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https://www.readbyqxmd.com/read/29227673/crystal-structure-of-cleaved-serp-1-a-myxomavirus-derived-immune-modulating-serpin-structural-design-of-serpin-reactive-center-loop-rcl-peptides-with-improved-therapeutic-function
#1
Brian P Mahon, Sriram Ambadapadi, Jordan R Yaron, Carrie L Lomelino, Melissa A Pinard, Shahar Keinan, Igor Kurnikov, Colin Macaulay, Liqiang Zhang, Westley Reeves, Grant McFadden, Scott Tibbetts, Robert McKenna, Alexandra Lucas
The Myxomavirus-derived protein Serp-1 has potent anti-inflammatory activity in models of vasculitis, lupus, viral sepsis, and transplant. Serp-1 has also been tested successfully in a Phase IIa clinical trial in unstable angina, representing a 'first-in-class' therapeutic. Recently, peptides derived from the reactive center loop (RCL) have been developed as stand-alone therapeutics for reducing vasculitis and improving survival in MHV68-infected mice. However, both Serp-1 and the RCL peptides lose activity in MHV68-infected mice after antibiotic suppression of intestinal microbiota...
December 11, 2017: Biochemistry
https://www.readbyqxmd.com/read/29227167/diagnosis-of-platelet-function-disorders-a-standardized-rational-and-modular-flow-cytometric-approach
#2
Oliver Andres, Katja Henning, Gabriele Strauß, Annerose Pflug, Georgi Manukjan, Harald Schulze
A high proportion of patients with mucocutaneous bleeding diathesis and suspected inherited or acquired platelet disorder remain without diagnosis even after comprehensive laboratory testing. Since flow cytometry allows investigation of resting and activated platelets on the single cell level by requiring only minimal amounts of blood, this method has become an important assay within the diagnostic algorithm, especially in pediatrics. We therefore developed a standardized and modular flow cytometric approach that contributes to clarify impaired platelet function in a rational step-by-step manner...
December 11, 2017: Platelets
https://www.readbyqxmd.com/read/29225327/plasma-fibrin-clot-structure-and-thromboembolism-clinical-implications
#3
Michał Ząbczyk, Anetta Undas
Fibrin formed as a result of fibrinogen polymerization is a main protein component of a clot in a test tube and intravascular thrombi in vivo. Fibrin clot structure characterized by fibers diameter and pore size differs between healthy subjects and those with thromboembolic diseases, in part due to the quality and quantity of fibrinogen and the magnitude of thrombin generation. A key measure of plasma clot structure is its permeability, reflected by the Darcy constant, Ks. Reduced Ks is a typical feature of the prothrombotic fibrin clot phenotype, which is associated with faster formation of denser fibrin mesh, relatively resistant to lysis...
December 11, 2017: Polish Archives of Internal Medicine
https://www.readbyqxmd.com/read/29224364/new-anticoagulants-for-venous-thromboembolism-and-atrial-fibrillation-what-the-future-holds
#4
Gerasimos Dimitropoulos, S M Zubair Rahim, Alexandra Sophie Moss, Gregory Y H Lip
Introduction The field of anticoagulation has seen impressive progress over the last decade. The introduction of the Non Vitamin K Oral Anticoagulants (NOACs) has revolutionized practice surrounding thromboprophylaxis, treatment of thromboembolic disease and stroke prevention in atrial fibrillation (AF). However, the search for the "holy grail" of anticoagulation, an agent that combines optimal efficacy with minimal bleeding diathesis, continues. Areas covered In this paper we aim to summarize the current evidence from pre-clinical studies and early phase clinical trials, presenting the pharmacodynamic and pharmacokinetic properties as well as the safety and efficacy profiles of the most important antithrombotic agents in development...
December 9, 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/29223926/an-update-on-factor-xi-structure-and-function
#5
REVIEW
Bassem M Mohammed, Anton Matafonov, Ivan Ivanov, Mao-Fu Sun, Qiufang Cheng, S Kent Dickeson, Chan Li, David Sun, Ingrid M Verhamme, Jonas Emsley, David Gailani
Factor XI (FXI) is the zymogen of a plasma protease, factor XIa (FXIa), that contributes to thrombin generation during blood coagulation by proteolytic activation of several coagulation factors, most notably factor IX (FIX). FXI is a homolog of prekallikrein (PK), a component of the plasma kallikrein-kinin system. While sharing structural and functional features with PK, FXI has undergone adaptive changes that allow it to contribute to blood coagulation. Here we review current understanding of the biology and enzymology of FXI, with an emphasis on structural features of the protein as they relate to protease function...
October 10, 2017: Thrombosis Research
https://www.readbyqxmd.com/read/29218045/factor-h-c-terminal-domains-are-critical-for-regulation-of-platelet-granulocyte-aggregate-formation
#6
Adam Z Blatt, Gurpanna Saggu, Claudio Cortes, Andrew P Herbert, David Kavanagh, Daniel Ricklin, John D Lambris, Viviana P Ferreira
Platelet/granulocyte aggregates (PGAs) increase thromboinflammation in the vasculature, and PGA formation is tightly controlled by the complement alternative pathway (AP) negative regulator, Factor H (FH). Mutations in FH are associated with the prothrombotic disease atypical hemolytic uremic syndrome (aHUS), yet it is unknown whether increased PGA formation contributes to the thrombosis seen in patients with aHUS. Here, flow cytometry assays were used to evaluate the effects of aHUS-related mutations on FH regulation of PGA formation and characterize the mechanism...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29217384/biocompatible-sulfenamide-and-sulfonamide-derivatives-of-metformin-can-exert-beneficial-effects-on-plasma-haemostasis
#7
Magdalena Markowicz-Piasecka, Kristiina M Huttunen, Elżbieta Mikiciuk-Olasik, Joanna Sikora
As the pharmacokinetic properties of metformin are unfavourable, several analogues and prodrugs have been synthesised to improve its bioavailability. The aim of this study was to assess the plasma stability of sulfenamide and sulfonamide derivatives of metformin and establish their effects on plasma haemostasis and integrity of red blood cells (RBCs). The overall haemostasis potential was evaluated spectrophotometrically by clot formation and lysis test (CL-test). PT (Prothrombin Time) and APTT (Activated Partial Tromboplastin Time) were used to evaluate the effects if the compounds on the extrinsic and intrinsic coagulation pathway...
December 4, 2017: Chemico-biological Interactions
https://www.readbyqxmd.com/read/29215956/effect-of-thrombopoietin-receptor-agonists-on-markers-of-coagulation-and-p-selectin-in-patients-with-immune-thrombocytopenia
#8
Lamya Garabet, Waleed Ghanima, Christine Monceyron Jonassen, Vibe Skov, René Holst, Marie-Christine Mowinckel, C Hasselbalc Hans, A Kruse Torben, Mads Thomassen, Howard Liebman, James B Bussel, Per Morten Sandset
Thrombopoietin-receptor-agonists (TPO-RA) are effective treatments of immune thrombocytopenia (ITP). Previous long-term TPO-RA clinical trials have shown that thrombotic events occurred in 6% of TPO-RA-treated ITP patients. To explore the increased risk of thrombosis, the effects of TPO-RA on markers of coagulation and P-selectin were studied. The study comprised two ITP cohorts and controls. Cohort 1 included 26 patients with sequential samples acquired before and during treatment with TPO-RA. Cohort 2 included a single sample in 18 patients on TPO-RA for more than one year...
December 7, 2017: Platelets
https://www.readbyqxmd.com/read/29213245/implication-of-free-fatty-acids-in-thrombin-generation-and-fibrinolysis-in-vascular-inflammation-in-zucker-rats-and-evolution-with-aging
#9
Jérémy Lagrange, Mélusine Didelot, Amel Mohamadi, Lucy A Walton, Saartje Bloemen, Bas de Laat, Huguette Louis, Simon N Thornton, Brian Derby, Michael J Sherratt, Bruno Fève, Pascal Challande, Riaz Akhtar, J Kennedy Cruickshank, Patrick Lacolley, Véronique Regnault
Background: The metabolic syndrome (MetS) and aging are associated with modifications in blood coagulation factors, vascular inflammation, and increased risk of thrombosis. Objectives: Our aim was to determine concomitant changes in thrombin generation in the blood compartment and at the surface of vascular smooth muscle cells (VSMCs) and its interplay with adipokines, free fatty acids (FFA), and metalloproteinases (MMPs) in obese Zucker rats that share features of the human MetS. Methods: Obese and age-matched lean Zucker rats were compared at 25 and 80 weeks of age...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/29206074/a-novel-flow-cytometry-assay-using-dihydroethidium-as-redox-sensitive-probe-reveals-nadph-oxidase-dependent-generation-of-superoxide-anion-in-human-platelets-exposed-to-amyloid-peptide-%C3%AE
#10
Aisha Alsheikh Abubaker, Dina Vara, Ian Eggleston, Ilaria Canobbio, Giordano Pula
Reactive oxygen species (ROS) generation is critical in the regulation of platelets, which has important implications in the modulation of hemostasis and thrombosis. Nonetheless, despite several assays have been described and successfully utilized in the past, the analysis of ROS generation in human platelets remains challenging. Here we show that dihydroethidium (DHE) allows the characterization of redox responses upon platelet activation by physiological and pathological stimuli. In particular, the flow cytometry assay that we describe here allowed us to confirm that thrombin, collagen-related peptide (CRP) and arachidonic acid but not adenosine diphosphate (ADP) stimulate superoxide anion formation in a concentration-dependent manner...
December 5, 2017: Platelets
https://www.readbyqxmd.com/read/29204262/the-role-of-oral-anticoagulant-therapy-in-patients-with-acute-coronary-syndrome
#11
REVIEW
Jae Youn Moon, Deepa Nagaraju, Francesco Franchi, Fabiana Rollini, Dominick J Angiolillo
Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor antagonist represents the current standard of care to prevent atherothrombotic recurrences in patients with acute coronary syndrome (ACS). However, despite the use of DAPT, the recurrence rate of cardiovascular ischemic events still remains high. This persistent risk may be in part attributed to the sustained activation of the coagulation cascade leading to generation of thrombin, which may continue to play a key role in thrombus formation. The use of vitamin K antagonists (VKAs) as a strategy to reduce atherothrombotic recurrences after an ACS has been previously tested, leading to overall unfavorable outcomes due to the high risk of bleeding complications...
December 2017: Therapeutic Advances in Hematology
https://www.readbyqxmd.com/read/29202603/the-influence-of-race-on-plasma-thrombin-generation-in-healthy-subjects-in-singapore
#12
Chuen Wen Tan, Wan Hui Wong, Chin Kimg Tan, Yiong Huak Chan, Hartirathpal Kaur, Lai Heng Lee, Heng Joo Ng
Race is touted as an independent risk factor for venous thromboembolism (VTE), although the basis for this is varied and contentious. Comparison of plasma thrombin generation (TG) using calibrated automated thrombogram (CAT) across races offers a modality that objectively measures global hemostatic function to evaluate this influence. Direct comparative data across races are currently not available. Aim is to establish the influence of race on plasma TG. Sixty normal participants, matched for age and gender, equally representing 4 races-Caucasian, Chinese, Indian, and Malay-were recruited...
January 1, 2017: Clinical and Applied Thrombosis/hemostasis
https://www.readbyqxmd.com/read/29202210/differential-effects-on-haemostatic-markers-by-metformin-and-the-contraceptive-pill-a-randomized-comparative-trial-in-pcos
#13
Genia F Burchall, Terrence J Piva, Sanjeeva Ranasinha, Helena J Teede
Background Polycystic ovarian syndrome (PCOS) affects up to 18% of reproductive-aged women with increased risks of cardiovascular disease and venous thromboembolic disease, related to metabolic and hormonal features, obesity and an apparent hypofibrinolytic state, possibly exacerbated by current PCOS treatments. Objective To investigate and compare haemostatic impacts of common pharmacological treatments and explore relationships with hormonal and metabolic variables in PCOS. Patients/Methods This mechanistic sub-study using biobanked samples from a 6-month randomized comparative trial of pharmacological treatments assessed pro- and anti-thrombotic markers and overall haemostatic activity...
November 2017: Thrombosis and Haemostasis
https://www.readbyqxmd.com/read/29197958/immunohaemostasis-a-new-view-on-haemostasis-during-sepsis
#14
REVIEW
Xavier Delabranche, Julie Helms, Ferhat Meziani
Host infection by a micro-organism triggers systemic inflammation, innate immunity and complement pathways, but also haemostasis activation. The role of thrombin and fibrin generation in host defence is now recognised, and thrombin has become a partner for survival, while it was seen only as one of the "principal suspects" of multiple organ failure and death during septic shock. This review is first focused on pathophysiology. The role of contact activation system, polyphosphates and neutrophil extracellular traps has emerged, offering new potential therapeutic targets...
December 2, 2017: Annals of Intensive Care
https://www.readbyqxmd.com/read/29187198/preliminary-reference-intervals-and-the-impact-of-citrate-storage-time-for-thrombelastography-in-cats-including-delta-and-the-velocity-curve
#15
Carolin Engelen, Andreas Moritz, Franziska Barthel, Natali Bauer
BACKGROUND: Thrombelastography is a useful tool in assessment of hemostasis. Beside the traditional variables, the velocity curve and the variable delta have lately earned attention. The velocity curve provides knowledge about the speed of clot formation including information about thrombin generation. Delta, which only reflects enzymatic coagulation, allows the determination of the origin of hypercoagulability when compared to clot rigidity, a variable that reflects both platelet and enzymatic activity...
November 29, 2017: BMC Veterinary Research
https://www.readbyqxmd.com/read/29181141/correlation-to-fviii-c-in-two-thrombin-generation-tests-tga-cat-and-innovance-etp
#16
Marcus Ljungkvist, Maria Berndtsson, Margareta Holmström, Danijela Mikovic, Ivo Elezovic, Jovan P Antovic, Eva Zetterberg, Erik Berntorp
Introduction: Several thrombin-generation tests are available, but few have been directly compared. Our primary aim was to investigate the correlation of two thrombin generation tests, thrombin generation assay-calibrated automated thrombogram (TGA-CAT) and INNOVANCE ETP, to factor VIII levels (FVIII:C) in a group of patients with hemophilia A. The secondary aim was to investigate inter-laboratory variation for the TGA-CAT method. Methods: Blood samples were taken from 45 patients with mild, moderate and severe hemophilia A...
2017: Mediterranean Journal of Hematology and Infectious Diseases
https://www.readbyqxmd.com/read/29176379/thrombin-generation-estimates-the-anticoagulation-effect-of-direct-oral-anticoagulants-with-significant-interindividual-variability-observed
#17
Joseph Rigano, Cheryl Ng, Harshal Nandurkar, Prahlad Ho
: Direct oral anticoagulants (DOACs) are increasingly being used, primarily due to their drug stability and patient convenience. Although these drugs have been evaluated to be well tolerated in numerous clinical trials, their impact on in-vivo anticoagulation effect, variability and therapeutic drug level remains unknown. Hence, we aim to study the effect and variability of DOACs on thrombin generation via the calibrated automated thrombogram. Anonymized coagulation specimens from outpatients on warfarin were collected...
November 25, 2017: Blood Coagulation & Fibrinolysis: An International Journal in Haemostasis and Thrombosis
https://www.readbyqxmd.com/read/29170316/19%C3%A2-accuracy-of-biomarkers-for-venous-thromboembolism-in-pregnancy-the-diagnosis-of-pulmonary-embolism-in-pregnancy-dipep-biomarker-study
#18
Steve Goodacre, Beverley Hunt, Kiran Parmar, Neil Shephard, Kimberley Horspool
OBJECTIVE: To estimate the accuracy of biomarkers for venous thromboembolism (VTE) in pregnant and postpartum women with suspected pulmonary embolism (PE). DESIGN: Observational cohort study augmented with additional cases with VTE. SETTING: Emergency departments and maternity units at eleven prospectively recruiting sites. PARTICIPANTS: Pregnant or postpartum women presenting with suspected PE or diagnosed DVT. INTERVENTIONS: Research nurses/midwives collected a blood sample from women with suspected PE or diagnosed DVT and data relating to diagnostic imaging, treatment and adverse outcomes...
December 2017: Emergency Medicine Journal: EMJ
https://www.readbyqxmd.com/read/29158361/prochemerin-cleavage-by-factor-xia-links-coagulation-and-inflammation
#19
Xiaomei Ge, Yasuto Yamaguchi, Lei Zhao, Loredana Bury, Paolo Gresele, Caroline Berube, Lawrence L Leung, John Morser
Chemerin is a chemoattractant and adipokine that circulates in blood as inactive prochemerin (chem163S). Chem163S is activated by a series of C-terminal proteolytic cleavages resulting in diverse chemerin forms with different levels of activity. We screened a panel of proteases in the coagulation, fibrinolytic and inflammatory cascades to identify those that process prochemerin in plasma. Factor XIa (FXIa) cleaved chem163S, generating a novel chemerin form, chem162R, as an intermediate product, and chem158K, as the final product...
November 20, 2017: Blood
https://www.readbyqxmd.com/read/29156107/hemodynamic-force-triggers-rapid-netosis-within-sterile-thrombotic-occlusions
#20
X Yu, J Tan, S L Diamond
BACKGROUND: Neutrophil extracellular traps (NETs) are released when neutrophils encounter infectious pathogens, especially during sepsis. Additionally, NETosis occurs during venous and arterial thrombosis, disseminated intravascular coagulation, and trauma. OBJECTIVE: We tested if hemodynamic forces trigger NETosis during sterile thrombosis. METHODS: NETs were imaged with Sytox-green during microfluidic perfusion of Factor XIIa-inhibited or thrombin-inhibited human whole blood over fibrillar collagen (± tissue factor)...
November 20, 2017: Journal of Thrombosis and Haemostasis: JTH
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