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Journal of Thrombosis and Haemostasis: JTH

Nicola Mumoli, Daniela Mastroiacovo, Matteo Giorgi-Pierfranceschi, Raffaele Pesavento, Matteo Mochi, Marco Cei, Fulvio Pomero, Antonino Mazzone, Josè Vitale, Walter Ageno, Francesco Dentali
BACKGROUND: Ultrasound Elastography (UE) imaging is a novel sonographic technique commonly employed for relative quantification of tissue elasticity. Its applicability to venous thromboembolic events has not yet been fully established; in particular, it is unclear if this technique may be useful in determining the age of deep vein thrombosis (DVT). Thus, the aim of this study was to assess the role of UE in distinguishing acute from chronic DVT. METHODS: Consecutive patients with a first unprovoked acute and chronic (= 3 months old) DVT of the lower limbs were analyzed...
September 17, 2018: Journal of Thrombosis and Haemostasis: JTH
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September 14, 2018: Journal of Thrombosis and Haemostasis: JTH
Roelof H Bekendam, David Iyu, Freda Passam, Jack D Stopa, Karen De Ceunynck, Oluwatoyosi Muse, Pavan K Bendapudi, Céline L Garnier, Srila Gopal, Lydie Crescence, Joyce Chiu, Bruce Furie, Laurence Panicot-Dubois, Philip J Hogg, Christophe Dubois, Robert Flaumenhaft
BACKGROUND: Protein disulfide isomerase (PDI) serves an essential role in thrombus formation and PDI inhibition is being evaluated clinically as a novel anticoagulant. Yet little is known about the regulation of PDI in the vasculature. Thiols within the catalytic motif of PDI are essential for its role in thrombosis. These same thiols bind nitric oxide (NO), a potent regulator of vessel function. To determine whether regulation of PDI represents a mechanism by which NO controls vascular quiescence, we evaluated the effect of NO on PDI function in endothelial cells, platelets, and thrombus formation in vivo...
September 12, 2018: Journal of Thrombosis and Haemostasis: JTH
Jamie Nourse, Juliane Braun, Karl Lackner, Stefan Hüttelmaier, Sven Danckwardt
BACKGROUND: microRNAs (miRNAs) confer robustness to complex molecular networks regulating biological functions. However, despite the involvement of miRNAs in almost all biological processes, and the importance of the hemostatic system for a multitude of actions in and beyond blood coagulation, the role of miRNAs in hemostasis is poorly defined. OBJECTIVES: Here we comprehensively illuminate miRNA-mediated regulation of the hemostatic system in an unbiased manner...
September 12, 2018: Journal of Thrombosis and Haemostasis: JTH
Thomas J Girard, Kristin Grunz, Nina M Lasky, James P Malone, George J Broze
BACKGROUND: Mouse models can provide insight into the pathophysiology of human thrombosis and hemostasis. Tissue factor pathway inhibitor (TFPI) regulates coagulation through protein S (PS)-enhanced factor (F)Xa inhibition and FXa-dependent inhibition of FVIIa/tissue factor (TF) activity. TFPI is expressed as isoforms α and β in man, and α, β and γ in the mouse. OBJECTIVE: Assess the reliability of extending TFPI-related studies in mice to humans. METHOD: Compare mouse and human TFPI physiology using a variety of methods...
September 8, 2018: Journal of Thrombosis and Haemostasis: JTH
Line H Evensen, Trond Isaksen, Kristian Hindberg, Sigrid K Braekkan, John-Bjarne Hansen
BACKGROUND: Whether physical activity influences the risk of incident venous thromboembolism (VTE) remains controversial, potentially due to methodological challenges, such as regression dilution bias. OBJECTIVES: To investigate whether physical activity was associated with VTE risk, and explore the role of body mass index (BMI) as a mediator in a population-based cohort with repeated assessments of physical activity. METHODS: Participants (n=30 002) attending one or more surveys of the Tromsø Study 4-6 (1994-95, 2001-02, 2007-08) were included and categorized based on weekly physical activity...
September 6, 2018: Journal of Thrombosis and Haemostasis: JTH
Kimberly Nellenbach, Nina A Guzzetta, Ashley C Brown
BACKGROUND: Bleeding is a serious complication of neonates undergoing cardiopulmonary bypass (CPB) and associated with substantial morbidity and mortality. Bleeding is addressed through the transfusion of adult blood products including platelets and cryoprecipitate. However, significant differences exist between neonatal and adult clotting components, specifically fibrinogen. Our recent ex vivo studies have shown that neonatal fibrinogen does not fully integrate with adult fibrinogen, leading to decreased susceptibility to fibrinolysis...
September 4, 2018: Journal of Thrombosis and Haemostasis: JTH
Andaleb Kholmukhamedov, Rae Janecke, Hyo-Jung Choo, Shawn M Jobe
BACKGROUND: Procoagulant platelets comprise a phenotypically-distinct subpopulation of activated platelets with high-level phosphatidylserine externalization. When initiated by co-stimulation with thrombin and a glycoprotein VI (GPVI) agonist, the transition to the procoagulant phenotype is mediated by extracellular calcium entry and mitochondrial permeability transition pore (mPTP) formation. OBJECTIVES: The intracellular mechanisms coordinating these distinct cytoplasmic and mitochondrial processes remain unclear...
September 4, 2018: Journal of Thrombosis and Haemostasis: JTH
Jens Sundbøll, Bianka Darvalics, Erzsébet Horváth-Puhó, Kasper Adelborg, Kristina Laugesen, Morten Schmidt, Victor W Henderson, Henrik Toft Sørensen
BACKGROUND: Glucocorticoid users have high mortality following stroke, but the underlying clinical pathways are poorly understood. OBJECTIVES: To examine the risk of cardiovascular events among ischemic stroke patients using glucocorticoids. METHODS: We conducted a nationwide population-based cohort study using medical registries in Denmark. We identified all patients hospitalized with a first-time ischemic stroke (2004-2013). We categorized glucocorticoid use into current use (last prescription redemption ≤90 days before admission), former use, and non-use...
September 4, 2018: Journal of Thrombosis and Haemostasis: JTH
Rolinda L R Carter, Kimberley Talbot, Woosuk S Hur, Scott C Meixner, J Grace Van Der Gugten, Daniel T Holmes, Hélène C F Côté, Christian J Kastrup, Tyler W Smith, Agnes Y Y Lee, Edward L G Pryzdial
BACKGROUND: When bound to an anionic phospholipid-containing membrane, activated clotting factor X (FXa) is sequentially cleaved by plasmin from the intact form, FXaα, to FXaβ and then to Xa33/13. Tissue plasminogen activator (tPA) produces plasmin and is the initiator of fibrinolysis. Both FXaβ and Xa33/13 enhance tPA. Although stable in experiments using purified proteins, Xa33/13 rapidly loses tPA cofactor function in plasma. Bypassing this inhibition, covalent modification of the FXaα active site prevents Xa33/13 formation by plasmin and the persistent FXaβ enhances plasma fibrinolysis...
September 3, 2018: Journal of Thrombosis and Haemostasis: JTH
H G de Haan, A van Hylckama Vlieg, L A Lotta, Marcin M Gorski, P Bucciarelli, I Martinelli, T P Baglin, F Peyvandi, F R Rosendaal
BACKGROUND: Although several genetic risk factors for deep vein thrombosis (DVT) are known, almost all related to hemostasis, a large genetic component remains unexplained. OBJECTIVES: We aimed to identify novel genetic determinants using targeted DNA sequencing. PATIENTS/METHODS: We included 899 DVT patients and 599 controls from three case-control studies (DVT-Milan, MEGA, and THE-VTE) for sequencing of the coding regions of 734 genes involved in hemostasis or related pathways...
August 31, 2018: Journal of Thrombosis and Haemostasis: JTH
Banne Nemeth, J F Timp, A van Hylckama Vlieg, Frits R Rosendaal, Suzanne C Cannegieter
BACKGROUND: Patients with lower-leg cast immobilization have a substantially increased risk to develop a first venous thrombosis (VT) while the risk in patients with a history of VT is as yet unknown. AIMS: To estimate the risk of recurrent VT after lower-leg cast immobilization in patients with a history of VT. METHODS: Case-control study nested within a cohort of 4597 patients with a first VT who were followed over time for recurrence from 1999-2010 (MEGA follow-up study)...
August 30, 2018: Journal of Thrombosis and Haemostasis: JTH
Lisa Baumann Kreuziger, Keyvan Karkouti, James Tweddell, M Patricia Massicotte
Despite the development of catheter-based interventions for ischemic and valvular heart disease, hundreds of thousands of people undergo open heart surgery annually for coronary artery bypass graft (CABG), valve replacement, or cardiac assist device implantation. Cardiac surgery patients are unique because therapeutic anticoagulation is required during cardiopulmonary bypass. Developmental hemostasis and altered drug metabolism affect management in children. This narrative review summarizes the current evidence-based and consensus guidelines regarding perioperative, intraoperative, and post-operative antithrombotic therapy in patients undergoing cardiac surgery...
August 28, 2018: Journal of Thrombosis and Haemostasis: JTH
Gregory N Adams, Bal Krishan Sharma, Leah Rosenfeldt, Malinda Frederick, Matthew J Flick, David P Witte, Laurent O Mosnier, Eleana Harmel-Laws, Kris A Steinbrecher, Joseph S Palumbo
BACKGROUND: Multiple studies have implicated Protease Activated Receptor-1 (PAR-1), a G-protein coupled receptor activated by proteolytic cleavage of its N-terminus, as one target coupling thrombin-mediated proteolysis to tumor progression. OBJECTIVE: We analyzed the role of PAR-1 in the setting of two distinct spontaneously developing tumor models in mice. METHODS: We interbred PAR-1-deficient mice with TRAMP (Transgenic Adenocarcinoma of the Mouse Prostate) mice, which spontaneously develop prostate tumors, and adenomatous polyposis coli Min (APCM in/+ ) mice, which spontaneously develop intestinal adenomas...
August 28, 2018: Journal of Thrombosis and Haemostasis: JTH
Kieron South, Frederik Denorme, Isabelle I Salles-Crawley, Simon F De Meyer, David A Lane
BACKGROUND: ADAMTS13 circulates in a closed conformation, only achieving full proteolytic activity against von Willebrand Factor (VWF) following a substrate-induced conformational change. A gain of function (GoF) ADAMTS13 variant (R568K/F592Y/R660K/Y661F/Y665F) is conformationally pre-activated. OBJECTIVES: To establish how the hyperactivity of GoF ADAMTS13 is manifest in experimental models mimicking the occlusive arterial thrombi present in acute ischaemic stroke...
August 28, 2018: Journal of Thrombosis and Haemostasis: JTH
K Brettschneider, A Schmidt, J Kahle, A Orlowski, D Stichel, D Schwabe, C Königs
BACKGROUND: Today, the most serious complication for patients with hemophilia A undergoing factor VIII (FVIII) replacement therapy is the development of neutralizing antibodies (inhibitors). While inhibitors can be eradicated by application of high doses of FVIII the immune tolerance induction therapy fails in up to 30% of patients. Hence, there is still an urgent need for novel therapeutic approaches for patients with persisting inhibitors. OBJECTIVES: In the present study, the potential use of immunotoxins containing Exotoxin A (ETA) from Pseudomonas aeruginosa for selective elimination of FVIII-specific B cells was explored...
August 27, 2018: Journal of Thrombosis and Haemostasis: JTH
R A Gruppo, D Malan, J Kapocsi, L Nemes, C R M Hay, L Boggio, P Chowdary, G Tagariello, A von Drygalski, F Hua, M Scaramozza, S Arkin
Essentials Marzeptacog alfa (activated) [MarzAA] is a novel variant of activated human factor VII. A phase 1 dose escalation trial of MarzAA was conducted in subjects with severe hemophilia. MarzAA was safe and tolerated at intravenous doses up to 30 μg kg-1 Data observed support further trials for hemophilia patients with inhibitors to factors VIII/IX. SUMMARY: Background Marzeptacog alfa (activated) (MarzAA), a new recombinant activated human factor VII (rFVIIa) variant with four amino acid substitutions, was developed to provide increased procoagulant activity and a longer duration of action in people with hemophilia...
August 27, 2018: Journal of Thrombosis and Haemostasis: JTH
Miriayi Aibibula, Khalid M Naseem, Roger Sturmey
BACKGROUND: Platelet activation is an energy-dependent process, but the type and integrated use of metabolic fuels required to drive activation remains unclear. OBJECTIVE: To dissect the metabolic fuel and pathway plasticity required for platelet activation. METHODS: Platelet Oxygen Consumption rate (OCR) and Extracellular Acidification Rate (ECAR) were measured as markers of oxidative phosphorylation (OXPHOS) and glycolysis respectively. Glucose and glycogen were quantified by enzyme-coupled fluorometric assay...
August 27, 2018: Journal of Thrombosis and Haemostasis: JTH
Heng Fan, Jian-Hua Zhu
We read with great interest the article by Dekkers et al. [1] in which the authors reported their attempt to investigate whether estimated glomerular filtration rate (eGFR), urinary albumin-creatinine ratio (UACR), and pulse wave velocity (PWV) were associated with a procoagulant state. In their cross-sectional analysis of the Netherlands Epidemiology of Obesity Study, eGFR, UACR, fibrinogen, and coagulation factors (F)VIII, FIX, and FXI were determined in 6536 participants, and PWV was assessed in 2433 participants...
August 23, 2018: Journal of Thrombosis and Haemostasis: JTH
Hermann Eichler, Pantep Angchaisuksiri, Kaan Kavakli, Paul Knoebl, Jerzy Windyga, Victor Jiménez-Yuste, Agon Hyseni, Ute Friedrich, Pratima Chowdary
BACKGROUND: Concizumab is a humanized monoclonal antibody targeting tissue factor pathway inhibitor (TFPI), leading to enhanced thrombin generation (TG) potential. explorer™ 3 (NCT02490787) was a phase 1b, double-blinded, multiple-dose escalation trial of subcutaneous concizumab in people with severe hemophilia A without inhibitors. OBJECTIVES: The primary objective was to evaluate safety. Assessments of pharmacokinetics (PK), pharmacodynamics (PD) and subcutaneous concizumab immunogenicity were secondary objectives...
August 23, 2018: Journal of Thrombosis and Haemostasis: JTH
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