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DWI/FLAIR mismatch assessment for ischemic stroke patients shows promising results in determining if patients are eligible for recombinant tissue-type plasminogen activator (r-tPA) treatment. However, the mismatch criteria suffer from two major issues: binary classification of a non-binary problem and the subjectiveness of the assessor. In this article, we present a simple automatic method for segmenting stroke-related parenchymal hyperintensities on FLAIR, allowing for an automatic and continuous DWI/FLAIR mismatch assessment. We further show that our method's segmentations have comparable inter-rater agreement (DICE 0.820, SD 0.12) compared to that of two neuro-radiologists (DICE 0.856, SD 0.07), that our method appears robust to hyper-parameter choices (suggesting good generalizability), and lastly, that our methods continuous DWI/FLAIR mismatch assessment correlates to mismatch assessments made for a cohort of wake-up stroke patients at hospital submission. The proposed method shows promising results in automating the segmentation of parenchymal hyperintensity within ischemic stroke lesions and could help reduce inter-observer variability of DWI/FLAIR mismatch assessment performed in clinical environments as well as offer a continuous assessment instead of the current binary one.

Background: Each year, stroke-related death and disability claim over 143 million years of healthy life globally. Despite accounting for much of the global stroke burden, acute stroke care in Low-and-Middle-Income Countries remains suboptimal. Thrombolysis, an effective treatment option for stroke, is only received by a minority of stroke patients in these settings., Aim: To determine the context-specific barriers and facilitators for the implementation of mainstream stroke thrombolysis in a Ghanaian hospital., Methods: We employed a mixed-methods approach involving key stakeholders (recipients, providers, and leaders) in the acute stroke care continuum. Surveys were administered to acute stroke patients, and in-depth key informant interviews were conducted with experts in stroke care, including a neurologist, medical director, neurology residents, a stroke nurse, emergency physicians, a radiologist, and a pharmacist. The data collected from these interviews were transcribed and analysed using content analysis with the CFIR (Consolidated Framework for Implementation Research) model as a guiding template. Two independent coders were involved in the analysis process to ensure reliability and accuracy., Results: The stroke thrombolysis rate over a 6-month period was 0.83% (2 out of 242), with an average door-to-needle time among thrombolyzed patients being 2 hours, 37 minutes. Only 12.8% of patients (31 out of 242) presented within 4.5 hours of stroke symptom onset. The most significant obstacle to the implementation of acute stroke thrombolysis was related to the characteristics of the individuals involved, notably delays in presenting to the hospital among stroke patients due to a lack of knowledge about stroke symptoms and cultural beliefs. Additionally, a significant bottleneck that contributed to the discrepancy between the number of patients who presented within the 4.5-6 hour window and the number of patients who actually received thrombolysis was the inability to pay for the cost of thrombolytic agents. This was followed by challenges in the implementation processes., Conclusions: Addressing challenges related to stroke awareness, and financial constraints via multi-level stakeholder engagement, and enactment of stroke protocols are crucial steps in ensuring a successful implementation of a stroke thrombolysis program in a resource-limited setting., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Intravenous 0.9 mg/kg recombinant tissue plasminogen activator (r-tPA) is one of the most effective treatments in acute ischemic stroke patients. Practically, the dose of r-tPA is still a topic that is constantly being discussed., Methods: For this observational study, data were obtained from 537 patients who received r-tPA thrombolysis at Shanghai Sixth People's Hospital stroke center over 5 years (2014-2019). Patients were divided into two groups: a non-standard dose group (0.6 mg/kg ≤ dose < 0.9 mg/kg) and a standard dose group (0.9 mg/kg). Different outcomes were observed: efficacy: 3 months mRS 0-1 (3m-mRS0-1); safety: symptomatic intracranial hemorrhage within 24 h (24h-sICH) and 3 months mortality (3m-death). We also observed the effect of r-tPA dose coefficient on outcomes in different age groups and baseline National Institute of Health stroke scale (NIHSS) score subgroups., Results: There were 265 patients who gave the standard dose treatment and 272 gave the nonstandard dose. There was no significant difference between the non-standard dose group and the standard dose group in 3m-mRS0-1, 3m-death, and 24h-sICH ( p = 0.567, 0.327, and 0.415, respectively). The dose coefficient presents a significant negative correlation ( p = 0.034, B = -4.290) with 3m-death in NIHSS < 16 sub-group. Door-to-needle time (DNT) is the most important independent outcome-influential factor (MIOIF) in the NIHSS ≥16 sub-group. The diabetes history and baseline NIHSS score were the MIOIF in the age ≥80-year sub-group., Conclusions: The non-standard dose group (0.6 mg/kg ≤ dose < 0.9 mg/kg) shows no difference in safety and effectiveness than the standard dose group (0.9 mg/kg) in our study. The standard dose should be considered first according to current evidence and Guidelines, but the non-standard dose (0.6 mg/kg ≤ dose < 0.9 mg/kg) might be an option in the actual diagnosis and treatment process considering the patient's clinical profile and financial condition., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer JS declared a shared affiliation with the authors to the handling editor at the time of review., (Copyright © 2022 Yuan, Wu, Xiang, Deng, Zhang, Lu, Cao, Zhao, Zhao and Wang.)

Background and Purpose: Given recent evidence suggesting the clot composition may be associated with revascularization outcomes and stroke etiology, clot composition research has been a topic of growing interest. It is currently unclear what effect, if any, pre-thrombectomy thrombolysis has on clot composition. Understanding this association is important as it is a potential confounding variable in clot composition research. We retrospectively evaluated the composition of retrieved clots from ischemic stroke patients who did and did not receive pre-treatment tPA to study the effect of tPA on clot composition., Materials and Methods: Consecutive patients enrolled in the Stroke Thromboembolism Registry of Imaging and Pathology (STRIP) were included in this study. All patients underwent mechanical thrombectomy and retrieved clots were sent to a central core lab for processing. Histological analysis was performed using Martius Scarlett Blue (MSB) staining and area of the clot was also measured on the gross photos. Student's t test was used for continuous variables and chi-squared test for categorical variables., Results: A total of 1430 patients were included in this study. Mean age was 68.4±13.5 years. Overall rate of TICI 2c/3 was 67%. A total of 517 patients received tPA (36%) and 913 patients did not (64%). Mean RBC density for the tPA group was 42.97±22.62% compared to 42.80±23.18% for the non-tPA group (P=0.89). Mean WBC density for the tPA group was 3.74±2.60% compared to 3.42±2.21% for the non-tPA group (P=0.012). Mean fibrin density for the tPA group was 26.52±15.81% compared to 26.53±15.34% for the non-tPA group (P=0.98). Mean platelet density for the tPA group was 26.22±18.60% compared to 26.55±19.47% for the non-tPA group (P=0.75). tPA group also had significantly smaller clot area compared to non-tPA group., Conclusions: Our study 1430 retrieved emboli and ischemic stroke patients shows no interaction between tPA administration and clot composition. These findings suggest that tPA does not result in any histological changes in clot composition., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Thrombolysis with r-tPA is recommended for patients after acute ischemic stroke (AIS) within 4.5 h of symptom onset. However, only a few patients benefit from this therapeutic regimen. Thus, we aimed to develop an interpretable machine learning (ML)-based model to predict the thrombolysis effect of r-tPA at the super-early stage. Methods: A total of 353 patients with AIS were divided into training and test data sets. We then used six ML algorithms and a recursive feature elimination (RFE) method to explore the relationship among the clinical variables along with the NIH stroke scale score 1 h after thrombolysis treatment. Shapley additive explanations and local interpretable model-agnostic explanation algorithms were applied to interpret the ML models and determine the importance of the selected features. Results: Altogether, 353 patients with an average age of 63.0 (56.0-71.0) years were enrolled in the study. Of these patients, 156 showed a favorable thrombolysis effect and 197 showed an unfavorable effect. A total of 14 variables were enrolled in the modeling, and 6 ML algorithms were used to predict the thrombolysis effect. After RFE screening, seven variables under the gradient boosting decision tree (GBDT) model (area under the curve = 0.81, specificity = 0.61, sensitivity = 0.9, and F1 score = 0.79) demonstrated the best performance. Of the seven variables, activated partial thromboplastin clotting time (time), B-type natriuretic peptide, and fibrin degradation products were the three most important clinical characteristics that might influence r-tPA efficiency. Conclusion: This study demonstrated that the GBDT model with the seven variables could better predict the early thrombolysis effect of r-tPA., Competing Interests: Authors LY and MS were employed by the company DHC Mediway Technology Co. Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhu, Zhao, Cao, Du, Yang, Su, Tian, Wu, Wu, Wang, Zhao and Zhao.)

Background: Fibrin degradation products (FDPs) are fragments released by the plasmin-mediated degradation of fibrinogen or fibrin. Whether plasma levels of these fragments can predict the thrombolytic effect of recombinant tissue plasminogen activator (r-tPA) remains unknown. Methods: We performed a hospital-based study of patients with acute ischemic stroke (AIS) to explore the relationship between FDP levels at admission and the NIH Stroke Scale (NIHSS) score 1 h after thrombolysis treatment. In this retrospective, single-center study, the data of all patients with AIS who received r-tPA treatment at Beijing Tiantan Hospital from January 2019 to October 2020 were collected and analyzed. Demographic and clinical data, including laboratory examinations, were also analyzed. Results: A total of 339 patients with AIS were included in this study. Of these, 151 showed favorable effects of r-tPA, and 188 showed unsatisfactory effects at 1 h after thrombolysis. Overall, we found an inverse relationship between the FDPs levels at admission and the NIHSS score. A significant difference was observed when using the interquartile range of the FDPs levels (1.31 μg/mL) as a cutoff value ( P = 0.003, odds ratio [OR] = 1.95, 95% confidence interval [CI]: 1.26-3.01), even after adjusting for confounding factors ( P = 0.003, OR = 2.23, 95% CI: 1.31-3.77). In addition, significant associations were observed in the tertile (T3) and quartile (Q3, Q4) FDP levels when compared with T1 or Q1. A nomogram was also employed to create a model to predict an unsatisfactory effect of r-tPA. We found that FDP levels, white blood cell count, age, D-dimer level, and body mass index could influence the thrombolytic effect of r-tPA. Conclusion: In conclusion, the present study demonstrated that the levels of FDPs at admission can be used as a prognostic factor to predict the curative effect of r-tPA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhu, Zhang, Du, Yang, Tian, Wu, Wu, Ling, Liu, Zhao and Zhao.)

Introduction: Macular subretinal hematoma is a complication of age related macular degeneration (AMD) responsible for a severe change in vision. We evaluated anatomic and functional results of surgical treatment of hematoma by vitrectomy, subretinal injection of r-tPA (recombinant tissue plasminogen activator), intravitreal bevacizumab injection and air tamponade., Methods: Retrospective case series including 26 patients with submacular hemorrhage who underwent vitrectomy within 15 days after the onset of symptoms. Optical coherence tomography (OCT) was performed to measure the diameter of the hemorrhage and specify the location in relation to the retinal pigment epithelium. Anatomical success was defined as a total displacement of the hemorrhage out of the fovea at the first postoperative visit. Visual acuity improvement was measured at 1 and 6 months and at final postoperative visit., Results: The procedure resulted in hemorrhage displacement away from the fovea in 20 eyes (81%). Visual acuity significantly improved by 5.8 (±7.2) lines (P=0.0003) at 1 month postoperatively, 7.4 (±6.7) lines (P=0.0004) at 6 months and 7.4 (±7.4) lines (P=0.0002) at the final postoperative visit (16.5±19.8 months). There was an inverse correlation between hemorrhage diameter and final acuity improvement (Pearson correlation coefficient ρ=-0.60 (IC 95% [-0.81; -0.26]; P=0.002))., Conclusion: Vitrectomy with subretinal r-tPA injection was found to be effective for the displacement of AMD hemorrhage in 81% of the patients. Mean final visual acuity improved by more than 7 lines, confirming the efficacy and functional benefit of surgical displacement., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Purpose: To evaluate the anatomical and functional outcome of patients with traumatic submacular hemorrhage (SMH)., Methods: A retrospective, interventional case series of patients presenting between January 2016 and April 2018 was carried out at 4 tertiary eye care centers of India. Medical records of the patients with a history of blunt trauma and SMH were retrospectively reviewed. The intervention done was any one of the following: pneumatic displacement with 0.3 ml of intravitreal gas [100% perfluoropropane (C3F8) gas], pneumatic displacement with intravitreal 0.3 ml of 100% C3F8 gas combined with 100 μg/0.1 ml of recombinant tissue plasminogen activator (r-tpa), pars plana vitrectomy (PPV) with subretinal r-tpa and gas tamponade. The primary outcome measures included change in visual and anatomical status., Results: Twenty eyes of 20 patients with blunt trauma were analyzed. Thirteen patients had small size SMH, 5 patients had medium size SMH, and 2 patients had massive size SMH. Sixteen patients had a favorable functional outcome, and eighteen patients had favorable anatomical outcome. The size and duration of post-traumatic SMH did not significantly affect the anatomical ( P  = 0.123) or functional ( P  = 0.293) outcome in our study. The patients who presented with initial visual acuity of 6/60 or better showed better functional outcome, which was statistically significant ( P  = 0.007)., Conclusion: Minimally non-invasive procedure including intravitreal r-tpa and gas appear to be effective in the displacement of post-traumatic SMH., (© 2019 Iranian Society of Ophthalmology. Production and hosting by Elsevier B.V.)

Administration of tissue plasminogen activator (tPA) during first 3-4.5 h after ischemic stroke is the main therapeutic strategy; however, its using after that, leads to reperfusion injury and neurotoxic effects. Additionally, inflammation has a critical role in secondary injury after late reperfusion therapy. Thus, this project was designed to explore the effects of JZL-184 (JZL), an agonist of type 1 cannabinoid receptor (CB1), on the side effects of recombinant tPA (r-tPA), which is administrated after 5 h of stroke onset in the mice middle cerebral artery occlusion (MCAO) model. After established the model of MCAO mouse, they were put to six groups, including intact, control, vehicle, JZL (4 mg/kg), r-tPA (9 mg/kg), and JZL plus r-tPA. Thereafter, brain levels of IL-10, TNF-α, and matrix metalloproteinase - 9 (MMP9), brain edema and infarction, and behavioral functions have been determined in the groups. JZL alone or in combination with r-tPA, but not r-tPA, reduced brain edema, infarct volume, brain levels of TNF-α, MMP9, and also improved behavioral tests. JZL and JZL plus r-tPA also increased brain levels of IL-10. According to the results, JZL can improve the effects of r-tPA to overcome stroke SSE, when used after 5 h of stroke onset. Based on the fact that there is limitation regarding using r-tPA after 3 h of stroke onset, using a combination of r-tPA/JZL can be considered for a future therapeutic strategy.

A 42-year-old female admitted with new-onset atrial fibrillation had a wake-up stroke on the high-dependency unit and the time last seen well (TLSW) was 6.5 h. She suffered left-sided body weakness and her National Institutes of Health Stroke Scale (NIHSS) score was 17. An emergency CT perfusion showed right M1 segment occlusion with more than 50% penumbra. She was given recombinant tissue plasminogen activator (r-tPA) at 9 h from TLSW. An immediate diagnostic angiogram with intention to treat, owing to the presence of large vessel occlusion, showed complete reperfusion after intravenous r-tPA. She was discharged with NIHSS of 2, and at 3-month follow up her Modified Rankin Scale was 0. We demonstrated a successful reperfusion and excellent clinical recovery with intravenous thrombolysis in a patient who presented with a wake-up stroke with underlying valvular atrial fibrillation despite evidence of large vessel occlusion., Competing Interests: No financial or competing interests declared

Background: Stroke induces immune alterations such as impaired oxidative burst and reduced release of neutrophil extracellular traps (NETs). We hypothesised that key enzymes of these defence mechanisms may be altered in ischaemic stroke. Therefore, we analysed the intra- and extracellular amounts of myeloperoxidase (MPO) and neutrophil elastase (NE) in patient sera and granulocytes and monocytes. Because the autonomous nervous system is thought to mediate stroke-induced immune alterations, we also studied the influence of stress hormones and acetylcholine on MPO and NE. Rapid recanalization by recombinant tissue plasminogen activator (r-tPA) is the only available treatment for ischaemic stroke besides thrombectomy, and its influence on antibacterial defence mechanisms of granulocytes and monocytes were addressed here., Methods: Ex vivo: Intracellular and serum MPO and NE were measured on days 0, 1, 3 and 5 post-stroke by either flow cytometry or enzyme-linked immunosorbent assay (ELISA) and compared to controls. In vitro: Blood from healthy donors was incubated with catecholamines, dexamethasone and acetylcholine, and the percentage of NET-producing cells and the area covered by NETs were quantified immunohistochemically. Intra- and extracellular MPO and NE were quantified by flow cytometry or ELISA. Blood samples from healthy donors were incubated with r-tPA, and oxidative burst, phagocytosis, NETosis, cytokine release, MPO and NE were quantified by flow cytometry, ELISA and microscopy., Results: MPO was reduced in granulocytes but increased in sera obtained from stroke patients compared to controls. NE was not altered intracellularly but was elevated in patient sera. The percentage of NET-producing neutrophils was decreased by stress hormones and increased by acetylcholine. Neither intracellular MPO nor NE was altered by hormone treatment; however, adrenaline and acetylcholine induced NE release. r-tPA led to reduced phagocytosis and oxidative burst in granulocytes and monocytes in vitro. NETosis, MPO release and cytokines were not altered, whereas NE release was enhanced by r-tPA., Conclusions: Intracellular reduction of MPO might be responsible for reduced NETosis in stroke patients. The impact of enhanced MPO and NE serum levels in stroke patients should be addressed in future studies. r-tPA impaired antibacterial defence function in vitro. Therefore, patients who undergo unsuccessful recanalization therapy might be at higher risk for infection, which should be analysed in future investigations. Immune alterations due to r-tPA effects in stroke patients should also be investigated.

Objective: To investigate the risk factors for hemorrhagic transformation (HT) after intravenous thrombolysis using a recombinant tissue plasminogen activator (r-tPA) in acute cerebral infarction., Methods: Patients with acute cerebral infarction receiving r-tPA thrombolysis in Shanghai Eastern Hospital were retrospectively studied. Based on the cranial computed tomography or magnetic resonance imaging examination, after the intravenous thrombolysis, the patients were divided into 2 groups: an HT group and a non-HT group. The information was collected before or after thrombolysis., Results: A total of 162 patients were included in the analysis. The age ranged from 25 to 86 years, with an average age of 65.6 ± 10.6 years. The average time from disease onset to thrombolysis was 188 ± 53.1 minutes. Cranial computed tomography or magnetic resonance imaging showed that 20 patients (12.3%) had HT after thrombolysis. Using univariate analysis, history of atrial fibrillation, positive expression of urinary protein, and high National Institutes of Health Stroke Scale (NIHSS) score before thrombolysis, we found that there was a significant difference between the HT and non-HT group (P < 0.05) in the level of mean systolic pressure (MSP) 24 hours after thrombolysis. Multivariate logistic regression analysis indicated that age ≥80 years, MSP ≥140 mm Hg, NIHSS score, and fibrinogen concentration before thrombolysis were risk factors for HT after thrombolysis in patients with acute cerebral infarction., Conclusions: Age, MSP, NIHSS score, and fibrinogen concentration before thrombolysis are risk factors for HT after thrombolysis in acute cerebral infarction. These 4 factors should be carefully taken into account before thrombolysis., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The information about the thromboembolic events, the optimal treatment choice, the dose, and duration of antithrombotic therapy in children are limited. More clinical data are required. Recombinant tissue plasminogen activator (r-tPA) is increasingly used in pediatric thrombosis. We retrospectively analyzed the clinical course of 7 children (9.3 ± 2.1 years; 34 days to 16 years) with arterial thrombosis (n = 1) and intracardiac thrombosis (n = 6). The children were treated with r-tPA. The dose ranged between 0.2 and 0.4 mg/kg per h infused for 3 to 4 hours. This dose was repeated between 2 to 7 times till the thrombolysis was achieved. Treatment side effects were closely monitored. Complete clot lysis was achieved in all cases. None of them had severe bleeding except mild recurrent epistaxis occurring in 2 cases. In conclusion, r-tPA is an effective and safe therapy under close hemostatic control in children.

Unlabelled: Given the constraints of resources, thrombolysis for acute ischemic stroke (AIS) is under evaluation in developing countries like India, especially in areas such as western Utter Pradesh, where it is overly crowded and there is poor affordability., Aim: This study was done to evaluate recombinant tissue plasminogen activator r-tpa in acute ischemic stroke in hyper acute phase, in selected patients of western Utter Pradesh, in terms of feasibility and effectivity., Design: Open, non randomized study., Materials and Methods: Thirty two patients were classified using Trial of ORG 10172 in Acute Stroke treatment (TOAST) criteria (large artery atherosclerotic = 8; cardio embolic = 6; small vessel occlusion = 14; other determined etiology = 2; undetermined etiology = 2). The mean time to reach the hospital was 2 h (1.15-3.0), the mean door to CT scan 20 min (10-40) and door to r-tpa injection was 30 min (24-68). The National Institute of Health Stroke Scale (NIHSS) scores ranged from 11-22 (mean 15.5 +2.7). The dose of r-tpa administered was 0.9 mg/kg., Results: Twenty one patients (65.6%) showed significant improvement on the NIHSS score, at 48 h (4 points). (Mean change = 10; range = 4-17). At one month, 25 (78%) recorded improvement on the Barthel index (mean change = 45%). One developed frontal lobe hemorrhage and another developed recurrent stroke; one died of aspiration; and four showed no improvement. Modified Rankin score (m RS) was administered at the end of three months to 28 patients (90%); however, the rest could not be directly observed. The average modified Rankin Score was 1.2 (0-2)., Conclusions: Hyperacute thrombolysis was found feasible and effective in selected patients with AIS from western Utter Pradesh and who had poor affordability.