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A Bar-Ilan, T Livnat, M Hoffmann, L Binder, M Zakar, R Guy, Y Felikman, L Moschcovich, B Shenkman, D Monroe, O Hershkovitz, G Kenet, G Hart
INTRODUCTION: Recombinant FVIIa (rFVIIa) is an effective treatment for haemophilia through frequent administration. However, the short half-life of rFVIIa decreases its prophylactic ability to reduce bleeding. Carboxy-terminal peptide (CTP)-modified FVIIa (MOD-5014) is a long-acting rFVIIa developed for on-demand treatment of haemophilia using either an intravenous or subcutaneous injection with the aim of less frequent administrations, as well as for prophylactic use. AIM: The comprehensive evaluation of the activity MOD-5014 vs commercially available rhFVIIa, as well as their interaction with cofactors and inhibitors...
March 14, 2018: Haemophilia: the Official Journal of the World Federation of Hemophilia
S Tabibian, M Shams, M Naderi, A Dorgalaleh
Intracranial haemorrhage (ICH) is the most dreadful complication, and the main cause of death among patients with rare bleeding disorders (RBD) and prenatal diagnosis (PND) is a preventative lifesaving program. A total of 39 PNDs were reported in the literature through a search on PubMed, EMBASE, SCOPUS and Web of Science databases, most often for congenital factor (F) XIII and FVII deficiencies and rarely in FX, FV deficiencies and afibrinogenemia. The main cause to request a PND is ICH and related morbidity and mortality...
February 24, 2018: International Journal of Laboratory Hematology
Lu Yang, Arup Bhattacharya, Yun Li, Yuesheng Zhang
We recently discovered a plasma proteolysis pathway, termed the FXII-FVII pathway which is composed of coagulation proteases, and found it to be mainly responsible for the clearance of Aβ42 in the plasma in mice. Aβ42 and Aβ40 are the main Aβ forms in Alzheimer's disease (AD). In the present study, in vitro assays, wild type (WT) mice and J20 mice (a transgenic AD model) are used to assess the degradation of Aβ40 and Aβ42 by the FXII-FVII pathway and the impact of anticoagulants on such degradation. Four clinically available and mechanistically distinct anticoagulants are evaluated, including dabigatran, enoxaparin (EP), rivaroxaban and warfarin...
January 19, 2018: Oncotarget
Steven P Grover, Nigel Mackman
Tissue factor (TF) is the high-affinity receptor and cofactor for FVII/VIIa. The TF-FVIIa complex is the primary initiator of blood coagulation and plays an essential role in hemostasis. TF is expressed on perivascular and epithelial cells at organ and body surfaces where it forms a hemostatic barrier. TF also provides additional hemostatic protection to vital organs, such as the brain, lung, and heart. Under pathological conditions, TF can trigger both arterial and venous thrombosis. For instance, atherosclerosis plaques contain high levels of TF on macrophage foam cells and microvesicles that drives thrombus formation after plaque rupture...
February 8, 2018: Arteriosclerosis, Thrombosis, and Vascular Biology
D L Beeler, W C Aird, M A Grant
BACKGROUND: Previous studies have provided insight into the molecular basis of human tissue factor (TF) activation of activated factor VII (FVIIa). TF-induced allosteric networks of FVIIa activation have been rationalized through analysis of the dynamic changes and residue connectivities in the human soluble TF (sTF)/FVIIa complex structure during molecular dynamics (MD) simulation. Evolutionary conservation of the molecular mechanisms for TF-induced allosteric FVIIa activation between human and extant vertebrate jawless fish (lamprey), where blood coagulation emerged more than 500 million years ago, is unknown and of considerable interest...
February 8, 2018: Journal of Thrombosis and Haemostasis: JTH
Matthew Gissel, Lidia Tomkiewicz-Pajak, Piotr Podolec, Piotr Hoffman, Olga Trojnarska, Magdalena Lipczyńska, Anetta Undas, Kathleen E Brummel-Ziedins
: Single-ventricle defects are associated with increased risk of thromboembolic events. To analyze the prothrombotic potential in a long-term follow-up on Fontan patients via plasma contribution to thrombin and factor (F)Xa generation profiles. Thrombin and FXa generation was simulated from plasma concentrations of FII, FV, FVII, FVIII, FIX, FX, antithrombin and tissue factor (TF) pathway inhibitor from Fontan patients (n = 48) and healthy controls (n = 34). TF and thrombin-antithrombin complex (TAT) were measured by ELISA...
February 5, 2018: Blood Coagulation & Fibrinolysis: An International Journal in Haemostasis and Thrombosis
E A Linskens, K M J Devreese
INTRODUCTION: Haemostasis testing is influenced by many pre-analytical variables, such as storage time and temperature, which can affect the stability of coagulation factors and influence the results of coagulation assays. We investigated the stability of haemostasis tests after storage of aliquoted plasma at RT, including the variability of measurement principle and reagent used for determination. METHODS: Blood samples from 20 healthy volunteers were obtained, processed to PPP and aliquoted...
February 5, 2018: International Journal of Laboratory Hematology
Shihoko Okabayashi, Satoru Ogawa, Kenichi A Tanaka, Takashi Nishiyama, Shusuke Takeshita, Yoshinobu Nakayama, Yasufumi Nakajima, Teiji Sawa, Toshiki Mizobe
OBJECTIVE: Point-of-care (POC) devices allow for prothrombin time/international normalized ratio (PT/INR) testing in whole blood (WB) and timely administration of plasma or prothrombin complex concentrate during cardiopulmonary bypass surgery. This study evaluated the sensitivities of a new POC PT test, a dry-hematology method with heparin neutralization technology (DRIHEMATO PT-S [DRI PT-S]; A&T Corporation, Kanagawa, Japan), and compared it with other POC tests currently available. DESIGN: Prospective, observational study...
December 29, 2017: Journal of Cardiothoracic and Vascular Anesthesia
Joseph S Biedermann, Marieke J H A Kruip, Felix J van der Meer, Frits R Rosendaal, Frank W G Leebeek, Suzanne C Cannegieter, Willem M Lijfering
Aims: Observational studies indicate that statins reduce the risk of recurrent venous thrombosis (VT). However, trials have not been performed and the mechanism is unknown. We aimed to determine whether statin therapy improves the coagulation profile in patients with prior VT. Methods and results: Randomized clinical trial (NCT01613794). Patients were randomized to rosuvastatin 20 mg/day for 4 weeks or no intervention. Blood was drawn at baseline and at end of study...
January 30, 2018: European Heart Journal
Wen-Bin He, Yue-Qiu Tan, Xiao Hu, Wen Li, Bo Xiong, Ke-Li Luo, Fei Gong, Guang-Xiu Lu, Ge Lin, Juan Du
BACKGROUND: Preimplantation genetic diagnosis (PGD) is a powerful tool for preventing the transmission of Mendelian disorders from generation to generation. However, PGD only can identify monogenically inherited diseases, but not other potential monogenic pathologies. We aimed to use PGD to deliver a healthy baby without congenital FVII deficiency or other common Mendelian diseases in a couple in which both individuals carried a deleterious mutation in the F7 gene. METHODS: After both members of the couple were confirmed to be carriers of the F7 gene mutation by Sanger sequencing, expanded carrier screening (ECS) for 623 recessive inheritance diseases was performed to detect pathological mutations in other genes...
January 24, 2018: BMC Medical Genetics
Yanhui Jin, Xiaoli Cheng, Jiayong Zheng, Hong Xia, Lihong Yang, Mingshan Wang
: Coagulation factor X and factor VII (FVII) are both very important components in blood coagulation. To study the molecular pathogenic mechanism of the inherited factor X and FVII deficiency, the factor X activity (FX:C) and FVII activity were tested with one-stage clotting methods. The factor X antigen and factor FVII antigen were tested with ELISA. All the exons, intron-exon boundaries and 5',3'-flanking regions of F10 and F7 genes were amplified by PCR with direct sequencing. The ClustalX software was used to analyze the conservative property of the mutation sites...
December 14, 2017: Blood Coagulation & Fibrinolysis: An International Journal in Haemostasis and Thrombosis
Maria Eugenia Chollet, Elisabeth Andersen, Ellen Skarpen, Christiane F Myklebust, Christian Koehler, Jens Preben Morth, Ampaiwan Chuansumrit, Mirko Pinotti, Francesco Bernardi, Bernd Thiede, Per Morten Sandset, Grethe Skretting
Activated factor (F) VII is a vitamin K-dependent glycoprotein that initiates blood coagulation upon interaction with tissue factor. FVII deficiency is the most common of the rare congenital bleeding disorders. While the mutational pattern has been extensively characterized, the pathogenic molecular mechanisms of mutations, particularly at the intracellular level, have been poorly defined. Here, we aimed at elucidating the mechanisms underlying altered FVII biosynthesis in the presence of three mutation types in the catalytic domain: a missense change, a microdeletion and a frameshift/elongation, associated with severe or moderate to severe phenotypes...
December 12, 2017: Biochimica et Biophysica Acta
Kuang-Tzu Huang, I-Ying Kuo, Ming-Chao Tsai, Chun-Hsien Wu, Li-Wen Hsu, Li-Yu Chen, Chao-Pin Kung, Yu-Fan Cheng, Shigeru Goto, Yu-Wei Chou, Chao-Long Chen, Chih-Che Lin, Kuang-Den Chen
Hepatocellular carcinoma (HCC) is one of the most common and aggressive malignancies worldwide. Treatment outcomes remain poor mainly due to lack of good diagnostic/prognostic markers and limited therapeutic strategies. We previously characterized aberrant activation of the TF/FVII/PAR2 pathway, which subsequently results in decreased autophagy, as a crucial event in malignant progression of HCC. Here, we identified miR-135a as a highly upregulated miRNA in HCC in response to TF/FVII/PAR2 activation. Analyzing 103 HCC patient specimens, we confirmed that miR-135a was frequently elevated in HCC tissues with higher FVII expression compared to adjacent non-cancerous counterparts...
December 15, 2017: Molecular Therapy. Nucleic Acids
Matteo N D Di Minno, Mariasanta Napolitano, Alberto Dolce, Guglielmo Mariani
Perioperative bleeding is a major concern in patients with factor VII (FVII) deficiency. Evaluating data of 95 FVII-deficient patients undergoing 110 surgical procedures (61 major, 49 minor), we assessed the impact of type of surgery, bleeding phenotype and FVII coagulant activity (FVII:C) levels on perioperative replacement therapy (RT). Compared to those with higher FVII:C levels, patients with <3% FVII:C received a higher number of RT doses (8 vs. 2, P = 0·003) for a longer RT duration (3 days vs...
February 2018: British Journal of Haematology
Amir Mashayekhi, Shirin Shahbazi, Mirdavood Omrani, Reza Mahdian
Factor VII (FVII) serves an essential role in the initiation of blood coagulation. Mutations in conserved residues within its serine protease domain may lead to dysregulated coagulation activity. The objective of the present study was to elucidate the impact of altering two conserved residues, H348R and S282R, on the functional properties of the FVII protein. The mutation‑harboring fragments were derived from genomic DNA of a FVII deficient patient. The fragments were integrated into a pcDNA vector containing FVII cDNA of HepG2 cells...
February 2018: Molecular Medicine Reports
Muriel Giansily-Blaizot, Jean-François Schved
Recombinant activated factor VII (rFVIIa) is a bypassing agent widely used both in the treatment and prevention of hemorrhagic complications due to hemophilia with inhibitor. In such cases, antihemophilic factors cannot be used. The normal physiology of factor VII/ factor VIIa (FVII/FVIIa) in the hemostatic process requires the presence of tissue factor (TF) that links to FVII leading to a FVIIa-TF complex which activates both factor X and factor IX. The therapeutic use of rFVIIa requires high amount of FVIIa...
December 2017: Therapeutic Advances in Hematology
William E Winter, Sherri D Flax, Neil S Harris
Primary hemostasis begins with endothelial injury. VWF, produced by endothelial cells, binds to platelets and links them to subendothelial collagen. Platelet-derived ADP and thromboxane activate non-adhered platelets via their GPIIb/IIIa receptors, allowing these platelets to participate in platelet aggregation. Secondary hemostasis is initiated with the binding of factor VII to extravascular tissue factor (TF). Factors II, VII, IX and X are vitamin K-dependent factors. The role of vitamin K is to assist in the addition of gamma carboxylate groups to glutamic acids in the "GLA" domains of these factors...
November 8, 2017: Laboratory Medicine
N C Olson, L M Raffield, L A Lange, E M Lange, W T Longstreth, G Chauhan, S Debette, S Seshadri, A P Reiner, R P Tracy
ESSENTIALS: Essentials A fraction of coagulation factor VII circulates in blood as an activated protease (FVIIa). We evaluated FVIIa and FVIIa-antithrombin (FVIIa-AT) levels in the Cardiovascular Health Study. Polymorphisms in the F7 and PROCR loci were associated with FVIIa and FVIIa-AT levels. FVIIa may be an ischemic stroke risk factor in older adults and FVIIa-AT may assess mortality risk. SUMMARY: Background A fraction of coagulation factor (F) VII circulates as an active protease (FVIIa)...
January 2018: Journal of Thrombosis and Haemostasis: JTH
Mariasanta Napolitano, Sergio Siragusa
Aging with rare bleeding disorders such as factor VII (FVII) deficiency poses several challenges to treatment because of the occurrence of cerebral and cardiovascular age-related comorbidities and high bleeding risks. We report a case of long-term treatment with antiplatelet agents and contemporary prophylaxis of bleeding in a woman affected by severe FVII deficiency diagnosed with symptomatic coronary artery stenosis. Information on the management of antithrombotic treatment in rare bleeding disorders is lacking and mainly limited to anecdotal reports or side effects secondary to replacement therapy...
November 1, 2017: Transfusion and Apheresis Science
Aurélie Rousseau, Annette K Larsen, Patrick Van Dreden, Michele Sabbah, Ismail Elalamy, Grigoris T Gerotziafas
Most cancer cells trigger thrombin generation (TG) to various extent. In the present study, we dissected the mechanisms responsible for the procoagulant activity of pancreatic adenocarcinoma cells (BXPC3), a highly thrombogenic cancer type, and breast cancer cells (MCF7), a less thombogenic tumor type. TG of normal plasma was assessed by the Thrombinoscope (CAT®) in the presence or absence of cancer cells. TG was also assessed in plasma depleted of clotting factors, in plasma spiked with tissue factor (TF) and/or procoagulant phospholipids, in plasma spiked with an anti-TF monoclonal antibody or with corn trypsin inhibitor (CTI)...
October 20, 2017: International Journal of Oncology
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