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new coagulation cascade

Louis M Kwong, Jon A Kimball
Elective total hip or knee arthroplasty places patients at risk for venous thromboembolism (VTE). As our understanding of the pathophysiology of VTE after joint arthroplasty has increased, pharmacologic strategies have been developed to target different aspects of the coagulation cascade. Various approaches have been used as risk reduction strategies. In 2011 and 2014 the Food and Drug Administration approved rivaroxaban and apixaban as new oral antithrombotic agents. Although controversies remain with regard to the ideal VTE pharmacoprophylactic agent, this class of novel oral anticoagulants has been demonstrated to be safe and to be more effective than enoxaparin...
October 2016: Hematology/oncology Clinics of North America
Konstantin Stark, Vanessa Philippi, Sven Stockhausen, Johanna Busse, Antonella Antonelli, Meike Miller, Irene Schubert, Parandis Hoseinpour, Sue Chandraratne, Marie-Luise von Brühl, Florian Gärtner, Michael Lorenz, Alessandra Agresti, Raffaele Coletti, Daniel J Antoine, Ralf Heermann, Kirsten Jung, Sven Reese, Iina Laitinen, Markus Schwaiger, Axel Walch, Markus Sperandio, Peter P Nawroth, Christoph Reinhardt, Sven Jäckel, Marco E Bianchi, Steffen Massberg
Deep venous thrombosis (DVT) is one of the most common cardiovascular diseases, but its pathophysiology remains incompletely understood. While sterile inflammation has recently been shown to boost coagulation during DVT, the underlying molecular mechanisms are not fully resolved, which could potentially identify new anti-inflammatory approaches to prophylaxis and therapy of DVT. Using a mouse model of venous thrombosis induced by flow reduction in the vena cava inferior we identified blood-derived high-mobility group box 1 protein (HMGB1) - a prototypical mediator of sterile inflammation - to be a master regulator of the prothrombotic cascade involving platelets and myeloid leukocytes fostering occlusive DVT formation...
August 29, 2016: Blood
Rosaria Viola Abbritti, Francesca Polito, Maria Cucinotta, Claudio Lo Giudice, Maria Caffo, Chiara Tomasello, Antonino Germanò, Mohammed Aguennouz
Meningiomas are one of the most common tumors affecting the central nervous system, exhibiting a great heterogeneity in grading, treatment and molecular background. This article provides an overview of the current literature regarding the molecular aspect of meningiomas. Analysis of potential biomarkers in serum, cerebrospinal fluid (CSF) and pathological tissues was reported. Applying bioinformatic methods and matching the common proteic profile, arising from different biological samples, we highlighted the role of nine proteins, particularly related to tumorigenesis and grading of meningiomas: serpin peptidase inhibitor alpha 1, ceruloplasmin, hemopexin, albumin, C3, apolipoprotein, haptoglobin, amyloid-P-component serum and alpha-1-beta-glycoprotein...
September 2016: Cancer Genomics & Proteomics
Solenne Tillet, Sébastien Giraud, Thomas Kerforne, Thibaut Saint-Yves, Sandrine Joffrion, Jean-Michel Goujon, Jerôme Cau, Gérard Mauco, Maurice Petitou, Thierry Hauet
Coagulation is an important pathway in the pathophysiology of ischemia-reperfusion injuries. In particular, deceased after circulatory death (DCD) donors undergo a no-flow period, a strong activator of coagulation. Hence, therapies influencing the coagulation cascade must be developed. We evaluated the effect of a new highly specific and effective anti-Xa/IIa molecule, with an integrated innovative antidote site (EP217609), in a porcine preclinical model mimicking injuries observed in DCD donor kidney transplantation...
July 25, 2016: Translational Research: the Journal of Laboratory and Clinical Medicine
Pierre A J Mourier, Fréderic Herman, Philippe Sizun, Christian Viskov
Enoxaparin sodium, a low-molecular-weight heparin (LMWH) prepared from porcine intestinal heparin, is widely used for the prevention and treatment of venous thromboembolism. The antithrombotic activity of heparin is mediated mainly through its activation of antithrombin (AT) and subsequent inhibition of coagulation factors. Heparin is a complex heteropolymer and the sulfation pattern of its alternating uronic acid and glucosamine sugar units is a major factor influencing its biological activity. The manufacturing process itself is associated with the introduction of exogenous microheterogeneities that may further affect its biological efficacy...
September 10, 2016: Journal of Pharmaceutical and Biomedical Analysis
Peter G W Gettins, Steven T Olson
Serpins are a widely distributed family of high molecular mass protein proteinase inhibitors that can inhibit both serine and cysteine proteinases by a remarkable mechanism-based kinetic trapping of an acyl or thioacyl enzyme intermediate that involves massive conformational transformation. The trapping is based on distortion of the proteinase in the complex, with energy derived from the unique metastability of the active serpin. Serpins are the favoured inhibitors for regulation of proteinases in complex proteolytic cascades, such as are involved in blood coagulation, fibrinolysis and complement activation, by virtue of the ability to modulate their specificity and reactivity...
August 1, 2016: Biochemical Journal
Ece Balkuv, Asuman Orhan Varoglu, Nihal Isik, Banu Isbilen, Saadettin Duruyen, Recep Basaran, Abdulkadir Kocer
BACKGROUND: Various molecules of the coagulation cascade are thought to have varying roles in the pathophysiology of multiple sclerosis (MS). We aimed to find new information about the effects of the coagulation cascade molecules to develop new therapeutic strategies for MS. MATERIALS AND METHODS: Patients with MS were chosen from among patients who were followed up at our hospital. We examined the thrombomodulin (TM) and activated protein C (APC) serum levels in patients with MS and the healthy controls...
July 2016: Multiple Sclerosis and related Disorders
Teena Bhakuni, Mohammad Farhan Ali, Irshad Ahmad, Shadabi Bano, Shoyab Ansari, Mohamad Aman Jairajpuri
Pro-coagulant, anti-coagulant and fibrinolytic pathways are responsible for maintaining hemostatic balance under physiological conditions. Any deviation from these pathways would result in hypercoagulability leading to life threatening diseases like myocardial infarction, stroke, portal vein thrombosis, deep vein thrombosis (DVT) and pulmonary embolism (PE). Angiogenesis is the process of sprouting of new blood vessels from pre-existing ones and plays a critical role in vascular repair, diabetic retinopathy, chronic inflammation and cancer progression...
August 15, 2016: Archives of Biochemistry and Biophysics
Laura L Swystun, Patricia C Liaw
In recent years, the traditional view of the hemostatic system as being regulated by a coagulation factor cascade coupled with platelet activation has been increasingly challenged by new evidence that activation of the immune system strongly influences blood coagulation and pathological thrombus formation. Leukocytes can be induced to express tissue factor and release proinflammatory and procoagulant molecules such as granular enzymes, cytokines, and damage-associated molecular patterns. These mediators can influence all aspects of thrombus formation, including platelet activation and adhesion, and activation of the intrinsic and extrinsic coagulation pathways...
August 11, 2016: Blood
Li Min, Jianbo Cheng, Shengguo Zhao, He Tian, Yangdong Zhang, Songli Li, Hongjian Yang, Nan Zheng, Jiaqi Wang
UNLABELLED: Heat stress (HS) has an enormous economic impact on the dairy industry. In recent years, many researchers have investigated changes in the gene expression and metabolomics profiles in dairy cows caused by HS. However, the proteomics profiles of heat-stressed dairy cows have not yet been completely elucidated. We compared plasma proteomics from HS-free and heat-stressed dairy cows using an iTRAQ labeling approach. After the depletion of high abundant proteins in the plasma, 1472 proteins were identified...
September 2, 2016: Journal of Proteomics
Xiaohong Ruby Xu, Dan Zhang, Brigitta Elaine Oswald, Naadiya Carrim, Xiaozhong Wang, Yan Hou, Qing Zhang, Christopher Lavalle, Thomas McKeown, Alexandra H Marshall, Heyu Ni
Platelets are small anucleate blood cells generated from megakaryocytes in the bone marrow and cleared in the reticuloendothelial system. At the site of vascular injury, platelet adhesion, activation and aggregation constitute the first wave of hemostasis. Blood coagulation, which is initiated by the intrinsic or extrinsic coagulation cascades, is the second wave of hemostasis. Activated platelets can also provide negatively-charged surfaces that harbor coagulation factors and markedly potentiate cell-based thrombin generation...
December 2016: Critical Reviews in Clinical Laboratory Sciences
Youssef Bennis, Subashini Vengadessane, Sandra Bodeau, Valérie Gras, Giampiero Bricca, Saïd Kamel, Sophie Liabeuf
Despite the availability of new oral anticoagulants, vitamin K antagonists (VKA, such as fluindione, acenocoumarol or warfarin) remain currently the goal standard medicines for oral prevention or treatment of thromboembolic disorders. They inhibit the cycle of the vitamin K and its participation in the enzymatic gamma-carboxylation of many proteins. The VKA prevent the activation of the vitamin K-dependent blood clotting factors limiting thus the initiation of the coagulation cascade. But other proteins are vitamin K-dependent and also remain inactive in the presence of VKA...
September 2016: Thérapie
Makoto Kurano
Along with the established evidence on the association between a low HDL cholesterol level and arterial thrombosis, several limited studies have suggested that low HDL cholesterol is also a risk factor for venous thrombosis, such as deep vein thrombosis and pulmonary embolism. As well as emerging evidence from clinical studies, basic research has proposed the interaction between HDL and key molecules in the field of thrombosis and hemostasis; HDL interacts with megakaryocytes to affect the production of platelets, suppresses the aggregation of platelets, protects against the injury of endothelial cells, and inhibits coagulation and fibrinolysis cascades...
January 2016: Rinsho Byori. the Japanese Journal of Clinical Pathology
Mônica L Vieira, Clément Naudin, Matthias Mörgelin, Eliete C Romero, Ana Lucia T O Nascimento, Heiko Herwald
Leptospirosis is a worldwide spread zoonotic and neglected infectious disease of human and veterinary concern that is caused by pathogenic Leptospira species. In severe infections, hemostatic impairments such as coagulation/fibrinolysis dysfunction are frequently observed. These complications often occur when the host response is controlled and/or modulated by the bacterial pathogen. In the present investigation, we aimed to analyze the modulation of the hemostatic and inflammatory host responses by the bacterial pathogen Leptospira...
May 2016: PLoS Neglected Tropical Diseases
Ramyashree Tummala, Ana Kavtaradze, Anjan Gupta, Raktim Kumar Ghosh
The Vitamin K antagonist warfarin was the only oral anticoagulant available for decades for the treatment of thrombosis and prevention of thromboembolism until Direct Oral Anticoagulants (DOACs); a group of new oral anticoagulants got approved in the last few years. Direct thrombin inhibitor: dabigatran and factor Xa inhibitors: apixaban, rivaroxaban, and edoxaban directly inhibit the coagulation cascade. DOACs have many advantages over warfarin. However, the biggest drawback of DOACs has been the lack of specific antidotes to reverse the anticoagulant effect in emergency situations...
July 1, 2016: International Journal of Cardiology
Stephen Verespy, Akul Y Mehta, Daniel Afosah, Rami A Al-Horani, Umesh R Desai
Allosteric partial inhibition of soluble, monomeric proteases can offer major regulatory advantages, but remains a concept on paper to date; although it has been routinely documented for receptors and oligomeric proteins. Thrombin, a key protease of the coagulation cascade, displays significant conformational plasticity, which presents an attractive opportunity to discover small molecule probes that induce sub-maximal allosteric inhibition. We synthesized a focused library of some 36 sulfated coumarins to discover two agents that display sub-maximal efficacy (~50%), high potency (<500 nM) and high selectivity for thrombin (>150-fold)...
2016: Scientific Reports
Daoliang Lan, Xianrong Xiong, Cai Huang, Tserang Donko Mipam, Jian Li
BACKGROUND: Yaks (Bos grunniens) are endemic species that can adapt well to thin air, cold temperatures, and high altitude. These species can survive in harsh plateau environments and are major source of animal production for local residents, being an important breed in the Qinghai-Tibet Plateau. However, compared with ordinary cattle that live in the plains, yaks generally have lower fertility. Investigating the basic physiological molecular features of yak ovary and identifying the biological events underlying the differences between the ovaries of yak and plain cattle is necessary to understand the specificity of yak reproduction...
2016: PloS One
Silvia Guglietta, Andrea Chiavelli, Elena Zagato, Carsten Krieg, Sara Gandini, Paola Simona Ravenda, Barbara Bazolli, Bao Lu, Giuseppe Penna, Maria Rescigno
Excessive activation of blood coagulation and neutrophil accumulation have been described in several human cancers. However, whether hypercoagulation and neutrophilia are linked and involved in cancer development is currently unknown. Here we show that spontaneous intestinal tumorigenesis correlates with the accumulation of low-density neutrophils with a pro-tumorigenic N2 phenotype and unprompted neutrophil extracellular traps (NET) formation. We find that increased circulating lipopolysaccharide induces upregulation of complement C3a receptor on neutrophils and activation of the complement cascade...
March 21, 2016: Nature Communications
Yuqi Zhao, Jing Chen, Johannes M Freudenberg, Qingying Meng, Deepak K Rajpal, Xia Yang
OBJECTIVE: Recent genome-wide association studies of coronary artery disease (CAD) have revealed 58 genome-wide significant and 148 suggestive genetic loci. However, the molecular mechanisms through which they contribute to CAD and the clinical implications of these findings remain largely unknown. We aim to retrieve gene subnetworks of the 206 CAD loci and identify and prioritize candidate regulators to better understand the biological mechanisms underlying the genetic associations. APPROACH AND RESULTS: We devised a new integrative genomics approach that incorporated (1) candidate genes from the top CAD loci, (2) the complete genetic association results from the 1000 genomes-based CAD genome-wide association studies from the Coronary Artery Disease Genome Wide Replication and Meta-Analysis Plus the Coronary Artery Disease consortium, (3) tissue-specific gene regulatory networks that depict the potential relationship and interactions between genes, and (4) tissue-specific gene expression patterns between CAD patients and controls...
May 2016: Arteriosclerosis, Thrombosis, and Vascular Biology
Shiri Gur-Cohen, Orit Kollet, Claudine Graf, Charles T Esmon, Wolfram Ruf, Tsvee Lapidot
The common developmental origin of endothelial and hematopoietic cells is manifested by coexpression of several cell surface receptors. Adult murine bone marrow (BM) long-term repopulating hematopoietic stem cells (LT-HSCs), endowed with the highest repopulation and self-renewal potential, express endothelial protein C receptor (EPCR), which is used as a marker to isolate them. EPCR/protease-activated receptor-1 (PAR1) signaling in endothelial cells has anticoagulant and anti-inflammatory roles, while thrombin/PAR1 signaling induces coagulation and inflammation...
April 2016: Annals of the New York Academy of Sciences
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