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Coagulation Pathways (coagulation + pathway)
Selected AbstractsSuperantigens from Staphylococcus aureus induce procoagulant activity and monocyte tissue factor expression in whole blood and mononuclear cells via IL-1,JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 12 2003E. Mattsson Summary.,Background:,Staphylococcus aureus is one of the most common bacteria in human sepsis, a condition in which the activation of blood coagulation plays a critical pathophysiological role. During severe sepsis and septic shock microthrombi and multiorgan dysfunction are observed as a result of bacterial interference with the host defense and coagulation systems. Objectives:,In the present study, staphylococcal superantigens were tested for their ability to induce procoagulant activity and tissue factor (TF) expression in human whole blood and in peripheral blood mononuclear cells. Methods and results:,Determination of clotting time showed that enterotoxin A, B and toxic shock syndrome toxin 1 from S. aureus induce procoagulant activity in whole blood and in mononuclear cells. The procoagulant activity was dependent on the expression of TF in monocytes since antibodies to TF inhibited the effect of the toxins and TF was detected on the surface of monocytes by flow cytometry. In the supernatants from staphylococcal toxin-stimulated mononuclear cells, interleukin (IL)-1, was detected by ELISA. Furthermore, the increased procoagulant activity and TF expression in monocytes induced by the staphylococcal toxins were inhibited in the presence of IL-1 receptor antagonist, a natural inhibitor of IL-1,. Conclusions:,The present study shows that superantigens from S. aureus activate the extrinsic coagulation pathway by inducing expression of TF in monocytes, and that the expression is mainly triggered by superantigen-induced IL-1, release. [source] Has Time Come for New Goals in Human Islet Transplantation?AMERICAN JOURNAL OF TRANSPLANTATION, Issue 6 2008R. Lehmann The enthusiasm regarding clinical islet transplantation has been dampened by the long-term results. Concerns about the associated risks of life-long immunosuppression and the striking imbalance between potential recipients and available donor pancreata warrant changes in some of the current goals. Islet transplantation will never be a cure of type 1 diabetes in the majority of patients with no secondary complications, but is a valid option for a limited number of patients with brittle diabetes waiting for an organ or after organ transplantation. Furthermore, insulin independence should not be the main goal of islet transplantation, but avoidance of severe hypoglycemia and good glycemic control, which can be achieved with a relatively small functional beta-cell mass. Therefore, initially one islet infusion is sufficient. Retransplantation at a later time point remains an option, if glucose control deteriorates. Efforts to improve islet transplantation should no longer focus on islet isolation and immunosuppression, but rather on the low posttransplant survival rate of islets caused by activation of the coagulation pathway and the limited oxygen delivery to the islets. Transplantation of smaller islets be it naturally small or size tailored reaggregated islets has the potential to facilitate these processes. [source] Beta2 -glycoprotein I protects thrombin from inhibition by heparin cofactor II: Potentiation of this effect in the presence of anti,,2 -glycoprotein I autoantibodiesARTHRITIS & RHEUMATISM, Issue 4 2008Soheila Rahgozar Objective Beta2 -glycoprotein I (,2GPI) is an important autoantigen in the antiphospholipid syndrome (APS). In vitro studies suggest that it may have multifaceted physiologic functions, since it displays both anticoagulant and procoagulant properties. We have previously reported that ,2GPI can directly bind thrombin, a key serine protease in the coagulation pathway. The present study was undertaken to examine the influence of ,2GPI on thrombin inactivation by the serpin heparin cofactor II (HCII). The effect of anti-,2GPI antibodies was also examined. Methods HCII inactivation of thrombin was assessed using chromogenic and various platelet functional assays. The influence of intact and proteolytically cleaved ,2GPI and anti-,2GPI antibodies was determined in these systems. Results ,2GPI protected thrombin against inactivation by HCII/heparin. Cleavage of ,2GPI at Lys317,Thr318 abrogated its protective effect. Patient polyclonal IgG and murine monoclonal anti-,2GPI antibodies potentiated the procoagulant influence of ,2GPI in this system. Conclusion These novel findings suggest that ,2GPI may regulate thrombin inactivation by HCII/heparin. The observation that anti-,2GPI antibodies potentiate the protective effect of ,2GPI on thrombin in this system, thereby promoting a procoagulant response, may potentially delineate one of the pathophysiologic mechanisms contributing to the prothrombotic tendency in patients with APS. [source] FEIBAź safety profile in multiple modes of clinical and home-therapy applicationHAEMOPHILIA, Issue 2004H. Luu Summary., The development of neutralizing antibodies to factor VIII or IX therapeutic concentrates remains the most serious and challenging complication in the management of patients with haemophilia A and B. FEIBAź, Anti-Inhibitor Coagulant Complex, is an activated prothrombin complex concentrate that has been used to treat patients with such complications for almost 30 years. The mechanism of action of FEIBAź has been proposed to involve simultaneous FVIII/FIX inhibitor bypassing action in the common, intrinsic and extrinsic coagulation pathways. FEIBAź is derived from human plasma that undergoes stringent viral screening followed by significant viral inactivation and removal. To date, there have been no confirmed reports of transmission of hepatitis A, B or C, or of human immunodeficiency viruses associated with the use of the current, vapour-heat-treated FEIBAź concentrate. The incidence of thrombotic adverse events recorded in the Baxter pharmacovigilance database for the 10-year postmarket period (1990,99) was approximately 4 : 100 000 infusions of FEIBAź. Almost all documented thrombotic events with FEIBAź occurred with doses that exceeded dosing recommendations, and known risk factors for cardiovascular disease were evident in more than 80% of the patients involved. Overall, clinical data have shown FEIBAź to be safe and well-tolerated for use in a wide variety of clinical settings, including treatment of bleeding episodes, management of surgical procedures, home therapy, long-term prophylaxis, and prophylaxis during immune tolerance induction, when used according to dosing guidelines. [source] Vascular and dendritic cell coagulation signaling in sepsis progressionJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 2009W. RUF Summary., The intrinsic signaling networks of the coagulation pathways have recently emerged as crucial determinants for survival in sepsis and systemic inflammatory response syndromes. Protease activated receptor (PAR) 1 is central to both lethality promoting and vascular protective signaling. In the vascular anticoagulant pathway, EPCR/aPC-PAR1 signaling prevents vascular leakage and genetic or acute deficiencies in this pathway promote lethality. In addition, coagulation signaling acts directly on cells of the innate immune system. Dendritic cell (DC) thrombin-PAR1 signaling is coupled to the migration promoting sphingosine 1 phosphate receptor 3 (S1P3). Thrombin generated in the lymphatic compartment perturbs DCs to promote systemic inflammation and disseminated intravascular coagulation in severe sepsis. Signaling-selective aPC variants and selective modulators of the S1P receptor system attenuate sepsis lethality, suggesting novel therapeutic approaches that can be employed to rebalance alterations in the coagulation signaling pathways in severe inflammatory disorders. [source] Active site inhibited factor VIIa attenuates myocardial ischemia/reperfusion injury in miceJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 2 2009S. T. B. G. LOUBELE Summary.,Background:,Inhibition of specific coagulation pathways such as the factor VIIa-tissue factor complex has been shown to attenuate ischemia/reperfusion (I/R) injury, but the cellular mechanisms have not been explored. Objectives:,To determine the cellular mechanisms involved in the working mechanism of active site inhibited factor VIIa (ASIS) in the protection against myocardial I/R injury. Methods:,We investigated the effects of a specific mouse recombinant in a mouse model of myocardial I/R injury. One hour of ischemia was followed by 2, 6 or 24 h of reperfusion. Mouse ASIS or placebo was administered before and after induction of reperfusion. Results:,ASIS administration reduced myocardial I/R injury by more than 40% at three reperfusion times. Multiplex ligation dependent probe amplification (MLPA) analysis showed reduced mRNA expression in the ischemic myocardium of CD14, TLR-4, interleukin-1 (IL-1) receptor-associated kinase (IRAK) and I,B, upon ASIS administration, indicative of inhibition of toll-like receptor-4 (TLR-4) and subsequent nuclear factor-,B (NF-,B) mediated cell signaling. Levels of nuclear activated NF-,B and proteins influenced by the NF-,B pathway including tissue factor (TF) and IL-6 that were increased after I/R, were attenuated upon ASIS administration. After 6 and 24 h of reperfusion, neutrophil infiltration into the area of infarction was decreased upon ASIS administration. There was, however, no evidence of an effect of ASIS on apoptosis (Tunel staining and MLPA analysis). Conclusions:,We conclude that the diminished amount of myocardial I/R injury after ASIS administration is primarily due to attenuated inflammation-related lethal I/R injury, probably mediated through the NF-,B mechanism. [source] Differential effect of materials for surface hemostasis on red blood cell morphologyMICROSCOPY RESEARCH AND TECHNIQUE, Issue 10 2008Carr J. Smith Abstract The design of devices for surface (topical) hemostasis has been based on maximizing activation of platelets and accelerating coagulation pathways. The studies reported herein examine another aspect of blood contact with topical hemostasis materials, i.e., surface binding of red blood cells (RBCs) and related alterations in RBC morphology. Whole blood was allowed to contact poly- N -acetyl glucosamine (pGlcNAc) containing materials: pGlcNAc nanofibers with parallel polymer alignment (,-pGlcNAc), chitin, and chitosan. The effect on RBC morphology and function via contact with the artificial surfaces on the cell's morphology was examined with scanning and transmission electron microscopy (TEM). ,-pGlcNAc was found to densely bind RBCs and induce a stomatocytic-like morphology. Chitin and chitosan also bound RBCs, but with approximately 10-fold lower levels and with less distinct general morphologies. ,-pGlcNAc is thus unique in the nature of its interaction with RBCs. These studies indicate that the differential ability of various materials to bind and alter the morphology of RBCs at the artificial surface interface with blood is an important consideration in the design of devices for surface hemostasis. Microsc. Res. Tech., 2008. © 2008 Wiley-Liss, Inc. [source] Tolerance Signaling Molecules and Pregnancy: IDO, Galectins, and the Renaissance of Regulatory T CellsAMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 3 2007Peter Terness Problem, Is the concept of maternal tolerance preventing rejection of the semi-allogeneic ,fetal allograft' still valid? Method of study, Compilation of expert reviews of literature and recent advances in research on indoleamine-2,3 dioxygenase (IDO), regulatory T cells and galectin-1. Results and Conclusion, A role for IDO in pregnancy success remains speculative, but solid data exist to support a role for Treg cells, and for galectin-1 in induction and action of Treg cells. Just as several signals may need to be simultaneously present to induce Th1 cytokine-triggered abortions, more than 1 signal may need to be simultaneously present to prevent rejection and ensure success. Both complement and coagulation pathways appear necessary for embryo execution. [source] Subtype-specific peripheral blood gene expression profiles in recent-onset juvenile idiopathic arthritisARTHRITIS & RHEUMATISM, Issue 7 2009Michael G. Barnes Objective To identify differences in peripheral blood gene expression between patients with different subclasses of juvenile idiopathic arthritis (JIA) and healthy controls in a multicenter study of patients with recent-onset JIA prior to treatment with disease-modifying antirheumatic drugs (DMARDs) or biologic agents. Methods Peripheral blood mononuclear cells (PBMCs) from 59 healthy children and 136 patients with JIA (28 with enthesitis-related arthritis [ERA], 42 with persistent oligoarthritis, 45 with rheumatoid factor [RF],negative polyarthritis, and 21 with systemic disease) were isolated from whole blood. Poly(A) RNA was labeled using a commercial RNA amplification and labeling system (NuGEN Ovation), and gene expression profiles were obtained using commercial expression microarrays (Affymetrix HG-U133 Plus 2.0). Results A total of 9,501 differentially expressed probe sets were identified among the JIA subtypes and controls (by analysis of variance; false discovery rate 5%). Specifically, 193, 1,036, 873, and 7,595 probe sets were different in PBMCs from the controls compared with those from the ERA, persistent oligoarthritis, RF-negative polyarthritis, and systemic JIA patients, respectively. In patients with persistent oligoarthritis, RF-negative polyarthritis, and systemic JIA subtypes, up-regulation of genes associated with interleukin-10 (IL-10) signaling was prominent. A hemoglobin cluster was identified that was underexpressed in ERA patients but overexpressed in systemic JIA patients. The influence of JAK/STAT, ERK/MAPK, IL-2, and B cell receptor signaling pathways was evident in patients with persistent oligoarthritis. In systemic JIA, up-regulation of innate immune pathways, including IL-6, Toll-like receptor/IL-1 receptor, and peroxisome proliferator,activated receptor signaling, were noted, along with down-regulation of gene networks related to natural killer cells and T cells. Complement and coagulation pathways were up-regulated in systemic JIA, with a subset of these genes being differentially expressed in other subtypes as well. Conclusion Expression analysis identified differentially expressed genes in PBMCs obtained early in the disease from patients with different subtypes of JIA and in healthy controls, providing evidence of immunobiologic differences between these forms of childhood arthritis. [source] Are Standard Human Coagulation Tests Suitable in Pigs and Calves During Extracorporeal Circulation?ARTIFICIAL ORGANS, Issue 7 2001Xavier M. Mueller Abstract: The thrombogenicity of membrane oxygenators as well as clotting parameters profiles, using standard human clotting tests, was analyzed in calves and pigs during 6 h perfusion. Three calves and 3 pigs were connected to extracorporeal circulation with standard heparinization. Blood samples were taken for coagulation variables throughout perfusion, and oxygenators were examined for clot deposits at the end of the experiment. Two out of 3 oxygenators of the calf group presented clot deposits while none in the pig group did. Baseline coagulation variables of pigs showed values similar to those of humans while neither extrinsic nor intrinsic pathways could be activated in calves with standard human coagulation tests. The calf model, in conclusion, was confirmed to be a difficult model for the testing of extracorporeal circulation device resistance to thrombus formation, which is, however, not reflected by standard human coagulation tests. The pig model is a better model in which both coagulation pathways could be activated with standard human coagulation tests. [source] | ||||||||||