Comparison of Flow Reduction Efficacy of Nominal and Oversized Flow Diverters Using a Novel Measurement-assisted in Silico Method.

PURPOSE: The high efficacy of flow diverters (FD) in the case of wide-neck aneurysms is well demonstrated, yet new challenges have arisen because of reported posttreatment failures and the growing number of new generation of devices. Our aim is to present a measurement-supported in silico workflow that automates the virtual deployment and subsequent hemodynamic analysis of FDs. In this work, the objective is to analyze the effects of FD deployment variability of two manufacturers on posttreatment flow reduction. METHODS: The virtual deployment procedure is based on detailed mechanical calibration of the flow diverters, while the flow representation is based on hydrodynamic resistance (HR) measurements. Computational fluid dynamic simulations resulted in 5 untreated and 80 virtually treated scenarios, including 2 FD designs in nominal and oversized deployment states. The simulated aneurysmal velocity reduction (AMVR) is correlated with the HR values and deployment scenarios. RESULTS: The linear HR coefficient and AMVR revealed a power-law relationship considering all 80 deployments. In nominal deployment scenarios, a significantly larger average AMVR was obtained (60.3%) for the 64-wire FDs than for 48-wire FDs (51.9%). In oversized deployments, the average AMVR was almost the same for 64-wire and 48-wire device types, 27.5% and 25.7%, respectively. CONCLUSION: The applicability of our numerical workflow was demonstrated, also in large-scale hemodynamic investigations. The study revealed a robust power-law relationship between a HR coefficient and AMVR. Furthermore, the 64 wire configurations in nominal sizing produced a significantly higher posttreatment flow reduction, replicating the results of other in vitro studies.

Fractals and Chaos in the Hemodynamics of Intracranial Aneurysms.

Computing the emerging flow in blood vessel sections by means of computational fluid dynamics is an often applied practice in hemodynamics research. One particular area for such investigations is related to the cerebral aneurysms, since their formation, pathogenesis, and the risk of a potential rupture may be flow-related. We present a study on the behavior of small advected particles in cerebral vessel sections in the presence of aneurysmal malformations. These malformations cause strong flow disturbances driving the system toward chaotic behavior. Within these flows, the particle trajectories can form a fractal structure, the properties of which are measurable by quantitative techniques. The measurable quantities are well established chaotic properties, such as the Lyapunov exponent, escape rate, and information dimension. Based on these findings, we propose that chaotic flow within blood vessels in the vicinity of the aneurysm might be relevant for the pathogenesis and development of this malformation.

Investigating the Role of Brain Natriuretic Peptide (BNP) and N-Terminal-proBNP in Thrombosis and Acute Ischemic Stroke Etiology.

The need for biomarkers for acute ischemic stroke (AIS) to understand the mechanisms implicated in pathological clot formation is critical. The levels of the brain natriuretic peptides known as brain natriuretic peptide (BNP) and NT-proBNP have been shown to be increased in patients suffering from heart failure and other heart conditions. We measured their expression in AIS clots of cardioembolic (CE) and large artery atherosclerosis (LAA) etiology, evaluating their location inside the clots, aiming to uncover their possible role in thrombosis. We analyzed 80 thrombi from 80 AIS patients in the RESTORE registry of AIS clots, 40 of which were of CE and 40 of LAA etiology. The localization of BNP and NT-BNP, quantified using immunohistochemistry and immunofluorescence, in AIS-associated white blood cell subtypes was also investigated. We found a statistically significant positive correlation between BNP and NT-proBNP expression levels (Spearman's rho = 0.668 p < 0.0001 *). We did not observe any statistically significant difference between LAA and CE clots in BNP expression (0.66 [0.13-3.54]% vs. 0.53 [0.14-3.07]%, p = 0.923) or in NT-proBNP expression (0.29 [0.11-0.58]% vs. 0.18 [0.05-0.51]%, p = 0.119), although there was a trend of higher NT-proBNP expression in the LAA clots. It was noticeable that BNP was distributed throughout the thrombus and especially within platelet-rich regions. However, NT-proBNP colocalized with neutrophils, macrophages, and T-lymphocytes, suggesting its association with the thrombo-inflammatory process.

White blood cell subtypes and neutrophil extracellular traps content as biomarkers for stroke etiology in acute ischemic stroke clots retrieved by mechanical thrombectomy.

BACKGROUND: Lymphocytes, macrophages, neutrophils, and neutrophil extracellular traps (NETs) associate with stroke risk factors and form a thrombus through different mechanisms. We investigated the total WBCs, WBC subtypes and NETs composition in acute ischemic stroke (AIS) clots to identify possible etiological differences that could help us further understand the process of thrombosis that leads to AIS. METHODS: AIS clots from 100 cases each of atherothrombotic (AT), cardioembolic (CE) and cryptogenic stroke etiology were collected per-pass as part of the CÚRAM RESTORE registry of AIS clots. Martius Scarlet Blue stain was used to identify the main histological components of the clots. Immunohistochemical staining was used to identify neutrophils, lymphocytes, macrophages, and NETs patterns. The cellular and histological components were quantified using Orbit Image Analysis software. RESULTS: AT clots were larger, with more red blood cells and fewer WBCs than CE clots. AT clots had more lymphocytes and cryptogenic clots had fewer macrophages than other etiologies. Most significantly, CE clots showed higher expression of neutrophils and extracellular web-like NETs compared to AT and cryptogenic clots. There was also a significantly higher distribution of web-like NETs around the periphery of the CE clots while a mixed distribution was observed in AT clots. CONCLUSION: The difference in neutrophil and NETs expression in clots from different etiologies may provide insight into the mechanism of clot formation.

CLinical EValuation of WEB 17 device in intracranial aneuRysms (CLEVER): procedural, 30-day and 1-year safety results for ruptured and unruptured aneurysms.

BACKGROUND: Intrasaccular flow disruption is an endovascular approach for the treatment of wide-neck aneurysms and, more specifically, wide-neck bifurcation aneurysms, which are challenging to treat with previously developed technologies. The Woven EndoBridge (WEB) device has demonstrated its efficacy and safety, for both unruptured and ruptured aneurysms. METHODS: The CLEVER study was an observational, multicenter, prospective study conducted in 17 European investigational sites using the WEB 17 device, for the treatment of ruptured and unruptured aneurysms. The study objective was to provide safety and efficacy data on the WEB 17 device in the treatment of wide-neck bifurcation aneurysms. Imaging results were assessed independently by a Corelab and adverse events adjudicated by a Clinical Event Adjudicator. This analysis reports procedural results and safety at 30 days and 12 months. RESULTS: A total of 163 patients (mean age 58.1 years; 68.1% women) with 103 unruptured aneurysms and 60 ruptured aneurysms were enrolled. Most aneurysms were located on the anterior communicating artery (ACom) (37.4%) or the middle cerebral artery (MCA) bifurcation (30.1%). Aneurysm widths ranged from 2.0-9.2 mm, and the mean sac width was 5.0 mm. The WEB procedure was successfully completed in 163 patients (100%). At the 12-month follow-up, major stroke events occurred in 3 of 163 patients (1.8%), and no device-related mortality was observed. CONCLUSION: Endovascular treatment of ruptured and unruptured wide-neck bifurcation aneurysms using WEB 17 is safe, with a low complication rate and no device-related mortality. In particular, none of the ruptured aneurysms bled again up to 1 year of follow-up. TRIAL REGISTRATION NUMBER: NCT03844334.

Medical Management Versus Endovascular Treatment for Large-Vessel Occlusion Anterior Circulation Stroke With Low NIHSS.

BACKGROUND: Endovascular treatment (EVT) for acute ischemic stroke (AIS) patients presenting with National Institutes of Health Stroke Scale score of 0 to 5 is common in clinical practice but has not yet been proven safe and effective. Our objective is to assess whether EVT on top of best medical treatment (BMT) in AIS patients with large-vessel occlusion of the anterior circulation presenting with mild symptoms is beneficial compared with BMT. METHODS: We searched MEDLINE, SCOPUS, and reference lists of retrieved articles published until December 28, 2022. A systematic literature search was conducted to identify clinical trials or observational cohort studies evaluating patients with AIS due to anterior circulation large-vessel occlusion and admission National Institutes of Health Stroke Scale score ≤5 treated with EVT versus BMT alone. The primary outcome was excellent functional outcome (modified Rankin Scale score 0-1) at 3 months. The protocol had been registered before data collection (PROSPERO). RESULTS: Eleven observational eligible studies were included in the meta-analysis, comprising a total of 2019 AIS patients with National Institutes of Health Stroke Scale score ≤5 treated with EVT versus 3171 patients treated with BMT. EVT was not associated with excellent functional outcome (risk ratio, 1.10 [95% CI, 0.93-1.31]). When stratified for different study design (per-protocol versus intention-to-treat), there were no significant subgroup differences. EVT was not associated with good functional outcome (modified Rankin Scale score 0-2; risk ratio, 1.01 [95% CI, 0.89-1.16]) or reduced disability at 3 months (common odds ratio, 0.92 [95% CI, 0.60-1.41]). Symptomatic intracranial hemorrhage was more common in the patients receiving EVT (risk ratio, 3.53 [95% CI, 2.35-5.31]). No correlation was found between EVT and mortality at 3 months (risk ratio, 1.34 [95% CI, 0.83-2.18]). The same overall associations were confirmed in the sensitivity analysis of studies that performed propensity score matching. CONCLUSIONS: EVT appears equivalent to BMT for patients with anterior circulation large-vessel occlusion AIS with low baseline National Institutes of Health Stroke Scale, despite the increased risk for symptomatic intracranial hemorrhage. REGISTRATION: URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD42022334417.

Safety and effectiveness of the Woven EndoBridge (WEB) system for the treatment of wide necked bifurcation aneurysms: final 5 year results of the pivotal WEB Intra-saccular Therapy study (WEB-IT).

INTRODUCTION: The US Woven EndoBridge Intra-saccular Therapy (WEB-IT) study is a pivotal, prospective, single arm, investigational device exemption study to evaluate the safety and effectiveness of the WEB device for the treatment of wide neck bifurcation aneurysms (WNBAs). We present complete 5 year data for the cohort of 150 patients. METHODS: 150 patients with WNBAs were enrolled at 21 US and six international centers. Imaging from the index procedure, 6 month, 1 year, 3 year, and 5 year follow-up were reviewed by a core laboratory. Adverse events were reviewed and adjudicated by a clinical events adjudicator. RESULTS: 83 patients had 5 year follow-up imaging and 123 had clinical follow-up. No ruptured (0/9) or unruptured aneurysm (0/141) rebled or bled during follow-up. No new device or procedure related adverse events or serious adverse events were reported after 1 year. At 5 years, using the LOCF method, complete occlusion was observed in 58.1% and adequate occlusion in 87.2% of patients. For patients with both 1 year and 5 year occlusion statuses available, 76.8% (63/82) of aneurysms remained stable or improved with no retreatment. After 1 year, 18 aneurysms were retreated, 11 of which were adequately occluded at 1 year, and 15 of which were retreated in the absence of any deterioration in occlusion grade. CONCLUSIONS: Five year follow-up data from the WEB-IT study demonstrated that the WEB device was safe and effective when used in the treatment of WNBAs. Aneurysm occlusion rates achieved at 1 year follow-up were durable, with rates of progressive thrombosis far exceeding rates of recurrence over time.

Aneurysm treatment with the Woven EndoBridge (WEB) device in the combined population of two prospective, multicenter series: 5-year follow-up.

BACKGROUND: Evaluating a new endovascular treatment for intracranial aneurysms must not only demonstrate short-term safety and efficacy, but also evaluate longer-term outcomes (eg, delayed complications, anatomical results, retreatment). The current analysis reports the 5-year clinical and anatomical results of Woven EndoBridge (WEB) treatment in two European combined trial populations (WEBCAST (WEB Clinical Assessment of Intrasaccular Aneurysm Therapy) and WEBCAST-2). METHODS: All adverse events occurring between the procedure and 5-year follow-up were independently evaluated by an expert. Aneurysm occlusion was evaluated by an independent core laboratory using a three-grade scale: complete occlusion, neck remnant, and aneurysm remnant. In cases where data were not available at 5-year follow-up, the last observation carry forward (LOCF) method was used. RESULTS: The safety and efficacy populations comprised 100 patients and 95 aneurysms, respectively. No adverse event related to the device occurred after the procedure during the 5-year follow-up period. Mortality at 5 years was 7.0% (7/100 patients) including mortality related to the WEB (0/100, 0.0%), the procedure (1/100, 1.0%), and another condition (6/100, 6.0%). At 5 years, complete aneurysm occlusion was observed in 49/95 (51.6%) aneurysms, neck remnant in 25/95 (26.3%), and aneurysm remnant in 21/95 (22.1%). Retreatment rate at 5 years was 11.6% (11/95 aneurysms). CONCLUSIONS: This analysis conducted in a population of patients with wide-neck bifurcation aneurysms confirms WEB's safety profile. Additional evidence demonstrates good stability of aneurysm occlusion with adequate occlusion (complete occlusion or neck remnant) at 5 years in 77.9% of aneurysms with a low retreatment rate (11.6%). CLINICAL TRIAL REGISTRATION: WEBCAST and WEBCAST-2: Unique identifier: NCT01778322.

Initial clinical experience with a novel mechanical thrombectomy device-the ThrombX retriever.

BACKGROUND AND PURPOSE: The ThrombX Retriever is a novel mechanical thrombectomy device that adjusts the distance between two mesh segments to axially hold thrombus. A post-market study assessed safety and performance in acute ischemic stroke patients with large artery occlusion. METHODS: A single-arm prospective multi-center study enrolled patients at 5 European Centers. Patients had a symptomatic large-artery occlusion of the intracranial Internal Carotid or the Middle Cerebral Artery, M1 segment. The primary outcome measure was the modified treatment in cerebral infarction (mTICI) score, on the immediate post-procedure angiogram after up to three device passes. Key secondary outcome measures were the mTICI score after a single pass and functional independence, defined as an mRS score ≤ 2 at 90 days. RESULTS: Thirty patients (16 Females, mean age 72 years), with NIHSS 4-25 (mean 15.5) were treated. Twenty-eight (93%) achieved mTICI 2b-3 within 3 passes, and 24 (80%) were with the first pass (FP). FP mTICI 2c-3 reperfusion was achieved in 19 (63%) cases. Seventeen of 24 (71%) patients treated with a balloon guide and the ThrombX Retriever had a FP mTICI 2c-3 reperfusion. After all interventions, mTICI 2b-3 was seen in 30 (100%) patients. Twenty-one of the 29 (73%) patients with 90-day follow-up were functionally independent (mRS≤2). No device-related serious adverse events were observed. CONCLUSION: This preliminary study suggests the ThrombX Retriever is safe and has a high rate of substantial reperfusion. A larger prospective trial to assess the device effectiveness is planned.

Endovascular treatment for anterior circulation large-vessel occlusion ischemic stroke with low ASPECTS: a systematic review and meta-analysis.

Background: Endovascular treatment (EVT) for acute ischemic stroke (AIS) patients presenting with Alberta Stroke Program Early CT Score (ASPECTS) 0-5 has not yet proven safe and effective by clinical trials. Objectives: The aim of the study was to assess whether EVT in AIS patients presenting with low ASPECTS is beneficial. Design: Systematic review and meta-analysis of available studies in accordance with the PRISMA statement. Data sources and Methods: We have searched MEDLINE, the Cochrane Central Register of Controlled Trials, and reference lists of articles published until 28 May 2022 with the aim to calculate (1) modified Rankin scale (mRS) score 0-3 at 3 months, (2) mRS score 0-2 at 3 months, (3) symptomatic intracranial hemorrhage (sICH), and (3) mortality at 3 months. Results: Overall, 24 eligible studies were included in the meta-analysis, comprising a total of 2539 AIS patients with ASPECTS 0-5 treated with EVT. The pooled proportion of EVT-treated patients achieving mRS 0-3 at 3 months was calculated at 38.4%. The pooled proportion of EVT-treated patients achieving mRS 0-2 at 3 months was 25.7%. Regarding safety outcomes, sICH occurred in 12.8% of patients. The 3-month pooled mortality was 30%. In pairwise meta-analysis, patients treated with EVT had a higher likelihood of achieving mRS 0-3 at 3 months compared with patients treated with best medical therapy (BMT, OR: 2.41). sICH occurred more frequently in EVT-treated patients compared with the BMT-treated patients (OR: 2.30). Mortality at 3 months was not different between the two treatment groups (OR: 0.71). Conclusion: EVT may be beneficial for AIS patients with low baseline ASPECTS despite an increased risk for sICH. Further data from randomized-controlled clinical trials are needed to elucidate the role of EVT in this subgroup of AIS patients. Registration: The protocol has been registered in the International Prospective Register of Ongoing Systematic Reviews PROSPERO; Registration Number: CRD42022334417.

Potential Biomarkers of Acute Ischemic Stroke Etiology Revealed by Mass Spectrometry-Based Proteomic Characterization of Formalin-Fixed Paraffin-Embedded Blood Clots.

Background and Aims: Besides the crucial role in the treatment of acute ischemic stroke (AIS), mechanical thrombectomy represents a unique opportunity for researchers to study the retrieved clots, with the possibility of unveiling biological patterns linked to stroke pathophysiology and etiology. We aimed to develop a shotgun proteomic approach to study and compare the proteome of formalin-fixed paraffin-embedded (FFPE) cardioembolic and large artery atherosclerotic (LAA) clots. Methods: We used 16 cardioembolic and 15 LAA FFPE thrombi from 31 AIS patients. The thrombus proteome was analyzed by label-free quantitative liquid chromatography-tandem mass spectrometry (LC-MS/MS). MaxQuant v1.5.2.8 and Perseus v.1.6.15.0 were used for bioinformatics analysis. Protein classes were identified using the PANTHER database and the STRING database was used to predict protein interactions. Results: We identified 1,581 protein groups as part of the AIS thrombus proteome. Fourteen significantly differentially abundant proteins across the two etiologies were identified. Four proteins involved in the ubiquitin-proteasome pathway, blood coagulation or plasminogen activating cascade were identified as significantly abundant in LAA clots. Ten proteins involved in the ubiquitin proteasome-pathway, cytoskeletal remodeling of platelets, platelet adhesion or blood coagulation were identified as significantly abundant in cardioembolic clots. Conclusion: Our results outlined a set of 14 proteins for a proof-of-principle characterization of cardioembolic and LAA FFPE clots, advancing the proteome profile of AIS human thrombi and understanding the pathophysiology of ischemic stroke.

Improved Stroke Care in a Primary Stroke Centre Using AI-Decision Support.

BACKGROUND: Patient selection for reperfusion therapies requires significant expertise in neuroimaging. Increasingly, machine learning-based analysis is used for faster and standardized patient selection. However, there is little information on how such software influences real-world patient management. AIMS: We evaluated changes in thrombolysis and thrombectomy delivery following implementation of automated analysis at a high volume primary stroke centre. METHODS: We retrospectively collected data on consecutive stroke patients admitted to a large university stroke centre from two identical 7-month periods in 2017 and 2018 between which the e-Stroke Suite (Brainomix, Oxford, UK) was implemented to analyse non-contrast CT and CT angiography results. Delivery of stroke care was otherwise unchanged. Patients were transferred to a hub for thrombectomy. We collected the number of patients receiving intravenous thrombolysis and/or thrombectomy, the time to treatment; and outcome at 90 days for thrombectomy. RESULTS: 399 patients from 2017 and 398 from 2018 were included in the study. From 2017 to 2018, thrombolysis rates increased from 11.5% to 18.1% with a similar trend for thrombectomy (2.8-4.8%). There was a trend towards shorter door-to-needle times (44-42 min) and CT-to-groin puncture times (174-145 min). There was a non-significant trend towards improved outcomes with thrombectomy. Qualitatively, physician feedback suggested that e-Stroke Suite increased decision-making confidence and improved patient flow. CONCLUSIONS: Use of artificial intelligence decision support in a hyperacute stroke pathway facilitates decision-making and can improve rate and time of reperfusion therapies in a hub-and-spoke system of care.

Automated quantification of atrophy and acute ischemic volume for outcome prediction in endovascular thrombectomy.

Background: Short- and long-term outcomes from endovascular thrombectomy (EVT) for large vessel occlusion stroke remain variable. Numerous relevant predictors have been identified, including severity of neurological deficits, age, and imaging features. The latter is typically defined as acute changes (most commonly Alberta Stroke Programme Early CT Score, ASPECTS, at presentation), but there is little information on the impact of imaging assessment of premorbid brain health as a determinant of outcome. Aims: To examine the impact of automated measures of stroke severity and underlying brain frailty on short- and long-term outcomes in acute stroke treated with EVT. Methods: In 215 patients with anterior circulation stroke, who subsequently underwent EVT, automated analysis of presenting non-contrast CT scans was used to determine acute ischemic volume (AIV) and e-ASPECTS as markers of stroke severity, and cerebral atrophy as a marker of brain frailty. Univariate and multivariate logistic regression were used to identify significant predictors of NIHSS improvement, modified Rankin scale (mRS) at 90 and 30 days, mortality at 90 days and symptomatic intracranial hemorrhage (sICH) following successful EVT. Results: For long-term outcome, atrophy and presenting NIHSS were significant predictors of mRS 0-2 and death at 90 days, whereas age did not reach significance in multivariate analysis. Conversely, for short-term NIHSS improvement, AIV and age were significant predictors, unlike presenting NIHSS. The interaction between age and NIHSS was similar to the interaction of AIV and atrophy for mRS 0-2 at 90 days. Conclusion: Combinations of automated software-based imaging analysis and clinical data can be useful for predicting short-term neurological outcome and may improve long-term prognostication in EVT. These results provide a basis for future development of predictive tools built into decision-aiding software in stroke.

Impact of Design and Deployment Technique on the Hydrodynamic Resistance of Flow Diverters : An in Vitro Experimental Study.

PURPOSE: Despite the high efficacy of flow diverters (FD) in treating sidewall intracranial aneurysms, failures are reported. One of the physical factors determining efficacy is the flow reducing capacity of the FD that is currently unknown to the operator. Our aim was to measure the flow reducing capacity expressed as the hydrodynamic resistance (HR), the metallic surface area (MSA) and pore density (PD) of two different FD designs and quantitatively investigate the impact of sizing and the deployment technique on these parameters. METHODS: Altogether 38 Pipeline (Medtronic) and P64 (Phenox) FD­s were implanted in holder tubes by a neurointerventionist in nominally sized, oversized and longitudinally compressed or elongated manners. The tubes were placed in a flow model with the flow directed across the FD through a side hole on the tube. HR was expressed by the measured pressure drop as the function of the flow rate. Deployed length, MSA and PD were also measured and correlated with the HR. RESULTS: Both PD and MSA changed with varying deployment length, which correlates well with the change in HR. Oversizing the device by 1 mm in diameter has reduced the HR on average to one fifth of the original value for both manufacturers. CONCLUSION: This study demonstrates experimentally that different FD designs have different flow diverting capacities (HR). Parameters are greatly influenced by radial sizing and longitudinal compression or elongation during implantation. Our results might be useful in procedure planning, predicting clinical outcome, and in patient-specific numerical flow simulations.

Does prior administration of rtPA influence acute ischemic stroke clot composition? Findings from the analysis of clots retrieved with mechanical thrombectomy from the RESTORE registry.

BACKGROUND AND PURPOSE: There is still much debate whether bridging-therapy [intravenous thrombolysis (IVT) prior to mechanical thrombectomy (MT)] might be beneficial compared to MT alone. We investigated the effect of IVT on size and histological composition of the clots retrieved from patients undergoing bridging-therapy or MT alone. METHODS: We collected mechanically extracted thrombi from 1000 acute ischemic stroke (AIS) patients included in RESTORE registry. Patients were grouped according to the administration (or not) of IVT before thrombectomy. Gross photos of each clot were taken and Extracted Clot Area (ECA) was measured using ImageJ software. Martius Scarlett Blue stain was used to characterize the main histological clot components [red blood cells (RBCs), fibrin (FIB), platelets/other (PTL)] and Orbit Image Analysis was used for quantification. Additionally, we calculated the area of each main component by multiplying the component percent by ECA. Chi-squared and Kruskal-Wallis tests were used for statistical analysis. RESULTS: 451 patients (45%) were treated with bridging-therapy while 549 (55%) underwent MT alone. When considering only percent histological composition, we did not find any difference in RBC% (P = 0.895), FIB% (P = 0.458) and PTL% (P = 0.905). However, bridging-therapy clots were significantly smaller than MT-alone clots [32.7 (14.8-64.9) versus 36.8 (20.1-79.8) mm2, N = 1000, H1 = 7.679, P = 0.006*]. A further analysis expressing components per clot area showed that clots retrieved from bridging-therapy cases contained less RBCs [13.25 (4.29-32.06) versus 14.97 (4.93-39.80) mm2, H1 = 3.637, P = 0.056] and significantly less fibrin [9.10 (4.62-17.98) versus 10.54 (5.57-22.48) mm2, H1 = 7.920, P = 0.005*] and platelets/other [5.04 (2.26-11.32) versus 6.54 (2.94-13.79) mm2, H1 = 9.380, P = 0.002*] than MT-alone clots. CONCLUSIONS: Our results suggest that previous IVT administration significantly reduces thrombus size, proportionally releasing all the main histological components.

Fibrin to von Willebrand factor ratio in arterial thrombi is associated with plasma levels of inflammatory biomarkers and local abundance of extracellular DNA.

INTRODUCTION: The composition of thrombi determines their structure, mechanical stability, susceptibility to lysis, and consequently, the clinical outcome in coronary artery disease (CAD), acute ischemic stroke (AIS), and peripheral artery disease (PAD). Fibrin forms the primary matrix of thrombi intertwined with DNA, derived from neutrophil extracellular traps (NETs), and von Willebrand factor (VWF) bridging DNA and platelets. Here we examined the relative content of fibrin, DNA and VWF in thrombi and analyzed their interrelations and quantitative associations with systemic biomarkers of inflammation and clinical characteristics of the patients. PATIENTS, METHODS: Thrombi extracted from AIS (n = 17), CAD (n = 18) or PAD (n = 19) patients were processed for scanning electron microscopy, (immune)stained for fibrin, VWF and extracellular DNA. Fibrin fiber diameter, cellular components, fibrin/DNA and fibrin/VWF ratios were measured. RESULTS: Patients' age presented as a strong explanatory factor for a linear decline trend of the VWF content relative to fibrin in thrombi from CAD (adjusted-R2 = 0.43) and male AIS (adjusted-R2 = 0.66) patients. In a subgroup of CAD and PAD patients with dyslipidemia and high (above 80%) prevalence of atherothrombosis a significant correlation was observed between the VWF and DNA content in thrombi (adjusted-R2 = 0.40), whereas a 3.7-fold lower linear regression coefficient was seen in AIS patients, in whom the fraction of thrombi of atherosclerotic origin was 57%. Independently of anatomical location, in patients with atherosclerosis the VWF in thrombi correlated with the plasma C-reactive protein levels. CONCLUSIONS: The observed interrelations between thrombus constituents and systemic inflammatory biomarkers suggest an intricate interplay along the VWF/NET/fibrin axis in arterial thrombosis.

S100b in acute ischemic stroke clots is a biomarker for post-thrombectomy intracranial hemorrhages.

Background and purpose: Post-thrombectomy intracranial hemorrhages (PTIH) are dangerous complications of acute ischemic stroke (AIS) following mechanical thrombectomy. We aimed to investigate if S100b levels in AIS clots removed by mechanical thrombectomy correlated to increased risk of PTIH. Methods: We analyzed 122 thrombi from 80 AIS patients in the RESTORE Registry of AIS clots, selecting an equal number of patients having been pre-treated or not with rtPA (40 each group). Within each subgroup, 20 patients had developed PTIH and 20 patients showed no signs of hemorrhage. Gross photos of each clot were taken and extracted clot area (ECA) was measured using ImageJ. Immunohistochemistry for S100b was performed and Orbit Image Analysis was used for quantification. Immunofluorescence was performed to investigate co-localization between S100b and T-lymphocytes, neutrophils and macrophages. Chi-square or Kruskal-Wallis test were used for statistical analysis. Results: PTIH was associated with higher S100b levels in clots (0.33 [0.08-0.85] vs. 0.07 [0.02-0.27] mm2, H1 = 6.021, P = 0.014*), but S100b levels were not significantly affected by acute thrombolytic treatment (P = 0.386). PTIH was also associated with patients having higher NIHSS at admission (20.0 [17.0-23.0] vs. 14.0 [10.5-19.0], H1 = 8.006, P = 0.005) and higher number of passes during thrombectomy (2 [1-4] vs. 1 [1-2.5], H1 = 5.995, P = 0.014*). S100b co-localized with neutrophils, macrophages and with T-lymphocytes in the clots. Conclusions: Higher S100b expression in AIS clots, higher NIHSS at admission and higher number of passes during thrombectomy are all associated with PTIH. Further investigation of S100b expression in AIS clots by neutrophils, macrophages and T-lymphocytes could provide insight into the role of S100b in thromboinflammation.

Correlation between acute ischaemic stroke clot length before mechanical thrombectomy and extracted clot area: Impact of thrombus size on number of passes for clot removal and final recanalization.

INTRODUCTION: We assessed the correlation between thrombus size before and after mechanical thrombectomy, measured as length by Computed Tomography Angiography/Non-Contrast Computed Tomography (CTA/NCCT) and Extracted Clot Area, ECA, respectively. We also assessed the influence of thrombus size on the number of passes required for clot removal and final recanalization outcome. MATERIALS AND METHODS: Acute ischaemic stroke (AIS) thrombi retrieved by mechanical thrombectomy from 500 patients and data of clot length by CTA/NCCT were collected from three hospitals in Europe. ECA was obtained by measuring the area of the extracted clot. Non-parametric tests were used for data analysis. RESULTS: A strong positive correlation was found between clot length on CTA/NCCT and ECA (rho = 0.619,N = 500,P < 0.0001*). Vessel size influences clot length on CTA/NCCT (H2 = 98.6, P < 0.0001*) and ECA (H2 = 105.6,P < 0.0001*), but the significant correlation between CTA/NCCT length and ECA was evident in all vessels. Poorer revascularisation outcome was associated with more passes (H5 = 73.1, P < 0.0001*). More passes were required to remove longer clots (CTA/NCCT; H4 = 31.4, P < 0.0001*; ECA; H4 = 50.2, P < 0.0001*). There was no significant main association between recanalization outcome and length on CTA/NCCT or ECA, but medium sized clots (ECA 20-40 mm2) were associated with least passes and highest revascularisation outcome (N = 500, X2 = 16.2, P < 0.0001*). CONCLUSION: Clot length on CTA/NCCT strongly correlates with ECA. Occlusion location influences clot size. More passes are associated with poorer revascularisation outcome and bigger clots. The relationship between size and revascularisation outcome is more complex. Clots of medium ECA take less passes to remove and are associated with better recanalization outcome than both smaller and larger clots.

Characterization of the 'White' Appearing Clots that Cause Acute Ischemic Stroke.

OBJECTIVES: Most clots retrieved from patients with acute ischemic stroke are 'red' in color. 'White' clots represent a less common entity and their histological composition is less known. Our aim was to investigate the composition, imaging and procedural characteristics of 'white' clots retrieved by mechanical thrombectomy. MATERIALS AND METHODS: Seventy five 'white' thrombi were selected by visual inspection from a cohort of 760 clots collected as part of the RESTORE registry. Clots were evaluated histopathologically. RESULTS: Quantification of Martius Scarlett Blue stain identified platelets/other as the major component in 'white' clots' (mean of 55% of clot overall composition) followed by fibrin (31%), red blood cells (6%) and white blood cells (3%). 'White' clots contained significantly more platelets/other (p<0.001*) and collagen/calcification (p<0.001*) and less red blood cells (p<0.001*) and white blood cells (p=0.018*) than 'red' clots. The mean platelet and von Willebrand Factor expression was 43% and 24%, respectively. Adipocytes were found in four cases. 'White' clots were significantly smaller (p=0.016*), less hyperdense (p=0.005*) on computed tomography angiography/non-contrast CT and were associated with a smaller extracted clot area (p<0.001*) than 'red' clots. They primarily caused the occlusion of middle cerebral artery, were less likely to be removed by aspiration and more likely to require rescue-therapy for retrieval. CONCLUSIONS: 'White' clots represented 14% of our cohort and were platelet, von Willebrand Factor and collagen/calcification-rich. 'White' clots were smaller, less hyperdense, were associated with significantly more distal occlusions and were less successfully removed by aspiration alone than 'red' clots.

Impact of COVID-19 on ischemic stroke care in Hungary.

Data about the coronavirus disease 2019 (COVID-19) pandemic's collateral damage on ischemic stroke (IS) care during the second epidemic wave in Central Europe are limited. We sought to evaluate the impact of the COVID-19 outbreak on Hungarian IS care during the two epidemic waves. This retrospective observational study was based on a nationwide reimbursement database that encompasses all IS admissions and all reperfusion interventions, i.e., intravenous thrombolysis (IVT) and endovascular therapy (EVT) from 2 January 2017 to 31 December 2020 in Hungary. COVID-19 pandemic's effect on the number of IS admissions and reperfusion interventions were analyzed using different statistics: means, medians, trends, relative rates, and linear relationships. The mean and median values of IS admissions and reperfusion interventions decreased only in some measure during the COVID-periods. However, trend analysis demonstrated a significant decline from the trends. The decline's dynamic and amplitude have differed for each variable. In contrast to IVT, the number of IS admissions and EVTs negatively correlated with the epidemic waves' amplitude. Besides, the decrease in the number of IS admissions was more pronounced than the decrease in the number of reperfusion interventions. Our study demonstrated a significant disruption in IS care during the COVID-19 epidemic in Hungary, in which multiple different factors might play a role. The disproportionate reduction of IS admission numbers could partially be explained by the effect of health emergency operative measures and changes in patients' social behavior. Further studies are needed to evaluate the causes of our observations.