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https://www.readbyqxmd.com/read/28294177/rational-design-of-protein-c-activators
#1
Sergio Barranco-Medina, Mary Murphy, Leslie Pelc, Zhiwei Chen, Enrico Di Cera, Nicola Pozzi
In addition to its procoagulant and proinflammatory functions mediated by cleavage of fibrinogen and PAR1, the trypsin-like protease thrombin activates the anticoagulant protein C in a reaction that requires the cofactor thrombomodulin and the endothelial protein C receptor. Once in the circulation, activated protein C functions as an anticoagulant, anti-inflammatory and regenerative factor. Hence, availability of a protein C activator would afford a therapeutic for patients suffering from thrombotic disorders and a diagnostic tool for monitoring the level of protein C in plasma...
March 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28289017/activated-tafi-promotes-the-development-of-chronic-thromboembolic-pulmonary-hypertension-a-possible-novel-therapeutic-target
#2
Taijyu Satoh, Kimio Satoh, Nobuhiro Yaoita, Nobuhiro Kikuchi, Junichi Omura, Ryo Kurosawa, Kazuhiko Numano, Elias Al-Mamun, Mohammad Abdul Hai Siddique, Shinichiro Sunamura, Masamichi Nogi, Kota Suzuki, Satoshi Miyata, John Morser, Hiroaki Shimokawa
Rationale: Pulmonary hypertension (PH) is a fatal disease; however, its pathogenesis still remains to be elucidated. Thrombin-activatable fibrinolysis inhibitor (TAFI) is synthesized by the liver and inhibits fibrinolysis. Plasma TAFI levels are significantly increased in chronic thromboembolic PH (CTEPH) patients. Objective: To determine the role of activated TAFI (TAFIa) in the development of CTEPH. Methods and Results: Immunostaining showed that TAFI and its binding partner thrombomodulin (TM) were highly expressed in the pulmonary arteries (PA) and thrombus in patients with CTEPH...
March 13, 2017: Circulation Research
https://www.readbyqxmd.com/read/28271063/pharmacokinetics-of-standard-and-reduced-dose-recombinant-human-soluble-thrombomodulin-in-patients-with-septic-disseminated-intravascular-coagulation-during-continuous-hemodiafiltration
#3
Eizo Watanabe, Shingo Yamazaki, Daisuke Setoguchi, Tomohito Sadahiro, Yoshihisa Tateishi, Tatsuya Suzuki, Itsuko Ishii, Shigeto Oda
INTRODUCTION: Recombinant human soluble thrombomodulin (rTM) is reportedly excreted by the kidneys; therefore, the recommended dose for patients with renal impairment is one-third of the standard dose. The aim of this study was to evaluate whether this reduced dose of rTM achieves effective drug concentrations that are comparable to those of the standard dose in treating sepsis-induced disseminated intravascular coagulation (DIC) during continuous hemodiafiltration (CHDF). METHODS: Eight patients in an intensive care unit were randomized to receive either reduced-dose (0...
2017: Frontiers in Medicine
https://www.readbyqxmd.com/read/28267383/whole-exome-sequencing-identifies-a-mutation-in-thrombomodulin-as-the-genetic-cause-of-a-suspected-platelet-disorder-in-a-family-with-normal-platelet-function
#4
Annabel Maclachlan, Gerry Dolan, Charlotte Grimley, Steve P Watson, Neil V Morgan, On Behalf Of The Uk Gapp Study Group
Here, we describe a mother and son with a lifelong bleeding tendency and posttraumatic bleeding who were recruited to the UK Genotyping and Phenotyping of Platelets (GAPP) study with a suspected platelet function disorder. However, despite a clinically significant bleeding score, both had normal platelet counts and normal platelet function. The patients' blood was analyzed by light transmission aggregometry and genotyping by whole exome sequencing, as outlined by the GAPP study. Approximately 25 000 genetic variants were found for each patient as a result of sequencing and were filtered using a specialized bioinformatics pipeline...
March 7, 2017: Platelets
https://www.readbyqxmd.com/read/28267132/pentraxin3-as-a-new-indicator-of-cardiovascular-related-death-in-patients-with-advanced-chronic-kidney-disease
#5
Marcin Krzanowski, Katarzyna Krzanowska, Mariusz Gajda, Paulina Dumnicka, Artur Dziewierz, Karolina Woziwodzka, Jan A Litwin, Władysław Sułowicz
INTRODUCTION    Pentraxin3 (PTX3) play an important role in the inflammatory response, taking part in recognizing pathogens and damaged tissues. OBJECTIVES    The aim of the study was to assess the relationship between PTX3 levels and all-cause and cardiovascular (CV) mortality in chronic kidney disease (CKD) patients during five-year observation period.  PATIENTS AND METHODS    The study comprised 78 patients (51 hemodialyzed, 27 predialysis). The examined parameters included PTX3, calcium, phosphate, iPTH, interleukin-6 (IL-6), fibroblast growth factor 23 (FGF-23), osteopontin (OPN), osteoprotegerin (OPG), osteocalcin (OC), osteopontin (OPN), osteoprotegerin (OPG), osteocalcin, tumor necrosis factor receptor II (TNF-R II), transforming growth factor-β (TGF-β), hepatocyte growth factor (HGF), stromal cell-derived factor α (SDF1α), and thrombomodulin (TM)...
February 27, 2017: Pol Arch Intern Med
https://www.readbyqxmd.com/read/28248715/incorporating-inflammation-into-mortality-risk-in-pediatric-acute-respiratory-distress-syndrome
#6
Matt S Zinter, Benjamin E Orwoll, Aaron C Spicer, Mustafa F Alkhouli, Carolyn S Calfee, Michael A Matthay, Anil Sapru
OBJECTIVES: In pediatric acute respiratory distress syndrome, lung injury is mediated by immune activation and severe inflammation. Therefore, we hypothesized that patients with elevated pro- and anti-inflammatory cytokines would have higher mortality rates and that these biomarkers could improve risk stratification of poor outcomes. DESIGN: Multicenter prospective observational study. SETTING: We enrolled patients from five academic PICUs between 2008 and 2015...
February 28, 2017: Critical Care Medicine
https://www.readbyqxmd.com/read/28239987/effects-of-alloantibodies-to-human-leukocyte-antigen-on-endothelial-expression-and-serum-levels-of-thrombomodulin
#7
S Béland, P Vallin, O Désy, E Lévesque, S A De Serres
Essentials The effect of alloantibodies on the endothelial expression of thrombomodulin is unknown. Thrombomodulin was quantified in stimulated endothelial cells and measured in serum samples. Anti-human leukocyte antigen (HLA) I vs. II antibodies have different effects on thrombomodulin. Anti-HLA II antibodies may promote a prothrombotic state and contribute to microangiopathy. SUMMARY: Rationale Thrombomodulin (TBM) is an anticoagulant and anti-inflammatory transmembrane protein expressed on endothelial cells...
February 26, 2017: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/28229162/pharmacokinetics-of-recombinant-human-soluble-thrombomodulin-in-disseminated-intravascular-coagulation-patients-with-acute-renal-dysfunction
#8
Mineji Hayakawa, Shigeki Kushimoto, Eizo Watanabe, Koji Goto, Yasushi Suzuki, Toru Kotani, Takeyuki Kiguchi, Tomoaki Yatabe, Jun Tagawa, Fumiyo Komatsu, Satoshi Gando
Recombinant human soluble thrombomodulin (ART-123) is a novel anticoagulant for patients with disseminated intravascular coagulation (DIC). It is widely used in clinical settings throughout Japan. Furthermore, a global Phase 3 study is currently being conducted. In healthy subjects, ART-123 is excreted mainly via the kidneys. Therefore, ART-123 dose decrease was recommended in DIC patients with severe renal dysfunction. However, the pharmacokinetics of ART-123 in DIC patients with severe acute renal dysfunction has not been elucidated...
February 23, 2017: Thrombosis and Haemostasis
https://www.readbyqxmd.com/read/28229158/detection-of-procoagulant-imbalance-modified-endogenous-thrombin-potential-with-results-expressed-as-ratio-of-values-with-to-without-thrombomodulin
#9
Armando Tripodi
Each individual possesses his/her own endogenous-thrombin-potential (ETP) (i. e. the ability to generate thrombin) which depends on the relative strength of the pro- and anticoagulant drivers operating in plasma. This ability depends in turn on the clinical conditions in which the balance between the two drivers is variably affected. One of the major determinants of this balance is the factor (F)VIII-protein C(PC) axis and its effect can be conveniently explored by the thrombin generation procedures with results expressed as ETP ratio with/without thrombomodulin (TM) (ETP-TM ratio)...
February 23, 2017: Thrombosis and Haemostasis
https://www.readbyqxmd.com/read/28223734/early-thrombomodulin-%C3%AE-administration-outcome-for-acute-disseminated-intravascular-coagulopathy-in-gastrointestinal-surgery
#10
Hirotaka Konishi, Kazuma Okamoto, Katsutoshi Shoda, Tomohiro Arita, Toshiyuki Kosuga, Ryo Morimura, Shuhei Komatsu, Yasutoshi Murayama, Atsushi Shiozaki, Yoshiaki Kuriu, Hisashi Ikoma, Masayoshi Nakanishi, Daisuke Ichikawa, Hitoshi Fujiwara, Eigo Otsuji
AIM: To investigate the efficacy of thrombomodulin (TM)-α for treatment of disseminated intravascular coagulopathy (DIC) in the field of gastrointestinal surgery. METHODS: Thirty-six peri-operative DIC patients in the field of gastrointestinal surgery who were treated with TM-α were retrospectively investigated. The relationships between patient demographics and the efficacy of TM-α were examined. Analysis of survival at 28 d was also performed on some parameters by means of the Kaplan-Meier method...
February 7, 2017: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/28219843/the-impact-of-the-endothelial-protein-c-receptor-on-thrombin-generation-and-clot-lysis
#11
Laura Pepler, Chengliang Wu, Dhruva J Dwivedi, Cynthia Wu, Paul Y Kim, Patricia C Liaw
INTRODUCTION: When thrombin is bound to thrombomodulin (TM), it becomes a potent activator of protein C (PC) and thrombin-activable fibrinolysis inhibitor (TAFI). Activation of PC is enhanced when PC is bound to the endothelial protein C receptor (EPCR). Activated protein C (APC) inhibits thrombin generation while activated TAFI (TAFIa) attenuates fibrinolysis. To determine the impact of diminished EPCR function on thrombin generation and fibrinolysis we generated cells that expressed TM and a variant of EPCR (R96C) that does not bind PC...
February 3, 2017: Thrombosis Research
https://www.readbyqxmd.com/read/28218444/evaluation-of-late-outgrowth-endothelial-progenitor-cell-and-umbilical-vein-endothelial-cell-responses-to-thromboresistant-collagen-mimetic-hydrogels
#12
Dany J Munoz-Pinto, Josh D Erndt-Marino, Silvia M Becerra-Bayona, Viviana R Guiza-Arguello, Satyavrata Samavedi, Sarah Malmut, William M Reichert, Brooke Russell, Magnus Hӧӧk, Mariah S Hahn
Bioactive coatings which support the adhesion of late-outgrowth peripheral blood endothelial progenitor cells (EOCs) are actively being investigated as a means to promote rapid endothelialization of "off-the-shelf," small-caliber arterial graft prostheses following implantation. In the present work, we evaluated the behavior of EOCs on thromboresistant graft coatings based on the collagen-mimetic protein Scl2-2 and poly(ethylene glycol) (PEG) diacrylate. Specifically, the attachment, proliferation, migration, and phenotype of EOCs on PEG-Scl2-2 hydrogels were evaluated as a function of Scl2-2 concentration (4, 8, and 12 mg/mL) relative to human umbilical vein endothelial cells (HUVECs)...
February 20, 2017: Journal of Biomedical Materials Research. Part A
https://www.readbyqxmd.com/read/28215474/establishment-of-disseminated-intravascular-coagulation-dic-model-by-a-single-iv-administration-of-escherichia-coli-derived-lipopolysaccharide-lps-to-cynomolgus-monkeys-and-evaluation-of-its-pathophysiological-status
#13
Hirofumi Minomo, Kengo Inoue, Shuko Sakaki, Takanobu Okazaki, Kinji Kobayashi, Kazuhiko Inoue, Atsuro Miyata
We prepared a DIC model by administrating LPS to cynomolgus monkeys, and investigated its potential for evaluations of new medicines for DIC therapy. Peripheral blood mononuclear cells (PBMC) collected from cynomolgus monkeys were incubated with LPS (8 types), and TNF-α levels in the media were measured. LPS from Escherichia coli (K-235) was most appropriate in terms of larger increases and smaller variation in TNF-α levels. PBMC from rats, cynomolgus monkeys or humans were incubated with LPS (K-235), and the TNF-α response to LPS was investigated...
February 2, 2017: Journal of Pharmacological Sciences
https://www.readbyqxmd.com/read/28212524/role-of-nrf2-and-protective-effects-of-metformin-against-tobacco-smoke-induced-cerebrovascular-toxicity
#14
Shikha Prasad, Ravi K Sajja, Mohammad Abul Kaisar, Jee Hyun Park, Heidi Villalba, Taylor Liles, Thomas Abbruscato, Luca Cucullo
Cigarette smoking (CS) is associated with vascular endothelial dysfunction in a causative way primarily related to the TS content of reactive oxygen species (ROS), nicotine, and inflammation. TS promotes glucose intolerance and increases the risk of developing type-2 diabetes mellitus (2DM) with which it shares other pathogenic traits including the high risk of cerebrovascular and neurological disorders like stroke via ROS generation, inflammation, and blood-brain barrier (BBB) impairment. Herein we provide evidence of the role played by nuclear factor erythroid 2-related factor (Nrf2) in CS-induced cerebrobvascular/BBB impairments and how these cerebrovascular harmful effects can be circumvented by the use of metformin (MF; a widely prescribed, firstline anti-diabetic drug) treatment...
February 12, 2017: Redox Biology
https://www.readbyqxmd.com/read/28176226/evaluation-of-the-safety-and-efficacy-of-recombinant-soluble-thrombomodulin-for-patients-with-disseminated-intravascular-coagulation-associated-with-acute-leukemia-multicenter-prospective-study-by-the-tohoku-hematology-forum
#15
Hisayuki Yokoyama, Naoto Takahashi, Yuna Katsuoka, Mitsue Inomata, Toshihiro Ito, Kuniaki Meguro, Yoshihiro Kameoka, Riko Tsumanuma, Kazunori Murai, Hideyoshi Noji, Kenichi Ishizawa, Shigeki Ito, Yasushi Onishi, Hideo Harigae
It has been suggested that use of recombinant soluble thrombomodulin (rTM) is superior to conventional drugs in treatment of disseminated intravascular coagulation (DIC) complicating acute leukemia. However, its safety and efficacy have not been fully examined in prospective studies. Here, we performed a multicenter prospective study to examine outcomes of rTM treatment for DIC in patients with acute leukemia. Of 33 patients registered in this study, 13 had acute myeloid leukemia (AML), three had acute lymphoblastic leukemia (ALL), and 17 had acute promyelocytic leukemia (APL)...
February 7, 2017: International Journal of Hematology
https://www.readbyqxmd.com/read/28167153/the-fifth-epidermal-growth-factor-like-region-of-thrombomodulin-alleviates-murine-graft-versus-host-disease-in-a-g-protein-coupled-receptor-15-dependent-manner
#16
Bin Pan, Xiangmin Wang, Shinsuke Kojima, Chie Nishioka, Akihito Yokoyama, Goichi Honda, Kailin Xu, Takayuki Ikezoe
Thrombomodulin (TM) exerts anti-inflammatory functions. We previously found that recombinant human soluble TM alleviated murine graft-versus-host disease (GVHD). Nevertheless, it is unclear how TM mediates its anti-inflammatory functions in GVHD. Here, we identified G-protein coupled receptor 15 (GPR15) expressed on T cells as a receptor/sensor of TM. The fifth region of epidermal growth factor-like domain of TM (TME5) bound GPR15 in vitro. TME5 prolonged survival of mice undergoing acute GVHD after allogeneic hematopoietic stem cell transplantation (allo-HSCT)...
February 3, 2017: Biology of Blood and Marrow Transplantation
https://www.readbyqxmd.com/read/28150854/imaging-analyses-of-coagulation-dependent-initiation-of-fibrinolysis-on-activated-platelets-and-its-modification-by-thrombin-activatable-fibrinolysis-inhibitor
#17
Tomasz Brzoska, Yuko Suzuki, Hideto Sano, Seiichirou Suzuki, Martyna Tomczyk, Hiroki Tanaka, Tetsumei Urano
Using intravital confocal microscopy, we observed previously that the process of platelet phosphatidylserine (PS) exposure, fibrin formation and lysine binding site-dependent plasminogen (plg) accumulation took place only in the center of thrombi, not at their periphery. These findings prompted us to analyse the spatiotemporal regulatory mechanisms underlying coagulation and fibrinolysis. We analysed the fibrin network formation and the subsequent lysis in an in vitro experiment using diluted platelet-rich plasma supplemented with fluorescently labelled coagulation and fibrinolytic factors, using confocal laser scanning microscopy...
February 2, 2017: Thrombosis and Haemostasis
https://www.readbyqxmd.com/read/28148301/protective-effects-of-molecular-hydrogen-on-steroid-induced-osteonecrosis-in-rabbits-via-reducing-oxidative-stress-and-apoptosis
#18
Jia Li, Zhaogang Ge, Lihong Fan, Kunzheng Wang
BACKGROUND: The objective of this study was to investigate the protective effects of molecular hydrogen, a novel and selective antioxidant, on steroid-induced osteonecrosis (ON) in a rabbit model. METHODS: Sixty rabbits were randomly divided into two groups (model group and hydrogen group). Osteonecrosis was induced according to an established protocol of steroid-induced ON. Rabbits in the hydrogen group were treated with intraperitoneal injections of molecular hydrogen at 10 ml/kg body weight for seven consecutive days...
February 2, 2017: BMC Musculoskeletal Disorders
https://www.readbyqxmd.com/read/28129465/evaluation-of-coagulation-during-treatment-with-directly-acting-antivirals-in-patients-with-hepatitis-c-virus-related-cirrhosis
#19
Armando Tripodi, Roberta D'Ambrosio, Lidia Padovan, Giulia Tosetti, Alessio Aghemo, Massimo Primignani, Veena Chantarangkul, Flora Peyvandi, Massimo Colombo
BACKGROUND & AIMS: The effect of direct-acting-antivirals (DAA) on coagulation of hepatitis-C-virus (HCV)-related cirrhosis is unknown. METHODS: We investigated 28 patients on DAA treatment and performed prothrombin-time, thrombin generation with and without thrombomodulin, whole-blood thromboelastometry, as well as the individual procoagulants (II, VIII, XIII, von Willebrand) and anticoagulants, antithrombin and protein-C. RESULTS: Patients had undetectable HCV-RNA at the end-of- treatment and at 12-weeks after end-of-treatment (sustained virological response)...
January 27, 2017: Liver International: Official Journal of the International Association for the Study of the Liver
https://www.readbyqxmd.com/read/28124276/activated-thrombin-activatable-fibrinolysis-inhibitor-attenuates-the-angiogenic-potential-of-endothelial-cells-potential-relevance-to-the-breast-tumour-microenvironment
#20
Zainab A Bazzi, Jennifer Balun, Dora Cavallo-Medved, Lisa A Porter, Michael B Boffa
Thrombin-activatable fibrinolysis inhibitor (TAFI) is a basic carboxypeptidase zymogen present in blood plasma. Proteolytic activation of TAFI by thrombin, thrombin in complex with the endothelial cell cofactor thrombomodulin, or plasmin results in an enzyme (TAFIa) that removes carboxyl-terminal lysine residues from protein and peptide substrates, including cell-surface plasminogen receptors. TAFIa is therefore capable of inhibiting plasminogen activation in the pericellular milieu. Since plasminogen activation has been linked to angiogenesis, TAFIa could therefore have anti-angiogenic properties, and indeed TAFIa has been shown to inhibit endothelial tube formation in a fibrin matrix...
February 2017: Clinical & Experimental Metastasis
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