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Target-specific anticoagulant

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https://www.readbyqxmd.com/read/29741249/direct-oral-anticoagulants-when-to-consider-laboratory-testing
#1
REVIEW
H Ten Cate, R H Olie, A J Ten Cate-Hoek, Y M C Henskens
INTRODUCTION: Direct oral anticoagulants (DOACs) are increasingly prescribed for prevention of thromboembolic stroke, as well as for prevention and treatment of venous thromboembolism. Dose adjustment based on laboratory testing is not required; however, there are several potential situations that deserve insight into a DOAC plasma activity level. METHODS: Based on a series of real-life case descriptions, we discuss indications for dedicated DOAC testing, as well as the interpretation and consequences...
May 2018: International Journal of Laboratory Hematology
https://www.readbyqxmd.com/read/29727017/recent-advances-in-the-discovery-and-development-of-factor-xi-xia-inhibitors
#2
REVIEW
Rami A Al-Horani, Daniel K Afosah
Factor XIa (FXIa) is a serine protease homodimer that belongs to the intrinsic coagulation pathway. FXIa primarily catalyzes factor IX activation to factor IXa, which subsequently activates factor X to factor Xa in the common coagulation pathway. Growing evidence suggests that FXIa plays an important role in thrombosis with a relatively limited contribution to hemostasis. Therefore, inhibitors targeting factor XI (FXI)/FXIa system have emerged as a paradigm-shifting strategy so as to develop a new generation of anticoagulants to effectively prevent and/or treat thromboembolic diseases without the life-threatening risk of internal bleeding...
May 4, 2018: Medicinal Research Reviews
https://www.readbyqxmd.com/read/29724133/discovery-of-fixa-inhibitors-by-combination-of-pharmacophore-modeling-molecular-docking-and-3d-qsar-modeling
#3
Penghua Li, Jiale Peng, Yeheng Zhou, Yaping Li, XingYong Liu, LiangLiang Wang, ZhiLi Zuo
Human Coagulation Factor IXa (FIXa), specifically inhibited at the initiation stage of the blood coagulation cascade, is an excellent target for developing selective and safe anticoagulants. To explore this inhibitory mechanism, 86 FIXa inhibitors were selected to generate pharmacophore models and subsequently SAR models. Both best pharmacophore model and ROC curve were built through the Receptor-Ligand Pharmacophore Generation module. CoMFA model based on molecular docking and PLS factor analysis methods were developed...
May 4, 2018: Journal of Receptor and Signal Transduction Research
https://www.readbyqxmd.com/read/29703481/mechanisms-coupling-thrombin-to-metastasis-and-tumorigenesis
#4
Allison S Remiker, Joseph S Palumbo
The association of malignancy and thrombophilia is bidirectional, as evidenced by four decades of studies in animal models showing that hemostatic system components support cancer progression. Consistent with this view, clinical studies have suggested that anticoagulants not only limit thromboembolic complications associated with cancer, but also improve survival by impeding cancer progression, and may even prevent the development of cancer. In order to fully capitalize on this association, a detailed understanding of the mechanisms coupling hemostatic factors to cancer pathogenesis is required...
April 2018: Thrombosis Research
https://www.readbyqxmd.com/read/29573721/novel-heparin-mimetics-reveal-cooperativity-between-exosite-2-and-sodium-binding-site-of-thrombin
#5
May H Abdel Aziz, Umesh R Desai
INTRODUCTION: Thrombin is a primary target of most anticoagulants. Yet, thrombin's dual and opposing role in pro- as well as anti- coagulant processes imposes considerable challenges in discovering finely tuned regulators that maintain homeostasis, rather than disproportionately changing the equilibrium to one side. In this connection, we have been studying exosite 2-mediated allosteric modulation of thrombin activity using synthetic agents called low molecular weight lignins (LMWLs)...
March 17, 2018: Thrombosis Research
https://www.readbyqxmd.com/read/29566097/the-gag-specific-branched-peptide-nt4-reduces-angiogenesis-and-invasiveness-of-tumor-cells
#6
Luisa Bracci, Elisabetta Mandarini, Jlenia Brunetti, Lorenzo Depau, Alessandro Pini, Lucia Terzuoli, Silvia Scali, Chiara Falciani
Heparan sulfate proteoglycans, HSPGs, modulate major transformations of cancer cells, leading to tumor growth, invasion and metastasis. HSPGs also regulate neo-angiogenesis which prompts cancer progression and metastatic spread. A different aspect of heparin and analogs is their prominent role in the coagulation of blood. The interplay between coagulation and metastasis is being actively studied: anticoagulants such as heparin-derivatives have anticancer activity and procoagulants, such as thrombin, positively modulate proliferation, migration and invasion...
2018: PloS One
https://www.readbyqxmd.com/read/29538795/how-i-manage-patients-with-anticoagulation-associated-bleeding-or-urgent-surgery
#7
Thomas C Sauter, Balthasar Eberle, Walter A Wuillemin, Thomas Thiele, Anne Angelillo-Scherrer, Aristomenis K Exadaktylos, Gabor Erdoes, Adam Cuker, Michael Nagler
Antithrombotic treatment puts patients at risk of major bleeding. Fast and adequate response to anticoagulant-associated bleeding may not only stop the bleeding but prevent severe complications. However, practical treatment algorithms to guide physicians in emergency situations are lacking. Important principles that arise from management of bleeding in general are (a) implementation of an in-house algorithm, (b) rapid identification and treatment of the bleeding source, (c) adequate fluid resuscitation, (d) consideration of the application of tranexamic acid and (e) appropriate coagulation testing...
March 14, 2018: Swiss Medical Weekly
https://www.readbyqxmd.com/read/29467183/the-search-for-new-antithrombotic-mechanisms-and-therapies-that-may-spare-hemostasis
#8
REVIEW
Edward F Plow, Yunmei Wang, Daniel I Simon
Current antithrombotic drugs, including widely used antiplatelet agents and anticoagulants, are associated with significant bleeding risk. Emerging experimental evidence suggests that the molecular and cellular mechanisms of hemostasis and thrombosis can be separated, thereby increasing the possibility of new antithrombotic therapeutic targets with reduced bleeding risk. We review new coagulation and platelet targets and highlight the interaction between integrin αM β2 (Mac-1, CD11b/CD18) on leukocytes and GPIbα on platelets that seems to distinguish thrombosis from hemostasis...
April 26, 2018: Blood
https://www.readbyqxmd.com/read/29464007/diagnosis-of-lvad-thrombus-using-a-high-avidity-fibrin-specific-99m-tc-probe
#9
Grace Cui, Walter J Akers, Michael J Scott, Michael Nassif, John S Allen, Anne H Schmieder, Krishna S Paranandi, Akinobu Itoh, Dmitry D Beyder, Samuel Achilefu, Gregory A Ewald, Gregory M Lanza
Treatment of advanced heart failure with implantable LVADs is increasing, driven by profound unmet patient need despite potential serious complications: bleeding, infection, and thrombus. The experimental objective was to develop a sensitive imaging approach to assess early thrombus accumulation in LVADs under operational high flow and high shear rates. Methods : A monomeric bifunctional ligand with a fibrin-specific peptide, a short spacer, and 99m Tc chelating amino acid sequence (F1A) was developed and compared to its tetrameric PEG analogue (F4A)...
2018: Theranostics
https://www.readbyqxmd.com/read/29455115/therapeutic-use-of-heparin-and-derivatives-beyond-anticoagulation-in-patients-with-bronchial-asthma-or-copd
#10
REVIEW
Janis K Shute, Ermanno Puxeddu, Luigino Calzetta
In this review, we identify potential targets for the therapeutic effects of heparin in asthma and chronic obstructive pulmonary disease (COPD), consider the safety and delivery modalities of this therapeutic approach. Specifically, we point to the anti-inflammatory, antioxidant and mucolytic effects of unfractionated heparin with potential to modify disease progression in COPD and asthma when administered via the inhaled route. Inhaled heparin may represent an effective add-on therapy in COPD and asthma patient groups, especially when taking into consideration the relative deficiency in endogenous heparin reported in asthma patients...
February 15, 2018: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/29452582/to-what-extent-can-behaviour-change-techniques-be-identified-within-an-adaptable-implementation-package-for-primary-care-a-prospective-directed-content-analysis
#11
Liz Glidewell, Thomas A Willis, Duncan Petty, Rebecca Lawton, Rosemary R C McEachan, Emma Ingleson, Peter Heudtlass, Andrew Davies, Tony Jamieson, Cheryl Hunter, Suzanne Hartley, Kara Gray-Burrows, Susan Clamp, Paul Carder, Sarah Alderson, Amanda J Farrin, Robbie Foy
BACKGROUND: Interpreting evaluations of complex interventions can be difficult without sufficient description of key intervention content. We aimed to develop an implementation package for primary care which could be delivered using typically available resources and could be adapted to target determinants of behaviour for each of four quality indicators: diabetes control, blood pressure control, anticoagulation for atrial fibrillation and risky prescribing. We describe the development and prospective verification of behaviour change techniques (BCTs) embedded within the adaptable implementation packages...
February 17, 2018: Implementation Science: IS
https://www.readbyqxmd.com/read/29406112/inhibition-of-thrombin-by-functionalized-c-60-nanoparticles-revealed-via-in-vitro-assays-and-in-silico-studies
#12
Yanyan Liu, Jianjie Fu, Wenxiao Pan, Qiao Xue, Xian Liu, Aiqian Zhang
The studies on the human toxicity of nanoparticles (NPs) are far behind the rapid development of engineered functionalized NPs. Fullerene has been widely used as drug carrier skeleton due to its reported low risk. However, different from other kinds of NPs, fullerene-based NPs (C60 NPs) have been found to have an anticoagulation effect, although the potential target is still unknown. In the study, both experimental and computational methods were adopted to gain mechanistic insight into the modulation of thrombin activity by nine kinds of C60 NPs with diverse surface chemistry properties...
January 2018: Journal of Environmental Sciences (China)
https://www.readbyqxmd.com/read/29385876/antiphospholipid-syndrome-the-best-prophet-of-the-future
#13
Olga Amengual, Tatsuya Atsumi
The antiphospholipid syndrome (APS) is an autoimmune disorder characterized by the occurrence of venous and arterial thromboses, often multiple, and obstetric-related adverse events in the presence of antiphospholipid antibodies (aPL). APS, first described in 1983, as thrombosis, abortion and cerebral disease, is nowadays recognised as a systemic disease with a wide constellation of clinical manifestations related to acute and chronic vascular lesions. The presence of aPL is the serological hallmark of APS representing a heterogeneous population of autoantibodies with many antigenic specificities directed to phospholipid-binding proteins, either alone or in combination with phospholipids...
May 2018: Modern Rheumatology
https://www.readbyqxmd.com/read/29378352/atherothrombosis-and-thromboembolism-position-paper-from-the-second-maastricht-consensus-conference-on-thrombosis
#14
H M H Spronk, T Padro, J E Siland, J H Prochaska, J Winters, A C van der Wal, J J Posthuma, G Lowe, E d'Alessandro, P Wenzel, D M Coenen, P H Reitsma, W Ruf, R H van Gorp, R R Koenen, T Vajen, N A Alshaikh, A S Wolberg, F L Macrae, N Asquith, J Heemskerk, A Heinzmann, M Moorlag, N Mackman, P van der Meijden, J C M Meijers, M Heestermans, T Renné, S Dólleman, W Chayouâ, R A S Ariëns, C C Baaten, M Nagy, A Kuliopulos, J J Posma, P Harrison, M J Vries, H J G M Crijns, E A M P Dudink, H R Buller, Y M C Henskens, A Själander, S Zwaveling, O Erküner, J W Eikelboom, A Gulpen, F E C M Peeters, J Douxfils, R H Olie, T Baglin, A Leader, U Schotten, B Scaf, H M M van Beusekom, L O Mosnier, L van der Vorm, P Declerck, M Visser, D W J Dippel, V J Strijbis, K Pertiwi, A J Ten Cate-Hoek, H Ten Cate
Atherothrombosis is a leading cause of cardiovascular mortality and long-term morbidity. Platelets and coagulation proteases, interacting with circulating cells and in different vascular beds, modify several complex pathologies including atherosclerosis. In the second Maastricht Consensus Conference on Thrombosis, this theme was addressed by diverse scientists from bench to bedside. All presentations were discussed with audience members and the results of these discussions were incorporated in the final document that presents a state-of-the-art reflection of expert opinions and consensus recommendations regarding the following five topics: 1...
February 2018: Thrombosis and Haemostasis
https://www.readbyqxmd.com/read/29344007/four-factor-prothrombin-complex-concentrate-improves-thrombin-generation-and-prothrombin-time-in-patients-with-bleeding-complications-related-to-rivaroxaban-a-single-center-pilot-trial
#15
Bettina Schenk, Stephanie Goerke, Ronny Beer, Raimund Helbok, Dietmar Fries, Mirjam Bachler
Background: Direct oral anticoagulants (DOACs) pose a great challenge for physicians in life-threatening bleeding events. The aim of this study was to test the efficacy of reversing the DOAC rivaroxaban using four-factor PCC (prothrombin complex concentrate), a non-specific reversing agent. Methods: Patients with life-threatening bleeding events during rivaroxaban treatment were included and administered 25 U kg-1 of PCC. Blood samples were collected immediately prior to as well as after PCC treatment at predefined time intervals...
2018: Thrombosis Journal
https://www.readbyqxmd.com/read/29338293/betrixaban-a-new-oral-factor-xa-inhibitor-for-extended-venous-thromboembolism-prophylaxis-in-high-risk-hospitalized-patients
#16
Scott G Garland, Christina E DeRemer, Steven M Smith, John G Gums
OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and safety of the factor Xa (FXa) inhibitor betrixaban for extended-duration prophylaxis of acute medically ill patients with venous thromboembolism (VTE) risk factors. DATA SOURCES: A MEDLINE/PubMed (January 1990 to October 2017) search was conducted using the following keywords: betrixaban, PRT054021, FXa inhibitor, novel oral anticoagulant, NOAC, direct oral anticoagulant, DOAC, and target specific oral anticoagulant, TSOAC...
January 1, 2018: Annals of Pharmacotherapy
https://www.readbyqxmd.com/read/29336885/structural-basis-for-activity-and-specificity-of-an-anticoagulant-anti-fxia-monoclonal-antibody-and-a-reversal-agent
#17
Lauren K Ely, Marco Lolicato, Tovo David, Kate Lowe, Yun Cheol Kim, Dharmaraj Samuel, Paul Bessette, Jorge L Garcia, Thomas Mikita, Daniel L Minor, Shaun R Coughlin
Coagulation factor XIa is a candidate target for anticoagulants that better separate antithrombotic efficacy from bleeding risk. We report a co-crystal structure of the FXIa protease domain with DEF, a human monoclonal antibody that blocks FXIa function and prevents thrombosis in animal models without detectable increased bleeding. The light chain of DEF occludes the FXIa S1 subsite and active site, while the heavy chain provides electrostatic interactions with the surface of FXIa. The structure accounts for the specificity of DEF for FXIa over its zymogen and related proteases, its active-site-dependent binding, and its ability to inhibit substrate cleavage...
February 6, 2018: Structure
https://www.readbyqxmd.com/read/29329680/correlation-of-severity-of-chronic-obstructive-pulmonary-disease-with-potential-biomarkers
#18
Seema Singh, S K Verma, Santosh Kumar, M K Ahmad, Anuradha Nischal, S K Singh, R K Dixit
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a non-specific inflammation, which involves the airways, lung parenchyma and pulmonary vessels. The inflammation causes the activation of inflammatory cells and the release of various inflammatory mediators such as interleukin-1 beta, interleukin-6 and tumor necrosis factor alpha (TNF-a). The present study was designed to assess the serum cytokines [Interleukin-1β (IL-1β), Interleukin-6 (IL-6), Tumor necrosis factor-α (TNF-α)] levels in chronic obstructive pulmonary disease (COPD) patients and they were correlated with severity of disease by spirometric measurements...
April 2018: Immunology Letters
https://www.readbyqxmd.com/read/29316202/anticoagulant-prophylaxis-and-therapy-in-children-current-challenges-and-emerging-issues
#19
F Newall, B Branchford, C Male
This review is aimed at describing the unique challenges of anticoagulant prophylaxis and treatment in children, and highlighting areas for research for improving clinical outcomes of children with thromboembolic disease. The evidence presented demonstrates the challenges of advancing the evidence base informing optimal management of thromboembolic disease in children. Recent observational studies have identified risk factors for venous thromboembolism in children, but there are few interventional studies assessing the benefit-risk balance of using thromboprophylaxis in risk-stratified clinical subgroups...
February 2018: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/29304529/passivating-injured-endothelium-with-kinexins-in-thrombolytic-therapy
#20
Yunn-Hwa Ma, Chao-Wei Huang, Chih-Jen Wen, Yi-Ching Lu, Shiaw-Pyng Wey, Tze-Chein Wun
Without conjunctive administration of an anticoagulant, endothelial injury-induced thrombosis is resistant to thrombolysis and prone to re-thrombosis. We hypothesized that co-delivery of recombinant tissue plasminogen activator (rtPA) with annexin V-containing anticoagulants that specifically target the injured endothelium may passivate the thrombogenic elements of the vascular injury site and enhance rtPA-induced thrombolysis. In this study, the effects of conjunctive administration of Kinexins (Kunitz inhibitor-annexin V fusion proteins) with rtPA on thrombolysis were determined in vitro and in vivo ...
January 2018: Thrombosis and Haemostasis
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