Efficiency Of Thrombolysis Research Articles

Improving thrombolysis efficiency for acute ischaemic stroke

Improving thrombolysis efficiency for acute ischaemic stroke

Beyond silence: evolving ultrasound strategies in the battle against cardiovascular thrombotic challenges.

Cardiovascular thrombotic events have long been a perplexing factor in clinical settings, influencing patient prognoses significantly. Ultrasound-mediated acoustic therapy, an innovative thrombolytic treatment method known for its high efficiency, non-invasiveness, safety, and convenience, has demonstrated promising potential for clinical applications and has gradually become a focal point in cardiovascular thrombotic disease research. The current challenge lies in the technical complexities of preparing ultrasound-responsive carriers with thrombus-targeting capabilities and high thrombolytic efficiency. Additionally, optimizing the corresponding acoustic treatment mode is crucial to markedly enhance the thrombolytic effectiveness of ultrasound-mediated acoustic therapy. In light of the current status, this article provides a comprehensive review of the research progress in innovative ultrasound-mediated acoustic therapy for cardiovascular thrombotic diseases. It explores the impact of technical methods, therapeutic mechanisms, and influencing factors on the thrombolytic efficiency and clinical potential of ultrasound-mediated acoustic therapy. The review places particular emphasis on identifying solutions and key considerations in addressing the challenges associated with this cutting-edge therapeutic approach.

Engineered Microrobots for Targeted Delivery of Bacterial Outer Membrane Vesicles (OMV) in Thrombus Therapy.

In the realm of thrombosis treatment, bioengineered outer membrane vesicles (OMVs) offer a novel and promising approach, as they have rich content of bacterial-derived components. This study centers on OMVs derived from Escherichia coli BL21 cells, innovatively engineered to encapsulate the staphylokinase-hirudin fusion protein (SFH). SFH synergizes the properties of staphylokinase (SAK) and hirudin (HV) to enhance thrombolytic efficiency while reducing the risks associated with re-embolization and bleeding. Building on this foundation, this study introduces two cutting-edge microrobotic platforms: SFH-OMV@H for venous thromboembolism (VTE) treatment, and SFH-OMV@MΦ, designed specifically for cerebral venous sinus thrombosis (CVST) therapy. These platforms have demonstrated significant efficacy in dissolving thrombi, with SFH-OMV@H showcasing precise vascular navigation and SFH-OMV@MΦ effectively targeting cerebral thrombi. The study shows that the integration of these bioengineered OMVs and microrobotic systems marks a significant advancement in thrombosis treatment, underlining their potential to revolutionize personalized medical approaches to complex health conditions.

Advances in Nano-Functional Materials in Targeted Thrombolytic Drug Delivery.

Thrombotic disease has been listed as the third most fatal vascular disease in the world. After decades of development, clinical thrombolytic drugs still cannot avoid the occurrence of adverse reactions such as bleeding. A number of studies have shown that the application of various nano-functional materials in thrombus-targeted drug delivery, combined with external stimuli, such as magnetic, near-infrared light, ultrasound, etc., enrich the drugs in the thrombus site and use the properties of nano-functional materials for collaborative thrombolysis, which can effectively reduce adverse reactions such as bleeding and improve thrombolysis efficiency. In this paper, the research progress of organic nanomaterials, inorganic nanomaterials, and biomimetic nanomaterials for drug delivery is briefly reviewed.

Abstract 148: Loss Of Tlr4 Signaling Inhibits Thrombus Resolution In A Non-monocyte Dependent Manner

Background: Loss of TLR4 signaling reduces Venous Thrombosis (VT) resolution. Leukocyte expression of TLR4 is elevated in humans undergoing acute to chronic DVT transformation. We hypothesized that TLR4 signaling in monocytes directs thrombus clearance. Methods: Wild type, Tlr4 -/- , LysM cre+/- Tlr4 fl/fl mice underwent VT via IVC stasis at 4/7/14d timepoints. Thrombi subtypes were identified by flow cytometry. Thrombus size was assessed, and fibrinolytic mediators were assayed in splenic/bone marrow Mφs. Whole blood from mice was stimulated with TLR2/4 and assayed for thrombolytic potential via HALO assay. Immunohistochemistry was performed for cellular infiltrate. Results: We observed elevated TLR4 cell surface expression on CD11b+/Ly6C- Mo/Mφ from wild type thrombi. Thrombus weight in Tlr4 -/ mice was elevated at 4d stasis, confirming impaired thrombus clearance. In basal conditions, circulating Mo/Mφ saw decreased Urokinase & MMP9 mRNA levels in LysM cre+/- mice. In post thrombotic conditions, we saw decreased protein levels of Urokinase and MMP9 in Cre+ bone marrow-derived Mφs. Whole blood thrombolysis efficiency increased with TLR4 agonism in Cre- mice compared to Cre+. Efficiency was restored with LPS-mediated dual TLR2/4 agonism. Total thrombus weight was unchanged. No difference was identified in monocyte infiltrate into the thrombus (Fig. 1) Conclusions: Genetic deficiency of Mo/Mφ TLR4 signaling alters induction of fibrinolytic/matrix remodeling gene expression. Ex vivo TLR4 agonism increased whole blood thrombolysis in Cre- but not Cre+ mice. Additional TLR2 agonism of Cre+ mice restored thrombolytic activity, suggesting TLR2 as a compensatory pathway that may account for the unchanged in vivo phenotype in LysMcreTlr4fl/fl mice. Further clarifying these cellular pathways may provide an alternate pathway to target VT resolution.

Targeting Nanomotor with Near-Infrared/Ultrasound Triggered-Transformation for Polystage-Propelled Cascade Thrombolysis and Multimodal Imaging Diagnosis.

Nowadays, cardiovascular and cerebrovascular diseases caused by venous thromboembolism become main causes of mortality around the world. The current thrombolytic strategies in clinics are confined primarily due to poor penetration of nanoplatforms, limited thrombolytic efficiency, and extremely-low imaging accuracy. Herein, a novel nanomotor (NM) is engineered by combining iron oxide/perfluorohexane (PFH)/urokinase (UK) into liposome nanovesicle, which exhibits near-infrared/ultrasound (NIR/US) triggered transformation, achieves non-invasive vein thrombolysis, and realizes multimodal imaging diagnosis altogether. Interestingly, a three-step propelled cascade thrombolytic therapy is revealed from such intelligent NM. First, the NM is effectively herded at the thrombus site under guidance of a magnetic field. Afterwards, stimulations of NIR/US propel phase transition of PFH, which intensifies penetration of the NM toward deep thrombus dependent on cavitation effect. Ultimately, UK is released from the collapsed NM and achieves pharmaceutical thrombolysis in a synergistic way. After an intravenous injection of NM invivo, the whole thrombolytic process is monitored in real-time through multimodal photoacoustic, ultrasonic, and color Doppler ultrasonic imagings. Overall, such advanced nanoplatform provides a brand-new strategy for time-critical vein thrombolytic therapy through efficient thrombolysis and multimodal imaging diagnosis.

Peptide‐Enabled Thrombus‐Targeting Nanoparticles for Highly Effective Targeted CT Imaging and Eradication of Thrombi

AbstractThrombotic disease poses a significant threat to human health as it blocks blood vessels and leads to severe symptoms. Effective treatment requires targeted therapy and precise localization of the thrombus, but traditional drugs are limited in their targeting ability and ability to locate the thrombus. To overcome these issues, a nanoparticle capable of both thrombus targeting and computed tomography (CT) imaging is developed. Phage display technology is used to screen for the thrombus‐targeting peptide termed GK, which is then linked to the surface of macroporous silica (Mp‐SiO2) with a Bi core to create Mp‐Bi@SiO2‐GK. The large pores of Mp‐Bi@SiO2‐GK enable the transport of the drug Urokinase (UK), while the Bi core provides the capabilities of CT imaging and photothermal therapy. The Mp‐Bi@SiO2‐GK nanoparticles precisely target thrombi in mouse carotid arteries and locate them via CT imaging. Furthermore, the combination of Bi‐enabled photothermal therapy and UK‐induced chemotherapy enhance the thrombolysis efficiency. Treatment with Mp‐Bi@SiO2‐GK nanoparticles do not harm tissues/organs or affect liver/kidney metabolism. These results show that Mp‐Bi@SiO2‐GK exhibits precise thrombus targeting and efficient imaging/treatment capability, making it a promising tool for the diagnosis and treatment of thrombosis.

Factors Affecting Efficiency of Thrombolysis Using Magnetically Controlled Fe3O4 Nanoparticles

Factors Affecting Efficiency of Thrombolysis Using Magnetically Controlled Fe3O4 Nanoparticles

USE OF SURGICAL METHODS OF TREATMENT FOR THROMBOSIS OF THE INFERIOR VENA CAVA SYSTEM

Objective. Develop surgical tactics in the treatment of acute deep venous thrombosis (DVT) of the inferior vena cava system.Materials and methods. We analyzed the results of the surgical treatment of 181 patients with DVT for the period from 2001 to 2014. Among the patients with DVT in our study, 37 (20.4%) patients had thrombosis of the inferior vena cava (IVC). Separately, we selected a group of 44 patients with floating DVT. During the treatment, catheter-directed thrombolysis (CDT) was used in 60 (33.1%) patients, systemic thrombolysis in 30 (16.5%), thrombectomy was performed in 44 (24.3%) patients, and anticoagulants were used in 47 (25.9%) patients. Catheter-directed thrombolysis was performed according to the developed method in 30 patients. Results. In the general assessment of the efficiency of the methods, we found that the efficiency of the patented method is 20.5% greater than the efficiency of thrombolysis in the back vein of the foot and 39% greater than the efficiency of systemic thrombolysis (p<0.001). In our study, out of 60 cases of CDT, hemorrhagic complications occurred in 2 (3.3%) cases. In the treatment of patients with floating DVT, we used active surgical tactics when the length of the floating part was more than 4 cm. In the treatment of occlusive thrombosis of the IVC, catheter-directed thrombolysis was used in 9 patients, systemic thrombolysis in 4 patients, and thrombolysis for pulmonary embolism (PE) in 1 patient. 1 patient with thrombosis of the vena cava inferior died of massive PE during anticoagulant therapy. The use of combined methods of DVT treatment of the IVC system made it possible to obtain good and satisfactory results in the immediate period in 166 (92%) patients and in the long-term period in 90 (49.7%) patients.Conclusions. Treatment tactics for thrombosis of IVC system requires an individual approach in each specific case, taking into account the etiological factors of the disease, anatomical features of the structure of IVC system, terms from the onset of the disease, the risk of pulmonary embolism (PE), the presence of concomitant pathology.

Effect of the timing of iliac vein stent implantation on catheter-directed thrombolysis in acute lower extremity deep venous thrombosis patients with severe iliac vein stenosis: a retrospective study.

To investigate the effect of the timing of iliac vein stent implantation on catheter-directed thrombolysis (CDT) in acute lower extremity deep venous thrombosis (DVT) patients with severe iliac vein stenosis. The clinical data of 66 patients with acute lower extremity DVT complicated with severe iliac vein stenosis from May 2017 to May 2020 were retrospectively analyzed. Patients were divided into two groups by timing of iliac vein stent implantation: group A (iliac vein stent implantation before CDT treatment) for 34 and group B (iliac vein stent implantation after CDT treatment) for 32. The detumescence rate of affected limb, the thrombus clearance rate, the thrombolytic efficiency, the complication rate, the hospitalization cost, the stent patency rate within 1year, and the scores (venous clinical severity score, Villalta, and chronic venous insufficiency questionnaire (CIVIQ) score) at 1year postoperatively were compared between the two groups. The thrombolytic efficiency of group A was higher than that of group B, while the incidence of complications and hospitalization expenses in group A were lower than those in group B. There was no statistical significance in the detumescence rate of affected limb, the thrombus clearance rate, the stent patency rate within 1year, and the scores (VCSS, Villalta, and CIVIQ score) at 1year postoperatively between the two groups. For acute lower extremity DVT patients with severe iliac vein stenosis, iliac vein stent implantation before CDT treatment can improve the thrombolytic efficiency, and reduce the incidence of complications and hospitalization costs.

A new machine learning algorithm with high interpretability for improving the safety and efficiency of thrombolysis for stroke patients: A hospital-based pilot study.

Thrombolysis is the first-line treatment for patients with acute ischemic stroke. Previous studies leveraged machine learning to assist neurologists in selecting patients who could benefit the most from thrombolysis. However, when designing the algorithm, most of the previous algorithms traded interpretability for predictive power, making the algorithms hard to be trusted by neurologists and be used in real clinical practice. Our proposed algorithm is an advanced version of classical k-nearest neighbors classification algorithm (KNN). We achieved high interpretability by changing the isotropy in feature space of classical KNN. We leveraged a cohort of patients to prove that our algorithm maintains the interpretability of previous models while in the meantime improving the predictive power when compared with the existing algorithms. The predictive powers of models were assessed by area under the receiver operating characteristic curve (AUC). In terms of interpretability, only onset time, diabetes, and baseline National Institutes of Health Stroke Scale (NIHSS) were statistically significant and their contributions to the final prediction were forced to be proportional to their feature importance values by the rescaling formula we defined. In terms of predictive power, our advanced KNN (AUC 0.88) outperformed the classical KNN (AUC 0.75, ). Our preliminary results show that the advanced KNN achieved high AUC and identified consistent significant clinical features as previous clinical trials/observational studies did. This model shows the potential to assist in thrombolysis patient selection for improving the successful rate of thrombolysis.

Platelet Membrane Cloaked Nanotubes to Accelerate Thrombolysis by Thrombus Clot‐Targeting and Penetration (Small 4/2023)

Platelet Membrane Cloaked Nanotubes In article number 2205260, Fazheng Ren, Yuan Li, and co-workers developed nature-inspired platelet membrane-cloaked nanotubes conjugated with targeting arginine glycine-aspartic peptide and thrombolytic agent urokinase to achieve clot-targeting and penetrating. This biomimetic carrier showed a promising effect in improving the thrombolytic efficiency in vitro and in vivo.

Nanodroplet-Coated Microbubbles Used in Sonothrombolysis with Two-Step Cavitation Strategy.

Thrombosis is a major cause of morbidity and mortality and sonothrombolysis is a promising method for its treatment. However, the slow diffusion of the thrombolytic agents into the thrombus results in slow recanalization. Here, nanodroplet-coated microbubbles (NCMBs) are designed and fabricated and a two-step cavitation strategy is used to accelerate the thrombolysis. The first cavitation of the NCMBs, cavitation and collapse of the microbubbles induced by low frequency ultrasound, drives the nanodroplets on the shell into the thrombus, while the second cavitation, the phase-change and volume expansion of drug-loaded nanodroplets triggered by high frequency ultrasound, loosens the thrombus by the sono-porosity effect. This two-step cavitation of the NCMBs is verified using a fibrin agarose model, where a rapid diffusion of the thrombolytic agents is observed. Furthermore, the NCMBs reach much higher thrombolysis efficiency in both in vitro and proof-of-concept experiments performed with living mice. The nanodroplet-coated microbubbles are a promising diffusion medicines carrier for efficient drug delivery.

Modeling the outcomes of thrombolytic therapy in ischemic stroke

Aim to predict the effectiveness of systemic thrombolysis based on a comprehensive assessment of risk factors at the stage of decision making for thrombolytic therapy.
 Material and methods. The study included 110 ischemic stroke patients hospitalized between 2016 and 2021 who received the rt-PA systemic thrombolytic therapy. Depending on the outcome of the disease, all patients were ranked into two groups. Group I (favorable outcome) included 79 patients who had regression of focal neurological deficit, assessed using the NIHSS, mRS, Rivermead scales. Group II (unfavorable outcome) included 31 patient, among whom 4 patients had a worsening condition, expressed as an increase in focal neurological deficit, assessed using the NIHSS scale, as well as 27 patients who developed a lethal outcome.
 Results. The following factors were revealed having the greatest impact on the outcome of the thrombolytic therapy: the age of patients, the time passed from the development of stroke symptoms to systemic thrombolysis, the severity of neurological deficit, the ASPECTS score at admission, the blood glucose level at admission. In order to group the array of processed clinical, laboratory and neuroimaging data, we used a two-stage cluster analysis. Four clusters were formed in the process of cluster analysis. A mathematical model was developed in order to improve the efficiency of systemic thrombolysis and to predict the outcome of the disease in patients with ischemic stroke, which was tested on the basis of the neurological department of the Regional Clinical Hospital named after V.D. Seredavin.
 Conclusion. The application of this mathematical model based on medical information systems will make it possible to stratify the risk of disease outcome in patients with ischemic stroke timely and effectively at the stage of the emergency department in the vascular centers and primary vascular departments of the city of Samara.

Platelet Membrane Cloaked Nanotubes to Accelerate Thrombolysis by Thrombus Clot-Targeting and Penetration.

Thrombotic diseases have a high rate of mortality and disability, and pose a serious threat to global public health. Currently, most thrombolytic drugs especially protein drugs have a short blood-circulation time, resulting in low thrombolytic efficiency. Therefore, a platelet membrane (Pm) cloaked nanotube (NT-RGD/Pm) biomimetic delivery system with enhanced thrombolytic efficiency is designed. Nanotubes (NT) with an excellent clot-penetration properties are used to load a protein thrombolytic drug urokinase (Uk). Platelet-targeting arginine glycine-aspartic peptide (RGD) is grafted onto the surface of the nanotubes (NT-RGD) prior to cloaking. Multiple particle tracking (MPT) technique and confocal laser scanning microscope (CLSM) analysis are applied and the results show that the nanotubes possess a strong penetration and diffusion capacity in thrombus clots. After the Pm cloaking on NT-RGD/Uk, it shows a thrombus microenvironmental responsive release property and the half-life of Uk is six times longer than that of free Uk. Most importantly, NT-RGD-Uk/Pm exhibits a 60% thrombolytic efficiency in the FeCl3 -induced thrombosis mouse model, and it is able to significantly reduce the bleeding side effects of Uk. This Pm-cloaked nanotube system is an effective and promising platform for the controlled and targeted delivery of drugs for the thrombus treatment.

The feasibility and accuracy of machine learning in improving safety and efficiency of thrombolysis for patients with stroke: Literature review and proposed improvements.

In the treatment of ischemic stroke, timely and efficient recanalization of occluded brain arteries can successfully salvage the ischemic brain. Thrombolysis is the first-line treatment for ischemic stroke. Machine learning models have the potential to select patients who could benefit the most from thrombolysis. In this study, we identified 29 related previous machine learning models, reviewed the models on the accuracy and feasibility, and proposed corresponding improvements. Regarding accuracy, lack of long-term outcome, treatment option consideration, and advanced radiological features were found in many previous studies in terms of model conceptualization. Regarding interpretability, most of the previous models chose restrictive models for high interpretability and did not mention processing time consideration. In the future, model conceptualization could be improved based on comprehensive neurological domain knowledge and feasibility needs to be achieved by elaborate computer science algorithms to increase the interpretability of flexible algorithms and shorten the processing time of the pipeline interpreting medical images.

Thrombus-targeted nano-agents for NIR-II diagnostic fluorescence imaging-guided flap thromboembolism multi-model therapy

In oral and maxillofacial surgery, flap repair is essential to the quality of postoperative life. Still, thrombosis is fatal for the survival of the flaps. Besides, some postoperative thrombotic diseases, such as pulmonary embolism, also intimidate patients’ life. The traditional diagnostic methods are still limited by a large amount of hardware and suffer from inconvenience, delay, and subjectivity. Moreover, the treatments mainly rely upon thrombolytics, such as urokinase (UK) plasminogen activator, which may cause bleeding risk, especially intracerebral hemorrhage. Herein, a kind of poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) containing a first near-infrared window (NIR-I) phototheranostic agent Y8 and urokinase plasminogen activator (UK) as the core, and modified with the fibrin-targeting peptide Gly–Pro–Arg–Pro–Pro (GPRPP) were developed for the flap and postoperative thromboembolism treatment (named GPRPP-Y8U@P). The conjugated molecule Y8 endows GPRPP-Y8U@P with the capacity of NIR-II imaging and excellent photothermal/photodynamic therapeutic effects. In vivo experiments demonstrated that GPRPP-Y8U@P could quickly locate thrombus by NIR-II fluorescence imaging, and semi-quantitative analysis of the embolized blood vessels' paraffin section verified its thrombolytic efficiency. Additionally, the urokinase trapped in the NPs would not result in nonspecific bleeding, tremendously improving physical security and curative effects with minimizing side effects. Overall, the advantages of GPRPP-Y8U@P, such as precise localization of the thrombus, thrombus ablation in the site, and mild side effects, demonstrated the attractiveness of this approach for effective clinical monitoring of thrombus therapy.

Enhanced Sonothrombolysis Induced by High-Intensity Focused Acoustic Vortex.

High-intensity focused ultrasound (HIFU) thrombolysis provides a targeted and non-invasive therapy for thrombosis-related diseases. Rapid thrombolysis and restoration of blood flow are vital to reduce the disability and death rate. The objective of this study was to explore the feasibility of using a high-intensity focused acoustic vortex (HIFAV) to enhance sonothrombolysis. The in vitro clots were treated with HIFU with a peak negative pressure (PNP) of 2.86 MPa (HIFU A) or 3.27 MPa (HIFU B) or HIFAV with a PNP of 2.14 MPa. The results revealed that HIFAV thrombolysis could achieve a significantly higher efficiency than HIFU (HIFAV: 65.4%, HIFU A: 24.1%, HIFU B: 31.6%, p < 0.01), even at a lower intensity. The average size of the debris particles generated in HIFAV thrombolysis was similar to that in HIFU. Additionally, the cavitation activities were found to be more intense in HIFAV thrombolysis. Although the efficiency of HIFAV thrombolysis was higher when the pulse repetition frequency increased from 100 to 500 Hz (41.4% vs. 65.4%, p < 0.05), it decreased when the PRF reached 1000 Hz (29.9%). Lastly, it was found that increasing the duty cycle from 5% to 15% led to a higher efficiency in HIFAV thrombolysis (40.3% vs. 75.2%, p < 0.001). This study illustrated that HIFAV provided enhanced thrombolysis and that its efficiency could be further increased by optimizing the ultrasound parameters.

Reconfigurable Magnetic Microswarm for Accelerating tPA-Mediated Thrombolysis Under Ultrasound Imaging

In this article, we propose a strategy to accelerate tissue plasminogen activator (tPA)-mediated thrombolysis using a microswarm under ultrasound imaging. The microswarm is formed in blood using an oscillating magnetic field and navigated with switchable locomotion modes. The aspect ratio of the microswarm can be reversibly tuned by modulating the input field, enabling the capability to adapt to different clot regions. Simulations show that 3-D flow is induced around the microswarm, which enhances the mass transfer and shear stress near the clot-fluid interface. Guided by ultrasound imaging, the microswarm can be navigated toward clot regions and deformed to adapt to blood clots with different widths. Affected by the enhanced fluid convection and shear stress, experimental results show that the microswarm-assisted lysis rate enhances up to 3.13-fold compared to that using tPA drug only. Moreover, the comparison between microswarm-assisted thrombolysis in phosphate buffered saline and blood environments validates our modeling and simulation results. Our method provides a strategy to increase the efficiency of tPA-mediated thrombolysis by applying an ultrasound-localized microrobotic swarm, indicating that swarming micro/nanorobots have the potential as effective tools toward imaging-guided therapy.

A new method of monitoring catheter-directed thrombolysis for deep venous thrombosis-application of D-dimer and fibrinogen testing.

Catheter-directed thrombolysis (CDT) is one of the main treatment methods for acute deep venous thrombosis (DVT), which has the characteristics of long treatment time and large dosage of thrombolytic drugs. In the absence of good monitoring methods, problems such as low thrombolytic efficiency and high risk of bleeding are easy to occur. To evaluate the value of D-dimer (D-D) and fibrinogen (FIB) testing as a thrombolysis-monitoring method during CDT for acute DVT. Twenty patients with acute DVT were divided into group A and group B. During CDT, the D-D and FIB testing every 8h were used in group A, and the venography and FIB testing every 24h in group B. The thrombolysis rate, thrombolysis time, urokinase dosage, and X-ray radiation dose were compared. The thrombolysis rate in group A was significantly higher than that in group B (p < 0.05), but the number of venography and radiation dose were significantly lower than those in group B (p < 0.05). D-D and FIB testing can improve the thrombolysis rate, reduce the risk of bleeding, and decrease the number of angiograms and X-ray radiation dose during CDT.