modulate synaptic transmission and neuronal conduction. This review summarizes the current evidence regarding the roles of the complement system and the coagulation cascade in the CNS and PNS. Possible crosstalk between the two systems regarding neuroinflammatory-related effects on synaptic transmission and neuronal conduction is explored. Novel treatment based on the modulation of crosstalk between complement and coagulation may perhaps help to alleviate neuroinflammatory effects in diseased states of the CNS and PNS.
5
Gavriilaki, Eleni, Akrivi Chrysanthopoulou, Ioanna Sakellari, et al. "Linking Complement Activation, Coagulation, and Neutrophils in Transplant-Associated Thrombotic Microangiopathy." Thrombosis and Haemostasis 119, no. 09 (2019): 1433–40. http://dx.doi.org/10.1055/s-0039-1692721.
Texto completoResumen
AbstractTransplant-associated thrombotic microangiopathy (TA-TMA) is a severe and life-threatening complication of hematopoietic cell transplantation (HCT) that often coincides with graft-versus-host-disease (GVHD). Although endothelial damage seems to be the common denominator for both disorders, the role of complement system, neutrophils, and coagulation has not been clarified. In an effort to distinguish the pathogenesis of TA-TMA from GVHD, we evaluated markers of complement activation, neutrophil extracellular trap (NET) release, endothelial damage, and activation of coagulation cascade in the circulation of patients with these two disorders, as well as control HCT recipients without TA-TMA or GVHD. We observed that the terminal complement product C5b-9 levels, the levels of markers of NET formation, and thrombin–antithrombin complex levels were significantly increased in the TA-TMA group compared with patients without complications, whereas there was no significant difference between the GVHD and the control group. On the other hand, the levels of circulating thrombomodulin, an endothelial damage marker, were significantly increased in both TA-TMA and GVHD patients. These findings propose a role for the interplay between complement system, neutrophil activation through NET release, and activation of the coagulation cascade in TA-TMA.
6
Arnout, J. "Mechanism of action of Lupus anticoagulants." Hämostaseologie 21, no. 02 (2001): 44–49. http://dx.doi.org/10.1055/s-0037-1619504.
Texto completoResumen
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.
7
Huber, Silke, Mariam Massri, Marco Grasse, et al. "Systemic Inflammation and Complement Activation Parameters Predict Clinical Outcome of Severe SARS-CoV-2 Infections." Viruses 13, no. 12 (2021): 2376. http://dx.doi.org/10.3390/v13122376.
Texto completoResumen
Overactivation of the complement system has been characterized in severe COVID-19 cases. Complement components are known to trigger NETosis via the coagulation cascade and have also been reported in human tracheobronchial epithelial cells. In this longitudinal study, we investigated systemic and local complement activation and NETosis in COVID-19 patients that underwent mechanical ventilation. Results confirmed significantly higher baseline levels of serum C5a (24.5 ± 39.0 ng/mL) and TCC (11.03 ± 8.52 µg/mL) in patients compared to healthy controls (p < 0.01 and p < 0.0001, respectively). Furthermore, systemic NETosis was significantly augmented in patients (5.87 (±3.71) × 106 neutrophils/mL) compared to healthy controls (0.82 (±0.74) × 106 neutrophils/mL) (p < 0.0001). In tracheal fluid, baseline TCC levels but not C5a and NETosis, were significantly higher in patients. Kinetic studies of systemic complement activation revealed markedly higher levels of TCC and CRP in nonsurvivors compared to survivors. In contrast, kinetic studies showed decreased local NETosis in tracheal fluid but comparable local complement activation in nonsurvivors compared to survivors. Systemic TCC and NETosis were significantly correlated with inflammation and coagulation markers. We propose that a ratio comprising systemic inflammation, complement activation, and chest X-ray score could be rendered as a predictive parameter of patient outcome in severe SARS-CoV-2 infections.
8
Mutch, Nicola J. "Polyphosphate as a haemostatic modulator." Biochemical Society Transactions 44, no. 1 (2016): 18–24. http://dx.doi.org/10.1042/bst20150207.
Texto completoResumen
Platelets are small anuclear cells that play a central role in haemostasis. Platelets become activated in response to various stimuli triggering release of their granular contents into the surrounding milieu. One of these types of granules, termed dense granules, have been found to contain polyphosphate (polyP) in addition to other inorganic biomolecules, such as serotonin, ADP, ATP, PPi. Individuals deficient in dense granules exhibit bleeding tendencies, emphasizing their importance in haemostasis. Platelet polyP is of a relatively defined size, approximately 60–100 phosphate monomers in length. These linear polymers act at various points in the coagulation and fibrinolytic systems thereby modulating the haemostatic response. Due to its highly anionic nature, polyP lends itself to being a natural activator of the contact system. The contact system functions in multiple pathways including coagulation, fibrinolysis, inflammation and complement. Activation of the contact system accelerates thrombin generation, the terminal enzyme in the coagulation cascade. PolyP also modulates factors further downstream in the coagulation cascade to augment thrombin generation. The net effect is increased fibrin formation and platelet activation resulting in faster clot formation. PolyP is incorporated into the forming clot thereby modifying the structure of the resulting fibrin network and its susceptibility to degradation by certain plasminogen activators. In conclusion, release of platelet polyP at the site of injury may facilitate clot formation and augment clot stability thereby promoting wound healing.
9
Tiwari, Ritudhwaj, Anurag R. Mishra, Flora Mikaeloff, et al. "In silico and in vitro studies reveal complement system drives coagulation cascade in SARS-CoV-2 pathogenesis." Computational and Structural Biotechnology Journal 18 (2020): 3734–44. http://dx.doi.org/10.1016/j.csbj.2020.11.005.
Texto completo
10
Bazargani, Farhan, Russell P. Rother, and Magnus Braide. "The Roles of Complement Factor C5a and CINC-1 in Glucose Transport, Ultrafiltration, and Neutrophil Recruitment during Peritoneal Dialysis." Peritoneal Dialysis International: Journal of the International Society for Peritoneal Dialysis 26, no. 6 (2006): 688–96. http://dx.doi.org/10.1177/089686080602600614.
Texto completoResumen
Background In a recent experimental study, we showed that low molecular weight heparin improved ultrafiltration and blocked complement activation and coagulation in a single peritoneal dialysis (PD) dwell. Objective The aim of the present study was to evaluate the possible contribution of the complement factor C5a and the potential interactions between C5a, the coagulation system, and cytokines of the interleukin (IL)-8 family (cytokine-induced neutrophil chemoattractant; CINC-1). Methods Nonuremic rats were exposed through an indwelling catheter to a single dose of 20 mL glucose- (2.5%) based filter-sterilized PD fluid, with or without the addition of anti-rat C5 antibody. The dwell fluid was analyzed 2 and 4 hours later concerning activation of the coagulation cascades, neutrophil recruitment, ultrafiltration volume; CINC-1, glucose, urea, and histamine concentrations; and ex vivo intraperitoneal chemotactic activity. Results The numbers of neutrophils and levels of thrombin–antithrombin complex (TAT) and CINC-1 increased significantly during the PD dwell. C5 blockade significantly reduced the levels of TAT and increased the ultrafiltration volumes at 2 hours. Glucose concentrations were significantly positively correlated to ultrafiltration volumes. Conclusions Blockade of C5 leads to an increase in ultra-filtration, probably by a mechanism that involves a reduction in glucose transport. This effect may form a basis for improving PD efficiency in situations where high glucose transport limits ultrafiltration. Mechanisms connected to complement activation during PD may involve coagulation. Further studies of the intraperitoneal cascade systems under conditions of PD are indicated.
11
Cugno, Massimo, and Angelo Agostini. "Influence of Contact System Deficiencies during Cardiopulmonary Bypass." Thrombosis and Haemostasis 85, no. 02 (2001): 191–92. http://dx.doi.org/10.1055/s-0037-1615673.
Texto completoResumen
SummaryAs a result of the expanding indications for cardiopulmonary bypass (CPB) there is a growing number of patients undergoing this procedure who are at high surgical risk, and increasing efforts to investigate the mechanisms involved in CPB complications are warranted. Blood contact with foreign surfaces triggers systemic inflammatory response and may induce coagulation (1), this is believed to be responsible of most of the unwanted effects associated with CPB. During this procedure, contact phase activation occurs (2), involving factor XII (FXII), prekallikrein (PK) and high molecular weight kininogen (HK). FXII binds to negatively charged surfaces undergoing autoactivation with cleavage of Arg353-Val354 to form a two-chain molecule of 80 kD, i.e. activated FXII (FXIIa, also known as FXIIa). FXIIa can cleave PK to kallikrein which in turn cleaves FXII to produce FXIIa and a factor XII fragment of 28-30 kD (FXIIf, also known as FXIIa) and cleaves HK to HKa generating the nonapeptide bradykinin. FXIIa can cleave both FXI and PK to active enzymes, while FXIIf (which cannot bind to surfaces) cleaves PK (2) and the first component of complement (C1) (3). These mechanisms of activation differ from those initiating the coagulation cascade during in vivo haemostasis through the tissue factor pathway as a result of tissue injury (4).
12
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 (2019): 616. http://dx.doi.org/10.3390/v11070616.
Texto completoResumen
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.
13
Ayass, Mohamad Ammar, Wanying Cao, Jin Zhang, et al. "Noninvasive nasopharyngeal proteomics of COVID-19 patient identify abnormalities related to complement and coagulation cascade and mucosal immune system." PLOS ONE 17, no. 9 (2022): e0274228. http://dx.doi.org/10.1371/journal.pone.0274228.
Texto completoResumen
Serum or plasma have been the primary focus of proteomics studies for COVID-19 to identity biomarkers and potential drug targets. The nasal mucosal environment which consists of lipids, mucosal immune cells, and nasal proteome, has been largely neglected but later revealed to have critical role combating SARS-CoV-2 infection. We present a bottom-up proteomics investigation of the host response to SARS-CoV-2 infection in the nasopharyngeal environment, featuring a noninvasive approach using proteins in nasopharyngeal swabs collected from groups of 76 SARS-CoV-2 positive and 76 negative patients. Results showed that 31 significantly down-regulated and 6 up-regulated proteins were identified (p < 0.05, log2 FC > 1.3) in SARS-CoV-2 positive patient samples as compared to the negatives; these proteins carry potential value as markers for the early detection of COVID-19, disease monitoring, as well as be drug targets. The down-regulation of coagulation factor 5 indicates a thrombotic abnormality in COVID-19 patients and the decreased IgG4 suggests an abnormal immune response at the point of entry in human nasopharyngeal environment, which is in consistent with KEGG and GO pathway analysis. Our study also demonstrated that mass spectrometry proteomics analysis of nasopharyngeal swabs can be used as a powerful early approach to evaluate host response to SARS-CoV-2 viral infection.
14
Rekker, Kadri, Merli Saare, Elo Eriste, et al. "High-throughput mRNA sequencing of stromal cells from endometriomas and endometrium." Reproduction 154, no. 1 (2017): 93–100. http://dx.doi.org/10.1530/rep-17-0092.
Texto completoResumen
The aetiology of endometriosis is still unclear and to find mechanisms behind the disease development, it is important to study each cell type from endometrium and ectopic lesions independently. The objective of this study was to uncover complete mRNA profiles in uncultured stromal cells from paired samples of endometriomas and eutopic endometrium. High-throughput mRNA sequencing revealed over 1300 dysregulated genes in stromal cells from ectopic lesions, including several novel genes in the context of endometriosis. Functional annotation analysis of differentially expressed genes highlighted pathways related to cell adhesion, extracellular matrix–receptor interaction and complement and coagulation cascade. Most importantly, we found a simultaneous upregulation of complement system components and inhibitors, indicating major imbalances in complement regulation in ectopic stromal cells. We also performed in vitro experiments to evaluate the effect of endometriosis patients’ peritoneal fluid (PF) on complement system gene expression levels, but no significant impact of PF on C3, CD55 and CFH levels was observed. In conclusion, the use of isolated stromal cells enables to determine gene expression levels without the background interference of other cell types. In the future, a new standard design studying all cell types from endometriotic lesions separately should be applied to reveal novel mechanisms behind endometriosis pathogenesis.
15
Scambi, C., D. Biasi, S. Ugolini, et al. "AB0125 The crosstalk between the complement system and the coagulation cascade in the antiphospholipid syndrome. preliminary data from basic research." Annals of the Rheumatic Diseases 72, Suppl 3 (2013): A823.3—A824. http://dx.doi.org/10.1136/annrheumdis-2013-eular.2448.
Texto completo
16
Maroney, Susan, Julie Peterson, Wes Zwifelhofer, et al. "Plasma Proteolytic Cascade Activation during Neonatal Cardiopulmonary Bypass Surgery." Thrombosis and Haemostasis 118, no. 09 (2018): 1545–55. http://dx.doi.org/10.1055/s-0038-1667198.
Texto completoResumen
Background Neonates undergoing cardiopulmonary bypass (CPB) surgery to correct congenital heart defects often experience excessive bleeding. Exposure of blood to artificial materials during CPB may activate coagulation, complement and inflammatory pathways. In addition, the surgical stress placed on the haemostatic system may result in cross-activation of other plasma proteolytic cascades, which could further complicate physiological responses to the surgical procedure and post-operative recovery. Plasma protease inhibitors undergo distinct conformational changes upon interaction with proteases, and, thereby, can serve as endogenous biosensors to identify activation of the different proteolytic cascades. We tested the hypothesis that changes in the concentration and conformation of protease inhibitors regulating plasma proteolytic cascades during neonatal CPB are associated with post-operative bleeding. Patients and Methods Plasma samples from 44 neonates were obtained at four time points across the surgical procedure. Anti-thrombin, antitrypsin, anti-chymotrypsin, anti-plasmin, C1-inhibitor and tissue factor pathway inhibitor (TFPI) concentrations and conformations were evaluated by enzyme-linked immunosorbent assay, transverse urea gradient gel electrophoresis and sodium dodecyl sulphate-polyacrylamide gel electrophoresis. Results/Conclusion The most striking changes were observed following heparin administration and were associated with the appearance of inactive forms of anti-thrombin and an increase in the plasma concentration of TFPI. Changes in anti-thrombin and TFPI remained evident throughout surgery and into the post-operative period but were not different between patients with or without post-operative bleeding. The concentration of antitrypsin decreased across surgery, but there was no significant accumulation of inactive conformations of any inhibitor besides anti-thrombin, indicating that widespread cross-activation of other plasma proteolytic cascades by coagulation proteases did not occur.
17
Scholz, Tim, Rigmor Solberg, Cecilie Okkenhaug, et al. "Veno-venous bypass in liver transplantation: heparin-coated perfusion circuits reduce the activation of humoral defense systems in an in vitro model." Perfusion 16, no. 4 (2001): 285–92. http://dx.doi.org/10.1177/026765910101600404.
Texto completoResumen
We studied the effects of bypass circuit surface heparinization on kallikrein-kinin, coagulation, fibrinolytic and complement activation in a closed model system for simulating veno-venous bypass (VVBP) in orthotopic liver transplantation (OLT). The circuits were identical to those in routine use during clinical OLT in our institution. Fresh whole human blood diluted 1: 2 with Ringer’s acetate was circulated at a non-pulsatile flow (2 l/min) and at a constant temperature (37.5°C) for 12 h. In 10 experiments, the entire inner surface of the circuits was coated with end-point attached heparin (HC). In the remaining 10, non-treated PVC tubing was used (NC). Components of the plasma kallikrein-kinin, coagulation, fibrinolytic and complement systems were analyzed using functional techniques (chromogenic peptide substrate assays) and enzyme immunoassays at baseline, 3 and 12 h. Significant activation of the initial (C3bc) and terminal (TCC) components of the complement system were found in both the NC and HC groups after 3 and 12 h: C3bc: NC: baseline =4 (3.5-7.7), 3 h=17.3* (12.5-27), 12 h=31* (17.7-63.6), HC: baseline=4.9 (3.2-6.8), 3 h=9* (6-14.4), 12 h=13.7* (7.4-18.1). TCC: NC: baseline=0.4 (0.2-0.6), 3 h=5* (0.8-11.9), 12 h: 13.1* (4.2-25.7). HC: baseline=0.5 (0.1-0.6), 3 h=0.6* (0.1-0.8), 12 h=1.2* (0.3-2) AU/ml; median and range (*: p<0.05). The C3bc and TCC concentrations were significantly higher in the NC group at 3 and 12 h, compared to the HC group: C3bc (NC vs. HC group): 3 h, p<0.001; 12 h, p<0.001. TCC (NC vs. HC group): 3 h, p<0.001; 12 h, p<0.001. Significant increases in the values of thrombin-antithrombin complexes ( p<0.003), prothrombin fragment 1+2 ( p<0.006) and plasmin-α2-antiplasmin complexes ( p=0.016) were found in the non-coated group, but not in the heparin-coated group during the observation period, showing that the coagulation and fibrinolytic systems were activated in the non-coated circuits. We conclude that heparin-coating of the internal surface of the extracorporeal perfusion circuit used for VVBP reduces activation of the plasma cascade systems in a closed venous system in vitro.
18
Jarczak, Dominik, Stefan Kluge, and Axel Nierhaus. "Use of Intravenous Immunoglobulins in Sepsis Therapy—A Clinical View." International Journal of Molecular Sciences 21, no. 15 (2020): 5543. http://dx.doi.org/10.3390/ijms21155543.
Texto completoResumen
Sepsis is a life-threatening organ dysfunction, defined by a dysregulated host immune response to infection. During sepsis, the finely tuned system of immunity, inflammation and anti-inflammation is disturbed in a variety of ways. Both pro-inflammatory and anti-inflammatory pathways are upregulated, activation of the coagulation cascade and complement and sepsis-induced lymphopenia occur. Due to the manifold interactions in this network, the use of IgM-enriched intravenous immunoglobulins seems to be a promising therapeutic approach. Unfortunately, there is still a lack of evidence-based data to answer the important questions of appropriate patient populations, optimal timing and dosage of intravenous immunoglobulins. With this review, we aim to provide an overview of the role of immunoglobulins, with emphasis on IgM-enriched formulations, in the therapy of adult patients with sepsis and septic shock.
19
Hoffmeister, H. M., M. Ruf, H. P. Wendel, et al. "Activation of the contact phase of the coagulation, of the kinin system and of the complement cascade by streptokinase in acute myocardial infarction." Fibrinolysis and Proteolysis 11 (August 1997): 149–52. http://dx.doi.org/10.1016/s0268-9499(97)80089-6.
Texto completo
20
Dahlbäck, Björn. "Protein S and C4b-Binding Protein: Components Involved in the Regulation of the Protein C Anticoagulant System." Thrombosis and Haemostasis 66, no. 01 (1991): 049–61. http://dx.doi.org/10.1055/s-0038-1646373.
Texto completoResumen
SummaryThe protein C anticoagulant system provides important control of the blood coagulation cascade. The key protein is protein C, a vitamin K-dependent zymogen which is activated to a serine protease by the thrombin-thrombomodulin complex on endothelial cells. Activated protein C functions by degrading the phospholipid-bound coagulation factors Va and VIIIa. Protein S is a cofactor in these reactions. It is a vitamin K-dependent protein with multiple domains. From the N-terminal it contains a vitamin K-dependent domain, a thrombin-sensitive region, four EGF)epidermal growth factor (EGF)-like domains and a C-terminal region homologous to the androgen binding proteins. Three different types of post-translationally modified amino acid residues are found in protein S, 11 γ-carboxy glutamic acid residues in the vitamin K-dependent domain, a β-hydroxylated aspartic acid in the first EGF-like domain and a β-hydroxylated asparagine in each of the other three EGF-like domains. The EGF-like domains contain very high affinity calcium binding sites, and calcium plays a structural and stabilising role. The importance of the anticoagulant properties of protein S is illustrated by the high incidence of thrombo-embolic events in individuals with heterozygous deficiency. Anticoagulation may not be the sole function of protein S, since both in vivo and in vitro, it forms a high affinity non-covalent complex with one of the regulatory proteins in the complement system, the C4b-binding protein (C4BP). The complexed form of protein S has no APC cofactor function. C4BP is a high molecular weight multimeric protein with a unique octopus-like structure. It is composed of seven identical α-chains and one β-chain. The α-and β-chains are linked by disulphide bridges. The cDNA cloning of the β-chain showed the α- and β-chains to be homologous and of common evolutionary origin. Both subunits are composed of multiple 60 amino acid long repeats (short complement or consensus repeats, SCR) and their genes are located in close proximity on chromosome 1, band 1q32. Available experimental data suggest the β-chain to contain the single protein S binding site on C4BP, whereas each of the α-chains contains a binding site for the complement protein, C4b. As C4BP lacking the β-chain is unable to bind protein S, the β-chain is required for protein S binding, but not for the assembly of the α-chains during biosynthesis. Protein S has a high affinity for negatively charged phospholipid membranes, and is instrumental in binding C4BP to negatively charged phospholipid. This constitutes a novel mechanism for control of the complement system on phospholipid surfaces. Recent findings have shown circulating C4BP to be involved in yet another calcium-dependent protein-protein interaction with a protein known as the serum amyloid P-component (SAP). The binding sites on C4BP for protein S and SAP are independent. SAP, which is a normal constituent in plasma and in tissue, is a so-called pentraxin being composed of 5 non-covalently bound 25 kDa subunits. It is homologous to C reactive protein (CRP) but its function is not yet known. The specific high affinity interactions between protein S, C4BP and SAP suggest the regulation of blood coagulation and that of the complement system to be closely linked.
21
Satué, K., J. C. Gardón, and A. Muñoz. "Interpretation of Platelets in The Horse." Journal of Hematology Research 4 (February 27, 2017): 19–25. http://dx.doi.org/10.12974/2312-5411.2017.04.3.
Texto completoResumen
Currently we can consider that, in addition to its role in hemostasis, platelets also participate in other important processes such as thrombosis, inflammation, tissue remodeling and the innate defense mechanisms. The hemostatic activity of platelets includes different events to stop bleeding. Within these functions we can mention the adhesion to the endothelium of the affected blood vessel, the activation, the aggregation, and the release of substances that initiate hemostatic events, and also the providing a phospholipid surface for activation of numerous coagulation factors. Similarly, platelets release multiple growth factors responsible for regulating the growth and division of endothelial cells and fibroblasts. In this way, among other things, angiogenesis and tissue regeneration are favored. Platelets also participate in inflammatory processes by the release of factors that initiate the inflammatory cascade and favor the chemotaxis of neutrophils, monocytes, macrophages, acute phase proteins and target cell signaling. Finally, platelets participate in the immune response by interacting with the complement system and immunoglobulins.
22
Gustafson, Elisabet, Sana Asif, Huda Kozarcanin, et al. "Control of IBMIR Induced by Fresh and Cryopreserved Hepatocytes by Low Molecular Weight Dextran Sulfate versus Heparin." Cell Transplantation 26, no. 1 (2017): 71–81. http://dx.doi.org/10.3727/096368916x692609.
Texto completoResumen
Rapid destruction of hepatocytes after hepatocyte transplantation has hampered the application of this procedure clinically. The instant blood-mediated inflammatory reaction (IBMIR) is a plausible underlying cause for this cell loss. The present study was designed to evaluate the capacity of low molecular weight dextran sulfate (LMW-DS) to control these initial reactions from the innate immune system. Fresh and cryopreserved hepatocytes were tested in an in vitro whole-blood model using ABO-compatible blood. The ability to elicit IBMIR and the capacity of LMW-DS (100 μg/ml) to attenuate the degree of activation of the cascade systems were monitored. The effect was also compared to conventional anticoagulant therapy using unfractionated heparin (1 IU/ml). Both fresh and freeze–thawed hepatocytes elicited IBMIR to the same extent. LMW-DS reduced the platelet loss and maintained the cell counts at the same degree as unfractionated heparin, but controlled the coagulation and complement systems significantly more efficiently than heparin. LMW-DS also attenuated the IBMIR elicited by freeze–thawed cells. Therefore, LMW-DS inhibits the cascade systems and maintains the cell counts in blood triggered by both fresh and cryopreserved hepatocytes in direct contact with ABO-matched blood. LMW-DS at a previously used and clinically applicable concentration (100 μg/ml) inhibits IBMIR in vitro and is therefore a potential IBMIR inhibitor in hepatocyte transplantation.
23
Elek, N., S. Sandor, G. Balazs, and P. Dahlem. "Pediatric Sepsis: Genetic Considerations." Journal of Child Science 07, no. 01 (2017): e76-e88. http://dx.doi.org/10.1055/s-0037-1603803.
Texto completoResumen
AbstractThe mortality of childhood sepsis continues to be rather high. When it comes to prevention and adequate therapy, individual differences and genetic alterations are becoming more and more important. These may affect molecules involved in pathogen recognition (e.g., lipopolysaccharide-binding protein, mannose-binding lectin, bactericidal/permeability-increasing protein, Toll-like receptors), signal transduction pathways (e.g., cRel), proinflammatory (e.g., tumor necrosis factor-α, interleukin-1 [IL-1], IL-6, IL-8) as well as anti-inflammatory cytokines (e.g., IL-4, IL-10, IL-1 receptor antagonist), members of the coagulation cascade, and other molecules active in the process of systemic inflammatory response syndrome (e.g., heat shock proteins, complement system). The most common genetic polymorphisms are the so-called single-nucleotide polymorphisms, which entail the change of a single base. Genetic mutations have an impact on susceptibility, severity, and outcome of sepsis. Understanding such mutations may improve treatment efficiency; although there is a considerably limited choice of causal treatments today, they may become available upon future developments in genetic therapy.
24
Ratajczak, Mariusz Z., and Janina Ratajczak. "Innate Immunity Communicates Using the Language of Extracellular Microvesicles." Stem Cell Reviews and Reports 17, no. 2 (2021): 502–10. http://dx.doi.org/10.1007/s12015-021-10138-6.
Texto completoResumen
AbstractThe innate immunity system and extracellular microvesicles (ExMVs) both emerged early in the evolution of life, which is why its innate immunity cellular arm and its soluble-component arm learned, understood, and adapted to the “language” of ExMVs. This was most likely the first language of cell–cell communication during evolution, which existed before more specific intercellular crosstalk involving specific ligands and receptors emerged. ExMVs are involved in several processes in the body, including immune and coagulation responses, which are part of inflammation. In this review we will briefly highlight what is known about how ExMVs regulate the function of the cellular arm of innate immunity, including macrophages, monocytes, granulocytes, natural killer cells, and dendritic cells, and affect the soluble components of this system, which consists of the complement cascade (ComC) and soluble, circulating, pattern-recognition receptors (collectins, ficolins, and pentaxrins). These effects are direct, due to the fact that ExMVs affect the biological functions of innate immunity cells and may directly interact with soluble components of this system. Moreover, by activating coagulation proteases, ExMVs may also indirectly activate the ComC. In this review, we will use the term “extracellular microvesicles” (ExMVs) to refer to these small, spheroidal blebs of different sizes, which are surrounded by a membrane lipid layer. We will focus on the role of both ExMVs released during cell-surface membrane budding and smaller ExMVs, known as exosomes, which are derived from the budding of the endosomal membrane compartment. Finally, we will provide a brief update on the potential therapeutic applications of ExMVs, with a special emphasis on innate immunity. Graphical Abstract
25
Tu, Chengcheng, Feng Tao, Ying Qin, et al. "Serum proteins differentially expressed in early- and late-onset preeclampsia assessed using iTRAQ proteomics and bioinformatics analyses." PeerJ 8 (September 1, 2020): e9753. http://dx.doi.org/10.7717/peerj.9753.
Texto completoResumen
Background Preeclampsia remains a serious disorder that puts at risk the lives of perinatal mothers and infants worldwide. This study assessed potential pathogenic mechanisms underlying preeclampsia by investigating differentially expressed proteins (DEPs) in the serum of patients with early-onset preeclampsia (EOPE) and late-onset preeclampsia (LOPE) compared with healthy pregnant women. Methods Blood samples were collected from four women with EOPE, four women with LOPE, and eight women with normal pregnancies, with four women providing control samples for each preeclampsia group. Serum proteins were identified by isobaric tags for relative and absolute quantitation combined with liquid chromatography–tandem mass spectrometry. Serum proteins with differences in their levels compared with control groups of at least 1.2 fold-changes and that were also statistically significantly different between the groups at P < 0.05 were further analyzed. Bioinformatics analyses, including gene ontology and Kyoto Encyclopedia of Genes and Genomes signaling pathway analyses, were used to determine the key proteins and signaling pathways associated with the development of PE and to determine those DEPs that differed between women with EOPE and those with LOPE. Key protein identified by mass spectrometry was verified by enzyme linked immunosorbent assay (ELISA). Results Compared with serum samples from healthy pregnant women, those from women with EOPE displayed 70 proteins that were differentially expressed with significance. Among them, 51 proteins were significantly upregulated and 19 proteins were significantly downregulated. In serum samples from women with LOPE, 24 DEPs were identified , with 10 proteins significantly upregulated and 14 proteins significantly downregulated compared with healthy pregnant women. Bioinformatics analyses indicated that DEPs in both the EOPE and LOPE groups were associated with abnormalities in the activation of the coagulation cascade and complement system as well as with lipid metabolism. In addition, 19 DEPs in the EOPE group were closely related to placental development or invasion of tumor cells. Downregulationof pregnancy-specific beta-1-glycoprotein 9 (PSG9) in the LOPE group was confirmed by ELISA. Conclusion The pathogenesis of EOPE and LOPE appeared to be associated with coagulation cascade activation, lipid metabolism, and complement activation. However, the pathogenesis of EOPE also involved processes associated with greater placental injury. This study provided several new proteins in the serum which may be valuable for clinical diagnosis of EOPE and LOPE, and offered potential mechanisms underpinning the development of these disorders.
26
Jacobi, Judith. "The pathophysiology of sepsis—2021 update: Part 1, immunology and coagulopathy leading to endothelial injury." American Journal of Health-System Pharmacy 79, no. 5 (2021): 329–37. http://dx.doi.org/10.1093/ajhp/zxab380.
Texto completoResumen
Abstract Purpose To provide an overview of current literature on the pathophysiology of sepsis, with a focus on mediators of endothelial injury and organ dysfunction. Summary Sepsis is a dysregulated response to infection that triggers cascades of interconnected systems. Sepsis has been a significant cause of mortality worldwide, and the recent viral pandemic that may produce severe sepsis and septic shock has been a major contributor to sepsis-related mortality. Understanding of the pathophysiology of sepsis has changed dramatically over the last several decades. Significant insight into the components of the inflammatory response that contribute to endothelial injury and trigger coagulation pathways has been achieved. Similarly, characterization of anti-inflammatory pathways that may lead to secondary infections and poor outcome has illustrated opportunities for improved therapies. Description of an increasing number of important mediators and pathways has occurred and may point the way to novel therapies to address immune dysregulation. Pharmacists will need a fundamental understanding of the overlapping pathways of the immune response to fully prepare for use of novel treatment options. While pharmacists typically understand coagulation cascade how to utilize anticoagulants, the issues in sepsis related coagulopathy and role of mediators such as cytokines and complement and role of activated platelets and neutrophils require a different perspective. Conclusion Pharmacists can benefit from understanding both the cellular and organ system issues in sepsis to facilitate assessment of potential therapies for risk and benefit.
27
Montilla, Marcela, Andrea Liberato, Pablo Ruiz-Ocaña, et al. "Proinflammatory Polyphosphate Increases in Plasma of Obese Children with Insulin Resistance and Adults with Severe Type 2 Diabetes." Nutrients 14, no. 21 (2022): 4601. http://dx.doi.org/10.3390/nu14214601.
Texto completoResumen
Obesity increases the risk of insulin resistance and type 2 diabetes through increased inflammation at cellular and tissue levels. Therefore, study of the molecular elements involved in obesity-related inflammation may contribute to preventing and controlling it. Inorganic polyphosphate is a natural phosphate polymer that has recently been attracting more attention for its role in inflammation and hemostasis processes. Polyphosphates are one of the main constituents of human platelets, which are secreted after platelet activation. Among other roles, they interact with multiple proteins of the coagulation cascade, trigger bradykinin release, and inhibit the complement system. Despite its importance, determinations of polyphosphate levels in blood plasma had been elusive until recently, when we developed a method to detect these levels precisely. Here, we perform cross sectional studies to evaluate plasma polyphosphate in: 25 children, most of them with obesity and overweight, and 20 adults, half of them with severe type 2 diabetes. Our results show that polyphosphate increases, in a significant manner, in children with insulin resistance and in type 2 diabetes patients. As we demonstrated before that polyphosphate decreases in healthy overweight individuals, these results suggest that this polymer could be an inflammation biomarker in the metabolic disease onset before diabetes.
28
Adamiak, Mateusz, Malwina Suszynska, Ahmed Abdel-Latif, et al. "Novel Evidence That the Mannan-Binding Lectin (MBL) Pathway of Complement Activation Plays a Pivotal Role in Triggering Mobilization of Hematopoietic Stem/Progenitor Cells By Activation of Both the Complement and Coagulation Cascades." Blood 128, no. 22 (2016): 3371. http://dx.doi.org/10.1182/blood.v128.22.3371.3371.
Texto completoResumen
Abstract Background . The complement cascade (ComC), which is part of the innate immune system, exerts several pleiotropic effects, and, as we have demonstrated, it is required for mobilization of hematopoietic stem/progenitor cells (HSPCs) during infection or tissue/organ injury as well as in response to administration of pharmacological mobilizing agents, such as G-CSF or AMD3100 (Blood 2004, 103, 2071-2078). The ComC is activated by three pathways: the classical, mannan-binding lectin (MBL), and alternative pathways. Activation of the ComC and generation of cleavage fragments of the fifth component of the ComC (C5), such as C5a, desArgC5a, and C5b, by classical C5 convertase initiates events that are required for egress of HSPCs from bone marrow (BM) into peripheral blood (PB) (Leukemia 2009, 23, 2052-2062). Recent results indicate that the coagulation cascade (CoaC) is activated in parallel with activation of the ComC during the mobilization process and plays a supportive role, because thrombin has "C5 convertase-like activity" (Leukemia 2014, 28, 2148-2154). While a requirement for ComC activation and the pivotal roles of the distal part of complement activation and the generation of C5 cleavage fragments have been previously demonstrated (Leukemia 2009, 23, 2052-2062), mice with mutations in components of the classical pathway (C1q-/- mice), in which the distal pathway of C5 activation remained intact, do not show impairment of HSPC mobilization (Leukemia 2010, 24, 1667-1675). Aim of the study. Since no studies have yet been performed to address the role of the MBL pathway in triggering the mobilization of HSPCs, we became interested in its involvement in both ComC and CoaC activation after administration of G-CSF or AMD3100. The MBL pathway is homologous to the classical pathway but contains a soluble MBL receptor instead of C1q, and MBL functions as activator of the MBL-associated serine proteases, MASP-1 and MASP-2, which are activated downstream of both the ComC and the CoaC. Hypothesis. We hypothesized that the MBL-initiated ComC and CoaC activation pathways are involved in triggering mobilization of HSPCs and that MBL deficiency may result in poor mobilization efficiency.Materials and Methods. In our experiments, 2-month-old, MBL-deficient (MBL-/-) and MASP-1-deficient (MASP-1-/-) mice as well as their normal wild type (WT) littermates were mobilized with G-CSF or AMD3100. Following mobilization, we measured i) the total number of white blood cells (WBCs), ii) the number of circulating clonogenic colony-forming unit granulocyte/macrophage (CFU-GM) progenitors, and iii) the number of Sca-1+c-kit+lineage- (SKL) cells in PB. In parallel, we evaluated activation of the ComC after administration of G-CSF and AMD3100 in experimental animals by employing C5a ELISA. To address the role of the CoaC in MBL-MASP-1- and MBL-MASP-2-induced mobilization, MBL-/- mice were treated with inhibitors of the CoaC (refludan) in some of the experiments. Results. We found that the MBL-MASP ComC activation pathway is involved in pharmacological G-CSF- and AMD3100-induced mobilization of HSPCs. As predicted, MBL-/- and MASP-1-/- mice were found to be poor mobilizers. Furthermore, inhibition of the CoaC by refludan inhibited mobilization in wild type animals but did not generate the additional defects seen in MBL-/- mice. Conclusions. We identified a previously unrecognized role for the MBL-MASP-1 pathway in triggering ComC and CoaC activation in the HSPC mobilization process. This finding explains the pivotal role of the MBL pathway in triggering activation of the proximal part of the ComC and explains why, even with a deficiency in activation of classical pathway components (C1q), mobilization of HSPCs proceeds normally as long as the MBL pathway is intact. Taking into consideration that ~10% of normal people are poor activators of the MBL pathway and that this percentage corresponds with the ~10% of the normal healthy population that are poor mobilizers, we are currently investigating whether MBL deficiency correlates with poor mobilization status in patients. MBL could be an important predictive parameter for identifying poor mobilizers. Disclosures No relevant conflicts of interest to declare.
29
Lim, Jongwon, and Suhee Hong. "Transcriptome Analysis in the Head Kidney of Rainbow Trout (Oncorhynchus mykiss) Immunized with a Combined Vaccine of Formalin-Inactivated Aeromonas salmonicida and Vibrio anguillarum." Vaccines 9, no. 11 (2021): 1234. http://dx.doi.org/10.3390/vaccines9111234.
Texto completoResumen
This study aimed to identify the molecular mechanisms regulated by a combined vaccine against Aeromonas salmonicida and Vibrio anguillarum (O1 serotype). These bacteria cause furunculosis and vibriosis, respectively, and are associated with a high mortality in rainbow trout in Korea. The vaccine upregulated gene expression of TCRα, T-bet, sIgM, and mIgM, markers of an activated adaptive immune response. On days 1, 3, and 5, transcriptome analysis revealed 862 (430 up- and 432 downregulated), 492 (204 up- and 288 downregulated), and 741 (270 up- and 471 downregulated) differentially expressed genes (DEGs), respectively. Gene ontology (GO) enrichment analysis identified 377 (108 MF, 132 CC, 137 BP), 302 (60 MF, 180 CC, 62 BP), and 314 (115 MF, 129 CC, 70 BP) GOs at days 1, 3, and 5, respectively. Kyoto Encyclopedia of Genetic and Genomic enrichment analysis identified eight immune system-related pathways like cytokine-cytokine receptor interaction, NF-kappaB signaling pathway, TNF signaling pathway, NOD-like receptor signaling pathway, cytosolic DNA sensing pathway, cell adhesion molecule, complement and coagulation cascade, and antigen processing and presentation. In the analysis of the protein–protein interaction of immune-related DEGs, a total of 59, 21, and 21 interactional relationships were identified at days 1, 3, and 5, respectively, with TNF having the highest centrality at all three time points.
30
Bertholim, Luciana, Alison F. A. Chaves, Ana K. Oliveira, et al. "Systemic Effects of Hemorrhagic Snake Venom Metalloproteinases: Untargeted Peptidomics to Explore the Pathodegradome of Plasma Proteins." Toxins 13, no. 11 (2021): 764. http://dx.doi.org/10.3390/toxins13110764.
Texto completoResumen
Hemorrhage induced by snake venom metalloproteinases (SVMPs) is a complex phenomenon that involves capillary disruption and blood extravasation. HF3 (hemorrhagic factor 3) is an extremely hemorrhagic SVMP of Bothrops jararaca venom. Studies using proteomic approaches revealed targets of HF3 among intracellular and extracellular proteins. However, the role of the cleavage of plasma proteins in the context of the hemorrhage remains not fully understood. The main goal of this study was to analyze the degradome of HF3 in human plasma. For this purpose, approaches for the depletion of the most abundant proteins, and for the enrichment of low abundant proteins of human plasma, were used to minimize the dynamic range of protein concentration, in order to assess the proteolytic activity of HF3 on a wide spectrum of proteins, and to detect the degradation products using mass spectrometry-based untargeted peptidomics. The results revealed the hydrolysis products generated by HF3 and allowed the identification of cleavage sites. A total of 61 plasma proteins were identified as cleaved by HF3. Some of these proteins corroborate previous studies, and others are new HF3 targets, including proteins of the coagulation cascade, of the complement system, proteins acting on the modulation of inflammation, and plasma proteinase inhibitors. Overall, the data indicate that HF3 escapes inhibition and sculpts the plasma proteome by degrading key proteins and generating peptides that may act synergistically in the hemorrhagic process.
31
Jiang, Chao, Hengtao Guo, Zhiying Zhang, et al. "Molecular, Pathological, Clinical, and Therapeutic Aspects of Perihematomal Edema in Different Stages of Intracerebral Hemorrhage." Oxidative Medicine and Cellular Longevity 2022 (September 17, 2022): 1–38. http://dx.doi.org/10.1155/2022/3948921.
Texto completoResumen
Acute intracerebral hemorrhage (ICH) is a devastating type of stroke worldwide. Neuronal destruction involved in the brain damage process caused by ICH includes a primary injury formed by the mass effect of the hematoma and a secondary injury induced by the degradation products of a blood clot. Additionally, factors in the coagulation cascade and complement activation process also contribute to secondary brain injury by promoting the disruption of the blood-brain barrier and neuronal cell degeneration by enhancing the inflammatory response, oxidative stress, etc. Although treatment options for direct damage are limited, various strategies have been proposed to treat secondary injury post-ICH. Perihematomal edema (PHE) is a potential surrogate marker for secondary injury and may contribute to poor outcomes after ICH. Therefore, it is essential to investigate the underlying pathological mechanism, evolution, and potential therapeutic strategies to treat PHE. Here, we review the pathophysiology and imaging characteristics of PHE at different stages after acute ICH. As illustrated in preclinical and clinical studies, we discussed the merits and limitations of varying PHE quantification protocols, including absolute PHE volume, relative PHE volume, and extension distance calculated with images and other techniques. Importantly, this review summarizes the factors that affect PHE by focusing on traditional variables, the cerebral venous drainage system, and the brain lymphatic drainage system. Finally, to facilitate translational research, we analyze why the relationship between PHE and the functional outcome of ICH is currently controversial. We also emphasize promising therapeutic approaches that modulate multiple targets to alleviate PHE and promote neurologic recovery after acute ICH.
32
Demichev, Vadim, Pinkus Tober-Lau, Tatiana Nazarenko, et al. "A proteomic survival predictor for COVID-19 patients in intensive care." PLOS Digital Health 1, no. 1 (2022): e0000007. http://dx.doi.org/10.1371/journal.pdig.0000007.
Texto completoResumen
Global healthcare systems are challenged by the COVID-19 pandemic. There is a need to optimize allocation of treatment and resources in intensive care, as clinically established risk assessments such as SOFA and APACHE II scores show only limited performance for predicting the survival of severely ill COVID-19 patients. Additional tools are also needed to monitor treatment, including experimental therapies in clinical trials. Comprehensively capturing human physiology, we speculated that proteomics in combination with new data-driven analysis strategies could produce a new generation of prognostic discriminators. We studied two independent cohorts of patients with severe COVID-19 who required intensive care and invasive mechanical ventilation. SOFA score, Charlson comorbidity index, and APACHE II score showed limited performance in predicting the COVID-19 outcome. Instead, the quantification of 321 plasma protein groups at 349 timepoints in 50 critically ill patients receiving invasive mechanical ventilation revealed 14 proteins that showed trajectories different between survivors and non-survivors. A predictor trained on proteomic measurements obtained at the first time point at maximum treatment level (i.e. WHO grade 7), which was weeks before the outcome, achieved accurate classification of survivors (AUROC 0.81). We tested the established predictor on an independent validation cohort (AUROC 1.0). The majority of proteins with high relevance in the prediction model belong to the coagulation system and complement cascade. Our study demonstrates that plasma proteomics can give rise to prognostic predictors substantially outperforming current prognostic markers in intensive care.
33
Aggarwal, Manisha, Janitta Kundaikar, Dinesh Manchikanti, et al. "Gall bladder carcinoma associated with anticoagulation-resistant, progressive, multi-focal venous thrombosis and gangrene of all limbs: a case report and review of literature." International Surgery Journal 8, no. 5 (2021): 1625. http://dx.doi.org/10.18203/2349-2902.isj20211844.
Texto completoResumen
Cancer being a prothrombotic state, frequently has vascular complications, venous thrombosis, embolism, recurrent venous thromboembolism and a high frequency of anticoagulant failure. We present a rare case of anticoagulant-resistant, progressive, multifocal venous thrombosis and gangrene in all four limbs in a patient with carcinoma gallbladder. A 49 year old lady with locally advanced gallbladder cancer who had been on routine perioperative deep venous thrombosis (DVT) prophylaxis presented two months later with deep venous thrombosis of both lower limbs progressing to venous gangrene of both feet, despite being on anticoagulation. 7 days later, she presented with venous gangrene of both hands. Shortly thereafter, she developed right facial paralysis due to thrombus in the segmental branch of the left MCA despite being on anticoagulation. The hypercoagulable state in cancer involves procoagulant molecules produced by tumor cells, suppression of fibrinolytic activity and platelet activation and is contributed by interactions between the coagulation cascade, complement pathway and immune system. Upto 15% of patients with cancer will develop DVT following surgery, despite standard DVT prophylaxis. Extended DVT prophylaxis should be considered in high-risk patients. Patients with metastases should continue with indefinite anticoagulant therapy after a thrombotic event. In patients without metastasis, anticoagulant treatment is recommended for as long as the cancer is active and while the patient is receiving antitumor therapy. This rare case has been presented to highlight the hypercoagulable state of cancer, the importance of long-term anticoagulation in advanced and metastatic cancers and the high rate of anticoagulation failure associated with unfavourable tumor biology.
34
Spichiger, Carlos, Claudia Torres-Farfan, Hugo A. Galdames, Natalia Mendez, Pamela Alonso-Vazquez, and Hans G. Richter. "Gestation under chronic constant light leads to extensive gene expression changes in the fetal rat liver." Physiological Genomics 47, no. 12 (2015): 621–33. http://dx.doi.org/10.1152/physiolgenomics.00023.2015.
Texto completoResumen
Recent reports account for altered metabolism in adult offspring from pregnancy subjected to abnormal photoperiod, suggesting fetal programming of liver physiology. To generate a pipeline of subsequent mechanistic experiments addressing strong candidate genes, here we investigated the effects of constant gestational light on the fetal liver transcriptome. At 10 days of gestation, dams were randomized in two groups ( n = 7 each): constant light (LL) and normal photoperiod (12 h light/12 h dark; LD). At 18 days of gestation, RNA was isolated from the fetal liver and subjected to DNA microarray (Affymetrix platform for 28,000 genes). Selected differential mRNAs were validated by quantitative PCR (qPCR), while integrated transcriptional changes were analyzed with Ingenuity Pathway Analysis and other bioinformatics tools. Comparison of LL relative to LD fetal liver led to the following findings. Significant differential expression was found for 3,431 transcripts (1,960 upregulated and 1,471 downregulated), with 393 of them displaying ≥ 1.5-fold change. We validated 27 selected transcripts by qPCR, which displayed fold-change values highly correlated with microarray ( r2 = 0.91). Different markers of nonalcoholic fatty liver disease were either upregulated (e.g., Ndn and Pnpla3) or downregulated (e.g., Gnmt, Bhmt1/2, Sult1a1, Mpo, and Mat1a). Diverse pathways were altered, including hematopoiesis, coagulation cascade, complement system, and carbohydrate and lipid metabolism. The microRNAs 7a-1, 431, 146a, and 153 were upregulated, while the abundant hepatic miRNA 122 was downregulated. Constant gestational light induced extensive modification of the fetal liver transcriptome. A number of differentially expressed transcripts belong to fundamental functional pathways, potentially contributing to long-term liver disease.
35
Borkowska, Sylwia, Malwina Suszynska, Janina Ratajczak, and Mariusz Z. Ratajczak. "Mice Deficient in the Fifth Complement Cascade Protein (C5) Do Not Display Circadian Changes in the Number of Circulating Hematopoietic Stem/Progenitor Cells (HSPCs) in Peripheral Blood (PB)—evidence for the Pivotal Role of the Distal Part of the Complement Cascade in Inducing the Circadian Release of HSPCs into PB." Blood 124, no. 21 (2014): 1122. http://dx.doi.org/10.1182/blood.v124.21.1122.1122.
Texto completoResumen
Abstract Introduction. Activation of three ancient serum proteolytic cascades, the complement cascade (ComC), the coagulation cascade (CoaC), and the fibrynolytic cascade (FibC), is essential for release of hematopoietic stem progenitor cells (HSPCs) from bone marrow (BM) into peripheral blood (PB) during stress- or pharmacology-induced mobilization (Leukemia 2014,doi:10.1038/leu.2014.115). On the other hand, it has been convincingly demonstrated that there is a circadian oscillation in the number of circulating HSPCs in PB, with the peak occurring in the early morning hours and the nadir at night (Nature 2008, 452, 442-447 ). The timing of this peak has been attributed to the enhanced tonus of the vegetative nervous system in the early morning hours. In support of such a role for the vegetative nervous system, it has been shown that UDP-galactose:ceramide galactosyltransferase-deficient mice, which exhibit aberrant nerve conduction and do not release norepinephrine (NE) into the BM microenvironment, do not mobilize HSPCs. However, by contrast, modification of the sympathetic output, as seen in normal human HSPC volunteer donors receiving NE reuptake inhibitors (NRI) for depression or β2-blockers for hypertension, induces mobilization in a similar manner as normal controls (Leukemia 2013, 27, 24–31). Mobilization in these patients was neither enhanced by NRI administration nor suppressed by β2-blockers, as one would expect based on the murine data reported in the literature. Aim of the study. Since it is known that the ComC, CoaC, and FibC show circadian activation at late/night early morning hours due to deep sleep hypoxia, we became interested in the role of these proteolytic cascades in the circadian release of HSPCs from the BM into PB. Materials and Methods. To address this important question, we studied the circadian oscillation in the number of circulating HSPCs in C5-deficient (C5–/–) mice, which do not activate the distal part of the ComC, unlike their wild type (WT) littermates. Mice were accustomed to alternating periods of 12 hours light and 12 hours darkness. Light was turned on at 6 AM (T0), and the number of circulating white blood cells (WBC), Sca-1+kit+Lin– HSCs, Sca-1+Lin–CD45+ HSCs, clonogenic CFU-GM progenitors, and the number of non-hematopoietic Sca-1+Lin–CD45– (VSELs) were measured at 7 AM (T1), 11 AM (T5), 7 PM (T13), and 3 AM (T21). At the same time points, we evaluated activation of the ComC (by C5a ELISA), the CoaC (by thrombin/antithrombin ELISA), and the FibC (by plasmin/antiplasmin complex ELISA). Results. We observed circadian changes in the number of circulating WBCs, HSCs, and non-HSCs at T5 in WT but not in C5–/– animals. This increase in the number of circulating cells in WT animals was preceeded by an increase in C5a concentration in PB at T1 as well as activation of the CoaC and FibC at T21. As expected, C5–/– mice did not have measurable levels of C5a; however, they displayed an increase in activation of the CoaC and FibC at T21 that was similar to WT. Conclusions. Our study confirms circadian activation of the ComC, CoaC, and FibC in WT animals at late night/early morning hours preceding the release of HSPCs from BM into PB. The fact that we did not observe circadian changes in the number of circulating cells in PB in C5a–/– mice confirms the pivotal role of the ComC in executing circadian release of HSPCs from BM into PB. Moreover, the fact that C5a–/– mice show normal activation of the CoaC and FibC indicates that, of the ancient proteolytic cascades tested, the ComC is the major player regulating circadian egress of HSPCs. Disclosures No relevant conflicts of interest to declare.
36
Coppola, Ludovico, Salvatore Guastafierro, Giovanni Verrazzo, Antonino Coppola, Domenico De Lucia, and Angelo Tirelli. "C1 Inhibitor Infusion Modifies Platelet Activity in Hereditary Angioedema Patients." Archives of Pathology & Laboratory Medicine 126, no. 7 (2002): 842–45. http://dx.doi.org/10.5858/2002-126-0842-ciimpa.
Texto completoResumen
Abstract Context.—C1 inhibitor (C1-INH) is an α2-globulin that blocks esterolytic activity of the first component of the classic complement cascade. The α-granules of normal human platelets also contain C1-INH, which is expressed on the platelet surface during platelet secretion in healthy patients, but it is clearly reduced in patients with hereditary angioedema (HAE). Objective.—To evaluate the effects of in vivo C1-INH concentrate infusion on platelet responsiveness and coagulation system activity in patients with HAE. Design.—Assessment of the platelet activity and plasma levels of C1-INH, activated factor XII (XIIa), and prothrombin fragment F1.2 (F1.2) before and after infusion of 15 U/kg of C1-INH concentrate. Patients.—In 6 patients (4 men and 2 women), HAE was diagnosed according to the accepted clinical and laboratory criteria. Measurements.—Platelet aggregation (final concentrations: adenosine diphosphate, 0.5, 1.25, and 2.5μM; collagen, 5 μg/mL), C1-INH antigen (radial immunodiffusion), C1-INH activity (chromogenic substrates), and XIIa and F1.2 (enzyme-linked immunosorbent assay). Results.—After C1-INH infusion, we observed a prompt increase of C1-INH level and a slow return toward its plasma preinfusion values within 4 to 7 days, a significant decrease of both adenosine diphosphate– and collagen-induced platelet aggregation versus preinfusion values (maximum after 1–2 days; P &lt; .001), and a rapid decrease of high basal values of XIIa and F1.2 in 30 and 120 minutes, respectively. Conclusions.—These data show a role of C1-INH in the control of platelet activity and that its deficiency increases platelet aggregability and plasma levels of XIIa and F1.2 in patients with HAE.
37
I, Anu R., Aastha Vatsyayan, Ambily Sivadas, Dileep Damodaran, and Kurt van der Speeten. "Abstract 1154: Multi-omic analysis classifies colorectal cancer into distinct angiogenic and immunogenic subtypes based on anatomical laterality." Cancer Research 82, no. 12_Supplement (2022): 1154. http://dx.doi.org/10.1158/1538-7445.am2022-1154.
Texto completoResumen
Abstract Background: Colorectal cancer is a heterogeneous disease of tumors from distinct anatomical and embryological sources. According to GLOBOCAN2020, it is the second leading cause of cancer-related mortality1. Methodology: Utilising NIH-GDC2 datasets, we applied Bioinformatic algorithms to categorize LCRC and RCRC based on multi-omic variables. Mutational analysis was done using STRING v11.53. Kaplan-Meier were plotted. Transcriptome data was accessed using Bioconductor4 package TCGABiolinks5 and annotated as ‘Left’ or ‘Right’ based on tissue of origin. DE analysis was performed using DESeq6. DEGs were analyzed using Enrichr7 for signaling pathways. Further, differential methylation analysis was performed. Results: Tumors from left and right sides represent early Stage IIA non-metastatic cancers largely. Mutational analysis showed dissimilar genes in left vs right-sided tumors. CSMD1, CDH23, PCDH15, DSCAM, CDH9, and NRXN1 formed unique hubs within LCRC network while FLNC, CACNA1H, KMT2B, KMT2D, FAT4 and BRAF formed hubs in RCRC network. LCRC-specific genes were cadherins and EMT based, while RCRC-specific genes were related to lymphocytic invasion and epigenetic markers. TTN (p-value=4.61e-2) and ABCA13 (p-value=4.78e-2) significantly influenced OS in LCRC while SOX11 (p-value=4.12e-2) influenced OS in RCRC. For transcriptomic analysis, we obtained 766 DE genes at p-adjusted value &lt;= 0.01, |log2 FC| &gt; 1. Enrichr KEGG pathway analysis highlighted neuroactive ligand-receptor interaction (OR=3.11) and complement-coagulation cascade (OR=6.07) activity in LCRC. Platelet interaction with cancer cells have been demonstrated8 to have therapeutic potential in CRCs. NK cell mediated cytotoxicity (OR=4.33) and antigen processing-presentation (OR=6.95) were enriched in RCRC. Mean methylation analysis showed higher values in RCRC than LCRC (p-value=1.5e-05). Differential methylation gave 998 hypo- and 45 hyper-methylated genes in RCRC and LCRC respectively. RCRC evidently has an underlying hypermethylated biology when compared to LCRC. RCRCs are dependent on immune-regulated biology explaining rationale of immunotherapy. Right colon develops from midgut and is supplied by SMA. It can be hypothesized that a vast lymphatic drainage system carrying increased T-cells may play a role in creating dissimilarity. On the other hand, angiogenic factors and coagulation cascade rule left colon. This could be the reason for early metastatic potential in LCRCs. Our study unambiguously differentiates LCRC from RCRC by correlating anatomical, physiological, and multi-omic variables. Citation Format: Anu R I, Aastha Vatsyayan, Ambily Sivadas, Dileep Damodaran, Kurt van der Speeten. Multi-omic analysis classifies colorectal cancer into distinct angiogenic and immunogenic subtypes based on anatomical laterality [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1154.
38
Viel, Kevin R., Benjamin Kim, Maria Elizabeth Tejero, Shelley S. Cole, Tom E. Howard, and Amparo Santamaría Ortiz. "The Spectrum of Amino Acid Substitutions Resulting from Single Nucleotide Substitutions in the Coagulation Biosystem: Impact on Identification By Mass Spectrometry." Blood 124, no. 21 (2014): 4221. http://dx.doi.org/10.1182/blood.v124.21.4221.4221.
Texto completoResumen
Abstract INTRODUCTION Mass spectrometry (MS) is a potentially useful tool for the study of the hemostasic system and its imbalances that lead to bleeding and thrombotic disorders. By harnessing the high throughput and broad scope of MS, vast data may be available to investigators and clinicians to help predict or manage hemostatic events. Although utilizing MS to evaluate coagulation proteins appears promising, amino acid (AA) substitutions resulting from genetic variation may yield a spectrum of mass-to-charge ratios (m/z) that can impede accurate protein identification. The goals of this study were to describe 1) the proteins present in a blood sample that might be involved in or otherwise affect coagulation, 2) the realm of variations that might occur with a single nucleotide substitution (SNS) in the reference coding sequences of these proteins, and 3) the variation of peptide fragments of these proteins when only one of the nucleotides is a variant. METHODS We obtained protein lists from the NCBI BioSystems database for the terms: Blood Clotting Cascade, Complement Cascade, Formation of Fibrin Clot, Hemostasis, Platelet Activation, Platelet Aggregation Plug Formation, Platelet Degranulation, Platelet Homeostasis, and Thrombin Signaling (e.g., http://www.ncbi.nlm.nih.gov/biosystems/198840). We linked the Symbol (gene) to the CCDS ID (consensus coding sequence, http://www.ncbi.nlm.nih.gov/CCDS/CcdsBrowse.cgi ). For each nucleotide, we enumerated the effect of a SNS relative to the other three nucleotides. We then generated every peptide of length 5-20, determined the change in mass based on the average, as opposed to the monoisotopic, mass of the substituted AA, and assessed whether the peptide was unique among those in the system. Finally, we determined whether possible N-linked glycosylation sites were preserved, destroyed, or created by SNS. We considered a putative site N[^P][S|T], that is N in position 1, not P in position 2, and either a S or T in position 3. RESULTS The proteins in the biosystems that were also in the CCDS database comprised 517 distinct Symbols and 951 distinct CCDS ID's, comprising 2,180,352 codons. The duplicate Symbols include transcript variants, for instance, the Symbol F8 linked to CCDS ID's 35457.1 and 44026.1, thereby diminishing the uniqueness of the peptides (transcript variants share some, if not most, of the reading frames). All of the codons were susceptible to an AA substitution; at least one variant nucleotide substation in position 1 or 2 of the codon always resulted in an AA substitution. SNS caused premature termination signals (stop codons) in 240,100 of these codons. Table 1 details the variations. A map of the N-glycosylation sites is available for each protein, although this may not affect MS directly. Of the 83,510 potential N-Linked Glycosylation sites, a SNS disrupted the putative AA sequence in 53,067 (64%). A SNS created a novel potential N-Linked Glycosylation site at 52,787 loci. Table 1. Wild-type Only Wild-type and Variants Peptide Length Peptides Distinct Peptides Peptides Distinct Peptides Relative Change in Mass 5 722,174 292,485 24,470,567 2,464,873 0.052250 10 717,564 350,570 47,911,535 20,982,641 0.025968 15 712,954 355,446 71,052,562 31,777,153 0.017273 20 708,344 357,177 93,893,423 42,465,377 0.012939 CONCLUSIONS Variant peptides due to a single SNS per peptide greatly outnumber wild-type peptides. The ability to identify a protein based on uniqueness of one of its peptides increases as the peptide size increases, but AA variations in those peptides that arise from one SNS will require 1) increased mass resolution and 2) both a search algorithm and database that accounts for the possible variations. Patients with hemostatic or thrombotic disorders may be more likely to have a variant, and these results highlight the need to know the genetic sequence associated with proteins being analyzes by MS if this technology is to be adopted for research and clinical purposes. The inclusion of currently identified SNPs and the effect of INDELs that preserve the reading frame is ongoing. Disclosures No relevant conflicts of interest to declare.
39
Adamiak, Mateusz, Andrzej Ciechanowicz, Monika Cymer, Marta Skoda, and Mariusz Z. Ratajczak. "Nlrp3 Inflammasome Activation in Bone Marrow-Residing Innate Immunity Cells Governs Circadian Changes in the Number of Circulating Hematopoietic Stem/Progenitor Cells in Peripheral Blood." Blood 134, Supplement_1 (2019): 1033. http://dx.doi.org/10.1182/blood-2019-125853.
Texto completoResumen
Background. The number of hematopoietic stem/progenitor cells (HSPCs) in peripheral blood (PB) undergoes a circadian oscillation, with the peak occurring in the early morning hours and the nadir at night, and, as nicely demonstrated, this peak has been attributed to the enhanced tonus of the vegetative nervous system in the early morning hours (Nature 2008, 452, 442-447). Moreover, our group has demonstrated that release of HSPCs from bone marrow (BM) into PB is regulated during stress- or pharmacology-induced mobilization by activation of three ancient serum proteolytic cascades, the complement cascade (ComC), the coagulation cascade (CoaC), and the fibrynolytic cascade (FibC) (Stem Cell Rev. 2018; 14:677-685). Since it is known that the ComC, CoaC, and FibC show circadian activation at late night/early morning hours due to deep sleep hypoxia, regulation of the circadian oscillation of HSPC numbers in PB becomes more complex. Moreover, as we recently demonstrated, an important role in egress of HSPCs from BM into PB is played by purinergic signaling involving adenosine triphosphate (ATP) released from cells, which, as signaling mediators in the extracellular space, activate the Nlrp3 inflammasome in hematopoietic cells (Leukemia 2019; 33:815-825). Activation of the Nlrp3 inflammasome induces a state of sterile inflammation in the BM microenvironment and activates the ComC, CoaC, and FibC. Hypothesis. Since Nlrp3 inflammasome activation regulates egress of HSPCs from BM into PB by inducing BM sterile inflammation and activation of the ComC, CoaC, and FibC undergoes circadian activation, we became interested in whether Nlrp3 protein complex orchestrates circadian changes in the number of HSPCs circulating in PB.Materials and Methods. To address this important question, we studied the circadian oscillation in the number of circulating HSPCs in mice. Mice were accustomed to alternating periods of 12 hours light and 12 hours darkness. Light was turned on at 6 AM (ZT0), and the numbers of circulating white blood cells (WBCs), Sca-1+kit+Lin- HSCs, Sca-1+Lin-CD45+ HSCs, clonogenic CFU-GM progenitors, and non-hematopoietic Sca-1+Lin-CD45- cells (VSELs) were measured at 7 AM (ZT1), 11 AM (ZT5), 7 PM (ZT13), and 3 AM (ZT21). At the same time points, we evaluated expression of the Nlrp3 inflammasome at the mRNA level; Nlrp3 activation by measuring Nlrp3 inflammasome activation markers, such as interleukin-1beta, interleukin-18, and Hmgb1, at the mRNA and protein levels; ComC activation (by C5a ELISA); CoaC activation (by thrombin/antithrombin ELISA); and FibC activation (by plasmin/antiplasmin complex ELISA). To confirm the role of the Nlrp3 inflammasome in the circadian oscillation of HSPCs released into PB, we inhibited its activity by employing the specific small-molecule inhibitor MCC950. Results. We observed circadian changes in the expression and activation of the Nlrp3 inflammasome, with a peak in the early morning hours at ZT1 that preceded the peak in the number of circulating HSPCs at ZT5. This increase in activation of the Nlrp3 inflammasome and the number of circulating cells in WT animals was preceded by an increase in C5a concentration in PB at ZT1 as well as activation of the CoaC and FibC at ZT21. As expected, inhibition of the Nlrp3 inflammasome by MCC950 inhibited circadian oscillation of circulating HSPCs in PB. Conclusions. Our study confirms circadian activation of the Nlrp3 inflammsome due to the ComC, CoaC, and FibC in mice at late-night/early-morning hours preceding the release of HSPCs from BM into PB. The fact that we observed significant decrease in circadian changes in the number of circulating cells in PB in mice exposed to an Nlrp3 inflammasome inhibitor confirms its pivotal role in executing circadian release of HSPCs from BM into PB. Moreover, the fact that mice exposed to an Nlrp3 inhibitor show defective activation of the ComC and normal activation of the the CoaC and FibC indicates that, of the ancient proteolytic cascades tested, the ComC is the major player regulating Nlrp3 inflammasome-dependent circadian egress of HSPCs. Disclosures No relevant conflicts of interest to declare.
40
Meroni, Pier Luigi, Claudia Grossi, and Francesco Tedesco. "Pathogenesis of the obstetric antiphospholipid syndrome: the key role of beta 2 glycoprotein I." Exploration of Immunology, August 19, 2022, 510–17. http://dx.doi.org/10.37349/ei.2022.00064.
Texto completoResumen
Antiphospholipid syndrome (APS) is defined by recurrent pregnancy morbidity and/or vascular thrombosis associated with the persistent presence of antibodies against anionic phospholipid-binding proteins. Beta 2 glycoprotein I (β2GPI) and prothrombin (PT) are the major antigens for antiphospholipid antibodies (aPL) detectable by functional coagulation [lupus anticoagulant (LA)] or solid-phase assays [anti-β2GPI-dependent cardiolipin (aCL) and anti-β2GPI]. β2GPI-dependent aPL are responsible for the positivity of the three classification laboratory criteria. While medium/high titers of antibodies against β2GPI are risk factors for both the vascular and the obstetric manifestations of APS, persistent low titers are also associated with pregnancy complications. There is evidence from animal models of aPL-dependent fetal loss and from in vitro systems that β2GPI-dependent aPL can be pathogenic. β2GPI is physiologically found in large quantities at the placental level being available for the specific antibodies circulating in the maternal blood. Once bound to the protein, the antibodies trigger a local inflammation via the activation of the complement cascade and affect trophoblast and decidual function. The final result is represented by defective placentation, while thrombotic events are apparently less important. β2GPI is a pleiotropic molecule with scavenging properties towards several molecules including apoptotic material and displays anti-oxidant activity. These functions may explain the β2GPI placental localization in an area of intensive tissue remodeling and low oxygen tension. Since β2GPI interacts also with the complement and the coagulation cascade, its binding with specific antibodies may affect the physiology of placentation in several ways.
41
Wong, Phing Sue, Thomas Rhys, Mangat Pamela, Beynon Huw, and Richard Stratton. "P02 Doctor, I just don't feel alright." Rheumatology Advances in Practice 5, Supplement_1 (2021). http://dx.doi.org/10.1093/rap/rkab068.001.
Texto completoResumen
Abstract Case report - Introduction Antiphospholipid syndrome (APS), also known as Hughes syndrome, was first reported by Dr. Graham Hughes in 1983. It can be primary or secondary, with the latter associated with underlying rheumatological conditions. APS is an immune-mediated disorder with the hallmark of pregnancy morbidity and vascular thrombotic events associated with persistent antiphospholipid antibodies (aPLs). Rarely it causes catastrophic APS or Asherson syndrome. Neurological manifestation of APS is not uncommon. It can affect central, peripheral as well as autonomic neural system through vascular thrombosis or autoimmune inflammatory-demyelination syndrome. Other relatively common clinical features livedo reticularis, thrombocytopenia, transient ischemic attack or movement disorders. Case report - Case description Case 1 A 52-year-old Caucasian lady was seen in outpatient clinic for involuntary non-rhythmic movement of face, trunk and limbs and writhing of the fingers (athetosis). Onset was 5 years ago and is progressing. She has Raynaud’s and livedo reticularis over her limbs. She had two previous miscarriages and one pre-eclampsia. Her immediate cousin has APS. Heart sounds were normal. Platelet: 98 x109/L Two samples of high titre of ACA IgG, B2 Glycoprotein 1 Ab IgG, and positive Lupus anticoagulant 3 months apart. Low complements C4 MRI brain showed T2/FLAIR signal within the supratentorial white matter. 3 weeks into treatments with steroid, hydroxychloroquine and VKA anticoagulation, patient reported improvement of symptoms. Diagnosis: Choreo-athetosis in primary APLS Case 2 A 42-year-old Caucasian female with chronic migraines was seen for imbalance gait and left upper limb compartment syndrome. Vascular images showed left cerebellar ischemic infarct and left subclavian and brachial artery thrombosis without vasculitis or vascular malformation. Patient had five obstretrics morbidities. Echocardiogram was normal, aPLs were negative. Patient underwent left arm fasciotomy. Immediate post operatively patient was anticoagulated and later switched to VKA and antiplatlet. She remains aPLs negative in outpatient visits. Diagnosis: Non-criteria (seronegative) APLS with arterial thrombosis Case 3 22-year-old, black female. Presented in 2018 with internal jugular, subclavian and pulmonary venous thrombosis. Her APTT was 38 and lupus anticoagulant were positive in two occasions 12 weeks apart. She received indefinite warfarin. She reported persistent migraine headache. Brain imagings were insignificant. She refused lumbar puncture. Neuronal antibodies were negative. Systemic glucocorticosteroid had improved her headache. Parenteral cyclophosphamide was started as she remained steroid refractory. Her headache resolved after completed course and reduced prednisolone dose. She received 3.75 mg of leuprolide according to protocol. Diagnosis: Refractory Migraine headache in Primary APS Case report - Discussion Neurological manifestation for APLS is not uncommon. One review published the frequency of different neurological syndrome (Table 1). Classically, aPLs target and bind to the phospholipid membranes of platelets with their subsequent activation and thrombosis. Recent evidence supports the concept of the mechanisms of immune-mediated vascular, inflammatory, and direct neurotoxic effects in neurological-APS manifestation. For instance, aPLs bind to endothelia, monocytes, neutrophils and interfere with complement activation. This results in immune-inflammatory response and coagulation cascade activation contributing to microcirculation thrombosis and ischemia. Combined procoagulation state, immune cascade activation plus aPL neurotoxicity, it further increases permeability of the blood—brain barrier with influx of inflammatory molecules into the nervous system. There are currently 30 aPLs identified. LA, ACA and B2GP1A are studied most and are included in the classification criteria, hence also termed criterion aPL. Non-criterion aPLs, although lacking clinical representation, are getting more attention in investigating their relevance for the diagnosis, pathogenesis, and phenotype in APS. Examples are antibodies against aB2GPI (including IgA), Phosphatidylserine/prothrombin complex, Anti-phosphatidylserine (aPS), Anti-vimentin, Anti-phosphatidic acid, Anti-phosphatidylethanolamine (aPE). Four other aPLs shown to strongly correlate in APS-CNS manifestation are IgG antibodies against prothrombin (aPT), phosphatidylglycerol (aPG), phosphatidylinositol (aPI), and annexin-5 (aAN). Antibodies against aB2GPI (including IgA) were strongly associated with chorea in one publication. 66—88% of APS patients with migraine headache are positive to ACA. Case report - Key learning points Sapporo classification criteria define definite APS as presence of one or more of clinical plus laboratory criteria. Clinical criteria include vascular thrombosis of venous, arterial, or small vessel and obstetric morbidity of early pregnancy loss or late pregnancy complications. Laboratory criteria are two positive results of either lupus anticoagulant, Anticardiolipin or Anti-β2-glycoprotein-I IgG or IgM (ELISA) in significant titre 12 weeks apart. Although APS patients can present with young stroke, other differentials are vascular malformation and arteriopathy (eg. Moya-moya and CADASIL), systemic infections, cardiac, metabolic disorders (e.g., ADA deficiency, Fabry’s disease, Homocystinuria), sickle cell disease, inherited prothrombotic conditions, paroxysmal nocturnal haemoglobinuria and substances abuse. APS management is largely based on serological risk stratification. Presence of Lupus anticoagulant with or without persistent ACA and B2GPA in high titre are considered high-risk group. Low-dose aspirin (LDA, 75-100mg) used in primary prophylaxis reduces half of thrombotic events. Addition of prophylaxis dose of heparin is recommended for all pregnant females with history of obstetrics APS. Anticoagulation therapy with vitamin-K antagonist (VKA) is the main strategy in secondary thromboprophylaxis in APS. Therapeutic target of INR varies. INR of 2–3 is the target in venous thrombosis, in arterial thrombosis INR should target at 2—4 based on bleeding risk in addition to LDA. Higher INR is also indicated in refractory cases, as well as addition of LDA or switch to LMWH. Patients of high-risk groups and with recurrent events should receive indefinite anticoagulant. Several major trials of DOACs failed to reach primary efficacy and safety endpoints, in particular rivaroxaban, hence these should be avoided particularly in arterial thrombosis. Evidence with immunosuppressants remain controversial; EULAR recommended HCQ and prednisolone in refractory obstetric APS. Immunoglobulin, plasma exchange, rituximab and eculizumab have been reported successfully used in CAPS, isolated cases as well as refractory APS.
42
Burmeister, Antonia, Sabine Vidal-y-Sy, Xiaobo Liu, et al. "Impact of neutrophil extracellular traps on fluid properties, blood flow and complement activation." Frontiers in Immunology 13 (December 16, 2022). http://dx.doi.org/10.3389/fimmu.2022.1078891.
Texto completoResumen
IntroductionThe intravascular formation of neutrophil extracellular traps (NETs) is a trigger for coagulation and blood vessel occlusion. NETs are released from neutrophils as a response to strong inflammatory signals in the course of different diseases such as COVID-19, cancer or antiphospholipid syndrome. NETs are composed of large, chromosomal DNA fibers decorated with a variety of proteins such as histones. Previous research suggested a close mechanistic crosstalk between NETs and the coagulation system involving the coagulation factor XII (FXII), von Willebrand factor (VWF) and tissue factor. However, the direct impact of NET-related DNA fibers on blood flow and blood aggregation independent of the coagulation cascade has remained elusive.MethodsIn the present study, we used different microfluidic setups in combination with fluorescence microscopy to investigate the influence of neutrophil-derived extracellular DNA fibers on blood rheology, intravascular occlusion and activation of the complement system.ResultsWe found that extended DNA fiber networks decelerate blood flow and promote intravascular occlusion of blood vessels independent of the plasmatic coagulation. Associated with the DNA dependent occlusion of the flow channel was the strong activation of the complement system characterized by the production of complement component 5a (C5a). Vice versa, we detected that the local activation of the complement system at the vascular wall was a trigger for NET release.DiscussionIn conclusion, we found that DNA fibers as the principal component of NETs are sufficient to induce blood aggregation even in the absence of the coagulation system. Moreover, we discovered that complement activation at the endothelial surface promoted NET formation. Our data envisions DNA degradation and complement inhibition as potential therapeutic strategies in NET-induced coagulopathies.
43
Yu, Liang, Huaji Shen, Xiaohan Ren, et al. "Multi‐omics analysis reveals the interaction between the complement system and the coagulation cascade in the development of endometriosis." Scientific Reports 11, no. 1 (2021). http://dx.doi.org/10.1038/s41598-021-90112-x.
Texto completoResumen
AbstractEndometriosis (EMS) is a disease that shows immune dysfunction and chronic inflammation characteristics, suggesting a role of complement system in its pathophysiology. To find out the hub genes and pathways involved in the pathogenesis of EMs, three raw microarray datasets were recruited from the Gene Expression Omnibus database (GEO). Then, a series of bioinformatics technologies including gene ontology (GO), Hallmark pathway enrichment, protein–protein interaction (PPI) network and gene co-expression correlation analysis were performed to identify hub genes. The hub genes were further verified by the Real-time quantitative polymerase chain reaction (RT-PCR) and Western Blot (WB). We identified 129 differentially expressed genes (DEGs) in EMs, of which 78 were up-regulated and 51 were down-regulated. Through GO functional enrichment analysis, we found that the DEGs are mainly enriched in cell adhesion, extracellular matrix remodeling, chemokine regulation, angiogenesis regulation, epithelial cell proliferation, et al. In Hallmark pathway enrichment analysis, coagulation pathway showed great significance and the terms in which included the central complement factors. Moreover, the genes were dominating in PPI network. Combined co-expression analysis with experimental verification, we found that the up-regulated expression of complement (C1S, C1QA, C1R, and C3) was positively related to tissue factor (TF) in EMs. In this study, we discovered the over expression complement and the positive correlation between complement and TF in EMs, which suggested that interaction of complement and coagulation system may play a role within the pathophysiology of EMS.
44
Gavriilaki, Eleni, Vincent T. Ho, Wilhelm Schwaeble, et al. "Role of the lectin pathway of complement in hematopoietic stem cell transplantation-associated endothelial injury and thrombotic microangiopathy." Experimental Hematology & Oncology 10, no. 1 (2021). http://dx.doi.org/10.1186/s40164-021-00249-8.
Texto completoResumen
AbstractHematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA) is a life-threatening syndrome that occurs in adult and pediatric patients after hematopoietic stem cell transplantation. Nonspecific symptoms, heterogeneity within study populations, and variability among current diagnostic criteria contribute to misdiagnosis and underdiagnosis of this syndrome. Hematopoietic stem cell transplantation and associated risk factors precipitate endothelial injury, leading to HSCT-TMA and other endothelial injury syndromes such as hepatic veno-occlusive disease/sinusoidal obstruction syndrome, idiopathic pneumonia syndrome, diffuse alveolar hemorrhage, capillary leak syndrome, and graft-versus-host disease. Endothelial injury can trigger activation of the complement system, promoting inflammation and the development of endothelial injury syndromes, ultimately leading to organ damage and failure. In particular, the lectin pathway of complement is activated by damage-associated molecular patterns (DAMPs) on the surface of injured endothelial cells. Pattern-recognition molecules such as mannose-binding lectin (MBL), collectins, and ficolins—collectively termed lectins—bind to DAMPs on injured host cells, forming activation complexes with MBL-associated serine proteases 1, 2, and 3 (MASP-1, MASP-2, and MASP-3). Activation of the lectin pathway may also trigger the coagulation cascade via MASP-2 cleavage of prothrombin to thrombin. Together, activation of complement and the coagulation cascade lead to a procoagulant state that may result in development of HSCT-TMA. Several complement inhibitors targeting various complement pathways are in clinical trials for the treatment of HSCT-TMA. In this article, we review the role of the complement system in HSCT-TMA pathogenesis, with a focus on the lectin pathway.
45
Rydbirk, Rasmus, Ole Østergaard, Jonas Folke, et al. "Brain proteome profiling implicates the complement and coagulation cascade in multiple system atrophy brain pathology." Cellular and Molecular Life Sciences 79, no. 6 (2022). http://dx.doi.org/10.1007/s00018-022-04378-z.
Texto completo
46
Grossi, Claudia, Nagaja Capitani, Marisa Benagiano, et al. "Beta 2 glycoprotein I and neutrophil extracellular traps: Potential bridge between innate and adaptive immunity in anti-phospholipid syndrome." Frontiers in Immunology 13 (January 9, 2023). http://dx.doi.org/10.3389/fimmu.2022.1076167.
Texto completoResumen
Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by recurrent vascular thrombosis and miscarriages in the absence of known causes. Antibodies against phospholipid-binding proteins (aPL) are pathogenic players in both clotting and pregnancy APS manifestations. There is sound evidence that antibodies specific for beta2 glycoprotein I (β2GPI) trigger thrombotic and pregnancy complications by interacting with the molecule on the membranes of different cell types of the coagulation cascade, and in placenta tissues. In addition to the humoral response against β2GPI, both peripheral and tissue CD4+ β2GPI-specific T cells have been reported in primary APS as well as in systemic lupus erythematosus (SLE)-associated APS. While adaptive immunity plays a clear role in APS, it is still debated whether innate immunity is involved as well. Acute systemic inflammation does not seem to be present in the syndrome, however, there is sound evidence that complement activation is crucial in animal models and can be found also in patients. Furthermore, neutrophil extracellular traps (NETs) have been documented in arterial and venous thrombi with different etiology, including clots in APS models. Keeping in mind that β2GPI is a pleiotropic glycoprotein, acting as scavenger molecule for infectious agents and apoptotic/damaged body constituents and that self-molecules externalized through NETs formation may become immunogenic autoantigens, we demonstrated β2GPI on NETs, and its ability to stimulate CD4+β2GPI-specific T cells. The aim of this review is to elucidate the role of β2GPI in the cross-talk between the innate and adaptive immunity in APS.
47
Moraes, Daniela, Camila Milioni, Carolina Friske Vieira, et al. "Immature Platelet Fraction and Thrombin Generation: Preeclampsia Biomarkers." Revista Brasileira de Ginecologia e Obstetrícia / RBGO Gynecology and Obstetrics, July 11, 2022. http://dx.doi.org/10.1055/s-0042-1743100.
Texto completoResumen
AbstractPreeclampsia, a human pregnancy syndrome, is characterized by elevated blood pressure and proteinuria after the 20th week of gestation. Its etiology remains unknown, and its pathophysiological mechanisms are related to placental hypoperfusion, endothelial dysfunction, inflammation, and coagulation cascade activation. Recently, the role of the complement system has been considered. This syndrome is one of the main causes of maternal and fetal mortality and morbidity. This article discusses the hypothesis of preeclampsia being triggered by the occurrence of inadequate implantation of the syncytiotrophoblast, associated with bleeding during the first stage of pregnancy and with augmented thrombin generation. Thrombin activates platelets, increasing the release of antiangiogenic factors and activating the complement system, inducing the membrane attack complex (C5b9). Immature platelet fraction and thrombin generation may be possible blood biomarkers to help the early diagnosis of preeclampsia.
48
van Erp, Inge A. M., Iliana Michailidou, Thomas A. van Essen, et al. "Tackling Neuroinflammation After Traumatic Brain Injury: Complement Inhibition as a Therapy for Secondary Injury." Neurotherapeutics, October 12, 2022. http://dx.doi.org/10.1007/s13311-022-01306-8.
Texto completoResumen
AbstractTraumatic brain injury (TBI) is a leading cause of mortality, sensorimotor morbidity, and neurocognitive disability. Neuroinflammation is one of the key drivers causing secondary brain injury after TBI. Therefore, attenuation of the inflammatory response is a potential therapeutic goal. This review summarizes the most important neuroinflammatory pathophysiology resulting from TBI and the clinical trials performed to attenuate neuroinflammation. Studies show that non-selective attenuation of the inflammatory response, in the early phase after TBI, might be detrimental and that there is a gap in the literature regarding pharmacological trials targeting specific pathways. The complement system and its crosstalk with the coagulation system play an important role in the pathophysiology of secondary brain injury after TBI. Therefore, regaining control over the complement cascades by inhibiting overshooting activation might constitute useful therapy. Activation of the complement cascade is an early component of neuroinflammation, making it a potential target to mitigate neuroinflammation in TBI. Therefore, we have described pathophysiological aspects of complement inhibition and summarized animal studies targeting the complement system in TBI. We also present the first clinical trial aimed at inhibition of complement activation in the early days after brain injury to reduce the risk of morbidity and mortality following severe TBI.
49
Lipcsey, Miklós, Barbro Persson, Oskar Eriksson, et al. "The Outcome of Critically Ill COVID-19 Patients Is Linked to Thromboinflammation Dominated by the Kallikrein/Kinin System." Frontiers in Immunology 12 (February 22, 2021). http://dx.doi.org/10.3389/fimmu.2021.627579.
Texto completoResumen
An important manifestation of severe COVID-19 is the ARDS-like lung injury that is associated with vascular endothelialitis, thrombosis, and angiogenesis. The intravascular innate immune system (IIIS), including the complement, contact, coagulation, and fibrinolysis systems, which is crucial for recognizing and eliminating microorganisms and debris in the body, is likely to be involved in the pathogenesis of COVID-19 ARDS. Biomarkers for IIIS activation were studied in the first 66 patients with COVID-19 admitted to the ICU in Uppsala University Hospital, both cross-sectionally on day 1 and in 19 patients longitudinally for up to a month, in a prospective study. IIIS analyses were compared with biochemical parameters and clinical outcome and survival. Blood cascade systems activation leading to an overreactive conjunct thromboinflammation was demonstrated, reflected in consumption of individual cascade system components, e.g., FXII, prekallikrein, and high molecular weight kininogen and in increased levels of activation products, e.g., C4d, C3a, C3d,g, sC5b-9, TAT, and D-dimer. Strong associations were found between the blood cascade systems and organ damage, illness severity scores, and survival. We show that critically ill COVID-19 patients display a conjunct activation of the IIIS that is linked to organ damage of the lung, heart, kidneys, and death. We present evidence that the complement and in particular the kallikrein/kinin system is strongly activated and that both systems are prognostic markers of the outcome of the patients suggesting their role in driving the inflammation. Already licensed kallikrein/kinin inhibitors are potential drugs for treatment of critically ill patients with COVID-19.
50
Malik, Astha, Unmesha Thanekar, Surya Amarachintha, et al. "“Complimenting the Complement”: Mechanistic Insights and Opportunities for Therapeutics in Hepatocellular Carcinoma." Frontiers in Oncology 10 (February 24, 2021). http://dx.doi.org/10.3389/fonc.2020.627701.
Texto completoResumen
Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and a leading cause of death in the US and worldwide. HCC remains a global health problem and is highly aggressive with unfavorable prognosis. Even with surgical interventions and newer medical treatment regimens, patients with HCC have poor survival rates. These limited therapeutic strategies and mechanistic understandings of HCC immunopathogenesis urgently warrant non-palliative treatment measures. Irrespective of the multitude etiologies, the liver microenvironment in HCC is intricately associated with chronic necroinflammation, progressive fibrosis, and cirrhosis as precedent events along with dysregulated innate and adaptive immune responses. Central to these immunological networks is the complement cascade (CC), a fundamental defense system inherent to the liver which tightly regulates humoral and cellular responses to noxious stimuli. Importantly, the liver is the primary source for biosynthesis of &gt;80% of complement components and expresses a variety of complement receptors. Recent studies implicate the complement system in liver inflammation, abnormal regenerative responses, fibrosis, carcinogenesis, and development of HCC. Although complement activation differentially promotes immunosuppressive, stimulant, and angiogenic microenvironments conducive to HCC development, it remains under-investigated. Here, we review derangement of specific complement proteins in HCC in the context of altered complement regulatory factors, immune-activating components, and their implications in disease pathogenesis. We also summarize how complement molecules regulate cancer stem cells (CSCs), interact with complement-coagulation cascades, and provide therapeutic opportunities for targeted intervention in HCC.