Activation Of Coagulation Pathways Research Articles

Engineering Pancreatic Islets to Transiently Codisplay on Their Surface Thrombomodulin and CD47 Immunomodulatory Proteins as a Means of Mitigating Instant Blood-Mediated Inflammatory Reaction following Intraportal Transplantation.

Most pancreatic islets are destroyed immediately after intraportal transplantation by an instant blood-mediated inflammatory reaction (IBMIR) generated through activation of coagulation, complement, and proinflammatory pathways. Thus, effective mitigation of IBMIR may be contingent on the combined use of agents targeting these pathways for modulation. CD47 and thrombomodulin (TM) are two molecules with distinct functions in regulating coagulation and proinflammatory responses. We previously reported that the islet surface can be modified with biotin for transient display of novel forms of these two molecules chimeric with streptavidin (SA), that is, thrombomodulin chimeric with SA (SA-TM) and CD47 chimeric with SA (SA-CD47), as single agents with improved engraftment following intraportal transplantation. This study aimed to test whether islets can be coengineered with SA-TM and SA-CD47 molecules as a combinatorial approach to improve engraftment by inhibiting IBMIR. Mouse islets were effectively coengineered with both molecules without a detectable negative impact on their viability and metabolic function. Coengineered islets were refractory to destruction by IBMIR ex vivo and showed enhanced engraftment and sustained function in a marginal mass syngeneic intraportal transplantation model. Improved engraftment correlated with a reduction in intragraft innate immune infiltrates, particularly neutrophils and M1 macrophages. Moreover, transcripts for various intragraft procoagulatory and proinflammatory agents, including tissue factor, HMGB1 (high-mobility group box-1), IL-1β, IL-6, TNF-α, IFN-γ, and MIP-1α, were significantly reduced in coengineered islets. These data demonstrate that the transient codisplay of SA-TM and SA-CD47 proteins on the islet surface is a facile and effective platform to modulate procoagulatory and inflammatory responses with implications for both autologous and allogeneic islet transplantation.

Tannic acid-crosslinked gelatin composite microspheres adsorbed with CQAS or Ca2+ for rapid hemostasis

In the case of massive blood loss due to natural disasters and wars, timely and rapid hemostasis is of great significance to improve the survival rate of injured people. Nevertheless, uncontrolled, noncompressible, and irregular bleeding wounds remain a giant challenge for rapid hemostasis. In this study, the tannic acid-crosslinked gelatin was first obtained by Michael addition reaction, and then the tannic acid-crosslinked gelatin composite microspheres (TGMs) were prepared by the emulsion cross-linking method. TGMs could significantly improve the water absorption and hemostatic performance compared with single component gelatin microspheres (GMs). Increasing the water absorption ratio and introducing blood coagulation factors into composite materials are simple and effective strategies to enhance the hemostatic properties. Therefore, chitosan quaternary ammonium salt (CQAS) and Ca2+ were electrostatic adsorbed to obtain two kinds of functional TGMs, which were respectively CQAS-absorbed TGMs (T2GMs-CQAS) and calcium ion-absorbed TGMs (T2GMs-Ca2+). Notably, T2GMs-CQAS, and T2GMs-Ca2+ could absorb water rapidly within 3seconds, in addition, especially the water absorption ratio of T2GMs-CQAS could reach 2.95 times compared with GMs. Benefited from rapid water absorption, coagulation pathway activation, and red blood cells aggregation of T2GMs-CQAS and T2GMs-Ca2+, resulting in rapid blood coagulation in vitro. In addition, CQAS and Ca2+ provided strong and intrinsic antibacterial activity due to positive charge. Moreover, in the tail amputation and liver hemostatic models, T2GMs-CQAS and T2GMs-Ca2+ demonstrated superior hemostatic effects compared to commercial Yunnan Baiyao®. In conclusion, T2GMs-CQAS and T2GMs-Ca2+ have potential applications as hemostatic dressings in uncontrolled, noncompressible, and irregular bleeding wounds.

Proteomics of serum-derived extracellular vesicles are associated with the severity and different clinical profiles of patients with COVID-19: An exploratory secondary analysis

Coronavirus disease 2019 (COVID-19) is characterized by a broad spectrum of clinical manifestations with the potential to progress to multiple organ dysfunction in severe cases. Extracellular vesicles (EVs) carry a range of biological cargoes, which may be used as biomarkers of disease state. An exploratory secondary analysis of the SARITA-2 and SARITA-1 datasets (randomized clinical trials on patients with mild and moderate/severe COVID-19) was performed. Serum-derived EVs were used for proteomic analysis to identify enriched biological processes and key proteins, thus providing insights into differences in disease severity. Serum-derived EVs were separated from patients with COVID-19 by size exclusion chromatography and nanoparticle tracking analysis was used to determine particle concentration and diameter. Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) was performed to identify and quantify protein signatures. Bioinformatics and multivariate statistical analysis were applied to distinguish candidate proteins associated with disease severity (mild versus moderate/severe COVID-19). No differences were observed in terms of the concentration and diameter of enriched EVs between mild (n = 14) and moderate/severe (n = 30) COVID-19. A total of 414 proteins were found to be present in EVs, of which 360 were shared while 48 were uniquely present in severe/moderate compared to mild COVID-19. The main biological signatures in moderate/severe COVID-19 were associated with platelet degranulation, exocytosis, complement activation, immune effector activation, and humoral immune response. Von Willebrand factor, serum amyloid A-2 protein, histone H4 and H2A type 2-C, and fibrinogen β-chain were the most differentially expressed proteins between severity groups. Exploratory proteomic analysis of serum-derived EVs from patients with COVID-19 detected key proteins related to immune response and activation of coagulation and complement pathways, which are associated with disease severity. Our data suggest that EV proteins may be relevant biomarkers of disease state and prognosis.

Bioactive glass incorporated dressing matrix for rapid hemostatic action with antibacterial activity

Uncontrolled bleeding stands as a leading cause of preventable death in both civilian trauma and military battlefield scenarios. Existing hemostatic dressings like HemCon, Celox, and QuickClot, often lack instant hemostasis at the bleeding site and may have biodegradability and exothermic issues. To address the above in this communication, we have synthesized a hemostatic glass (acronym AlBG, CaO-SiO2 system, incorporated with Al2O3 and ZnO) by sol gel route and carried out detail physicochemical characterizations, e.g., XRD, FESEM, FTIR, BET and particle size analysis etc. The AlBG of particle size range 140–253 nm was incorporated into the nonwoven surgical cotton gauze to obtain AlBGscg. In vitro biological assays including cytocomtability, hemocompatibility assays of the above coated gauze was undertaken using NIH3T3 of which, the later showed optimum hemocompatibility with <6 % lysis of red blood cells. Potent antibacterial action on both gram positive and gram negative strains were obtained with significant zone of inhibition of 17 ± 0.34 mm and 16 ± 0.56 mm, respectively. Importantly, significant reduction of the clotting time (31.81 ± 0.12 % for P time and 33.3 ± 0.23 % for aPTT) compared to the control group, indicated activation of both intrinsic and extrinsic coagulation pathways. Scanning electron microscope (SEM) images exhibited an enhanced in vitro blood clot formation in case of AlBGscg in comparison to the control (uncoated surgical cotton gauze), visually. Additionally, a noticeable reduction of ∼30 % in the time required for the blood clot formation, in case of AlBGscg, was observed. The in vivo hemostatic potential of AlBGscg was evaluated in Wistar rats through femoral artery injury and was compared with commercially available surgical cotton gauze. The results demonstrated substantial reduction in the time required for hemostasis (approximately 50 % reduction), a lower amount of blood loss (7.33 % with AlBGscg compared to 22.31 % with surgical cotton gauze), and importantly, there were no incidents of re-bleeding observed with AlBGscg, highlighting its promise as a candidate for effective hemostasis.

Proximity extension assay proteomics and renal single cell transcriptomics uncover novel urinary biomarkers for active lupus nephritis

ObjectiveTo identify urinary biomarkers that can distinguish active renal involvement in Lupus Nephritis (LN), a severe manifestation of systemic lupus erythematosus (SLE). MethodsUrine from 117 subjects, comprised of inactive SLE, active non-renal lupus, active LN, and healthy controls, were subjected to Proximity Extension Assay (PEA) based comprehensive proteomics followed by ELISA validation in an independent, ethnically diverse cohort. Proteomic data is also cross-referenced to renal transcriptomic data to elucidate cellular origins of biomarkers. ResultsSystems biology analyses revealed progressive activation of cytokine signaling, chemokine activity and coagulation pathways, with worsening renal disease. In addition to validating 30 previously reported biomarkers, this study uncovers several novel candidates. Following ELISA validation in an independent cohort of different ethnicity, the six most discriminatory biomarkers for active LN were urinary ICAM-2, FABP4, FASLG, IGFBP-2, SELE and TNFSF13B/BAFF, with ROC AUC ≥80%, with most correlating strongly with clinical disease activity. Transcriptomic analyses of LN kidneys mapped the likely origin of these proteins to intra-renal myeloid cells (CXCL16, IL-1RT2, TNFSF13B/BAFF), T/NK cells (FASLG), leukocytes (ICAM2) and endothelial cells (SELE). ConclusionIn addition to confirming the diagnostic potential of urine ALCAM, CD163, MCP1, SELL, ICAM1, VCAM1, NGAL and TWEAK for active LN, this study adds urine ICAM-2, FABP4, FASLG, IGFBP-2, SELE, and TNFSF13B/BAFF as additional markers that warrant systematic validation in larger cross-sectional and longitudinal cohorts.

Activation of coagulation and proinflammatory pathways in thrombosis with thrombocytopenia syndrome and following COVID-19 vaccination

Thrombosis with thrombocytopenia syndrome (TTS) is a rare but potentially severe adverse event following immunization with adenovirus vector-based COVID-19 vaccines such as Ad26.COV2.S (Janssen) and ChAdOx1 (AstraZeneca). However, no case of TTS has been reported in over 1.5 million individuals who received a second immunization with Ad26.COV2.S in the United States. Here we utilize transcriptomic and proteomic profiling to compare individuals who receive two doses of Ad26.COV2.S with those vaccinated with BNT162b2 or mRNA-1273. Initial Ad26.COV2.S vaccination induces transient activation of platelet and coagulation and innate immune pathways that resolve by day 7; by contrast, patients with TTS show robust upregulation of these pathways on days 15–19 following initial Ad26.COV2.S vaccination. Meanwhile, a second immunization or a reduced initial dose of Ad26.COV2.S induces lower activation of these pathways than does the full initial dose. Our data suggest a role of coagulation and proinflammatory pathways in TTS pathogenesis, which may help optimize vaccination regimens to reduce TTS risk.

Sepsis-induced coagulopathy is associated with new episodes of atrial fibrillation in patients admitted to critical care in sinus rhythm.

Sepsis is a life-threatening disease commonly complicated by activation of coagulation and immune pathways. Sepsis-induced coagulopathy (SIC) is associated with micro- and macrothrombosis, but its relation to other cardiovascular complications remains less clear. In this study we explored associations between SIC and the occurrence of atrial fibrillation (AF) in patients admitted to the Intensive Care Unit (ICU) in sinus rhythm. We also aimed to identify predictive factors for the development of AF in patients with and without SIC. Data were extracted from the publicly available AmsterdamUMCdb database. Patients with sepsis and documented sinus rhythm on admission to ICU were included. Patients were stratified into those who fulfilled the criteria for SIC and those who did not. Following univariate analysis, logistic regression models were developed to describe the association between routinely documented demographics and blood results and the development of at least one episode of AF. Machine learning methods (gradient boosting machines and random forest) were applied to define the predictive importance of factors contributing to the development of AF. Age was the strongest predictor for the development of AF in patients with and without SIC. Routine coagulation tests activated Partial Thromboplastin Time (aPTT) and International Normalized Ratio (INR) and C-reactive protein (CRP) as a marker of inflammation were also associated with AF occurrence in SIC-positive and SIC-negative patients. Cardiorespiratory parameters (oxygen requirements and heart rate) showed predictive potential. Higher INR, elevated CRP, increased heart rate and more severe respiratory failure are risk factors for occurrence of AF in critical illness, suggesting an association between cardiac, respiratory and immune and coagulation pathways. However, age was the most dominant factor to predict the first episodes of AF in patients admitted in sinus rhythm with and without SIC.

Monocytes and Macrophages: Emerging Mechanisms and Novel Therapeutic Targets in Pulmonary Fibrosis.

Pulmonary fibrosis (PF) results from a plethora of abnormal pathogenetic events. In Idiopathic Pulmonary Fibrosis (IPF), inhalational, environmental, or occupational exposures in genetically and epigenetically predisposed individuals, triggers recurrent cycles of alveolar epithelial cell injury, activation of coagulation pathways, chemoattraction, and differentiation of monocytes into monocyte-derived alveolar macrophages (Mo-AMs). When these events happen intermittently and repeatedly throughout the individual's life cycle, the wound repair process becomes aberrant leading to bronchiolization of distal airspaces, fibroblast accumulation, extracellular matrix deposition and loss of the alveolar-capillary architecture. The role of immune dysregulation in IPF pathogenesis and progression has been underscored in the past mainly after the disappointing results of immunosuppressant use in IPF patients, however, recent reports highlighting the prognostic and mechanistic roles of monocytes and Mo-AMs revived the interest of immune dysregulation in IPF. In this review, we will discuss the role of these cells in the onset and progression of IPF, as well as potential targeted therapies.

Acute Vascular Events: Cellular and Molecular Mechanisms

Cardiovascular diseases (CVDs) are the leading cause of death worldwide. An estimated 17.9 million individuals died from CVDs in 2019, representing 32% of all global deaths. Of these deaths, 85% were due to heart attack and stroke. Cardiometabolic risks, such as hypertension, excess weight, obesity, type 2 diabetes, and vascular diseases, contribute significantly to the progression of coronary artery disease. Known sequelae of events that lead to these cardiometabolic diseases include oxidative stress, inflammation, development of dysfunction of vascular adipose tissue, altered blood pressure and blood lipids, altered glucose metabolism, hardening of the arteries, endothelial dysfunction, development of atherosclerotic plaques, and activation of platelet and coagulation pathways. The Framingham Heart Study Group has developed a Risk Score that estimates the risk of developing heart disease in a 10-year period. This group of experts has developed mathematical functions for predicting clinical coronary disease events. These prediction capabilities are derived by assigning weights to major CVD risk factors such as sex, age, blood pressure, total cholesterol, low-density lipoprotein, high-density lipoprotein cholesterol, smoking behavior, and diabetes status. Currently, there is a growing interest in the use of artificial intelligence and machine learning applications. AI-based mimetic pattern-based algorithms seem to be better than the conventional Framingham Risk Score, in predicting clinical events related to CVDs. However, there are limitations to these applications as they do not have access to data on the specific factors that trigger acute vascular events, such as heart attack and stroke. This overview briefly discusses some salient cellular and molecular mechanisms involved in precipitating thrombotic conditions. Further improvements in emerging technologies will provide greater opportunities for patient selection and treatment options. Several clinical studies have demonstrated that most CVDs can be prevented by addressing behavioral risk factors such as tobacco use, unhealthy diet and obesity, physical activity, and harmful use of alcohol. Early detection and better management of the modifiable risks seem to be the only way to reduce, reverse, or prevent these diseases.

Carbonized Platycladus orientalis Derived Carbon Dots Accelerate Hemostasis through Activation of Platelets and Coagulation Pathways.

Achieving rapid and effective hemostasis remains a multidisciplinary challenge. Here, distinctive functional carbon dots derived from carbonized Platycladus orientalis (CPO-CDs) are developed using one-step hydrothermal method. The negatively charged surface of CPO-CDs retains partial functional groups from CPO precursor, exhibiting excellent water solubility and high biocompatibility. Both rat liver injury model and tail amputation model have confirmed the rapid and effective hemostatic performance of CPO-CDs on exogenous hemorrhage. Further, on endogenous blood-heat hemorrhage syndrome rat model, CPO-CDs could inhibit hemorrhage and alleviate inflammation response. Interestingly, the excellent hemostasis performance of CPO-CDs is ascribed to activate exogenous coagulation pathway and common coagulation pathway. More importantly, metabolomics of rat plasma suggests that the hemostasis effect of CPO-CDs is closely related to platelet functions. Therefore, the designed in vitro experiments are performed and it is discovered that CPO-CDs significantly promote platelets adhesion, activation, and aggregation. Further, the underlying mechanism investigation suggests that Src/Syk signal pathway plays a key role in platelets activation triggered by CPO-CDs. Overall, CPO-CDs with rapid and excellent hemostatic performance are discovered for the first time, which could be an excellent candidate for the treatment of hemorrhagic diseases.

Procoagulant genes may affect angiogenesis, epithelial-mesenchymal transition, survival prognosis and tumor immune microenvironment in patients with urothelial carcinoma.

Factors related to coagulation regulation are closely related to angiogenesis, epithelial-mesenchymal transition, tumor proliferation and metastasis, and tumor immune microenvironment remodeling in tumors. To date, there are no quantitative indicators of coagulation associated with urothelial cancer. We classified urothelial cancer into high coagulation and low coagulation subtypes by screening for procoagulant-related molecular features and screened out relevant genes representing the coagulation state of urothelial carcinoma. Tumors with increased procoagulant gene expression were consistently associated with higher T-staging (p < 0.001), lymph node metastasis (p < 0.001), stage (p < 0.001), and grade (p = 0.046). Furthermore, high expression of procoagulant genes predicts a worse prognosis, a higher tumor proliferation rate and increased angiogenesis within the tumor. In addition, according to cibersort algorithm, the increased expression of procoagulant gene was negatively correlated with the degree of T-lymphocyte infiltration and positively correlated with the degree of M2 macrophage infiltration. Increased expression of procoagulant genes in data sets treated with immune checkpoints also predicted worse response and worse prognosis. At the same time, the expression of procoagulant genes in bladder cancer promoted the activation of coagulation, EMT, TGF-β and WNT pathways.

Tissue factor expression in monocyte subsets during human immunothrombosis, endotoxemia and sepsis

IntroductionTissue factor expression on monocytes is implicated in the pathophysiology of sepsis-induced coagulopathy. How tissue factor is expressed by monocyte subsets (classical, intermediate and non-classical) is unknown. MethodsMonocytic tissue factor surface expression was investigated during three conditions. Primary human monocytes and microvascular endothelial cell co-cultures were used for in vitro studies. Volunteers received a bolus of lipopolysaccharide (2 ng/kg) to induce endotoxemia. Patients with sepsis, or controls with critical illness unrelated to sepsis, were recruited from four intensive care units. ResultsContact with endothelium and stimulation with lipopolysaccharide reduced the proportion of intermediate monocytes. Lipopolysaccharide increased tissue factor surface expression on classical and non-classical monocytes. Endotoxemia induced profound, transient monocytopenia, along with activation of coagulation pathways. In the remaining circulating monocytes, tissue factor was up-regulated in intermediate monocytes, though approximately 60 % of individuals (responders) up-regulated tissue factor across all monocyte subsets. In critically ill patients, tissue factor expression on intermediate and non-classical monocytes was significantly higher in patients with established sepsis than among non-septic patients. Upon recovery of sepsis, expression of tissue factor increased significantly in classical monocytes. ConclusionTissue factor expression in monocyte subsets varies significantly during health, endotoxemia and sepsis.

Assessment of systemic immune-inflammation index as an independent surrogate biomarker of no-reflow phenomenon in acute coronary syndrome patients with coronary artery bypass grafting undergoing percutaneous coronary intervention of saphenous vein graft.

Numerous mechanisms have been proposed for the no-reflow phenomenon (NRP) in the literature including leukocyte intravascular plugging, microembolisms, and extrinsic coagulation pathway activation. Some of the more recent studies suggested a relationship between NRP and systemic immune-inflammation index (SII) in different contexts. To this end, the objective of this study was to investigate the relationship between NRP and SII in acute coronary syndrome (ACS) patients with coronary artery bypass grafting (CABG) who underwent percutaneous transluminal coronary angioplasty (PTCA) or percutaneous coronary intervention (PCI) of saphenous vein graft (SVG). The sample of this retrospective study consisted of 124 ACS patients with CABG who underwent PTCA/PCI of SVG. The incidence of NRP in the study group was 30.6% (n=38). The results of the multivariate logistic regression analysis indicated that ST-elevation myocardial infarction (STEMI) and SII were independent predictors for NRP (p<0.05). The receiver operating characteristic (ROC) curve analysis revealed that the optimal cut-off value of SII in predicting the development of NRP in patients undergoing PTCA/PCI of SVG and the sensitivity and specificity values thereof are 975, 74%, and 80%, respectively [Area under the curve (AUC): 0.84, 95% confidence interval (CI): 0.76-0.91, p-value <0.001]. The study findings indicated that SII, which can be easily calculated from a single complete blood count test, is an independent predictor of the development of NRP in ACS patients undergoing PTCA/PCI of the SVG.

Blood transcriptome responses in patients correlate with severity of COVID-19 disease.

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Infected individuals display a wide spectrum of disease severity, as defined by the World Health Organization (WHO). One of the main factors underlying this heterogeneity is the host immune response, with severe COVID-19 often associated with a hyperinflammatory state. Our current study aimed to pinpoint the specific genes and pathways underlying differences in the disease spectrum and outcomes observed, through in-depth analyses of whole blood transcriptomics in a large cohort of COVID-19 participants. All WHO severity levels were well represented and mild and severe disease displaying distinct gene expression profiles. WHO severity levels 1-4 were grouped as mild disease, and signatures from these participants were different from those with WHO severity levels 6-9 classified as severe disease. Severity level 5 (moderate cases) presented a unique transitional gene signature between severity levels 2-4 (mild/moderate) and 6-9 (severe) and hence might represent the turning point for better or worse disease outcome. Gene expression changes are very distinct when comparing mild/moderate or severe cases to healthy controls. In particular, we demonstrated the hallmark down-regulation of adaptive immune response pathways and activation of neutrophil pathways in severe compared to mild/moderate cases, as well as activation of blood coagulation pathways. Our data revealed discrete gene signatures associated with mild, moderate, and severe COVID-19 identifying valuable candidates for future biomarker discovery.

Nephrological complications in patients after COVID-19 infection

In this review, we looked for correlations and health consequences between COVID-19 infection and kidney health. Although the main symptoms of COVID-19 are respiratory failure and hypoxemia, kidney involvement is also common. In an attempt to decipher how COVID-19 infection affects the kidneys, this review focuses on the pathophysiological and clinical links between COVID-19 infection and the kidneys. The aim of this work was to find long-term health consequences in patients who were discharged from the hospital and to investigate risk factors. COVID-19-related kidney disease is reported not only in infected patients with chronic kidney disease, but also in people with no previous history of kidney disease. The disease caused by the coronavirus (COVID-19) is a threat to public health. Chronic kidney disease (CKD) has been shown to be a risk factor for side effects. Although initial reports from China showed a low incidence (5%-10%) of acute kidney injury (AKI), subsequent articles documented a much higher incidence of AKI in hospitalized COVID-19 patients. Overall, renal biopsies showed a variety of histopathology, including acute glomerulonephritis and acute tubular injury. The pathophysiology of COVID-19-associated AKI is believed to include local and systemic inflammatory and immunological reactions, endothelial damage, and activation of coagulation pathways and the renin-angiotensin system. Histopathology results revealed both similarities and differences between AKI in COVID-19 patients and AKI patients in non-COVID-19 sepsis. Acute tubular injury is common, although it is often mild despite greatly reduced kidney function. Systemic haemodynamic instability most likely contributes to renal tubular damage. Despite the description of COVID-19 as a cytokine storm syndrome, circulating cytokine levels are often lower in patients with COVID-19 than in patients with acute respiratory distress syndrome from causes other than COVID-19. Also, an impaired response to type I interferon has been detected in patients with severe COVID-19. In the light of these observations, the potential pathophysiological mechanisms of COVID-19-associated AKI may provide knowledge to construct therapeutic strategies.

Urticaria and Angioedema: Understanding Complex Pathomechanisms to Facilitate Patient Communication, Disease Management, and Future Treatment

Chronic spontaneous urticaria (CSU) is primarily a T2-dominant disease with a complex genetic background. Skin mast cell activation can be induced not only via the IgE-FcεRI axis but also from several other distinct mechanisms, molecules, and receptors involved in CSU onset, persistence, and exacerbation. These include autoallergy, autoimmunity, central or peripheral neuroimmune dysregulation, activation of both extrinsic and intrinsic coagulation pathways, and microbial infections. Besides mast cells, recent reports suggest the active and direct involvement of basophils and eosinophils. Several biological characteristics or biomarkers have been linked with CSU's known endotypes and may help forecast therapeutic responses. The introduction of biologic therapy for CSU has been a major advance in the last 10 years. The cornerstone of angioedema (AE) pathogenesis is increased vascular permeability and plasma leakage into the deeper dermis and subcutis, either mediated by histamine or bradykinin (BK). C1-inhibitor deficiency, hereditary or acquired, is the primary cause of BK-mediated AE due to increased plasma BK concentration. Other complex conditions have been identified, with some likely involving contact system dysregulation and other putative mechanisms related to vascular endothelial dysfunction. The approval of multiple hereditary-AE-specific therapies for both prevention and acute attacks has revolutionized treatment of this disease. Any new knowledge of the pathogenesis of CSU and AE offers the opportunity to improve patient information, physician-patient communication, prediction of therapeutic responses, selection of precise tailor-made treatment for each patient, and exploration of novel treatment options for those who do not achieve disease control with current medications.

Glycated albumin modulates the contact system with implications for the kallikrein-kinin and intrinsic coagulation systems

BackgroundHuman serum albumin (HSA) is the most abundant plasma protein and is sensitive to glycation in vivo. The chronic hyperglycemic conditions in patients with diabetes mellitus (DM) induce a nonenzymatic Maillard reaction that denatures plasma proteins and forms advanced glycation end products (AGEs). HSA-AGE is a prevalent misfolded protein in patients with DM and is associated with factor XII activation and downstream proinflammatory kallikrein-kinin system activity without any associated procoagulant activity of the intrinsic pathway. ObjectivesThis study aimed to determine the relevance of HSA-AGE toward diabetic pathophysiology. MethodsThe plasma obtained from patients with DM and euglycemic volunteers was probed for activation of FXII, prekallikrein (PK), and cleaved high-molecular-weight kininogen by immunoblotting. Constitutive plasma kallikrein activity was determined via chromogenic assay. Activation and kinetic modulation of FXII, PK, FXI, FIX, and FX via in vitro–generated HSA-AGE were explored using chromogenic assays, plasma-clotting assays, and an in vitro flow model using whole blood. ResultsPlasma obtained from patients with DM contained increased plasma AGEs, activated FXIIa, and resultant cleaved cleaved high-molecular-weight kininogen. Elevated constitutive plasma kallikrein enzymatic activity was identified, which positively correlated with glycated hemoglobin levels, representing the first evidence of this phenomenon. HSA-AGE, generated in vitro, triggered FXIIa-dependent PK activation but limited the intrinsic coagulation pathway activation by inhibiting FXIa and FIXa-dependent FX activation in plasma. ConclusionThese data indicate a proinflammatory role of HSA-AGEs in the pathophysiology of DM via FXII and kallikrein-kinin system activation. A procoagulant effect of FXII activation was lost through the inhibition of FXIa and FIXa-dependent FX activation by HSA-AGEs.

A STUDY OF ALTERATION IN COAGULATION PROFILE IN PATIENTS UNDERGOING LAPAROSCOPIC CHOLECYSTECTOMY

Introduction: Laparoscopic cholecystectomy has become the gold standard for the treatment of cholelithiasis. It has many advantages such as better cosmetic, shorter hospitalization time, minimal postoperative pain, early return to normal life. However carbon dioxide pneumoperitoneum may cause alteration in the coagulation system and moreover the reverse Trendelenburg position adopted diring surgery can induce blood stagnation in the lower limbs leading to a hypercoagulable state. The aim Objective: of the study was to record the effect of carbon dioxide pneumoperitoneum on coagulation factors and brinolysis response during laparoscopic cholecystectomy and to assess if there is any risk of postoperative thromboembolic complications following laparoscopic cholecystectomy. Methods: The hospital based descriptive study of 50 patients undergoing elective laparoscopic cholecystectomy was designed to study alteration in Clotting time, Prothrombin time(PT), Activated partial thrombin time(aPTT), Fibrinogen and D-dimer, which were measured preoperatively and 6 hour postoperatively. Out of 50 Results: patients operated 38 were female and 12 were male. Signicant decrease in PT and aPTT suggested activation of coagulation pathways while signicant increase in d-dimer and brinogen suggested activation of brinolytic systems. None of the patients had any postoperative thromboembolic complications. From the study we found that there was activati Discussions: on of coagulation and brinolysis after laparoscopic cholecystectomy leading to a hypercoagulable state which may be either due to carbon dioxide pneumoperitoneum or due to increased intraabdominal pressure. Although none of the patients had any thromboembolic complications postoperatively, however there may be the need to use prophylactic measures for thrombosis in high risk patients.

Abstract 126: The Association Of Higher Or Lower Mean Arterial Pressure On Kidney Function After Cardiac Arrest: A Post-hoc Analysis Of The Comacare And Neuroprotect Trials

Introduction: Acute kidney injury (AKI) denotes a sudden reduction in kidney function manifested by a rise in S-creatine levels and reduced urine output. Studies have suggested an association between AKI severity and outcomes after OHCA. Various criteria have been used to define AKI, the Kidney Disease Improving Global Outcomes (KDIGO) published in 2012 being the currently used tool. AKI is a feature of post-cardiac arrest syndrome.During post-CA syndrome, possible causes of renal damage are direct renal ischaemic-reperfusion injury and indirect renal damage characterized by the activation of inflammatory and coagulation pathways. Although the overall mortality rate after CA mainly relates to hypoxic-ischaemic brain injury, damage to other organs also has prognostic implications. Methods: Pooled post-hoc analysis of the COMACARE (NCT02698917) and NEUROPROTECT (NCT02541591) trials that randomized patients to lower (MAP 65-70 mmHg) or higher (MAP 80-100 mmHg) targets for the first 36 hours of post-CA intensive care. Kidney function was categorised using the KDIGO classification during the first five days after OHCA. We used Cox regression analysis to identify factors associated with AKI after OHCA. Results: A total of 227 patients were included: 115 in the high MAP group and 112 in the low MAP group. Eighty-six (38%) patients developed AKI during the first five days; 40 (47%) patients had AKI in the high MAP group and 46 (54%) in the low MAP group (p = 0.51). The mean creatinine and mean daily diuresis were 104 (95% CI 94-115) μmol/l and 1989 (95% CI 1829-2150) mL/day in the high MAP group and 111 (95% CI 99-122) μmol/l and 1677 (95% CI 1530-1824) mL/day in the low MAP group. In a Cox regression model, independent AKI predictors were previous hypertension (HR 1.72; 95% CI 1.07-2.78; p = 0.03), bystander cardiopulmonary resuscitation (hazard ratio [HR] 0.46; 95% CI 0.29-0.73; p &lt; 0.01), shockable initial rhythm (HR 0.36; 95% CI 0.21-0.61; p ≤ 0.01), and time to ROSC (HR 1.04; 95% CI 1.02-1.06; p &lt; 0.01) whereas high/low MAP was not an independent predictor of AKI. Conclusions: KDIGO1-staged AKI is common after CA and is associated with previous hypertension and CA factors. Targeting higher MAP after CA does not appear to influence the development of AKI.

Preparation and blood compatibility of polyethersulfone dialysis membrane modified by apixaban as coagulation factor Xa inhibitor.

Blood purification therapy is widely used in the treatment of critically ill patients. However, most dialysis membranes are prone to thrombosis. Activated coagulation factor X (FXa) functions at the intersection of intrinsic, extrinsic, and common coagulation pathways and plays a central role in thrombogenesis. To date, few dialysis membranes that directly inhibit FXa have been reported. We modified a polyethersulfone(PES) membrane using apixaban as an FXa inhibitor and investigated the performance of this membrane (AMPES). The contact angle of the modified membrane was reduced. PWF and retention rates of BSA were increased, demonstrating good hydrophilicity and dialysis performance. Albumin adsorption was reduced from 141.8±15.5 to 114.1±6.9μgcm-2. Reduced protein adsorption, especially targeted anti-FXa effect, inhibited the activation of intrinsic, extrinsic, and common coagulation pathways, as evidenced by significant prolongations of activated partial thromboplastin time, prothrombin time, and thrombin time by 145.04, 46.84 and 11.46s, respectively. Furthermore, we determined the FXa concentration of each group, and found that the modified membrane had better anticoagulant performance through the inhibition of FXa. Favorable antiplatelet activity was also demonstrated. Thromboelastogram was used to comprehensively evaluate the anticoagulant and antithrombotic activities of the modified membrane. The R value was increased by 43.1min, while the reduction in α angle was 42.5°. The coagulation comprehensive index reduction was 34.3. In addition, C3a and C5a were decreased by 15.3% and 30.4%, respectively. Furthermore, in vitro cytotoxicity and erythrocyte stability testing as well as in vivo murine experiments demonstrated the biosafety of the modified membrane. These results indicate that the AMPES dialysis membrane has an excellent potential for clinical applications.