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
Rainer B Zotz, Man-Chiu Poon, Giovanni Di Minno, Roseline D'Oiron
Background  Standard treatment for Glanzmann thrombasthenia (GT), a severe inherited bleeding disorder, is platelet transfusion. Recombinant activated factor VII (rFVIIa) is reported to be effective in GT with platelet antibodies and/or refractoriness to platelet transfusions. Methods  We evaluated rFVIIa effectiveness and safety for the treatment and prevention of surgical and nonsurgical bleeding in children <18 years old, with or without platelet antibodies and/or refractoriness, as reported in the GT Registry (GTR)...
July 2019: TH Open: Companion Journal to Thrombosis and Haemostasis
Kazuki Sakatoku, Teruhito Takakuwa, Akiko Miura, Taku Araki, Yotaro Fujitani, Ryosuke Yamamura
Acquired factor V inhibitor (AFVI) is a rare coagulopathy. It may be triggered by specific antigens such as antibiotics. We herein report the first case of AFVI after treatment with prasugrel hydrochloride (prasugrel) in an 80-year-old male who underwent percutaneous coronary intervention because of angina pectoris 6 years ago and was initiated on aspirin and ticlopidine hydrochloride. He was switched from ticlopidine hydrochloride to prasugrel before undergoing percutaneous coronary intervention for myocardial infarction...
September 13, 2019: Acta Haematologica
Wojciech Jankowski, Joseph McGill, H A Daniel Lagassé, Stepan Surov, Gary Bembridge, Campbell Bunce, Edward Cloake, Mark H Fogg, Katarzyna I Jankowska, Abdul Khan, Joseph Marcotrigiano, Mikhail V Ovanesov, Zuben E Sauna
Vatreptacog alfa (VA), a recombinant activated human factor VII (rFVIIa) variant with 3 amino acid substitutions, was developed to provide increased procoagulant activity in hemophilia patients with inhibitors to factor VIII or factor IX. In phase 3 clinical trials, changes introduced during the bioengineering of VA resulted in the development of undesired anti-drug antibodies in some patients, leading to the termination of a potentially promising therapeutic protein product. Here, we use preclinical biomarkers associated with clinical immunogenicity to validate our deimmunization strategy applied to this bioengineered rFVIIa analog...
September 10, 2019: Blood Advances
Elisabeth Andersen, Maria Eugenia Chollet, Marcello Baroni, Mirko Pinotti, Francesco Bernardi, Ellen Skarpen, Per Morten Sandset, Grethe Skretting
Background: Congenital coagulation factor (F) VII deficiency is a rare bleeding disorder caused by mutations in the F7 gene. The missense factor FVII variant p.Q160R is the disease-causing mutation in all Norwegian FVII deficient patients and results in reduced biological activity and antigen levels of FVII in patient plasma. Previous in vitro studies on this variant demonstrated impaired intracellular trafficking and reduced secretion, possibly due to protein misfolding. The aim of the study was therefore to assess the impact of chemical chaperones on cellular processing and secretion of this variant using a cell model based on overexpression of the recombinant protein...
2019: Cell & Bioscience
K Sue Robinson
Factor VII (FVII) deficiency is the most common of the Rare Inherited Coagulation Disorders. The inheritance is autosomal recessive but there is variable penetrance. Overall there is poor correlation between the FVII level and the bleeding phenotype. Heterozygotes may have significant bleeding and severe homozygotes, or compound heterozygotes can be asymptomatic. Typically, homozygotes have FVII levels <10% and heterozygotes have levels above that. In most cases bleeding is uncommon with FVII levels>10-20%...
October 2019: Transfusion and Apheresis Science
David J Gladstone, Richard I Aviv, Andrew M Demchuk, Michael D Hill, Kevin E Thorpe, Jane C Khoury, Heidi J Sucharew, Fahad Al-Ajlan, Ken Butcher, Dar Dowlatshahi, Gord Gubitz, Stephanie De Masi, Judith Hall, David Gregg, Muhammad Mamdani, Michel Shamy, Richard H Swartz, C Martin Del Campo, Brett Cucchiara, Peter Panagos, Joshua N Goldstein, Janice Carrozzella, Edward C Jauch, Joseph P Broderick, Matthew L Flaherty
Importance: Intracerebral hemorrhage (ICH) is a devastating stroke type that lacks effective treatments. An imaging biomarker of ICH expansion-the computed tomography (CT) angiography spot sign-may identify a subgroup that could benefit from hemostatic therapy. Objective: To investigate whether recombinant activated coagulation factor VII (rFVIIa) reduces hemorrhage expansion among patients with spot sign-positive ICH. Design, Setting, and Participants: In parallel investigator-initiated, multicenter, double-blind, placebo-controlled randomized clinical trials in Canada ("Spot Sign" Selection of Intracerebral Hemorrhage to Guide Hemostatic Therapy [SPOTLIGHT]) and the United States (The Spot Sign for Predicting and Treating ICH Growth Study [STOP-IT]) with harmonized protocols and a preplanned individual patient-level pooled analysis, patients presenting to the emergency department with an acute primary spontaneous ICH and a spot sign on CT angiography were recruited...
August 19, 2019: JAMA Neurology
Amy Shapiro
Rare bleeding disorders (RBDs) are a heterogeneous group of coagulation factor deficiencies that include fibrinogen, prothrombin, α2 -antiplasmin, plasminogen activator inhibitor-1, and factors II, V, V/VIII, VII, X, XI and XIII. The incidence varies based upon the disorder and typically ranges from 1 in 500,000 to 1 per million population. Symptoms vary with the disorder and residual level of the clotting factor, and can range from relatively minor such as epistaxis, to life threatening, such as intracranial hemorrhage...
July 19, 2019: Thrombosis Research
Joseph J Pena, Brandi A Bottiger, Andrea N Miltiades
Perioperative allogeneic blood product transfusion is common in lung transplantation and has various implications on the short- and long-term outcomes of lung recipients. This review summarizes the effect of transfusion on outcomes including primary graft dysfunction, chronic lung allograft dysfunction, and all-cause mortality. We outline known risk factors for increased transfusion requirement in lung transplantation and present current evidence regarding the effect of hemostatic agents including antifibrinolytics, recombinant factor VII, and prothrombin complex concentrates...
March 2020: Seminars in Cardiothoracic and Vascular Anesthesia
Sarai Pongjantarasatian, Praguywan Kadegasem, Werasak Sasanakul, Khanit Sa-Ngiamsuntorn, Suparerk Borwornpinyo, Nongnuch Sirachainan, Ampaiwan Chuansumrit, Pansakorn Tanratana, Suradej Hongeng
Human mesenchymal stem cells (hMSCs) have the potential to differentiate into hepatocyte-like cells, indicating that these cells may be the new target cell of interest to produce biopharmaceuticals. Our group recently established a hMSC-derived immortalized hepatocyte-like cell line (imHC) that demonstrates several liver-specific phenotypes. However, the ability of imHC to produce coagulation factors has not been characterized. Here, we examined the potential for imHC as a source of coagulation protein production by investigating the ability of imHC to produce human factor VII (FVII) using a lentiviral transduction system...
2019: PloS One
Jules Russick, Sandrine Delignat, Peter Milanov, Olivier Christophe, Gábor Boros, Cecile V Denis, Peter J Lenting, Srinivas V Kaveri, Sébastien Lacroix-Desmazes
The treatment or prevention of bleeding in patients with hemophilia A rely on replacement therapy with different factor VIII containing products or on the use of by-passing agents, i.e., activated prothrombin complex concentrates or recombinant activated factor VII. Emerging approaches include the use of bispecific anti-factor IXa/factor X antibodies, anti-Tissue Factor Pathway Inhibitor antibodies, interfering RNA to antithrombin, APC-specific serpins or gene therapy. The latter strategies however meet with short term clinical experience and potential adverse effects including the absence of tight temporal and spatial control of coagulation or risk for uncontrolled insertional mutagenesis...
July 9, 2019: Haematologica
Paolo Ferraresi, Dario Balestra, Caroline Guittard, Delphine Buthiau, Brigitte Pan-Petesh, Iva Maestri, Roula Farah, Mirko Pinotti, Muriel Giansily-Blaizot
Despite the exhaustive screening of F7 gene exons and exon-intron boundaries and promoter region, a significant proportion of mutated alleles remains unidentified in patients with coagulation factor VII deficiency. Here, we applied next-generation sequencing to thirteen FVII-deficient patients displaying genotype-phenotype discrepancies upon conventional sequencing, and identified six rare intronic variants. Computational analysis predicted splicing effects for three of them, which would strengthen (c.571+78G>A; c...
July 4, 2019: Haematologica
Per Rexen, Jane Taaftegaard Jensen, Nina Bjorn Schwerin, Elena Kozina
Introduction  Eptacog alfa (activated) is a recombinant activated factor VII (rFVIIa) used for the treatment and prevention of bleeding episodes in patients with congenital hemophilia with inhibitors. Frequent dosing requirements make the use of an automated bolus infusion pump a promising alternative to manual administration. Aims  The objective of this in vitro study was to evaluate the physical and chemical stability of room temperature-stable rFVIIa at 25°C over 24 hours in an automated bolus infusion pump...
January 2019: TH Open: Companion Journal to Thrombosis and Haemostasis
Helmut Ostermann, Christian von Heymann
Introduction : Current guidelines recommend the administration of prothrombin complex concentrate in combination with vitamin K for normalization of coagulation in patients presenting with vitamin K antagonist-associated major bleeding, but until recently no adequately powered comparative trials had been conducted to support these recommendations. In this article, the authors review the evidence from studies assessing prothrombin complex concentrate treatment in these patients. Areas covered : A PubMed search (spanning January 1900 to September 2018) was conducted using the following search terms: prothrombin complex concentrate* AND (warfarin or (vitamin K antagonist*)), and papers relevant to major hemorrhagic events were identified; results from studies that used a randomized controlled trial (RCT) or a prospective design are presented here...
July 2019: Expert Review of Hematology
Gallia G Levy, Elina Asikanius, Peter Kuebler, Soraya Benchikh El Fegoun, Sille Esbjerg, Stephanie Seremetis
BACKGROUND: Recombinant activated factor VII (rFVIIa; eptacog alfa activated, NovoSeven® , Novo Nordisk A/S) is a bypassing agent used in congenital hemophilia A patients with inhibitors. Emicizumab (Hemlibra® ; F Hoffmann-La Roche Ltd) is a recombinant, humanized, bispecific monoclonal antibody used for routine prophylaxis in patients with congenital hemophilia A with inhibitors. Concomitant use of the hemostatic agents rFVIIa and emicizumab carries a theoretical increased risk of thrombotic complications...
May 24, 2019: Journal of Thrombosis and Haemostasis: JTH
Guang-Bin Huang, Ping Hu, Jin-Mou Gao, Xi Lin
PURPOSE: To summarize and analyze the early treatment of multiple injuries combined with severe pelvic fractures, especially focus on the hemostasis methods for severe pelvic fractures, so as to improve the successful rate of rescue for the fatal hemorrhagic shock caused by pelvic fractures. METHODS: A retrospective analysis was conducted in 68 cases of multiple trauma combined with severe pelvic fractures in recent 10 years (from Jan. 2006 to Dec. 2015). There were 57 males and 11 females...
April 11, 2019: Chinese Journal of Traumatology
Wataru Takahashi, Motoshi Ichikawa, Shiho Furuichi, Fusako Nagasawa, Hisako Iso, Honoka Arai, Shigeharu Tsurumi, Tomoyuki Handa, Jiro Tadokoro, Yuko Nakamura, Yuka Nakamura, Ko Sasaki, Kinuko Mitani
A 56-year-old man who sustained a right waist injury 1 month ago, reported to our department complaining of pain in the right waist and femur for 1 day. In a computed tomography examination, hematoma of the right iliopsoas muscle was revealed, and arterial embolization was immediately performed but was not effective. Laboratory findings showed hemoglobin levels as 5.4 g/dl, platelet of 20.2×104 /µl, prothrombine time of 13.1 s, partial thromboplastin time (APTT) of 81.1 s, and a convex upward curve of the APTT cross-mixing test...
2019: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Dario Nicosia, Antonino Federico, Ivan Vigna, Pasquale Iozzo, Giovanni Misseri, Andrea Cortegiani
In our case, the use of a low intravenous bolus dose of rFVIIa (recombinant factor VII activated; 15-20 mcg/kg) was effective and uneventful in controlling late postprocedural PDT bleeding associated with thrombocytopenia that cannot be corrected and after all other treatments failed.
April 2019: Clinical Case Reports
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