Thrombus Accumulation Research Articles

Safety and efficacy of aspiration thrombectomy with intracoronary tirofiban VS aspiration thrombectomy alone in patients undergoing primary PCI: a systematic review and meta-analysis

Abstract Background Primary percutaneous coronary intervention (PPCI) may be complicated by intracoronary thrombus accumulation in ST elevation myocardial infarction (STEMI) leading to decrease in myocardial perfusion and increase in infarct size. The utilization of aspiration thrombectomy and intracoronary tirofiban in STEMI patients undergoing PPCI hold clinical relevance by removal of thrombus burden, potentially reducing distal embolization and improving myocardial perfusion and by targeting platelet aggregation to mitigate thrombotic complications, respectively. Given the paramount importance of achieving rapid and effective reperfusion in STEMI, the evaluation of these interventions is warranted to assess overall impact on patient outcomes in terms of safety and efficacy. Purpose The current meta-analysis aims to investigate the clinical outcomes of aspiration thrombectomy (AT) with intracoronary tirofiban versus AT alone during PPCI. Methods A systematic search for randomized controlled trials that evaluate the safety and efficacy of aspiration thrombectomy with intracoronary tirofiban in STEMI patients who underwent PPCI was done using PubMed, MEDLINE, Embase, Cochrane, Clinicaltrials.gov. and Herdin PH. Studies included those between 2010 - 2023 and involved human subjects. Search terms included "Aspiration Thrombectomy", "Intracoronary Tirofiban", "Primary Percutaneous Coronary Intervention" and "STEMI patients". Results Four RCTs (n: 490 participants) were included in this meta-analysis comparing aspiration thrombectomy with intracoronary tirofiban versus aspiration thrombectomy alone in STEMI patients undergoing PPCI. The results revealed no statistically significant difference in ST segment resolution (RR 1.02, 95%, CI: 0.97 - 1.08, P = 0.41, I2 = 0%), myocardial blush grade 2-3, (risk ratio of 1.04, 95%, CI: 0.97 – 1.12, P = 0.22, I2 = 62%) and TIMI 3 flow (risk ratio of 1.0, 95% CI: 0.95 - 1.04, P = 0.87). The occurrence of major adverse cardiovascular events did not significantly differ between the two groups (RR 0.46, 95% CI: 0.19 – 1.09, P = 0.08, I2 = 0%). There was no statistically significant difference in terms of bleeding when combining intracoronary tirofiban to standard medical therapy (RR 1.35, 95% CI: 0.64 – 2.84, P= 0.78, 4 trials [490 patients]). Conclusion In primary percutaneous coronary intervention, MACE outcomes of aspiration thrombectomy with intracoronary tirofiban were similar to that for aspiration thrombectomy alone in terms of improving myocardial perfusion in STEMI patients without increasing the risk for bleeding. Our meta-analysis suggests that AT alone may be the more acceptable standard during PPCI when encountering heavy thrombus burden. Future validated studies may help further investigate the strategy of adding tirofiban during aspiration thrombectomy.1. Primary Outcomes2. Secondary Outcomes

Numerical analysis of blood flow in a branched modular stent-graft for aneurysms covering all zones of the aortic arch.

Due to the anatomical complexity of the aortic arch for the development of stent-grafts for total repair, this region remains without a validated and routinely used endovascular option. In this work, a modular stent-graft for aneurysms that covers all aortic arch zones, proposed by us and previously structurally evaluated, was evaluated from the point of view of haemodynamics using fluid-structural numerical simulations. Blood was assumed to be non-Newtonian shear-thinning using the Carreau model, and the arterial wall was assumed to be anisotropic hyperelastic using the Holzapfel model. Nitinol and expanded polytetrafluoroethylene (PTFE-e) were used as materials for the stents and the graft, respectively. Nitinol was modelled as a superelastic material with shape memory by the Auricchio model, and PTFE-e was modelled as an isotropic linear elastic material. To validate the numerical model, a silicone model representative of the aneurysmal aorta was subjected to tests on an experimental bench representative of the circulatory system. The numerical results showed that the stent-graft restored flow behaviour, making it less oscillatory, but increasing the strain rate, turbulence kinetic energy, and viscosity compared to the pathological case. Taking the mean of the entire cycle, the increase in turbulence kinetic energy was 198.82% in the brachiocephalic trunk, 144.63% in the left common carotid artery and 284.03% in the left subclavian artery after stent-graft implantation. Based on wall shear stress parameters, it was possible to identify that the internal branches of the stent-graft and the stent-graft fixation sites in the artery were the most favourable regions for the deposition and accumulation of thrombus. In these regions, the oscillating shear index reached the maximum value of 0.5 and the time-averaged wall shear stress was close to zero, which led the relative residence time to reach values above 15 Pa-1. The stent-graft was able to preserve flow in the supra-aortic branches.

ADAMTS13 or Caplacizumab Reduces the Accumulation of Neutrophil Extracellular Traps and Thrombus in Whole Blood of COVID-19 Patients under Flow.

Neutrophil NETosis and neutrophil extracellular traps (NETs) play a critical role in pathogenesis of coronavirus disease 2019 (COVID-19)-associated thrombosis. However, the extents and reserve of NETosis, and potential of thrombus formation under shear in whole blood of patients with COVID-19 are not fully elucidated. Neither has the role of recombinant ADAMTS13 or caplacizumab on the accumulation of NETs and thrombus in COVID-19 patients' whole blood under shear been investigated. Flow cytometry and microfluidic assay, as well as immunoassays, were employed for the study. We demonstrated that the percentage of H3Cit + MPO+ neutrophils, indicative of NETosis, was dramatically increased in patients with severe but not critical COVID-19 compared with that in asymptomatic or mild disease controls. Upon stimulation with poly [I:C], a double strain DNA mimicking viral infection, or bacterial shigatoxin-2, the percentage of H3Cit + MPO+ neutrophils was not significantly increased in the whole blood of severe and critical COVID-19 patients compared with that of asymptomatic controls, suggesting the reduction in NETosis reserve in these patients. Microfluidic assay demonstrated that the accumulation of NETs and thrombus was significantly enhanced in the whole blood of severe/critical COVID-19 patients compared with that of asymptomatic controls. Like DNase I, recombinant ADAMTS13 or caplacizumab dramatically reduced the NETs accumulation and thrombus formation under arterial shear. Significantly increased neutrophil NETosis, reduced NETosis reserve, and enhanced thrombus formation under arterial shear may play a crucial role in the pathogenesis of COVID-19-associated coagulopathy. Recombinant ADAMTS13 or caplacizumab may be explored for the treatment of COVID-19-associated thrombosis.

Ultrasound-powered hydrogen peroxide-responsive Janus micromotors for targeted thrombolysis and recurrence inhibition

Thrombosis seriously endangers human health with high incidence and mortality worldwide, and the clinical treatment is challenged by low bioavailability of thrombolytic agents, high bleeding risk and thrombosis relapse. Herein, ultrasound-powered Janus micromotors with stimuli-responsive multiple release capabilities are developed for efficient thrombolysis and inhibition of thrombosis recurrence. Resveratrol-loaded hyaluronic acid (HARes) nanoparticles (NPs) and urokinase plasminogen activator (uPA) were entrapped into H2O2-sensitive poly(1,4-cyclohexanedimethanol-co-oxalate) (POX) microparticles (MPs), followed by polydopamine capping and RGD grafting to obtain Janus rJPox@u-HARes MPs. After RGD-mediated delivery to the thrombus site, the peroxalate ester bonds of POX are oxidized by the elevated H2O2 to produce CO2, and the MP collapse accelerates the local release of uPA and HARes NPs. The resulting CO2 bubbles amplify the cavitation effect of ultrasound to promote thrombus penetration and site-specific uPA thrombolysis. The endothelial cell targeting and sustained resveratrol release from HARes NPs dramatically improve endothelial cell viability, nitric oxide production and migration. Compared with free drug administration, the uPA loading into MPs significantly extends the half-life (15 folds) and bioavailability (7 folds), while the resveratrol inoculation into NPs increases the bioavailability 29 times. On an acute lower limb thrombosis model, the thrombus accumulation of MPs is promoted by RGD-mediated interactions with the activated platelets and ultrasound-driven penetration into thrombi, leading to almost full removal of blood clots. The H2O2-scavenging capability of POX, sustained resveratrol release and efficient thrombolysis alleviate oxidative stresses, eliminate coagulation biomarkers and repair the damaged endothelial layer to effectively inhibit thrombosis relapse. It is demonstrated that rJPox@u-HARes/US treatment could not only achieve safe and site-specific thrombolytic therapy at the early stage but also restore vascular homeostasis to effectively prevent thrombosis recurrence.

Poor Diet Leading to the Increasing Risk of Atherosclerosis in the World

Atherosclerosis Ischemic Cardiovascular Disease (ASICD), one of the leading causes of global deaths, is mainly caused due to the development of plaque on the inner walls of arteries of the human heart. Ischemia refers to the lack of enough oxygen (O2), nutrient delivery, and improper waste removal in the cardiac cells. About 90% of cardiovascular diseases in the present world are due to the formation of lipid/cholesterol-based plaques that can form under the lining of the smooth epithelial blood cells. In the US, a study published in the Journal of the American College of Cardiology estimated that poor diet is responsible for about 45% of Cardiovascular Disease. Atherosclerosis doesn’t cause much effect until and unless the plaque becomes unstable due to the accumulation of thrombus that shows Acute Coronary Syndrome. Acute Coronary Syndrome is the result of blockage of blood vessels leading to Myocardial Infarction (Unstable Angina Pectoris). Cardiac Cells require a sufficient amount of Oxygen to function properly. Thus, the demand and supply of oxygen to the cardiac cells should be properly balanced. Atherosclerosis Ischemic Cardiovascular syndrome can worsen if the person is more involved in exercise or emotional stress because at that time their body requires higher oxygen but blood flow gets disrupted due to the formation of plague. Later in the paper, we will discuss the New York Heart Association classification, followed by the top 3 poor diets that are considered to be increasing the cases of cardiovascular disease around the world.

Near-infrared-II photoacoustic imaging and photo-triggered synergistic treatment of thrombosis via fibrin-specific homopolymer nanoparticles

The formation of an occlusive thrombus in the blood vessel is the main culprit for numerous life-threatening cardiovascular diseases that represent the leading cause of morbidity and mortality worldwide. Herein, we develop a polymer nanoplatform that integrates long-wavelength second near-infrared (NIR-II) photoacoustic imaging-based thrombosis detection and antithrombotic activity. We design and synthesize a semiconducting homopolymer with strong absorption in the NIR-II region and molecular motion that boosts photothermal conversion and photoacoustic signal. We dope the homopolymer with a thermosensitive nitric oxide donor to formulate a nanoplatform, on which a fibrin-specific ligand is functionalized to ensure selective thrombus targeting. We show that with strong NIR-II light harvesting capability, bright photoacoustic signal and active thrombus accumulation ability, the NIR-II photoacoustic nanoprobes are able to sensitively and selectively delineate thrombi. We find that the nanoplatform also displays rapid and efficient blood clot removal activity with nearly complete blood flow restoration in both carotid thrombosis models and low extremity arterial thrombosis models under NIR-II light trigger by integrating a thrombus-localized photothermal effect and on-demand nitric oxide release. This nanoplatform offers a versatile approach for the diagnosis and treatment of life-threatening diseases caused by various thrombotic disorders.

Deep Learning on Multiphysical Features and Hemodynamic Modeling for Abdominal Aortic Aneurysm Growth Prediction.

Prediction of abdominal aortic aneurysm (AAA) growth is of essential importance for the early treatment and surgical intervention of AAA. Capturing key features of vascular growth, such as blood flow and intraluminal thrombus (ILT) accumulation play a crucial role in uncovering the intricated mechanism of vascular adaptation, which can ultimately enhance AAA growth prediction capabilities. However, local correlations between hemodynamic metrics, biological and morphological characteristics, and AAA growth rates present high inter-patient variability that results in that the temporal-spatial biochemical and mechanical processes are still not fully understood. Hence, this study aims to integrate the physics-based knowledge with deep learning with a patch-based convolutional neural network (CNN) approach by incorporating important multiphysical features relating to its pathogenesis for validating its impact on AAA growth prediction. For this task, we observe that the unstructured multiphysical features cannot be directly employed in the kernel-based CNN. To tackle this issue, we propose a parameterization of features to leverage the spatio-temporal relations between multiphysical features. The proposed architecture was tested on different combinations of four features including radius, intraluminal thrombus thickness, time-average wall shear stress, and growth rate from 54 patients with 5-fold cross-validation with two metrics, a root mean squared error (RMSE) and relative error (RE). We conduct extensive experiments on AAA patients, the results show the effect of leveraging multiphysical features and demonstrate the superiority of the presented architecture to previous state-of-the-art methods in AAA growth prediction.

Association of vortical structures and hemodynamic parameters for regional thrombus accumulation in abdominal aortic aneurysms.

The intraluminal thrombus (ILT) has been shown to negatively impact the progression of the abdominal aortic aneurysms (AAAs). The formation of this thrombus layer has been connected to the local flow environment within AAAs, but the specific mechanisms leading to thrombus formation are still not fully understood. Our study investigated the association between vortical structures, near-wall hemodynamic metrics (e.g., time averaged wall shear stress (TAWSS) and oscillatory shear index (OSI)), and ILT accumulation in a longitudinal cohort of 14 AAAs (53 scans total). Vortices and hemodynamic parameters were estimated using hemodynamic simulations performed to each scan of each patient and compared to local 3D changes of ILT thickness between two consecutive scans (ΔILT). Results showed that vortices formed and remained strong and close to the lumen surface in AAAs without an ILT, while in AAAs with ILTs these detached from the lumen surface and dissipated nearby wall region where an increase in ILT thickness was observed. Although low TAWSS was observed in regions with and without ILT accumulation, an inverse correlation between and TAWSS was observed within the regions that experienced a thrombus growth. Our results support the idea that vortical structures might be playing a role modulating ILT accumulation into specific wall regions. Also, it submits the idea that the low TAWSS will be modulating the growth of thrombus within these preferred ILT accumulated regions.

A Phase 2 Trial of the Protein C Activator AB002 in End-Stage Renal Disease Patients on Chronic Hemodialysis

Background: During hemodialysis of patients with renal failure, thrombi that form within the dialyzer circuit cause blood entrapment, blood loss, reduced dialysis efficiency and may require dialyzer changeouts. Anticoagulation with heparin is effective in preventing clot formation within the circuit, but is contraindicated in a subset of end-stage renal disease (ESRD) patients on chronic hemodialysis due to bleeding risk or heparin intolerance. A safe, short-acting alternative to heparin is an unmet need for this patient population, and for others suffering from or at risk of thrombosis. AB002 is a first-in-class protein C activator thrombin analog that targets to the thrombus interface and generates endogenous activated protein C (APC) without cleaving prothrombotic substrates. In a preclinical baboon thrombosis model, AB002 rapidly interrupted thrombus development with no observable hemostasis impairment, and was similar in antithrombotic efficacy to high-dose enoxaparin while appearing superior to interventional tissue-plasminogen activator. This proof-of-concept phase 2 clinical trial was designed to evaluate the safety, tolerability, efficacy, and pharmacodynamics of AB002 as a heparin alternative for ESRD patients.Methods: In this phase 2, randomized, double-blind, placebo-controlled study, a single dose of AB002 (1.5 µg/kg or 3 µg/kg) or placebo was infused into the hemodialysis line over four hours in 36 ESRD patients undergoing heparin-free hemodialysis (NCT03963895). Patients underwent five sequential heparin-free hemodialysis sessions over a period of 10 days, with three occurring prior to dosing, one on the day of dosing, and one after dosing. A total of 179 hemodialysis sessions were evaluated. Safety parameters were recorded throughout the study and immunogenicity to AB002 or thrombin was monitored by validated assays. Clotting within the dialyzer circuit was visually assessed and the number of occlusive events requiring a changeout of the circuit recorded. Circulating plasma APC-protein C inhibitor complexes (APC-PCI) and thrombin-antithrombin (TAT) complexes, markers of drug exposure and thrombin generation, respectively, were quantified by ELISA. This study was approved by the local ethics review board and all patients provided informed consent.Results: AB002 demonstrated a favorable safety profile, with no treatment-related adverse events. Clinically relevant bleeding did not occur in any patient and the time to hemostasis at the vascular access site was not affected by AB002. There was no evidence of AB002-induced anti-drug or anti-thrombin antibodies at 14 days post-dose. The frequency of occlusive events requiring circuit changeouts was 13.9% (21/155) on days in which AB002 was not administered, compared to 0% (0/12) and 8.3% (1/12) at the 1.5 µg/kg and 3 µg/kg dose levels, respectively. Compared to placebo, the incidence of high-grade clotting in the hemodialyzer decreased by 49% and 62% at the 1.5 µg/kg and 3 µg/kg AB002 dose levels, respectively. Hemodialysis increased TAT levels measured at the end of hemodialysis approximately 12-fold over baseline in patients given placebo. By contrast, AB002 attenuated TAT generation to 4-fold and 2-fold over baseline at the 1.5 µg/kg and 3 µg/kg dose levels, respectively. Hemodialysis-induced TAT generation was not different across groups on non-dosing days. Drug exposure was confirmed by a transient, dose-dependent elevation of circulating APC-PCI complexes following AB002 administration.Conclusions: In ESRD patients undergoing heparin-free hemodialysis, AB002 was well-tolerated and reduced thrombus accumulation in the hemodialysis circuit without observable hemostasis impairment. The results of this study support further clinical evaluation of AB002 as a novel drug candidate to limit thrombus development or device-initiated clotting in patients with elevated bleeding risk, including ESRD patients on chronic heparin-free hemodialysis. DisclosuresVerbout: Aronora, Inc.: Current Employment. Lorentz: Aronora, Inc.: Current Employment. Markway: Aronora, Inc.: Current Employment. Wallisch: Aronora Inc,: Current Employment. Shatzel: Aronora Inc,: Consultancy. Gruber: Aronora Inc.: Current Employment, Current equity holder in publicly-traded company; Oregon Health and Science University: Current Employment.

Staphylococcus aureus accumulation at the tip of hemodialysis catheters with or without tip side holes in catheter related bloodstream infection in a large animal.

Eighty percent of hemodialysis patients start their dialysis with a tunneled hemodialysis catheter. Catheter related bacteremia is the second most common cause of death in these patients. Side holes near the tips of the tunneled cuffed central venous catheters are associated with accumulation of thrombus, which can lead to catheter dysfunction and, possibly, also to catheter-related infection. To assess the hypothesis that a catheter without side holes would be associated with less bacterial growth, this study compared the susceptibility of a side-hole-free catheter to accumulation of pathogenic bacteria at the catheter tip with that of two catheters which have side holes. Eight tunneled cuffed double-lumen central venous catheters were inserted into both jugular veins of four sheep; one side-hole-free and one control catheter with side holes at the tip in each animal. Staphylococcus aureus bacteria were then infused intravenously to cause bacteremia. Six hours later, the catheters were removed, the clots that accumulated in their tips were collected and cultured, and the bacterial colonies were counted after additional 12 h of incubation. Bacteria grew on culture plates seeded with the clot homogenate obtained from the tips of all catheters. The colony counts from the catheters with side holes at the tip exceeded the colony counts of bacteria accumulated in the tips of the side-hole-free hemodialysis catheters by one or more orders of magnitude, with a difference of at least two orders of magnitude observed in three of the four intra-animal comparisons. In paired intra-animal post-inoculation comparison made in this limited study, fewer colony forming units of pathogenic bacteria accumulated at the tip of the side-hole-free catheters than at the tips of the catheters which have side holes. This may translate to a decreased rate of catheter-related blood stream infections in the side-hole-free catheters.

Defining a master curve of abdominal aortic aneurysm growth and its potential utility of clinical management

ObjectiveThe maximum diameter measurement of an abdominal aortic aneurysm (AAA), which depends on orthogonal and axial cross-sections or maximally inscribed spheres within the AAA, plays a significant role in the clinical decision making process. This study aims to build a total of 21 morphological parameters from longitudinal CT scans and analyze their correlations. Furthermore, this work explores the existence of a “master curve” of AAA growth, and tests which parameters serve to enhance its predictability for clinical use. Methods106 CT scan images from 25 Korean AAA patients were retrospectively obtained. We subsequently computed morphological parameters, growth rates, and pair-wise correlations, and attempted to enhance the predictability of the growth for high-risk aneurysms using non-linear curve fitting and least-square minimization. ResultsAn exponential AAA growth model was fitted to the maximum spherical diameter, as the best representative of the growth among all parameters (r-square: 0.94) and correctly predicted to 15 of 16 validation scans based on a 95% confidence interval. AAA volume expansion rates were highly correlated (r=0.75) with thrombus accumulation rates. ConclusionsThe exponential growth model using spherical diameter provides useful information about progression of aneurysm size and enables AAA growth rate extrapolation during a given surveillance period.

Preclinical safety and efficacy evaluation of the Pipeline Vantage Embolization Device with Shield Technology

BackgroundThe Pipeline Vantage Embolization Device with Shield Technology is a next generation flow diverter developed to improve aneurysm occlusion and implant endothelialization in addition to lowering thrombogenicity. We report here...

Safety and Antithrombotic Efficacy of the Recombinant Protein C Activator AB002 (E-WE Thrombin) in End Stage Renal Disease Patients on Chronic Hemodialysis

AB002 is a recombinant thrombin analog that generates endogenous activated protein C (APC) on intravascular surfaces in a thrombomodulin-dependent manner but does not promote thrombosis. Endogenously generated APC downregulates thrombin generation, thereby reducing pathological clot formation. During hemodialysis (HD), thrombi can form within the dialyzer filter and circuit, reducing dialyzer efficiency, and increasing blood loss. Heparin administration reduces clotting within the filter and circuit, but increases bleeding risk and is not tolerated in all patients. Since end-stage renal disease (ESRD) patients undergoing HD are at higher risk of both thromboembolism and bleeding, a safe, short-term and self-limiting anticoagulant alternative to heparin is currently an unmet need for this population. This is a phase 2, randomized, double-blind, placebo-controlled, single-dose study designed to evaluate the safety and efficacy of AB002 at two dose levels when administered to ESRD patients during heparin-free HD. A total of 36 adult patients are planned to be enrolled into two cohorts and dosed sequentially. Within each cohort, patients will be randomized to active drug (12) or placebo (6). Dose levels (1.5 µg/kg or 3 µg/kg; iv infusion) were based on safety data from a completed phase 1 study performed in healthy adult subjects (NCT03453060), which demonstrated that a single dose of AB002 was well tolerated, as well as based on preclinical efficacy studies performed in a baboon vascular thrombosis model. The primary objective of this phase 2 proof-of-concept study is safety and tolerability assessed as the number and severity of adverse events (AE), changes in baseline physical and lab parameters and immunogenicity of AB002. The number and severity of AE will be tabulated and summary statistics evaluated. The secondary objectives are to assess 1) pharmacodynamics using activated protein C/protein C inhibitor complexes in plasma as a surrogate marker for drug exposure, and 2) efficacy via pre-post dialyzer pressures, visual inspection of thrombus accumulation in the HD filter and dialysis efficiency based on urea kinetics. The study population includes ESRD patients on a stable outpatient HD regimen at least 3 times per week and excludes patients with history of acute vaso-occlusive thrombotic events, concomitant use of anticoagulant/antiplatelet agents immediately prior to and during the study, active cancer and bleeding disorders. This study is currently recruiting participants at one study site (Orlando Clinical Research Center) in Orlando, FL and is estimated to complete in October 2020 (NCT03963895). Disclosures Verbout: Aronora, Inc.: Employment, Equity Ownership. Lorentz:Aronora, Inc.: Employment. Markway:Aronora, Inc.: Employment. Shatzel:Aronora, Inc.: Consultancy. Tucker:Aronora, Inc.: Employment, Equity Ownership. Gruber:Aronora, Inc.: Employment, Equity Ownership.

Abstract No. 588 A thromboresistant hydrogel material for vascular access

The peripherally inserted central catheter (PICC) has become increasingly popular over recent years as an alternative for venous access over traditional central venous lines. However, PICCs are more than twice as likely to experience catheter-related thrombus leading to dysfunction, infection, loss of central venous flow, or upper extremity deep vein thrombosis. Access Vascular, Inc.’s HydroPICC™ device is constructed of a proprietary combination of biocompatible polymers to create a high-strength thromboresistant hydrogel. Quantification of the thromboresistance of the HydroPICC material was evaluated in this work using established in vitro and in vivo models. Thrombus accumulation and platelet adhesion were assessed by Thrombodyne, Inc., using an in vitro blood flow loop model against two competitors (Bard PowerPICC & Navilyst BioFlo). In vivo assessment of the HydroPICC device thrombogenicity was evaluated in an ovine jugular model. The HydroPICC and BioFlo devices were found to exhibit a statistically significant reduction of thrombus formation compared to PowerPICC based on a paired, two-sided t-test (p-values of 0.017 and 0.035, respectively). The HydroPICC device was also found to exhibit a statistically significant decrease in thrombus accumulation when compared to BioFlo (p-value of 0.033). Six of the seven HydroPICC devices implanted in the ovine jugular model exhibited a sheath extending no more than 10-15% of the total length of the catheter after 14- and 28-days in vivo. This sheath was observed to be non-adherent and slid off with minimal force during explantation. The main bodies of all the implanted HydroPICC devices showed no signs of thrombosis and were functional at term. On average, the HydroPICC device exhibited a 97% reduction in thrombus accumulation as compared to a conventional TPU catheter (PowerPICC), and a 64% reduction in thrombus accumulation as compared to a fluoro-oligomer modified TPU catheter (BioFlo) based on an in vitro blood loop model. HydroPICC devices implanted for 28-days in an ovine jugular model were found to exhibit no significant thrombus formation.

Thrombogenicity assessment of Pipeline, Pipeline Shield, Derivo and P64 flow diverters in an in vitro pulsatile flow human blood loop model.

Flow diversion is a disruptive technology for the treatment of intracranial aneurysms. However, these intraluminal devices pose a risk for thromboembolic complications despite dual antiplatelet therapy. We report the thrombogenic potential of the following flow diversion devices measured experimentally in a novel human blood in-vitro pulsatile flow loop model: Pipeline™ Flex Embolization Device (Pipeline), Pipeline™ Flex Embolization Device with Shield Technology™ (Pipeline Shield), Derivo Embolization Device (Derivo), and P64 Flow Modulation Device (P64). Thrombin generation (Mean ± SD; μg/mL) was measured as: Derivo (28 ± 11), P64 (21 ± 4.5), Pipeline (21 ± 6.2), Pipeline Shield (0.6 ± 0.1) and Negative Control (1.5 ± 1.1). Platelet activation (IU/μL) was measured as: Derivo (4.9 ± 0.7), P64 (5.2 ± 0.7), Pipeline (5.5 ± 0.4), Pipeline Shield (0.3 ± 0.1), and Negative Control (0.9 ± 0.7). We found that Pipeline Shield had significantly lower platelet activation and thrombin generation than the other devices tested (p < .05) and this was comparable to the Negative Control (no device, p > .05). High resolution scanning electron microscopy performed on the intraluminal and cross-sectional surfaces of each device showed the lowest accumulation of platelets and fibrin on Pipeline Shield relative to Derivo, P64, and Pipeline. Derivo and P64 also had higher thrombus accumulation at the flared ends. Pipeline device with Phosphorylcholine surface treatment (Pipeline Shield) could mitigate device material related thromboembolic complications.

Diagnosis of LVAD Thrombus using a High-Avidity Fibrin-Specific 99mTc Probe.

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 99mTc chelating amino acid sequence (F1A) was developed and compared to its tetrameric PEG analogue (F4A).Results: 99mTc attenuation by LVAD titanium (1 mm) was 23%. 99mTc-F1A affinity to fibrin was Kd ~10 µM, whereas, the bound 99mTc-F4A probe was not displaced by F1A (120,000:1). Human plasma interfered with 99mTc-F1A binding to fibrin clot (p<0.05) in vitro, whereas, 99mTc-F4A targeting was unaffected. The pharmacokinetic half-life of 99mTc-F4A was 28% faster (124±41 min) than 99mTc-F1A (176±26 min) with both being bioeliminated through the urinary system with negligible liver or spleen biodistribution. In mice with carotid thrombus, 99mTc-F4A binding to the injured carotid was much greater (16.3±3.3 %ID/g, p=0.01) than that measured with an irrelevant negative control, 99mTc-I4A (3.4±1.6 %ID/g). In an LVAD mock flow-loop (1:1, PBS:human plasma:heparin) operating at maximal flow rate, 99mTc-F4A bound well to phantom clots in 2 min (p<0.05), whereas 99mTc-F1A had negligible targeting. Excised LVADs from patients undergoing pump exchange or heart transplant were rewired, studied in the mock flow loop, and found to have spatially variable fibrin accumulations in the inlet and outlet cannulas and bearings.Conclusions: 99mTc-F4A is a high-avidity prototype probe for characterizing thrombus in LVADs that is anticipated to help optimize anticoagulation, reduce thromboembolic events, and minimize pump exchange.

Elongated Plant Virus-Based Nanoparticles for Enhanced Delivery of Thrombolytic Therapies.

Thrombotic cardiovascular disease, including acute myocardial infarction, ischemic stroke, and venous thromboembolic disease, is the leading cause of morbidity and mortality worldwide. While reperfusion therapy with thrombolytic agents reduces mortality from acute myocardial infarction and disability from stroke, thrombolysis is generally less effective than mechanical reperfusion and is associated with fatal intracerebral hemorrhage in up to 2-5% of patients. To address these limitations, we propose the tobacco mosaic virus (TMV)-based platform technology for targeted delivery of thrombolytic therapies. TMV is a plant virus-based nanoparticle with a high aspect ratio shape measuring 300 × 18 nm. These soft matter nanorods have favorable flow and margination properties allowing the targeting of the diseased vessel wall. We have previously shown that TMV homes to thrombi in a photochemical mouse model of arterial thrombosis. Here we report the synthesis of TMV conjugates loaded with streptokinase (STK). Various TMV-STK formulations were produced through bioconjugation of STK to TMV via intervening PEG linkers. TMV-STK was characterized using SDS-PAGE and Western blot, transmission electron microscopy, cryo-electron microscopy, and cryo-electron tomography. We investigated the thrombolytic activity of TMV-STK in vitro using static phantom clots, and in a physiologically relevant hydrodynamic model of shear-induced thrombosis. Our findings demonstrate that conjugation of STK to the TMV surface does not compromise the activity of STK. Moreover, the nanoparticle conjugate significantly enhances thrombolysis under flow conditions, which can likely be attributed to TMV's shape-mediated flow properties resulting in enhanced thrombus accumulation and dissolution. Together, these data suggest TMV to be a promising platform for the delivery of thrombolytics to enhance clot localization and potentially minimize bleeding risk.

New Treatment for Vascular Thrombosis Prevention in Patients With Atrial Fibrillation: Left Atrial Appendage Occlusion

Atrial fibrillation (AF) is a common type of arrhythmia that increases significantly the risk of blood clots in the heart and of stroke. Therefore, stroke prevention is a key goal of AF treatment. In the past, patients were required to take anticoagulants for the remainder of their life, to regularly the monitor international normalized ratio (INR) of prothrombin time (PT), and to avoid possible negative interactions with various drugs and foods. Left atrial appendage occlusion (LAAO), a novel device and technique, was thus developed for AF patients with contraindications to anticoagulants and a high risk of bleeding. When using this technique, the occluder is placed on the left atrial appendage in order to effectively prevent blood stasis and thrombi accumulation. Transesophageal echocardiogram and computed tomography are conducted prior to the LAAO procedure, which is similar to the procedure used for cardiac catheterization. After the LAAO procedure, the patient remains in the intensive care unit (ICU), where vital signs, bleeding at the puncture site, and pericardial tamponade complications are monitored. Health education on daily activities, anticoagulant use, and regular follow-up should be given prior to hospital discharge. While LAAO may not reduce the incidence of stroke, the benefits of this procedure include a significant reduction in bleeding complications as compared to procedures that use oral anticoagulants. Further studies including long-term follow up and in-depth examinations of this procedure are necessary. The present article offers a reference for clinical staffs who are responsible for the care of patients treated using the LAAO procedure.

High fidelity computational simulation of thrombus formation in Thoratec HeartMate II continuous flow ventricular assist device.

Continuous flow ventricular assist devices (cfVADs) provide a life-saving therapy for severe heart failure. However, in recent years, the incidence of device-related thrombosis (resulting in stroke, device-exchange surgery or premature death) has been increasing dramatically, which has alarmed both the medical community and the FDA. The objective of this study was to gain improved understanding of the initiation and progression of thrombosis in one of the most commonly used cfVADs, the Thoratec HeartMate II. A computational fluid dynamics simulation (CFD) was performed using our recently updated mathematical model of thrombosis. The patterns of deposition predicted by simulation agreed well with clinical observations. Furthermore, thrombus accumulation was found to increase with decreased flow rate, and can be completely suppressed by the application of anticoagulants and/or improvement of surface chemistry. To our knowledge, this is the first simulation to explicitly model the processes of platelet deposition and thrombus growth in a continuous flow blood pump and thereby replicate patterns of deposition observed clinically. The use of this simulation tool over a range of hemodynamic, hematological, and anticoagulation conditions could assist physicians to personalize clinical management to mitigate the risk of thrombosis. It may also contribute to the design of future VADs that are less thrombogenic.

Trombo intraprotésico após tratamento endovascular de aneurismas da aorta

Intraprosthetic thrombus accumulation is a common event following EVAR. However, its’ natural course and clinical impact have remained controversial. Consequently, optimal treatment is yet to be established. This article provides a review of the literature which focuses highlighting the available evidence regarding the pathophysiology, clinical significance and therapeutic approach of this entity.