Residual Peak Research Articles

Transcatheter Pulmonary Valve Replacement With the Melody Valve in Small Diameter Expandable Right Ventricular Outflow Tract Conduits

ObjectivesThis study sought to evaluate the safety, feasibility, and outcomes of transcatheter pulmonary valve replacement (TPVR) in conduits ≤16 mm in diameter. BackgroundThe Melody valve (Medtronic, Minneapolis, Minnesota) is approved for the treatment of dysfunctional right ventricular outflow tract (RVOT) conduits ≥16 mm in diameter at the time of implant. Limited data are available regarding the use of this device in smaller conduits. MethodsThe study retrospectively evaluated patients from 9 centers who underwent percutaneous TPVR into a conduit that was ≤16 mm in diameter at the time of implant, and reported procedural characteristics and outcomes. ResultsA total of 140 patients were included and 117 patients (78%; median age and weight 11 years of age and 35 kg, respectively) underwent successful TPVR. The median original conduit diameter was 15 (range: 9 to 16) mm, and the median narrowest conduit diameter was 11 (range: 4 to 23) mm. Conduits were enlarged to a median diameter of 19 mm (29% larger than the implanted diameter), with no difference between conduits. There was significant hemodynamic improvement post-implant, with a residual peak RVOT pressure gradient of 7 mm Hg (p < 0.001) and no significant pulmonary regurgitation. During a median follow-up of 2.0 years, freedom from RVOT reintervention was 97% and 89% at 2 and 4 years, respectively, and there were no deaths and 5 cases of endocarditis (incidence rate 2.0% per patient-year). ConclusionsIn this preliminary experience, TPVR with the Melody valve into expandable small diameter conduits was feasible and safe, with favorable early and long-term procedural and hemodynamic outcomes.

Water suppression in the human brain with hypergeometric RF pulses for single-voxel and multi-voxel MR spectroscopy.

To develop and investigate a novel water suppression sequence with hypergeometric pulses at 3 T. Simulations were used to optimize the delays and amplitudes of 5 hypergeometric prepulses, to minimize the residual water over a range of T1 and B1 values. Single-voxel data with hypergeometric water suppression (HGWS) prepulses were acquired in the centrum semiovale, 2 parietal regions, and insula of 7 subjects, and compared with VAPOR water suppression. Magnetic resonance spectroscopic imaging (MRSI) data using both VAPOR and HGWS prepulses were also collected and compared. Water suppression performance was calculated as the residual water peak height relative to the unsuppressed water peak. MRSI voxel-by-voxel comparison was performed by calculating the ratio between HGWS and VAPOR residual water peaks. In simulations, HGWS and VAPOR are insensitive to B1 and water T1 variations, but with no B1 variation, HGWS has a lower average residual water fraction (0.0033) than that of VAPOR (0.0091). In single-voxel acquisitions, HGWS performs better than VAPOR in all regions with a 2.3-fold to 5.7-fold lower residual water. In MRSI acquisitions, HGWS performs on average 2.3-fold better than VAPOR in 98.9% of the voxels. HGWS provides better water suppression than VAPOR in both single-voxel and multivoxel acquisitions with a shorter sequence duration.

Modeling the cyclic shape memory and superelasticity of selective laser melting fabricated NiTi

Shape memory alloys (SMAs) have found several industrial and biomedical applications due to their superior mechanical and biological properties. Since SMA devices may experience several cyclic loadings during their function, assessment of their cyclic response is of vital importance. In this paper, an existing constitutive model based on small strains is generalized to investigate cyclic response in superelastic and shape memory regimes of additively manufactured NiTi. To do so, Microplane theory is utilized to calculate the elastic and transformation strain tensors while the associated flow rule is used in combination with linear isotropic hardening for plastic strain tensor. In this model, all the material parameters can be obtained using DSC, the stress-strain response in the first loading-unloading cycle, and the accumulated stress-strain curve. To validate the model, superelastic and shape memory NiTi compression samples are fabricated using selective laser melting. All the specimens are tested in stress-controlled cyclic tests at a constant temperature. The obtained cyclic stress-strain response is compared with the numerical results. The model predicts and the experimental results verify that the residual strain, peak strain, and dissipation energy converge to specific values.

Evaluation of the NanoAerosol Generator by Kanomax FMT Inc. in Aerosolization of Size Standard Nanoparticle and Protein

A new nebulizer called NanoAerosol Generator (NAG) by Kanomax FMT, Inc. was evaluated experimentally in their performance in aerosolizing sub-100 nm particles and sub-10 nm protein molecules which cannot be aerosolized with conventional compressed-air jet nebulizers due to the interference by a number of residue particles. For the challenge particles, 29 nm-polystyrene latex (PSL) particles and bovine serum albumin (BSA) protein molecules were used as sub-100 nm and sub-10 nm test materials, respectively. For both particles, the aerosolization by the NAG was successful with a clear separation between the peak of the challenge particles and the peak of residual particles in the size distribution spectra. The size distributions of aerosolized 29 nm-PSL particles were compared between the NAG and an electrospray aerosol generator (EAG) with liquid samples of the same particle concentration. The EAG showed clearer separation of the PSL peak from the residual peak; on the other hand, the peak height was taller for the NAG by a factor of 6 than for the EAG, which indicated the generation of airborne particles from a liquid suspension/solution of the same concentration was more efficient for the NAG than for the EAG.

Synthesis and Characterization of Poly(Lactic Acid)-Grafted Natural Rubber by Reactive Melt-Blending Technique

This study investigated the synthesis and characterization of poly(lactic acid)-grafted natural rubber (PLA-g-NR) in molten state. The grafting was carried out in an internal mixer without and with the presence of tin octoate catalyst (TO). The grafting of lactide onto NR was carried out by using maleic anhydride (MA) as a linker. The FTIR and 1H-NMR spectra revealed new peaks for the MA-grafted NR (NR-g-MA) and PLA indicating that MA was grafted onto NR and that LA was successfully polymerized into PLA. It was also found that MA grafted onto NR could assist as a linker for connecting PLA with NR via esterification reaction between hydroxyl group (OH) at the end chain of PLA and carboxylic group (COOH) from ring opening reaction of MA. Moreover, the decrease of residual LA peak in FTIR spectra suggested that the presence of TO catalyst in the reactive blend promoted higher degree of polymerization of PLA from ring opening reaction of LA.

Structure analysis and enhancement of creep resistance and thermal properties of eutectic Sn-Ag lead free solder alloy by Ti and Cd - addition

Eutectic (Sn-3.5wt.%Ag) solder alloy is used in electronic circuits in which the creep property of the solder joints is essential for their applications. The study of creep, structure and thermal properties of three solder alloys (Sn-3.5wt.%Ag,Sn-3.5wt.%Ag-0.27wt.%Ti and Sn-3.5wt.Ag-0.27wt.%Cd) is characterized by the presence of (Ag3Sn-IMC) beside the phase (β-Sn). The microstructure parameters obtained from the X-ray analysis represented by, lattice parameters (a, c), the axial ratio (c/a), the residual strains (Δa/a0, Δc/c0) and peak height intensities (hkl) of some crystallographic planes are given. All parameters were found to be sensitive to the additions of (Ti or Cd), applied stresses and working temperatures in the range (298-373K).The crystallite size of the (211) reflection was found to increase from (61-132nm) with the additions and to decrease from (115-79nm) with the working temperatures. The morphological studies show a remarkable decrease in the size of (β-Sn) grains with the addition of (Cd) content which confirms the X-ray data. The obtained results show a decrease in melting temperature with the additions. The creep properties are notably improved by the addition of either (Ti) or (Cd). In order to reveal the creep characteristics such as stress exponent (n) and activation energy (Q), the tensile creep tests were performed within the temperature range (298-373K) at constant applied stress (17.27MPa). Based on the obtained stress exponents and activation energies, it is explained that the dominant deformation mechanism is dislocation climb over all temperature range.&#x0D;

Positioning of head and neck patients for proton therapy using proton range probes: a proof of concept study

To exploit the full potential of proton therapy, accurate and on-line methods to verify the patient positioning and the proton range during the treatment are desirable. Here we propose and validate an innovative technique for determining patient misalignment uncertainties through the use of a small number of low dose, carefully selected proton pencil beams (‘range probes’) (RP) with sufficient energy that their residual Bragg peak (BP) position and shape can be measured on exit. Since any change of the patient orientation in relation to these beams will result in changes of the density heterogeneities through which they pass, our hypothesis is that patient misalignments can be deduced from measured changes in Bragg curve (BC) shape and range. As such, a simple and robust methodology has been developed that estimates average proton range and range dilution of the detected residual BC, in order to locate range probe positions with optimal prediction power for detecting misalignments. The validation of this RP based approach has been split into two phases. First we retrospectively investigate its potential to detect translational patient misalignments under real clinical conditions. Second, we test it for determining rotational errors of an anthropomorphic phantom that was systematically rotated using an in-house developed high precision motion stage. Simulations of RPs in these two scenarios show that this approach could potentially predict translational errors to lower than1.5 mm and rotational errors to smaller than 1° using only three or five RPs positions respectively.

Ground Motion Intensity Measures for Rocking Building Systems

This paper investigates the effectiveness of various ground motion intensity measures (IMs) in estimating the structural response of two types of rocking systems: (a) a controlled rocking steel braced frame system with self-centering action and (b) a rocking spine system for reinforced concrete infill frames. The IMs are evaluated based on the dispersion in engineering demand parameter (EDP) predictions (efficiency) and the sensitivity of the conditional distributions of EDPs to the distributions of the magnitudes, distances and spectral shape parameter (ε) of ground motion records (sufficiency). The EDPs include maximum transient and residual story drifts and peak floor accelerations. The spectral acceleration averaged over a range of periods (Saavg) is most effective for predicting transient and residual drift demands and peak ground acceleration (PGA) is generally the best predictor of peak floor accelerations. The proximity of the frequency range most affecting an EDP to that best reflected in an IM is found to be a good indicator of the performance of that IM.

On the aliasing of the solar cycle in the lower stratospheric tropical temperature

AbstractThe double‐peaked response of the tropical stratospheric temperature profile to the 11 year solar cycle (SC) has been well documented. However, there are concerns about the origin of the lower peak due to potential aliasing with volcanic eruptions or the El Niño–Southern Oscillation (ENSO) detected using multiple linear regression analysis. We confirm the aliasing using the results of the chemistry‐climate model (CCM) SOCOLv3 obtained in the framework of the International Global Atmospheric Chemisty/Stratosphere‐troposphere Processes And their Role in Climate Chemistry‐Climate Model Initiative phase 1. We further show that even without major volcanic eruptions included in transient simulations, the lower stratospheric response exhibits a residual peak when historical sea surface temperatures (SSTs)/sea ice coverage (SIC) are used. Only the use of climatological SSTs/SICs in addition to background stratospheric aerosols removes volcanic and ENSO signals and results in an almost complete disappearance of the modeled solar signal in the lower stratospheric temperature. We demonstrate that the choice of temporal subperiod considered for the regression analysis has a large impact on the estimated profile signal in the lower stratosphere: at least 45 consecutive years are needed to avoid the large aliasing effect of SC maxima with volcanic eruptions in 1982 and 1991 in historical simulations, reanalyses, and observations. The application of volcanic forcing compiled for phase 6 of the Coupled Model Intercomparison Project (CMIP6) in the CCM SOCOLv3 reduces the warming overestimation in the tropical lower stratosphere and the volcanic aliasing of the temperature response to the SC, although it does not eliminate it completely.

Nanofriction of Graphene/Ionic Liquid-Infused Block Copolymer Homoporous Membranes.

We have infused graphene/ionic liquid into block copolymer homoporous membranes (HOMEs), which have highly ordered uniform cylindrical nanopores, to form compact, dense, and continuous graphene/ionic liquid (Gr/IL) lubricating layers at interfaces, enabling a reduction in the friction coefficient. Raman and XPS analyses, confirmed the parallel alignment of the cation of ILs on graphene by the π-π stacking interaction of the imidazolium ring with the graphene layer. This alignment loosens the lattice spacing of Gr in Gr/ILs, leading to a larger lattice spacing of 0.36 nm in Gr of Gr/ILs hybrids than the pristine Gr (0.33 nm). The loose graphene layers, which are caused by the coexistence of graphene and ILs, would make the sliding easier, and favor the lubrication. An increase in the friction coefficient was observed on ILs-infused block copolymer HOMEs, as compared to Gr/ILs-infused ones, due to the absence of Gr and the unstably formed ILs film. Gr/ILs-infused block copolymer HOMEs also exhibit much smaller residual indentation depth and peak indentation depth in comparison with ILs-infused ones. This indicates that the existence of stably supported Gr/ILs hybrid liquid films aids the reduction of the friction coefficient by preventing the thinning of the lubricant layer and exposure of the underlying block copolymer HOMEs.

Paleogeomorphic genesis assembly method for paleogeomorphic recovery in the major region of the Tahe Oil Field, Tarim Basin, northwest China

Tahe oil field is the first marine origin oil field in China, with proven reserves of 500 million tons. Given the important role of the paleogeomorphology in controlling the formation and distribution of karst reservoirs, this paper restored the pre-Carboniferous paleokarst landform in the major blocks of the Tahe oil field, via the paleogeomorphic genesis assembly method. First, four types of secondary landform units (karst platform, karst gentle slope, karst steep slope, and karst intermountain basin) were defined. Next, landform identification factors were added to these four types, to further divide the paleokarst landform into ten tertiary landform units. This enabled a more precise identification of the paleogeomorphic landforms. The karst development and the properties of hydrocarbon reservoirs in micro-geomorphic units were assessed. In addition, the relationship between petroleum production and geomorphology was analysed to robustly predict karst reservoirs in the Tahe oil field. The results show that karst develops differently according to the ancient landform units it developed from and that the current karst function is highly dependent on the precursor ancient landform. In addition, the morphology of the ancient landform significantly controls hydrocarbon accumulation, with oil and gas production being highly associated with the degree of karst development in each landscape unit. The research results indicate that the position of the slope in the karst hill and residual peak is favorable for future oil and gas exploration.

Hydrogen generation by electrolysis and storage in salt caverns: Potentials, economics and systems aspects with regard to the German energy transition

The Plan-DelyKaD project focused on an in-depth comparison of relevant electrolysis technologies, identified criteria for and selected most relevant salt cavern sites in Germany, studied business case potentials for applying hydrogen taken from storage to different end-users and engaged in identifying the future role of hydrogen from large scale storage in the German energy system. The focus of this paper is on the latter three topics above. The bottom-up investigation of most suitable salt cavern sites was used as input for a model-based analysis of microeconomic and macroeconomic aspects. The results identify dimensions and locations of possible hydrogen storages mostly in Northern Germany with ample potential to support the integration of fluctuating renewable electricity into the German power system. The microeconomic analysis demonstrates that the most promising early business case for hydrogen energy from large scale storage is its application as a fuel for the mobility sector. From a system perspective the analysis reveals that an optimized implementation of hydrogen generation via electrolysis and storage in salt caverns will have a positive impact on the power system in terms of reduced curtailments of wind power plants and lower residual peak loads.

On the seismic response of steel buckling-restrained braced structures including soil-structure interaction

This paper summarizes estimated seismic response results from three-dimensional nonlinear inelastic time-history analyses of some steel buckling-restrained braced (BRB) structures taking into account soil-structure interaction (SSI). The response results involve mean values for peak interstorey drift ratios, peak interstorey residual drift ratios and peak floor accelerations. Moreover, mean seismic demands in terms of axial force and rotation in columns, of axial and shear forces and bending moment in BRB beams and of axial displacement in BRBs are also discussed. For comparison purposes, three separate configurations of the BRBs have been considered and the aforementioned seismic response and demands results have been obtained firstly by considering SSI effects and then by neglecting them. It is concluded that SSI, when considered, may lead to larger interstorey and residual interstorey drifts than when not. These drifts did not cause failure of columns and of the BRBs. However, the BRB beam may fail due to flexure.

Modeling strength degradation of fiber-reinforced ceramic-matrix composites under cyclic loading at room and elevated temperatures

In this paper, the strength degradation of fiber-reinforced ceramic-matrix composites (CMCs) under cyclic loading at room and elevated temperatures has been investigated. The shear-lag model combined with the matrix statistical multiple cracking model, interface debonding criterion and fiber fracture model has been adopted to analyze the stress distributions in damaged CMCs, considering the damage mechanism of the interface wear. The relationships between the residual strength and peak stress, interface debonding, fiber failure and cycle number have been established. The effects of fatigue peak stress, initial and steady-state interface shear stress, fiber Weibull modulus and fiber strength on the degradation of residual strength and fibers failure have been investigated. The evolution of residual strength versus cycle number curves of fiber-reinforced CMCs under cyclic loading at room and elevated temperatures have been predicted.

Experimental study on behavior of mortar-aggregate interface after elevated temperatures

A push-out test program was designed and conducted to study the meso-scale behavior of mortar-aggregate interface for concrete after elevated temperatures ranging from 20°C to 600°C with the concept of modeled concrete (MC) and modeled recycled aggregate concrete (MRAC). The MCs and MRACs were designed with different strength grade of mortar and were exposed to different elevated temperatures. Following that the specimens were cooled to room temperature and push-out tests were conducted. Failure process and mechanical behaviors were analyzed based on failure modes, residual load-displacement curves, residual peak loads and peak displacements. It is found that failure modes significantly depended on specimen type, the elevated temperature and the strength grade of mortar. For MC, major cracks started to propagate along the initial cracks caused by elevated temperatures at about 80% of residual peak load. For MRAC, the cracks appeared at a lower level of load with the increasing elevated temperatures. The cracks connected with each other, formed a failure face and the specimens were split into several parts suddenly when reaching the residual peak load. Residual load-displacement curves of different specimens had similarities in shape. Besides, effect of temperatures and strength grade of mortar on residual peak load and peak displacement were analyzed. For MC and MRAC with higher strength of new hardened mortar, the residual peak load kept constant when the temperature is lower than 400°C and dropped by 43.5% on average at 600°C. For MRAC with lower strength of new hardened mortar, the residual peak load began to reduce when the temperatures exceeded 200°C and reduced by 27.4% and 60.8% respectively at 400°C and 600°C. The properties of recycled aggregate concrete (RAC) may be more sensitive to elevated temperatures than those of natural aggregate concrete (NAC) due to the fact that the interfacial properties of RAC are lower than those of NAC, and are deteriorated at lower temperatures.

The influence of radiation-induced defects on thermoluminescence and optically stimulated luminescence of α-Al2O3:C

It is known that when α-Al2O3:C is exposed to excessive amounts of ionising radiation, defects are induced within its matrix. We report the influence of radiation-induced defects on the thermoluminescence (TL) and optically stimulated luminescence (OSL) measured from α-Al2O3:C after irradiation to 1000Gy. These radiation-induced defects are thermally unstable in the region 450–650°C and result in TL peaks in this range when the TL is measured at 1°C/s. Heating a sample to 700°C obliterates the radiation-induced defects, that is, the TL peaks corresponding to the radiation induced defects are no longer observed in the subsequent TL measurements when moderate irradiation doses below 10Gy are used. The charge traps associated with these radiation-induced defects are more stable than the dosimetric trap when the sample is exposed to either sunlight or 470-nm blue light from LEDs. TL glow curves measured following the defect-inducing irradiation produce a dosimetric peak that is broader and positioned at a higher temperature than observed in glow curves obtained before the heavy irradiation. In addition, sample sensitization/desensitization occurs due to the presence of these radiation-induced defects. Furthermore, both the activation energy and the kinetic order of the dosimetric peak evaluated when the radiation-induced defects are present in the sample are significantly lower in value than those obtained when these defects are absent. The radiation-induced defects also affect the shape and total light sum of the OSL signal as well as the position and width of the resultant residual phototransferred thermoluminescence main peak.

Percutaneous balloon valvuloplasty with Inoue balloon catheter technique for pulmonary valve stenosis in adolescents and adults

BackgroundPercutaneous balloon pulmonary valvuloplasty is the procedure of choice for uncomplicated severe or symptomatic pulmonary stenosis. The present study describes our experience in balloon pulmonary valvuloplasty using the Inoue balloon catheter in adolescent and adult patients. AimsTo assess the immediate and mid-term outcomes of percutaneous balloon valvuloplasty with Inoue balloon catheter in adolescent and adult patients. Methods and resultsBetween June 2010 and July 2015, we performed percutaneous balloon pulmonary valvuloplasty with Inoue balloon catheter in 32 patients (59.37% females) aged 8 to 54 years (mean 23.6±11.5). Following the procedure, the mean right ventricular systolic pressure and the pulmonary valvular peak-to-peak systolic gradient decreased from (121.6±42.4 to 61.19±24.5mmHg, p=0.001) and (100.9±43.3 to 36.4±22.5mmHg, p=0.001), respectively. Twenty patients (Group A) showed immediate optimal results with post-procedure peak systolic gradient <36mmHg while 12 patients (Group B) had suboptimal results. An increase in pulmonary regurgitation by one grade was detected in 17 patients (53.2%). Twenty-three patients available for follow-up (mean duration, 2.75 years [range 0.25–5 years]) had a mean residual peak gradient of 23.6±2.51mmHg on Doppler echocardiography with attenuation of reactive RVOT stenosis in all Group B patients. There was no further increase in grade of pulmonary regurgitation or restenosis on mid-term follow-up. ConclusionPercutaneous Inoue balloon technique is an attractive alternative with excellent mid-term results for adolescents and adults with isolated pulmonary stenosis.

Residual compressive stress-strain relation of recycled aggregate concrete after exposure to high temperatures

The complete compressive stress-strain curve of recycled aggregate concrete (RC) after exposure to high temperatures improves to assess the post-fire behavior of reinforced RC structures. In this paper, 60 specimens containing different levels of recycled coarse aggregate (RCA; i.e., 0, 30, 50, 70 and 100%) were produced to study the residual compressive stress-strain relation of RC after exposure to high temperatures. Those specimens designed for thermal temperatures were initially heated to temperatures of 300, 400 and 500°C for 6 hr and then being submitted to test the compressive stress-strain curves after cooling to ambient temperature. The test results were compared with specimens tested at room temperature (about 20°C). The effect of RCA and high temperatures on residual compressive strength, peak strain and elastic modulus are discussed and the empirical formulas for these parameters are also established. The recommended equation for the compressive constitutive relation for conventional concrete in the Chinese code for the design of concrete structures (GB50010-2010) was adopted to fit the test data and was shown to be applicable to heated RC for different temperatures.

Empirical Formula of Shear Strength of Rock Fractures Based on 3D Morphology Parameters

The prime objective of this work is to provide a reference to predict the peak shear strength of rock fractures. The paper studied some shear properties of rock fractures and proposed an empirical formula for the peak shear strength of rock fractures based on 3D morphology parameters. The rock fractures were induced in cylindrical sandstone and marble specimens by means of indirect tension. A rock direct shear apparatus (RDS-200) was adopted to conduct direct shear tests on five groups of rock fractures under different levels of normal load. Before the direct shear test, 3D morphology parameters of rock fracture surfaces were obtained using a 3D optical scanner. By analyses of direct shear test data, the relationships between peak shear strength, peak shear displacement, peak dilatancy angle, residual friction coefficient and peak normal stress were found. According to the evolution trends of peak shear strength and peak dilatancy angle along with the normal stress, an empirical formula was proposed to predict the peak shear strength of rock fractures in both sliding and cutting failure modes considering the 3D morphology parameters of rock fracture surfaces. The empirical formula could be commonly used for different types (sandstone and marble) and grain sizes (powder-grained, fine-grained, medium-grained and coarse-grained) of rock fractures.

A Novel Beneficial Role for Macitentan in Patients at High Thrombosis Risk: Attenuation of Platelet-Mediated Derangements of Blood Coagulation in Eisenmenger Syndrome

IntroductionEisenmenger syndrome is a rare manifestation of congenital cardiac disease with pulmonary hypertension. Potentially dangerous thrombotic and haemorrhagic complications frequently occur in patients with ES and raise significant clinical dilemmas. Underlying mechanisms are unknown but are thought to be linked to the underlying pulmonary vascular disease. Endothelin-1 (ET-1) signalling in the pulmonary vasculature is implicated in the pathogenesis of ES and Macitentan (a novel dual ET-1 receptor antagonist) has been shown to improve clinical outcomes. However the effect of Macitentan on reversing abnormal blood coagulation is unknown.We aimed to characterise derangements in physiological procoagulant and anticoagulant pathways in ES and to assess the effect of Macitentan therapy in modulating haemostasis in this disorder. We hypothesized that an enhanced understanding of pro-and anticoagulant mechanisms in these patients has the potential to improve risk stratification and targeting of antithrombotic therapy to patients at high risk of thrombosis.MethodsBlood was collected from subjects with ES and age/gender-matched healthy controls into citrated tubes, some containing corn trypsin inhibitor (CTI, a contact pathway inhibitor; final concentration 50µg/mL).Parameters of plasma thrombin generation in platelet-rich and platelet-poor plasma were assessed by calibrated automated thrombography (CAT) in the presence or absence of exogenous tissue factor (TF), anionic phospholipid (PL) and activated protein C (APC).ResultsPlatelet-dependent blood coagulation measured by CAT was enhanced in ES platelet-rich plasma (PRP) relative to healthy volunteers despite lower platelet counts: peak thrombin generation (TG) was significantly higher in ES subjects v controls in PRP (230.6±10.9 vs 188.3±13.1 nM; p=0.025) and lagtime to TG (6.1±0.3 vs 7.8±0.5 mins, p=0.005), time to peak TG (11.5±0.5 vs 15.2±0.6 mins, p=0.0003) and TG velocity index (43.9±3.7 vs 26.3±2.4 nM/min, p=0.001) were significantly accelerated. No significant differences in TG parameters in PPP were observed between groups suggesting a critical mechanistic role for platelet activity in supporting hypercoagulability in ES. TG in PRP was also found to be significantly enhanced in ES in the presence of CTI, suggesting that in vitro or in vivocontact pathway activation does not contribute to the enhanced coagulation activation observed in this disorder.The anticoagulant activity of APC is PL dependent and in healthy PPP incubated with exogenous PL (as a substitute for platelet PL), TG was potently inhibited. Conversely, in healthy PRP (in the absence of exogenous PL), APC activity was attenuated. Remarkably, this effect was not observed among the ES subjects, where APC anticoagulant activity was significantly increased in PRP, with significantly lower residual peak plasma thrombin generation and endogenous thrombin potential relative to that observed in healthy volunteer PRP. APC anticoagulant activity in PPP (both in the presence and absence of exogenous PL) was similar between groups. These findings suggest that platelets also modulate the activity of the APC pathway in ES, but in a manner which could promote bleeding.Among the 7 subjects who commenced macitentan therapy, at 6 months peak TG in PRP was significantly lower (234.5±9.8 vs 204.6±14.1 nM, p=0.002) and the enhanced sensitivity to APC in PRP was also attenuated. No significant difference in any parameter of TG was observed in PPP following macitentan therapy.ConclusionPlatelet activity appears to contribute significantly to hypercoagulability in ES but also appears to modulate the activity of endogenous anticoagulant pathways reflecting the clinical phenotype where bleeding and thrombotic risks frequently co-exist. Our findings suggest that targeted pharmacological agents such as the dual endothelin-1 antagonists (which crucially do not confer a bleeding risk) may attenuate platelet-mediated derangements in blood coagulation. Given the significant clinical dilemmas posed by the presence of competing thrombotic and haemorrhagic tendencies in ES, these finding are likely to be of significant translational relevance. DisclosuresWalsh:Actelion UK: Research Funding. Maguire:Actelion UK: Research Funding. Ní Áinle:Actelion UK: Research Funding.