Maria-Isabel Bravo, Aida Raventós, Alba Pérez, Montserrat Costa, Todd Willis
BACKGROUND: Emicizumab is an alternative non-factor approach for treating patients with hemophilia A. However, there is a potential risk of thrombotic events when emicizumab is concomitantly administered with pro-hemostatic therapies. OBJECTIVES: To assess the hemostatic effect in vitro when a plasma-derived factor VIII concentrate containing von Willebrand factor (pdFVIII/VWF) was added to hemophilia A plasma (HAp) in combination with emicizumab. METHODS: HAp and HAp with FVIII inhibitors (HAp-i) samples with different concentrations of emicizumab (50 and 100 μg/mL) were combined with activated prothrombin complex concentrate (aPCC) at 0...
May 7, 2020: Journal of Thrombosis and Haemostasis: JTH
Siti Kurniawati, Ni Made Mertaniasih, Manabu Ato, Toshiki Tamura, Soedarsono Soedarsono, Aulanni'am Aulanni'am, Shigetarou Mori, Yumi Maeda, Tetsu Mukai
Mycobacterium tuberculosis ( M. tuberculosis ) is the causative agent of tuberculosis in human. One of the major M. tuberculosis virulence factors is early secretory antigenic target of 6-kDa (ESAT-6), and EccB5 protein encoded by eccB5 is one of its components. EccB5 protein is a transmembrane protein in ESX-5 system. The aim of this study is to explore the characteristics of wild-type EccB5 and its mutant form N426I. We expressed the EccB5 protein by cloning the mutant and wild-type eccB5 gene in Escherichia coli ( E...
2020: BioResearch Open Access
Juliana Perez Botero, Kristy Lee, Brian R Branchford, Paul F Bray, Kathleen Freson, Michele P Lambert, Minjie Luo, Shruthi Mohan, Justyne E Ross, Wolfgang Bergmeier, Jorge Di Paola
Glanzmann thrombasthenia (GT) is an autosomal recessive disorder of platelet aggregation caused by quantitative or qualitative defects in integrins αIIb and β3. These integrins are encoded by the ITGA2B and ITGB3 genes and form platelet glycoprotein (GP)IIb/IIIa, which acts as the principal platelet receptor for fibrinogen. Although there is variability in the clinical phenotype, most patients present with severe mucocutaneous bleeding at an early age. A classic pattern of abnormal platelet aggregation, platelet glycoprotein expression and molecular studies confirm the diagnosis...
April 2020: Haematologica
John Fitzgerald, Robert McMonnies, Aidan Sharkey, Peter L Gross, Keyvan Karkouti
This narrative review discusses the role of thrombin generation in coagulation and bleeding in cardiac surgery, the laboratory methods for clinical detection of impaired thrombin generation, and the available hemostatic interventions that can be used to improve thrombin generation. Coagulopathy after cardiopulmonary bypass (CPB) is associated with excessive blood loss and adverse patient outcomes. Thrombin plays a crucial role in primary hemostasis, and impaired thrombin generation can be an important cause of post-CPB coagulopathy...
June 2020: Canadian Journal of Anaesthesia
Tami Livnat, Alfica Sehgal, Kun Qian, Huy Van Nguyen, Kate Madigan, Benny Sorensen, Gili Kenet
Antithrombin (AT) reduction has been shown to improve thrombin generation (TG) in haemophilia with or without inhibitors. As treatment with bypassing agents (BPAs) may be required in patients with breakthrough bleeding while receiving AT-lowering therapy, we assessed TG in platelet-poor plasma samples from haemophilia patients in the presence of BPA (recombinant activated factor VII [rFVIIa; 1.25 or 2.5 μg mL-1 ] or activated prothrombin complex concentrate [aPCC; 0.5 or 1 U mL-1 ]) and AT reduction (anti-AT antibody)...
May 2020: Blood Cells, Molecules & Diseases
Ali Ahmed Khudhair, Afrah Abdul-Mahdi Salih, Ausama Jamal Kadhum
Background and Objective: Factor VII (FVII) deficiency is probably one of the most common of the rare autosomal recessive coagulation disorders, with an estimated prevalence of l: 500000. All age groups can be affected with FVII deficiency. This study aimed to describe the demographic parameters, symptomatology, hemostatic values and the outcome of FVII deficiency. Methods: This is a retrospective descriptive study of patients with congenital FVII deficiency over a period of seven years from (August 2008 to August 2015)...
January 2020: Pakistan Journal of Medical Sciences Quarterly
Kourosh Goudarzipour, Vahid Amiri, Peyman Eshghi
By the advent of the effective therapies for many coagulation diseases and hereditary spherocytosis (HS), patient's survival has been improved significantly; however, if patients are diagnosed late or left untreated, both diseases could ominously be life threatening. Concurrent occurring of factor VII (FVII) deficiency and HS is extremely rare and there is no literature report that explain this condition, thus far. In this study, we confronted a 9-year-old female patient diagnosed with HS and enlarged spleen as a result of this blood disorder...
February 6, 2020: Journal of Pediatric Hematology/oncology
Jaime García-Chávez, Abraham Majluf-Cruz
Acquired hemophilia (AH) is an autoimmune hemostatic disorder mediated by autoantibodies directed against factor VIII: C. In 52% of cases, the cause is unknown or is not associated with other pathological entities; in the rest, there are concomitant factors: lupus, rheumatoid arthritis, cancer, pregnancy, and medications. In Mexico, there is not a registry of AH, and awareness of the disease among health personnel is low. The groups with the highest incidence are women of childbearing age and individuals older than 70 years...
2020: Gaceta Médica de México
Kristina Byskov, Sylvain M Le Gall, Bernd Thiede, Eric Camerer, Sandip M Kanse
Factor VII activating protease (FSAP) is a circulating serine protease implicated in thrombosis, atherosclerosis, stroke, and cancer. Using an overexpression strategy, we have systematically investigated the role of protease activated receptors (PAR)-1, -2, -3, and -4 on FSAP-mediated signaling in HEK293T and A549 cells. Cleavage of PAR-reporter constructs and MAPK phosphorylation was used to monitor receptor activation. FSAP cleaved PAR-2 and to a lesser degree PAR-1, but not PAR-3 or PAR-4 in both cell types...
January 2020: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Chong H Kim, Sierra C Simmons, Dandan Wang, Parisa Najafzadeh, Ameneh Azad, Huy P Pham
BACKGROUND: Acquired haemophilia A (AHA), with potentially high risk of morbidity and mortality, occurs as a result of inhibitors against factor VIII. Bleeding due to AHA can be treated with activated prothrombin complex concentrate (aPCC), recombinant activated factor VII (rFVIIa) or recently, recombinant porcine-sequence factor VIII (rpFVIII). We extended our previous cost-effectiveness analysis (CEA) comparing rpFVIII against the available traditional options. METHODS: For high-titred, haemorrhaging AHA patients treated with either aPCC, rFVIIa or rpFVIII, over the course of 6-days, a Markov simulation was conducted to evaluate the outcomes when these patients transitioned into any of the four following health states: (1) continuous bleeding, (2) thrombosis, (3) stop bleeding and (4) death, with states (2), (3) and (4) modelled as absorbing states...
December 26, 2019: Vox Sanguinis
Britta Laros-van Gorkom, Pål André Holme, Christine Joch, Tobias Rogosch, Annette Feussner, William McKeand, John Roberts, Waander van Heerde
Objectives: Recombinant fusion protein linking activated factor VIIa to human albumin (rVIIa-FP) is a therapeutic option designed to prevent and treat bleeding events in patients with congenital FVII deficiency with reduced infusion frequency compared to current FVII treatments. This study characterized the pharmacokinetics (PK) and pharmacodynamics (PD) of rVIIa-FP. Methods: A phase I multicenter, randomized, open-label, parallel-arm, single-dose study (NCT02470871) was conducted in nine patients with severe congenital FVII deficiency...
December 2020: Hematology (Amsterdam, Netherlands)
Kozue Yoshida, Ayako Yanagidani, Kazunori Murai, Hiroyuki Hamada, Akiyoshi Sato, Yasurou Miyairi, Masahiro Ieko, Yuji Wano
A 72-year-old man was hospitalized because of thrombocytopenia (0.5×104 /µl) and anemia. The bone marrow test result revealed excessive numbers of megakaryocytes and no platelet adhesion. Furthermore, platelet-associated immunoglobulin G levels were high, and he was tested positive for Helicobacter pylori antibody. On the basis of these findings, immune thrombocytopenia was diagnosed. The patient was initially treated with eradication therapy; prednisolone, 20 mg/day (0.5 mg/kg) and a thrombopoietin receptor agonist 12...
2019: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Nis V Nielsen, Elfie Roedel, Dipankar Manna, Michael Etscheid, Jens Preben Morth, Sandip M Kanse
Factor VII (FVII) activating protease (FSAP) is a circulating serine protease. Human genetic studies, based on the Marburg I (MI) (Gly221Glu, chymotrypsin numbering system) polymorphism, implicate FSAP in the pathogenesis of many diseases. Here, we describe the molecular and functional changes caused by the Gly221Glu substitution in the 220 loop using recombinant proteins expressed in E. coli. The serine protease domain (SPD) of wild type (WT) FSAP displayed auto-catalytic activation whereas the MI isoform displayed very low autocatalytic activation and low proteolytic activity against the chromogenic substrate S-2288, Factor VII, tissue factor pathway inhibitor as well as pro-urokinase...
December 12, 2019: Scientific Reports
A Yu Lubnin
The paper presents the author's analysis of the main trends in the development of modern neuroanesthesiology over the past five to ten years. These, in the author\s opinion, include the introduction and elaboration of blood-sparing techniques, monitoring the depth of anesthesia, fast track concept, applying regional (conduction) anesthesia techniques, xenon anesthesia, development of effective and safe protocols for DVT and PTE prophylaxis for neurosurgical patients, study of the hemostatic system using bedside methods for assessing hemostasis (thromboelastogram) and correcting hypocoagulation by activated recombinant VII factor...
2019: Zhurnal Voprosy Neĭrokhirurgii Imeni N. N. Burdenko
Keitaro Tachi, Shinji Takahashi, Maiko Ishigaki, Shin Nakayama, Soichiro Yamashita, Yuji Hiramatsu, Makoto Tanaka
No abstract text is available yet for this article.
October 2019: Indian Journal of Anaesthesia
Joel T Feih, Janelle J Juul, Joseph R G Rinka, Lisa M Baumann Kreuziger, Paul S Pagel, Justin N Tawil
Background: Excessive bleeding and surgical reexploration are common complications that increase the risk of multi-organ failure and prolonged hospitalization after cardiac surgery. Off-label use of recombinant activated factor VII (rFVIIa) is a recommended treatment for refractory bleeding. Objective: The objective of the study is to determine if the adequacy of hemostatic resuscitation enhances the efficacy of rFVIIa. Methods: This retrospective, observational, cohort study included patients who received rFVIIa for refractory postoperative bleeding after cardiac surgery...
October 2019: Annals of Cardiac Anaesthesia
Emerito-Carlos Rodriguez-Merchan
Introduction : The purpose of this article is to review which data about hemophilia are currently provided by the Cochrane database of systematic reviews (CDBSR). Methodological consideration: All statements about hemophilia in the Cochrane Collaboration are based on evidence generated in randomized controlled clinical trials. Areas covered : There is a high degree of evidence that prophylaxis preserves joint function in children with hemophilia compared to on-demand treatment. Also, that recombinant factor VII activated (rFVIIa) and activated prothrombin complex concentrates (APPCs) have similar efficacy and safety...
November 2019: Expert Review of Hematology
Jose Florencio F Lapeña, Olivia Agnes D Mejia
Epistaxis may be profuse in individuals with normal bleeding parameters, but in an individual with haemophilia, it may be life-threatening. It is even more dangerous when epistaxis is caused by an undetected concomitant juvenile angiofibroma, and only one such case has been reported in the English literature. We report another case, of an 18-year-old Filipino adolescent with severe haemophilia A who was referred for repeated massive epistaxis. The epistaxis had been attributed to his haemophilia and managed with nasal packing, multiple blood transfusions and Factor VIII administration...
2019: F1000Research
Madhvi Rajpurkar, Stacy E Croteau, Lisa Boggio, David L Cooper
Purpose: Recombinant activated factor VII (rFVIIa; NovoSeven® RT; Novo Nordisk A/S, Bagsvaerd, Denmark) is approved in the United States for the treatment of bleeding and perioperative management in congenital hemophilia with inhibitors (CHwI), acquired hemophilia (AH), congenital factor VII (FVII) deficiency, and Glanzmann's thrombasthenia (GT) with refractoriness to platelets. The aim of the current analysis was to review clinical trials and registries pre- and post-licensure for each indication to establish the estimated rate of thrombosis and then to establish the association of all reported thrombotic events (TEs) with certain risk factors listed for many years in the prescribing information (PI)...
2019: Journal of Blood Medicine
Matthias Misslinger, Mareike Thea Scheven, Peter Hortschansky, Manuel Sánchez López-Berges, Katharina Heiss, Nicola Beckmann, Thomas Heigl, Martin Hermann, Thomas Krüger, Olaf Kniemeyer, Axel A Brakhage, Hubertus Haas
Efficient adaptation to iron starvation is an essential virulence determinant of the most common human mold pathogen, Aspergillus fumigatus. Here, we demonstrate that the cytosolic monothiol glutaredoxin GrxD plays an essential role in iron sensing in this fungus. Our studies revealed that (i) GrxD is essential for growth; (ii) expression of the encoding gene, grxD, is repressed by the transcription factor SreA in iron replete conditions and upregulated during iron starvation; (iii) during iron starvation but not iron sufficiency, GrxD displays predominant nuclear localization; (iv) downregulation of grxD expression results in de-repression of genes involved in iron-dependent pathways and repression of genes involved in iron acquisition during iron starvation, but did not significantly affect these genes during iron sufficiency; (v) GrxD displays protein-protein interaction with components of the cytosolic iron-sulfur cluster biosynthetic machinery, indicating a role in this process, and with the transcription factors SreA and HapX, which mediate iron regulation of iron acquisition and iron-dependent pathways; (vi) UV-Vis spectra of recombinant HapX or the complex of HapX and GrxD indicate coordination of iron-sulfur clusters; (vii) the cysteine required for iron-sulfur cluster coordination in GrxD is in vitro dispensable for interaction with HapX; and (viii) there is a GrxD-independent mechanism for sensing iron sufficiency by HapX; (ix) inactivation of SreA suppresses the lethal effect caused by GrxD inactivation...
September 16, 2019: PLoS Genetics
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