Neutrophils can Promote Clotting via FXI and Impact Clot Structure via Neutrophil Extracellular Traps in a Distinctive Manner in vitro

Neutrophils and neutrophil extracellular traps (NETs) have been shown to be involved in coagulation. However, the interactions between neutrophils or NETs and fibrin(ogen) in clots, and the mechanisms behind these interactions are not yet fully understood. In this in vitro study, the role of neutrophils or NETs on clot structure, formation and dissolution was studied with a combination of confocal microscopy, turbidity and permeation experiments. Factor (F)XII, FXI and FVII-deficient plasmas were used to investigate which factors may be involved in the procoagulant effects. We found both neutrophils and NETs promote clotting in plasma without the addition of other coagulation triggers, but not in purified fibrinogen, indicating that other factors mediate the interaction. The procoagulant effects of neutrophils and NETs were also observed in FXII- and FVII-deficient plasma. In FXI-deficient plasma, only the procoagulant effects of NETs were observed, but not of neutrophils. NETs increased the density of clots, particularly in the vicinity of the NETs, while neutrophils-induced clots were less stable and more porous. In conclusion, NETs accelerate clotting and contribute to the formation of a denser, more lysis resistant clot architecture. Neutrophils, or their released mediators, may induce clotting in a different manner to NETs, mediated by FXI

Measurement of J/ψ -pair production in pp collisions at √s = 13 TeV and study of gluon transverse-momentum dependent PDFs

The production cross-section of J/ψ pairs in proton-proton collisions at a centre-of-mass energy of √s = 13 TeV is measured using a data sample corresponding to an integrated luminosity of 4.2 fb−1 collected by the LHCb experiment. The measurement is performed with both J/ψ mesons in the transverse momentum range 0 < pT< 14 GeV/c and rapidity range 2.0 < y < 4.5. The cross-section of this process is measured to be 16.36 ± 0.28 (stat) ± 0.88 (syst) nb. The contributions from single-parton scattering and double-parton scattering are separated based on the dependence of the cross-section on the absolute rapidity difference ∆y between the two J/ψ mesons. The effective cross-section of double-parton scattering is measured to be σeff = 13.1 ± 1.8 (stat) ± 2.3 (syst) mb. The distribution of the azimuthal angle ϕCS of one of the J/ψ mesons in the Collins-Soper frame and the pT-spectrum of the J/ψ pairs are also measured for the study of the gluon transverse-momentum dependent distributions inside protons. The extracted values of ⟨cos 2ϕCS⟩ and ⟨cos 4ϕCS⟩ are consistent with zero, but the presence of azimuthal asymmetry at a few percent level is allowed

Improved measurement of CP violation parameters in Bs0→J/ψK+K− decays in the vicinity of the ϕ(1020) resonance

The decay-time-dependent C P asymmetry in B 0 s → J / ψ ( → μ + μ − ) K + K − decays is measured using proton-proton collision data, corresponding to an integrated luminosity of 6     fb − 1 , collected with the LHCb detector at a center-of-mass energy of 13 TeV. Using a sample of approximately 349 000 B 0 s signal decays with an invariant K + K − mass in the vicinity of the ϕ ( 1020 ) resonance, the C P -violating phase ϕ s is measured, along with the difference in decay widths of the light and heavy mass eigenstates of the B 0 s − ¯ B 0 s system, Δ Γ s , and the difference of the average B 0 s and B 0 meson decay widths, Γ s − Γ d . The values obtained are ϕ s = − 0.039 ± 0.022 ± 0.006     rad , Δ Γ s = 0.0845 ± 0.0044 ± 0.0024     ps − 1 , and Γ s − Γ d = − 0.005 6 + 0.0013 − 0.0015 ± 0.0014     ps − 1 , where the first uncertainty is statistical and the second systematic. These are the most precise single measurements to date and are consistent with expectations based on the Standard Model and with the previous LHCb analyses of this decay. These results are combined with previous independent LHCb measurements. The phase ϕ s is also measured independently for each polarization state of the K + K − system and shows no evidence for polarization dependence

Current Understanding of Inherited Modifiers of FVIII Pharmacokinetic Variation

Laura L Swystun, David Lillicrap Department of Pathology and Molecular Medicine, Queen’s University, Kingston, ON, CanadaCorrespondence: David Lillicrap, Richardson Laboratory, Queen’s University, 88 Stuart Street, Kingston, Ontario, K7L 3N6, Canada, Tel +1 613 548-1304, Fax +1 613 548-1356, Email [email protected]: The inherited bleeding disorder hemophilia A involves the quantitative deficiency of the coagulation cofactor factor VIII (FVIII). Prophylactic treatment of severe hemophilia A patients with FVIII concentrates aims to reduce the frequency of spontaneous joint bleeding and requires personalized tailoring of dosing regimens to account for the substantial inter-individual variability of FVIII pharmacokinetics. The strong reproducibility of FVIII pharmacokinetic (PK) metrics between repeat analyses in the same individual suggests this trait is genetically regulated. While the influence of plasma von Willebrand factor antigen (VWF:Ag) levels, ABO blood group, and patient age on FVIII PK is well established, estimates suggest these factors account for less than 35% of the overall variability in FVIII PK. More recent studies have identified genetic determinants that modify FVIII clearance or half-life including VWF gene variants that impair VWF-FVIII binding resulting in the accelerated clearance of VWF-free FVIII. Additionally, variants in receptors that regulate the clearance of FVIII or the VWF-FVIII complex have been associated with FVIII PK. The characterization of genetic modifiers of FVIII PK will provide mechanistic insight into a subject of clinical significance and support the development of personalized treatment plans for patients with hemophilia A.Keywords: factor VIII, hemophilia A, von Willebrand factor, pharmacokinetics, clearance recepto

In Vitro models for thrombogenicity testing of blood-recirculating medical devices

IntroductionBlood-recirculating medical devices, such as mechanical circulatory support (MCS), extracorporeal membrane oxygenators (ECMO), and hemodialyzers, are commonly used to treat or improve quality of life in patients with cardiac, pulmonary, and renal failure, respectively. As part of their regulatory approval, guidelines for thrombosis evaluation in pre-clinical development have been established. In vitro testing evaluates a device's potential to produce thrombosis markers in static and dynamic flow loops.Areas coveredThis review focuses on in vitro static and dynamic models to assess thrombosis in blood-recirculating medical devices. A summary of key devices is followed by a review of molecular markers of contact activation. Current thrombosis testing guidance documents, ISO 10993-4, ASTM F-2888, and F-2382 will be discussed, followed by analysis of their application to in vitro testing models.Expert opinionIn general, researchers have favored in vivo models to thoroughly evaluate thrombosis, limiting in vitro evaluation to hemolysis. In vitro studies are not standardized and it is often difficult to compare studies on similar devices. As blood-recirculating devices have advanced to include wearable and implantable artificial organs, expanded guidelines standardizing in vitro testing are needed to identify the thrombotic potential without excessive use of in vivo resources during pre-clinical development