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Background: Thrombolytic recombinant tissue plasminogen activator (r-tPA) treatment is the only pharmacologic intervention available in the ischemic stroke acute phase. This treatment is associated with an increased risk of intracerebral hemorrhages, known as hemorrhagic transformations (HTs), which worsen the patient's prognosis., Objectives: To investigate the association between genetically determined natural hemostatic factors' levels and increased risk of HT after r-tPA treatment., Methods: Using data from genome-wide association studies on the risk of HT after r-tPA treatment and data on 7 hemostatic factors (factor [F]VII, FVIII, von Willebrand factor [VWF], FXI, fibrinogen, plasminogen activator inhibitor-1, and tissue plasminogen activator), we performed local and global genetic correlation estimation multitrait analyses and colocalization and 2-sample Mendelian randomization analyses between hemostatic factors and HT., Results: Local correlations identified a genomic region on chromosome 16 with shared covariance: fibrinogen-HT, P = 2.45 × 10 -11 . Multitrait analysis between fibrinogen-HT revealed 3 loci that simultaneously regulate circulating levels of fibrinogen and risk of HT: rs56026866 (PLXND1), P = 8.80 × 10 -10 ; rs1421067 (CHD9), P = 1.81 × 10 -14 ; and rs34780449, near ROBO1 gene, P = 1.64 × 10 -8 . Multitrait analysis between VWF-HT showed a novel common association regulating VWF and risk of HT after r-tPA at rs10942300 (ZNF366), P = 1.81 × 10 -14 . Mendelian randomization analysis did not find significant causal associations, although a nominal association was observed for FXI-HT (inverse-variance weighted estimate [SE], 0.07 [-0.29 to 0.00]; odds ratio, 0.87; 95% CI, 0.75-1.00; raw P = .05)., Conclusion: We identified 4 shared loci between hemostatic factors and HT after r-tPA treatment, suggesting common regulatory mechanisms between fibrinogen and VWF levels and HT. Further research to determine a possible mediating effect of fibrinogen on HT risk is needed., Competing Interests: Declaration of competing interests There are no competing interests to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Rationale and Objectives: A significant complication of endovascular treatment (EVT) is hemorrhagic transformation (HT), which can worsen the outcomes of patients with acute ischemic stroke (AIS). This study aimed to evaluate the predictive value of venous collateral circulation on HT in patients with AIS undergoing EVT., Materials and Methods: We retrospectively analyzed 126 patients with AIS who received EVT. The four-dimensional computed tomography angiography-based venous collateral score (4D-VCS) and arterial collateral circulation score (4D-ACS) were used to assess venous and arterial collaterals, respectively. Significant variables were identified using the least absolute shrinkage and selection operator algorithm. Logistic regression analysis, receiver operating characteristic (ROC) analysis, and DeLong's test were conducted., Results: HT occurred in 41.3% (52/126) of patients. Higher clot burden score (CBS; odds ratio [OR]: 0.82, 95% confidence interval [CI]: 0.71-0.95, p = 0.009), better arterial collateral circulation (OR: 0.59, 95% CI: 0.42-0.83, p = 0.003), and better venous collateral circulation (OR: 0.85, 95% CI: 0.73-0.97, p = 0.020) were significantly associated with reduced HT risk. The area under the curve (AUC) values for CBS, 4D-ACS, and 4D-VCS were 0.730, 0.772, and 0.795, respectively. Model 1 (4D-VCS+CBS) achieved AUC of 0.820, significantly improving over CBS alone (p = 0.0133). Model 2 (4D-VCS+4D-ACS) had an AUC of 0.829, significantly higher than 4D-ACS alone (p = 0.0271). Model 3 (4D-ACS+CBS) had an AUC of 0.790. Model 4 (4D-VCS+4D-ACS+CBS) showed highest AUC of 0.851. Significant correlations were found between 4D-VCS and ischemic core volume (r = -0.684, p < 0.001) and between 4D-VCS and mismatch ratio (r = 0.558, p < 0.001)., Conclusion: Evaluating venous collateral circulation using 4D-VCS could improve HT risk prediction in patients with AIS after EVT. When combined with other predictors, 4D-VCS may potentially enhance diagnostic performance, which suggests the potential role of venous collateral circulation in predicting HT risk., 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 © 2024 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

LT3001 is a novel synthetic small molecule with thrombolytic and free radical scavenging activities. In this study, we tested the effects of LT3001 as a potential alternative thrombolytic in focal embolic ischemic stroke rat model. Stroked rats received intravenous injection of 10 mg/kg LT3001 or tPA at 1.5, 3, or 4.5 h after stroke, respectively, and the outcomes were measured at different time points after stroke by performing multi-parametric MRI, 2,3,5-triphenyltetrazolium chloride (TTC) staining, and modified neurological severity score. Lastly, we assessed the effect of LT3001 on the tPA activity in vitro, the international normalized ratio (INR), and the serum levels of active tPA and plasminogen activator inhibitor-1 (PAI-1). LT3001 treated at 1.5 h after stroke is neuroprotective by reducing the CBF lesion size and lowering diffusion and T2 lesion size measured by MRI, which is consistent with the reduction in TTC-stained infarction. When treated at 3 h after stroke, LT3001 had significantly better therapeutic effects regarding reduction of infarct size, swelling rate, and hemorrhagic transformation compared to tPA. When treated at 4.5 h after stroke, tPA, but not LT3001, significantly increased brain swelling and intracerebral hemorrhagic transformation. Lastly, LT3001 did not interfere with tPA activity in vitro, or significantly alter the INR and serum levels of active tPA and PAI-1 in vivo. Our data suggests that LT3001 is neuroprotective in focal embolic stroke rat model. It might have thrombolytic property, not interfere with tPA/PAI-1 activity, and cause less risk of hemorrhagic transformation compared to the conventional tPA. Taken together, LT3001 might be developed as a novel therapy for treating thrombotic ischemic stroke., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

To investigate the predictive role of the neutrophil-platelet ratio (NPR) before intravenous thrombolysis (IVT) on hemorrhagic transformation (HT) in patients with acute ischemic stroke (AIS). AIS patients treated with IVT without endovascular therapy between June 2019 and February 2023 were included. Patients were divided into high NPR (>35) and low NPR (≤35) groups according to the optimal threshold NPR value for identifying high-risk patients before IVT. The baseline data and the incidence of HT and symptomatic intracranial hemorrhage (sICH) were compared between the two groups. The predictive role of the NPR and other related factors on HT after IVT was analyzed by multivariate logistic regression. A total of 247 patients were included, with an average age of 67.5 ± 12.4 years. Post-thrombolytic HT was observed in 18.6% of the patients, and post-thrombolytic sICH was observed in 1.2% of the patients. There were 69 patients in the high NPR group and 178 patients in the low NPR group. The incidence of HT in the high NPR group was significantly higher than that in the low NPR group (30.4% vs 16.3%, P  < .05). The incidence of sICH was significantly higher in the high NPR group than in the low NPR group (14.5% vs 1.7%, P  < .001). Multivariate logistic regression analysis showed that NPR > 35 was positively correlated with HT (odds ratio (OR) = 3.236, 95% confidence interval (CI): 1.481-7.068, P  = .003) and sICH (OR = 13.644, 95% CI: 2.392-77.833, P  = .003). A high NPR (>35) before IVT may be a predictor of HT in AIS patients. This finding may help clinicians make clinical decisions before IVT in AIS patients., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: The study goal was the assessment of heterogeneous treatment effects of Cerebrolysin as an early add-on to reperfusion therapy in stroke patients with varying risk of hemorrhagic transformation (HT)., Material and Methods: It was post hoc analysis of the CEREHETIS trial (ISRCTN87656744). Patients with middle cerebral artery infarction ( n =238) were stratified by HT risk with the HTI score. The study outcomes were symptomatic and any HT, and functional outcome measured with the modified Rankin Scale (mRS) on day 90. Favorable outcome was defined as an mRS score of ≤2. Heterogeneous treatment effect analysis was performed using techniques of meta-analysis and the matching-smoothing method., Results: Heterogeneity of Cerebrolysin treatment effects was moderate (I 2 =36.98-69.3%, H 2 =1.59-3.26) and mild (I 2 =18.33-32.39%, H 2 =1.22-1.48) for symptomatic and any HT, respectively. A positive impact of the Cerebrolysin treatment on HT and functional outcome was observed in patients with moderate (HTI=1) and high (HTI≥2) HT risk. However, the effect was neutral in those with low risk (HTI=0). In high HT risk patients, there was a steady decline in the rate of symptomatic (HTI=0 vs. HTI≥2: by 3.8%, p =0.120 vs. 14.3%, p <0.001) and any HT (HTI=0 vs. HTI≥2: by 0.6%, p =0.864 vs. 19.5%, p <0.001). Likewise, Cerebrolysin treatment resulted in an overall decrease in the mRS scores (HTI=0 vs. HTI≥2: by 2.1%, p =0.893 vs. 63%, p <0.001) with a reciprocal increase of the fraction with favorable outcome (HTI=0 vs. HTI≥2: by 2% p =0.634 vs. 19.2%, p <0.001)., Conclusion: Clinically meaningful heterogeneity of Cerebrolysin treatment effects on HT and functional outcome was established in stroke patients. The Cerebrolysin positive impact was significant in those whose estimated on-admission HT risk was either moderate or high.

Background and Purpose: Hemorrhagic transformation (HT) has been reported in up to 50% of acute ischemic stroke (AIS) patients with a large vessel occlusion (LVO) treated with endovascular thrombectomy (EVT). HT may be driven by postrecanalization hyperperfusion injury and is independently associated with worse functional outcomes. Strategies to identify patients at risk for HT may assist in developing preventive therapies., Methods: We prospectively included adult AIS patients with an anterior circulation LVO achieving successful recanalization after EVT. Consenting participants received transcranial Doppler ultrasound (TCD) within 18 hours of procedure completion. We compared flow velocities according to the presence of HT on the computed tomography scan performed within the first 24±12 hours from the end of EVT. We also evaluated the association of flow velocities with systemic blood pressure (BP) readings at the time of insonation., Results: A total of 48 patients consented to participate in the study. Six (12%) were excluded due to the absence of temporal windows. HT was detected in 20 participants (48%). Those with HT had higher peak systolic velocities on the middle cerebral arteries compared to those without HT for both the symptomatic (107±42 vs. 82±25 cm/second, p = .024) and asymptomatic (97±21 vs. 81±25 cm/second, p = .040) sides. No correlation of flow velocities on either the symptomatic or asymptomatic side and BP measurements at the time of insonation was detected., Conclusion: TCD can identify patients at risk of HT following successful EVT. TCD could serve as an inexpensive ancillary test to guide participant selection for clinical trials targeting postprocedural reperfusion injury., (© 2023 The Authors. Journal of Neuroimaging published by Wiley Periodicals LLC on behalf of American Society of Neuroimaging.)

Cerebral ischemia reperfusion (I/R) is one of the neurovascular diseases which leads to severe brain deterioration. Haemorrhagic transformation (HT) is the main complication of ischemic stroke. It exacerbates by reperfusion, causing a more deleterious effect on the brain and death. The current study explored the protective effect of sertraline (Sert) against cerebral I/R in rats by inhibiting HT, together with the molecular pathways involved in this effect. Forty-eight wister male rats were divided into 4 groups: Sham, Sert + Sham, I/R, and Sert + I/R. The ischemic model was induced by bilateral occlusion of the common carotid artery for 20 min, then reperfusion for 24 h. Sertraline (20 mg/kg, p.o.) was administrated for 14 days before exposure to ischemia. Pre-treatment with Sert led to a significant attenuation of oxidative stress and inflammation. In addition, Sert attenuated phosphorylation of extracellular regulated kinases and nuclear factor kappa-p65 expression, consequently modulating microglial polarisation to M2 phenotype. Moreover, Sert prevented the hemorrhagic transformation of ischemic stroke as indicated by the notable decrease in neuronal expression of CD163, activity of Heme oxygenase-2 and matrix metalloproteinase-2 and 9 levels. In the same context, Sert decreased levels of autophagy and apoptotic markers. Furthermore, histological examination, Toluidine blue, and Prussian blue stain aligned with the results. In conclusion, Sert protected against cerebral I/R damage by attenuating oxidative stress, inflammation, autophagy, and apoptotic process. It is worth mentioning that our study was the first to show that Sert inhibited hemorrhagic transformation. The protective effect of sertraline against injury induced by cerebral ischemia reperfusion via inhibiting Hemorrhagic transformation., (© 2023. The Author(s).)

Background: The optimal timing of initiating or resuming anticoagulation after acute ischemic stroke (AIS) or transient ischemic attack (TIA) in patients with atrial fibrillation (AF) is debated. Dabigatran, a non-vitamin K oral anticoagulant (NOAC), has shown superiority against vitamin K antagonists (VKA) regarding hemorrhagic complications., Aims: In this registry study, we investigated the initiation of dabigatran in the early phase after AIS or TIA., Methods: PRODAST (Prospective Record of the Use of Dabigatran in Patients with Acute Stroke or TIA) is a prospective, multicenter, observational, post-authorization safety study. We recruited 10,039 patients at 86 German stroke units between July 2015 and November 2020. A total of 3,312 patients were treated with dabigatran or VKA and were eligible for the analysis that investigates risks for major hemorrhagic events within 3 months after early (⩽ 7 days) or late (> 7 days) initiation of dabigatran or VKA initiated at any time. Further endpoints were recurrent stroke, ischemic stroke, TIA, systemic embolism, myocardial infarction, death, and a composite endpoint of stroke, systemic embolism, life-threatening bleeding and death., Results: Major bleeding event rates per 10,000 treatment days ranged from 1.9 for late administered dabigatran to 4.9 for VKA. Early or late initiation of dabigatran was associated with a lower hazard for major hemorrhages as compared to VKA use. The difference was pronounced for intracranial hemorrhages with an adjusted hazard ratio (HR) of 0.47 (95% confidence interval (CI): 0.10-2.21) for early dabigatran use versus VKA use and an adjusted HR of 0.09 (95% CI: 0.00-13.11) for late dabigatran use versus VKA use. No differences were found between early initiation of dabigatran versus VKA use regarding ischemic endpoints., Conclusions: The early application of dabigatran appears to be safer than VKA administered at any time point with regards to the risk of hemorrhagic complications and in particular for intracranial hemorrhage. This result, however, must be interpreted with caution in view of the low precision of the estimate., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: H-CD has received honoraria for participation in clinical trials, contribution to advisory boards or oral presentations from: Abbott, BMS, Boehringer Ingelheim, Daiichi-Sankyo, Novo-Nordisk, Pfizer, Portola, and WebMD Global. Boehringer Ingelheim provided financial support for research projects. H-CD received research grants from the German Research Council (DFG) and German Ministry of Education and Research (BMBF). H-CD serves as editor of Neurologie up2date, Info Neurologie & Psychiatrie and Arzneimitteltherapie, as co-editor of Cephalalgia, and on the editorial board of Lancet Neurology and Drugs. GR received speaker’s honoraria and reimbursement for congress traveling and accommodation from Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo and Pfizer. SP received research support from BMS/Pfizer, Boehringer-Ingelheim, Daiichi Sankyo, European Union, German Federal Joint Committee Innovation Fund, and German Federal Ministry of Education and Research, Helena Laboratories and Werfen as well as speakers’ honoraria/consulting fees from Alexion, AstraZeneca, Bayer, Boehringer-Ingelheim, BMS/Pfizer, Daiichi Sankyo, Portola, and Werfen (all outside the submitted work). KG received support by Alexion Pharma Germany GmbH, Abbott Medical GmbH, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer Pharma GmbH, Springer Medizin Verlag GmbH. CCE is an employee of Boehringer Ingelheim. The other authors declare no conflicts of interest related to the content of the presented work.

Background: Predictors of radiological complications attributable to reperfusion injury remain unknown when baseline setting is optimal for endovascular treatment and procedural setting is the best in stroke patients with large vessel occlusion (LVO)., Aims: To identify clinical and radiological/procedural predictors for hemorrhagic transformation (HT) and cerebral edema (CED) at 24 hr in patients obtaining complete recanalization in one pass of thrombectomy for ischemic stroke ⩽ 6 h from symptom onset with intra-cranial anterior circulation LVO and ASPECTS ⩾ 6., Methods: We conducted a cohort study on prospectively collected data from 1400 patients enrolled in the Italian Registry of Endovascular Treatment in Acute Stroke., Results: HT was reported in 248 (18%) patients and early CED was reported in 260 (19.2%) patients. In the logistic regression model including predictors from a first model with clinical variables and from a second model with radiological/procedural variables, diabetes mellitus (odds ratio (OR) = 1.832, 95% confidence interval (CI) = 1.201-2.795), higher National Institutes of Health Stroke Scale (NIHSS) (OR = 1.076, 95% CI = 1.044-1.110), lower Alberta Stroke Program Early CT (ASPECTS) (OR = 0.815, 95% CI = 0.694-0.957), and longer onset-to-groin time (OR = 1.005, 95% CI = 1.002-1.007) were predictors of HT, whereas general anesthesia was inversely associated with HT (OR = 0.540, 95% CI = 0.355-0.820). Higher NIHSS (OR = 1.049, 95% CI = 1.021-1.077), lower ASPECTS (OR = 0.700, 95% CI = 0.613-0.801), intravenous thrombolysis (OR = 1.464, 95% CI = 1.061-2.020), longer onset-to-groin time (OR = 1.002, 95% CI = 1.001-1.005), and longer procedure time (OR = 1.009, 95% CI = 1.004-1.015) were predictors of early CED. After repeating a fourth logistic regression model including also good collaterals, the same variables remained predictors for HT and/or early CED, except diabetes mellitus and thrombolysis, while good collaterals were inversely associated with early CED (OR = 0.385, 95% CI = 0.248-0.599)., Conclusions: Higher NIHSS, lower ASPECTS, and longer onset-to-groin time were predictors for both HT and early CED. General anesthesia and good collaterals were inversely associated with HT and early CED, respectively. Longer procedure time was predictor of early CED., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Manuel Cappellari received consultancy or advisory board fees or speaker’s honoraria from Boehringer Ingelheim, Pfizer/Bristol Meyer Squibb, and Daiichi Sankyo. Andrea Zini received consulting fees from Boehringer-Ingelheim consulting fees from Boehringer-Ingelheim, Alexion and CLS Behring. All other authors report no conflicts of interest. The other authors report no conflicts.

Ischemic stroke is one of the major causes of devastating neurological disabilities and mortality worldwide. Despite extensive research for treatment approaches, there remains limited therapy in the stroke field. Therefore, more research is required for reproducibility to understand stroke pathology in pre-clinical studies. In the current modified method, mice were subjected to photothrombotic stroke (pt-MCA; proximal-middle cerebral artery was exposed with a 532 nm laser beam for 4 min) by retro-orbital injection of photosensitive dye, Rose Bengal (15 mg/kg) before the laser light exposure. Sensorimotor deficits were assessed by rotarod and catwalk test at 72 h following post-pt-MCAO, and brain samples were collected for infarct volume and hemorrhagic transformation (HT) assessments. Cognitive impairments were assessed by a novel objective recognition and Morris's water maze tests at the end of the follow-up. pt-MCAO animals significantly reduced body weight and impaired motor and cognitive functions. Furthermore, pt-MCAO animals showed apparent infarction, brain edema, and increased HT compared to the sham animals. Additionally, this method enables concurrent measurement of short-term and long-term neurological dysfunction with relatively larger cortical and sub-cortical infarct volume following pt-MCAO. With respect to the other models, this modified model offers enhanced reproducibility regarding infarct volume and cognitive/functional outcomes and avoids complications associated with critical surgeries and craniotomy. In conclusion, this modified model helps to understand stroke pathogenesis and minimize the animals' numbers which help to increase the scientific and statistical potential in pre-clinical studies., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Posterior reversible encephalopathy syndrome (PRES) is considered a benign entity and is usually reversible with only medical management, but persistent neurologic deficits and disability or death can occur without adequate treatment. Favorable outcomes have been associated with surgical decompression in malignant-type PRES in which hemorrhagic transformation or brain stem compression has developed., Case Description: Here we report a case of malignant PRES in a 61-year-old female of Asian descent in which the disease rapidly progressed to coma and a near-fatal condition with uncal herniation caused by severe brain edema; however, this patient achieved a dramatic recovery without surgical decompression., Conclusion: After reviewing previous reports regarding malignant PRES, we propose that hemorrhagic transformation is a crucial indicator for surgical decompression and an important prognostic factor in malignant PRES.

Introduction: The routinely used computed tomography (CT)-based workup in the setting of acute ischemic stroke (AIS) includes non-contrast brain CT, CT angiography (CTA), and CT perfusion. Several CT, CTA, CTP-based radiological biomarkers of hemorrhagic transformation (HT) were reported., Aim of the Study: To assess the predictive value of the combined multimodal CT parameters for HT after AIS and proposal of predictive scoring scale., Methods: The source images of the NCCT, CTA and CTP of 282 AIS patients involving the anterior circulation (HT = 91, non-HT = 191) were retrospectively reviewed and the following biomarkers were recorded and analyzed: Early subtle ischemic signs, hyperdense middle cerebral artery sign (HMCAS) and Alberta Stroke Program Early CT Score (ASPECTS) < 7 in NCCT, large-vessel occlusion (LVO), clot burden score (CBS) < 6, large-vessel occlusion, poor collateral score (CS) and Tmax > 6 s ≥ 56.5 ml. A scoring system to predict HT based on these biomarkers was developed. Each biomarker counts for a single point with the total score ranging from 0 to 7., Results: All the aforementioned multimodal CT biomarkers and the selected cut offs were significantly associated with higher HT risk. The calculated scores were statistically significant different between the HT and the non-HT groups with AUC 0.761 (95% CI 0.703-0.819, P < 0.0000001). Rates of HT were approximately five times higher in patients with score ≥ 3., Conclusion: Multimodal CT-based scoring system may provide highly reliable predictive model of hemorrhagic transformation in acute ischemic stroke., (© 2023. The Author(s) under exclusive licence to Belgian Neurological Society.)

Objectives: Dual-energy CT allows differentiation between blood and iodinated contrast. We aimed to determine predictors of subarachnoid and intraparenchymal hemorrhage on dual-energy CT performed immediately post-thrombectomy and the impact of these hemorrhages on 90-day outcomes., Materials and Methods: A retrospective analysis was performed on patients who underwent thrombectomy for anterior circulation large-vessel occlusion and subsequent dual-energy CT at a comprehensive stroke center from 2018-2021. The presence of contrast, subarachnoid hemorrhage, or intraparenchymal hemorrhage immediately post-thrombectomy was assessed by dual-energy CT. Univariable and multivariable analyses were performed to identify predictors of post-thrombectomy hemorrhages and 90-day outcomes. Patients with unknown 90-day mRS were excluded., Results: Of 196 patients, subarachnoid hemorrhage was seen in 17, and intraparenchymal hemorrhage in 23 on dual-energy CT performed immediately post-thrombectomy. On multivariable analysis, subarachnoid hemorrhage was predicted by stent retriever use in the M2 segment of MCA (OR,4.64;p=0.017;95%CI,1.49-14.35) and the number of thrombectomy passes (OR,1.79;p=0.019;95%CI,1.09-2.94;per an additional pass), while intraparenchymal hemorrhage was predicted by preprocedural non-contrast CT-based ASPECTS (OR,8.66;p=0.049;95%CI,0.92-81.55;per 1 score decrease) and preprocedural systolic blood pressure (OR,5.10;p=0.037;95%CI,1.04-24.93;per 10 mmHg increase). After adjusting for potential confounders, intraparenchymal hemorrhage was associated with worse functional outcomes (OR,0.25;p=0.021;95%CI,0.07-0.82) and mortality (OR,4.30;p=0.023,95%CI,1.20-15.36), while subarachnoid hemorrhage was associated with neither., Conclusions: Intraparenchymal hemorrhage immediately post-thrombectomy was associated with worse functional outcomes and mortality and can be predicted by low ASPECTS and elevated preprocedural systolic blood pressure. Future studies focusing on management strategies for patients presenting with low ASPECTS or elevated blood pressure to prevent post-thrombectomy intraparenchymal hemorrhage are warranted., Competing Interests: Declaration of Competing Interest None, (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Precise risk of hemorrhagic transformation (HT) in acute ischemic stroke (AIS) remains unknown, leading to delays in anticoagulation initiation for secondary stroke prevention. We sought to assess the rate of HT associated with direct oral anticoagulant (DOAC) initiation within and beyond 48 h post-AIS., Methods: A pooled analysis of DOAC initiation within 14 days of AIS or transient ischemic attack (TIA) was conducted with six studies (four prospective open label treatment, blinded outcome studies and two randomized trials; NCT02295826 and NCT02283294). The primary endpoint was incident radiographic HT on follow-up imaging (days 7-30). Secondary endpoints included symptomatic HT, new parenchymal hemorrhage, recurrent ischemic events, extracranial hemorrhage, study period mortality, and follow-up modified Rankin Scale score. The results were reported as odds ratio (OR) or hazard ratio (HR) with 95% confidence interval (CI)., Results: We evaluated 509 patients; median infarct volume was 1.5 (0.1-7.8) ml, and median National Institutes of Health Stroke Scale was 2 (0-3). Incident radiographic HT was seen on follow-up scan in 34 (6.8%) patients. DOAC initiation within 48 h from index event was not associated with incident HT (adjusted OR 0.67, [0.30-1.50] P  = 0.32). No patients developed symptomatic HT. Conversely, 31 (6.1%) patients developed recurrent ischemic events, 64% of which occurred within 14 days. Initiating a DOAC within 48 h of onset was associated with similar recurrent ischemic event rates compared with those in which treatment was delayed (HR: 0.42, [0.17-1.008] P  = 0.052). In contrast to HT, recurrent ischemic events were associated with poor functional outcomes (OR = 6.8, [2.84-16.24], p < 0.001)., Conclusions: In this pooled analysis, initiation of DOAC within 48 h post-stroke was not associated with increased incident risk of HT, and none developed symptomatic HT. The analysis was underpowered to determine the effect of early DOAC use upon recurrent ischemic events.

Objective: To observe the effects of the Xingnao Kaiqiao (regaining consciousness and opening orifices) acupuncture on hemorrhagic transformation and limb motor function after intravenous thrombolysis with recombinant tissue plasminogen activator (rt-PA) in stroke patients., Methods: A total of 130 stroke patients after rt-PA thrombolytic were divided into an acupuncture group (58 cases, 1 case dropped off) and a non-acupuncture group (72 cases, 7 cases dropped off) according to whether they received acupuncture treatment. Propensity score matching (PSM) was used to match each group, with 38 patients in each group. The patients in the non-acupuncture group received rt-PA thrombolytic therapy and western medical basic treatment. In addition to the basic treatment, the patients in the acupuncture group received Xingnao Kaiqiao acupuncture at Shuigou (GV 26), bilateral Neiguan (PC 6), and ipsilateral Sanyinjiao (SP 6), Chize (LU 5), once a day for 14 days. The incidence of hemorrhagic transformation within 30 days after onset was compared between the two groups. The Fugl-Meyer assessment (FMA) score and activities of daily living (ADL) score were observed at baseline and 30 days, 6 months, 1 year after onset in the two groups. The disability rate at 6 months and 1 year after onset was recorded, and safety was evaluated in both groups., Results: The incidence of hemorrhagic transformation in the acupuncture group was 5.3% (2/38), which was lower than 21.1% (8/38) in the non-acupuncture group ( P <0.05). At 30 days, 6 month, and 1 year after onset, the FMA and ADL scores of both groups were higher than those at baseline ( P <0.01), and the scores in the acupuncture group were higher than those in the non-acupuncture group ( P <0.01). The disability rate in the acupuncture group at 1 year after onset was 10.5% (4/38), which was lower than 28.9% (11/38) in the non-acupuncture group ( P <0.05). There was no significant difference in the incidence of adverse events between the two groups ( P >0.05)., Conclusion: The Xingnao Kaiqiao acupuncture method could reduce the incidence of hemorrhagic transformation in stroke patients after intravenous thrombolysis with rt-PA, improve their motor function and daily living ability, and reduce the long-term disability rate.

Background: The incidence of hemorrhagic transformation (HT) during thrombolysis after acute cerebral infarction (ACI) is very high. We aimed to develop a model to predict the occurrence of HT after ACI and the risk of death after HT., Methods: Cohort 1 is divided into HT and non-HT groups, to train the model and perform internal validation. All first laboratory test results of study subjects were used as features to be selected for machine learning, and the models built by four machine learning algorithms were compared to screen the best algorithm and model. Following that, the HT group was divided into death and non-death for subgroup analysis. Receiver operating characteristic (ROC) curves etc. to evaluate the model. ACI patients in cohort 2 for external validation., Results: In cohort 1, the HT risk prediction model HT-Lab10 built by the XgBoost algorithm performed the best with AUC ROC =0.95 (95% CI, 0.93-0.96). Ten features were included in the model, namely B-type natriuretic peptide precursor, ultrasensitive C-reactive protein, glucose, absolute neutrophil value, myoglobin, uric acid, creatinine, Ca 2+ , Thrombin time, and carbon dioxide combining power. The model also had the ability to predict death after HT with AUC ROC =0.85 (95% CI, 0.78-0.91). The ability of HT-Lab10 to predict the occurrence of HT as well as death after HT was validated in cohort 2., Conclusions: The model HT-Lab10 built using the XgBoost algorithm showed excellent predictive ability in both the occurrence of HT and the risk of HT death, achieving a model with multiple uses., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Patients with atrial fibrillation (AF) and ischemic stroke are at high risk for stroke recurrence. Early anticoagulation may reduce the risk of recurrent events but is usually avoided due to the risk of hemorrhagic transformation (HT). Current guidelines are based on empiric expert opinion. The assumed risk of HT is based on historical data from an older generation of anticoagulants. The direct oral anticoagulants (DOACs) have demonstrated lower risk of intracranial hemorrhage compared to older anticoagulants. However, the optimal timing of DOAC initiation after AF-related ischemic stroke has remained an area of clinical equipoise, as the pivotal phase III trials did not include patients in the early period after ischemic stroke. Multiple prospective studies and a few smaller randomized controlled trials evaluating the safety and efficacy of early versus delayed DOAC initiation have been completed. These studies have reported promising results of early DOAC initiation after acute ischemic stroke. However, a standardized documentation of HT rates on follow-up imaging with objective assessment criteria is missing from most of these studies. Larger randomized trials of early versus delayed DOAC are ongoing. A literature review was performed using keywords and Medical Subject Headings in MEDLINE/PubMed and Google Scholar databases. For each relevant paper, the bibliography was scrutinized for other relevant articles and journals. In this article, we review the risk of recurrent ischemic stroke and HT in patients with AF, pathophysiology, classification, predictors, natural history, and outcomes of HT and discuss the studies of early anticoagulation after AF-related ischemic stroke.

Aims: This review focuses on the recent literature regarding the role of the gut-brain axis (GBA) following ischemic stroke., Discussion: Stroke is the 5th leading cause of death and disability in the United States; however, few therapies have been developed to improve prognoses. There is a plethora of evidence suggesting peripheral inflammatory responses play a large role in the pathogenesis of stroke. Additionally, hyperglycemic conditions may play a significant role in worsening stroke outcomes due to microbiome dysbiosis., Conclusion: Recent research has illuminated the vital role of the GBA in propagating poor clinical outcomes, such as hemorrhagic transformation, following ischemic stroke. Considering this detrimental consequence of stroke, and the apparent role of the GBA role, future therapeutics should aim to mitigate this peripheral contribution to stroke complications., (© 2022 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd.)

Background and Purpose: Inflammation and immune response play an important role in hemorrhage transformation after acute ischemic stroke. According to previous studies, systemic immune-inflammation index is associated with severity of stroke. We aimed to evaluate the association between systemic immune-inflammation index and hemorrhage transformation in anterior circulation acute ischemic stroke due to large-artery atherosclerosis., Methods: This was a retrospective analysis of patients with anterior circulation acute ischemic stroke due to large-artery atherosclerosis. The laboratory data were collected within 24 h after admission. Hemorrhage transformation was defined on follow-up magnetic resonance imaging or Computed Tomography. The univariate analysis and multivariate logistic regression were performed to assess the association of systemic immune-inflammation index with hemorrhage transformation. Then the relationship between systemic immune-inflammation index and hemorrhage transformation in different stroke subtypes was further studied., Results: We included 310 Chinese anterior circulation acute ischemic stroke patients due to large-artery atherosclerosis (mean age 65 ± 11.4 years; 72.6% male). Hemorrhage transformation occurred in 41 patients (13.2%). After multivariate regression analyses, systemic immune-inflammation index (odds ratio [OR] 1.109, 95% Confidence Interval [CI] 1.054-1.167, p ＜0.001) was independently associated with hemorrhage transformation. Systemic immune-inflammation index was found to be significantly related to hemorrhagic transformation in artery-to-artery embolization (OR 1.111, 95% CI 1.029-1.210, p ＜0.001) and in-situ thrombosis (OR 1.059, 95% CI 1.011-1.194, p  = 0.045)., Conclusions: Higher systemic immune-inflammation index is associated with greater risk of hemorrhagic transformation in patients with anterior circulation acute ischemic stroke due to large-artery atherosclerosis, especially in artery-to-artery embolization and in-situ thrombosis.

Ischemic stroke (IS) remains one of the most frequent causes of death and disability worldwide. Identifying possible prognosis factors for IS outcomes, including hemorrhagic transformation (HT), could improve patients' recovery. This study aimed to investigate the potential prognosis role of non-specific laboratory data at admission and baseline MMP-2 and MMP-9 serum levels in predicting HT risk, discharge, and 3-month follow-up status of IS patients. Data from 150 successive acute cerebral infarction patients were analyzed in a prospective cohort study. The active group included patients who developed HT during hospitalization (55 persons). There were no significant differences in age, gender distribution, time to admission, or time to blood sample collection for MMPs measurement between patients in the active and control groups. IS patients from the active group had a significantly higher rate of AF (atrial fibrillation) in the past (p=0.003), while differences in other factors such as diabetes, hypertension, myocardial infarction, previous stroke, obesity, smoking, and alcohol were not significant. Admission NIHSS score and mRS (modified Rankin Scale) values (at discharge and 90 days) were significantly worse in the active group (p<0.001). Among the analyzed admission laboratory factors (glycemia, lipid profile, coagulation panel, inflammatory reaction parameters, MMP-2, MMP-9), INR presented an inverse correlation, with lower values in the HT cohort (univariate analysis - p=0.01, OR=0.11; multivariate analysis - p=0.03, OR=0.09). Further research on larger cohorts is warranted to determine the specific laboratory biomarkers for predicting hemorrhagic transformation and ischemic stroke outcomes., Competing Interests: The authors declare no conflict of interest., (©2023 JOURNAL of MEDICINE and LIFE.)

Objective: The aim of this study was to evaluate the predictive value of the early venous filling (EVF) sign, the basal ganglia blush (BGB) sign and both the EVF and BGB signs for the hemorrhagic transformation (HT) and parenchymal hematoma (PH) in patients after endovascular thrombectomy., Methods: This study included patients with anterior circulation large vessel occlusive stroke treated with endovascular thrombectomy from May 2017 to December 2021. The predictive value of regional circulation signs for HT and PH were assessed using logistic regression models adjusted for confounders, and further a multiplicative interaction term was added to investigate the effect of different stroke severity on its predictive value., Results: Among the 350 patients included and after adjusting for confounders, those with the EVF sign (adjusted OR=3.934, 95% CI:2.326-6.655), the BGB sign (adjusted OR=3.776, 95% CI:2.341-6.089), and both the EVF and BGB signs (adjusted OR=3.250, 95% CI: 1.886-5.600) were more likely to have HT. The EVF sign (adjusted OR=3.545, 95% CI:2.036-6.170), the BGB sign (adjusted OR=3.742, 95% CI:2.110-6.639), and both the EVF and BGB signs (adjusted OR=3.139, 95% CI: 1.776-5.549) were also significantly correlated with PH. When stratified according to stroke severity, we further found there were significant interactions between regional circulation signs and stroke severity on postoperative HT and PH (all P for interaction < 0.001)., Conclusions: Regional circulation signs were independently associated with HT and PH after endovascular thrombectomy and had a higher predictive value in patients with severe stroke compared with mild to moderate stroke., Competing Interests: Conflicts of interest The authors declare that they have no known competing financial or personal relationships that could be viewed as influencing the work reported in this paper., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Background and Purpose: Hemorrhagic transformation (HT) is the most serious complication of intravenous thrombolysis in ischemic stroke patients. Inflammation plays a critical role in the pathological progression of HT. This study was to explore the relationship between fibrinogen-to-albumin ratio (FAR), a novel systemic inflammation biomarker, and HT after intravenous thrombolysis in patients with ischemic stroke., Methods: This retrospective study enrolled ischemic stroke patients who underwent intravenous thrombolysis between Jan 2017 to May 2022. The characteristic data of all patients at admission were retrospectively collected. The univariate and multivariate logistic regression analyses were performed to evaluate the correlation between FAR and HT after intravenous thrombolysis. The optimal cut-off value of FAR for predicting HT was determined by the receiver operating characteristic curve., Results: A total of 363 ischemic stroke patients were enrolled in the present study. Sixty-two patients had HT after intravenous thrombolysis. In multivariate regression analysis, FAR was significantly associated with HT (odds ratio [OR], 1.105; 95% confidential interval [CI], 1.029-1.186, P = 0.006). The receiver operating characteristic curve analysis indicated FAR predicts HT after intravenous thrombolysis with an AUC of 0.613 (95%CI, 0.530-0.695; P = 0.005) and an optimal cut-off value of 0.101. The correlation between FAR and HT after intravenous thrombolysis was still observed when patients were stratified according to FAR levels. A higher FAR level was independently related to the occurrence of HT after adjusting for the potential confounding factors., Conclusion: Higher FAR level was independently associated with HT after intravenous thrombolysis in patients with ischemic stroke., (© 2022. Fondazione Società Italiana di Neurologia.)

Introduction: The role of computed tomography perfusion (CTP) in prediction of hemorrhagic transformation (HT) has been evolving. We aimed to study the role of automated perfusion post-processing software in prediction of HT using the commercially available RAPID software., Methods: Two hundred eighty-two patients with anterior circulation ischemic stroke, who underwent CTP with RAPID automated post-processing, were retrospectively enrolled and divided into HT ( n = 91) and non-HT groups ( n = 191). The automated RAPID-generated perfusion maps were reviewed. Mismatch volume and ratio, time to maximum (Tmax) > 4-10s volumes, hypoperfusion index, cerebral blood flow (CBF) < 20-38% volumes, cerebral blood volume (CBV) < 34%-42% volumes, and CBV index were recorded and analyzed., Results: The volumes of brain tissues suffering from reduction of cerebral blood flow (CBF < 20%-38%), reduction in cerebral blood volumes (CBV < 34-42%), and delayed contrast arrival times (Tmax > 4-10s) were significantly higher in the HT group. The mismatch volumes were also higher in the HT group ( p = .001). Among these parameters, the Tmax > 6s volume was the most reliable and sensitive predictor of HT ( p = .001, AUC = 0.667). However, the combination of the perfusion parameters can slightly improve the diagnostic efficiency (AUC = 0.703). There was no statistically significant difference between the non-HT group and either the parenchymal or the symptomatic subtypes., Conclusion: The RAPID automated CTP parameters can provide a reliable predictor of HT overall but not the parenchymal or the symptomatic subtypes. The infarct area involving the penumbra and core represented by the Tmax > 6s threshold is the most sensitive predictor; however, the combination of the perfusion parameters can slightly improve the diagnostic efficiency.

Background: Cerebrolysin could mitigate reperfusion injury and hemorrhagic transformation (HT) in animal models of acute ischemic stroke., Methods: This was a prospective, randomized, open-label, parallel-group with active control, multicenter pilot study. Cerebrolysin (30 mL/day over 14 days) was administered concurrently with alteplase (0.9 mg/kg) in 126 patients, whereas 215 control patients received alteplase alone. The primary outcomes were the rate of any and symptomatic HT assessed from day 0 to 14. The secondary endpoints were drug safety and functional outcome measured with the National Institutes of Health Stroke Scale (NIHSS) on day 1 and 14, and the modified Rankin scale (mRS) on day 90. Advanced brain imaging analysis was applied on day 1 and 14 as a marker for in vivo pharmacology of Cerebrolysin., Results: Cerebrolysin treatment resulted in a substantial decrease of the symptomatic HT rate with an odds ratio (OR) of 0.248 (95% CI: 0.072-0.851; p = 0.019). No serious adverse events attributed to Cerebrolysin occurred. On day 14, the Cerebrolysin arm showed a significant decrease in the NIHSS score (p = 0.045). However, no difference in the mRS score was observed on day 90. A substantial improvement in the advanced brain imaging parameters of the infarcted area was evident in the Cerebrolysin group on day 14., Conclusions: Early add-on of Cerebrolysin to reperfusion therapy was safe and significantly decreased the rate of symptomatic HT as well as early neurological deficit. No effect on day 90 functional outcome was detected. Improvements in the imaging metrics support the neuroprotective and blood-brain barrier stabilizing activity of Cerebrolysin., Trial Registration: Name of Registry: ISRCTN., Trial Registration Number: ISRCTN87656744 . Trial Registration Date: 16/02/2021., (© 2023. The Author(s).)

Objectives: We evaluated the impact of malnutrition as estimated by the controlling nutritional status (CONUT) score and prognostic nutritional index (PNI) on hemorrhagic transformation (HT) and stroke outcomes after intravenous thrombolysis (IVT)., Materials and Methods: Using a multicenter registry database, we enrolled 808 patients with acute ischemic stroke who received IVT between August 2013 and May 2021. We defined malnutrition as a CONUT score ≥ 2 and low PNI. The primary outcome measure was the occurrence of symptomatic HT contributing to early neurologic deterioration (END-SHT) after IVT. Multivariable analysis was performed to analyze the association between CONUT score, PNI, and END-SHT after IVT., Results: The rate of END-SHT was higher with increasing CONUT scores and PNI values. In the multivariable analysis, CONUT score ≥ 5 and low PNI were significantly associated with END-SHT (odds ratio [95% confidence interval], CONUT score ≥ 5: 12.23 [2.41-62.07], p = 0.003; low PNI: 4.98 [1.76-14.09], p = 0.003). The receiver operating characteristic curve showed that both the CONUT score and PNI had good predictive ability. The cutoff values for CONUT and PNI were 5 and 42.3, respectively, for END-SHT., Conclusion: Malnutrition, as denoted by a higher CONUT score and lower PNI, was associated with END-SHT. The joint application of both nutritional markers could be useful in predicting END-SHT after IVT., (© 2023. The Author(s).)

Background: Hemorrhagic transformation (HT) is a common complication of acute ischemic stroke (AIS), and may develop into parenchyma hemorrhage (PH). We aimed to investigate the association between serum homocysteine levels and HT as well as PH in all AIS patients, and in those with and without thrombolysis by subgroup analysis., Methods: AIS patients who were admitted within 24 h after onset were enrolled and categorized into the higher homocysteine level group (≥ 15.5 µmol/L) and the lower homocysteine level group (< 15.5 µmol/L). HT was determined by a second round of brain imaging within 7 days during hospitalization, and PH was defined as hematoma in the ischemic parenchyma. Multivariate logistic regression was used to investigate the associations between serum homocysteine levels and HT and PH, respectively., Results: Of the 427 included patients (mean age 67.35 years, 60.0% males), 56 (13.11%) developed HT and 28 (6.56%) had PH. Serum homocysteine levels were significantly associated with HT (adjusted OR 1.029, 95%CI 1.003-1.055) and PH (adjusted OR 1.041, 95%CI 1.013-1.070). The higher homocysteine group was more likely to have HT (adjusted OR 1.902, 95% CI 1.022-3.539) and PH (adjusted OR 3.073, 95% CI 1.327-7.120) than the lower homocysteine group. Subgroup analysis of patients without thrombolysis also showed the significant differences in HT (adjusted OR 2.064, 95% CI 1.043-4.082) and PH (adjusted OR 2.926, 95% CI 1.196-7.156) between the two groups., Conclusion: Higher serum homocysteine levels are associated with an increased risk of HT and PH in AIS patients, especially in those without thrombolysis. Monitoring the serum homocysteine may be conducive to determining individuals at a high risk of HT., (© 2023. The Author(s).)

Introduction: We evaluated the effects of prior antiplatelet use (APU) on futile reperfusion (FR) after endovascular treatment (EVT) in acute ischemic stroke., Material and Methods: We consecutively collected data of 9369 patients with acute ischemic stroke from four university-affiliated multicenter registry databases over 92 months. We enrolled 528 patients with acute stroke receiving EVT. Among them, we defined FR in subjects as a 3-month modified Rankin Scale score of >2 despite successful reperfusion after EVT. We classified patients into two groups: prior APU and no prior APU. We used propensity score matching (PSM) to overcome the imbalance in multiple covariates between the two groups. After PSM, we compared the baseline characteristics between the two groups and performed multivariate analysis to determine whether prior APU affected FR and other stroke outcomes., Results: The overall FR rate in the present study was 54.2%. In the PSM cohort, the FR was lower in the prior APU group than that in the no prior APU group (66.2% vs 41.5%, p  < 0.001). In the multivariate analysis using the PSM cohort, prior APU significantly reduced the risk of FR (odds ratio (OR), 0.32; 95% confidence interval (CI), 0.18-0.55; p  = 0.001) and stroke progression (OR, 0.38; 95% CI, 0.15-0.93; p  = 0.03). Prior APU was not associated with symptomatic hemorrhagic transformation in this study., Conclusion: Prior APU potentially reduced FR and stroke progression. Further, prior APU was not associated with symptomatic hemorrhagic transformation in patients receiving EVT. APU pretreatment can be a modifiable predictor of FR in clinical practice., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© European Stroke Organisation 2022.)

Hemorrhagic transformation (HT) is one of the most serious complications after endovascular thrombectomy (EVT) in acute ischemic stroke (AIS) patients. The purpose of this study is to develop and validate deep-learning (DL) models based on multiparametric magnetic resonance imaging (MRI) to automatically predict HT in AIS patients. Multiparametric MRI and clinical data of AIS patients with EVT from two centers (data set 1 for training and testing: n = 338; data set 2 for validating: n = 54) were used in the DL models. The acute infarction area of diffusion-weighted imaging (DWI) and hypoperfusion of perfusion-weighted imaging (PWI) was labeled manually. Two forms of data sets (volume of interest [VOI] data sets and slice data sets) were analyzed, respectively. The models based on single parameter and multiparameter models were developed and validated to predict HT in AIS patients after EVT. Performance was evaluated by area under the receiver-operating characteristic curve (AUC), accuracy (ACC), sensitivity, specificity, negative predictive value, and positive predictive value. The results showed that the performance of single parameter model based on MTT (VOI data set: AUC = 0.933, ACC = 0.843; slice data set: AUC = 0.945, ACC = 0.833) and TTP (VOI data set: AUC = 0.916, ACC = 0.873; slice data set: AUC = 0.889, ACC = 0.818) were better than the other single parameter model. The multiparameter model based on DWI & MTT & TTP & Clinical (DMTC) had the best performance for predicting HT (VOI data set: AUC = 0.948, ACC = 0.892; slice data set: AUC = 0.932, ACC = 0.873). The DMTC model in the external validation set achieved similar performance with the testing set (VOI data set: AUC = 0.939, ACC = 0.884; slice data set: AUC = 0.927, ACC = 0.871) (p > 0.05). The proposed clinical, DWI, and PWI multiparameter DL model has great potential for assisting the periprocedural management in the early prediction HT of the AIS patients with EVT., (© 2021 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.)

Leukocytes are systematic inflammation indicators related to stroke prognosis and can exhibit large dynamic waves before and after recombinant tissue plasminogen activator (r-tPA) therapy. However, additional evidence is needed to determine the prognostic significance of various leukocytes including both static and dynamic data among patients who underwent r-tPA therapy. A total of 251 patients treated with r-tPA were included; their leukocyte data were collected at two time points, and patients were followed up for three months. Analysis revealed the following findings. (i) Patients with hemorrhagic transformation (HT) and unfavorable outcomes had a higher level of leukocytes after r-tPA therapy (leukocyte count (adjusted OR (aOR) 1.191 for HT and 1.184 for unfavorable outcomes), neutrophil count (aOR 1.215 and 1.214), neutrophil-to-lymphocyte ratio (NLR; aOR 1.084 and 1.091)) and larger dynamic leukocyte changes. (ii)Among all leukocytes, the NLR after r-tPA administration demonstrated the strongest correlation with HT and unfavorable outcomes. (iii) Patients with an NLR ≥ 3.322 had a 3.492-fold increased risk for HT, and those with an NLR ≥ 5.511 had a 3.024-fold increased risk for functional outcomes. Overall, this study shows that leukocytes, especially leukocyte count, neutrophil count and the NLR, are independently associated with HT and functional outcomes in stroke patients.

Objective: To investigate whether hyperdense middle cerebral artery sign (HMCAS) on pretreatment no-contrast CT (NCCT) is associated with hemorrhagic transformation (HT) after endovascular thrombectomy (EVT)., Methods: Patients with acute middle cerebral artery (MCA) occlusion who received EVT in three comprehensive hospitals were retrospectively evaluated. They were divided into four groups based on the presence or absence of HMCAS and corresponding CTA findings, among whom differences were compared. Univariate and multivariate logistic regression analyses were performed to investigate the association between HMCAS and HT and its subtypes., Results: 318 patients were included, among whom 149 (46.9%) had HMCAS. Patients in the proximal positive HMCAS group had higher National Institute of Health Stroke Scale scores and lower Alberta Stroke Program Early CT Scores (ASPECTS) than those in the proximal negative HMCAS group. The rate of HT was higher in the proximal positive HMCAS group than that in the proximal negative HMCAS group. In multivariate logistic regression analysis, the proximal HMCAS were independently associated with HT (adjusted OR = 2.073, 95% CI 1.211-3.551, p = 0.008) and aHT (adjusted OR = 2.271, 95% CI 1.294-3.986, p = 0.004), but not with sHT. Patients who developed HT, including aHT and sHT, had a lower rate of good outcome., Conclusion: Proximal HMCAS on initial NCCT was independently associated with aHT in patients who received EVT for acute MCA occlusion. Both aHT and sHT had a detrimental effect on clinical outcome., (© 2022. The Author(s).)

Diabetes mellitus (DM) is associated with poor stroke outcomes, including high mortality and disability rates. Ischemic injury modeling large artery stroke in diabetic animals also results in high mortality and poor acute and long-term outcomes. In this chapter, we describe middle cerebral artery occlusion (MCAO) in a high-fat diet/low-dose streptozotocin (STZ) model of diabetes including details on pre-op and post-op care that improve survival rate for successful completion of the studies., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Ischemic stroke is a common cerebrovascular disease with high morbidity, disability, and mortality worldwide. Currently, recombinant tissue plasminogen activator is the main intravenous thrombolysis agent for the treatment of acute ischemic stroke within 4.5 h after onset. Hemorrhagic transformation (HT) is the most serious complication of intravenous thrombolysis, which can significantly aggravate clinical poor prognosis. Therefore, it is important to early predict the risk of post-thrombolysis HT in patients with acute ischemic stroke., Summary: Recently, several studies have reported that neuroimaging techniques have potential value in predicting HT after intravenous thrombolysis in patients with acute ischemic stroke. The corresponding neuroimaging parameters may be effective predictors of HT after intravenous thrombolysis. In this review, we summarized and discussed the application of neuroimaging techniques and related parameters in predicting HT after intravenous thrombolysis., Key Messages: Recognizing and understanding the predictive performance of neuroimaging parameters for HT may help assess the risk of HT after intravenous thrombolysis in patients with acute ischemic stroke and make an appropriate treatment decision., (© 2022 S. Karger AG, Basel.)

Objectives: Hemorrhagic transformation (HT) is a complication occurring in patients with acute ischemic stroke (AIS) either spontaneously or post-thrombolysis leading to significant morbidity and mortality. We assessed circulating matrix metalloproteinase-9 (MMP-9), Claudin-5, and soluble serum stimulation-2 (sST2) in HT and stroke severity in AIS based on their temporal distribution., Materials and Methods: We prospectively enrolled 111 AIS patients within 12 h from onset. Patient demographic, clinical, and imaging details were documented. Follow-up imaging was conducted 24-48 h after admission. Blood samples were taken at three time-points from stroke onset. HT was classified according to the European Co-operative Acute Stroke Study-III(ECASS-III). Stroke severity was assessed using the National Institutes of Health Stroke Scale (NIHSS). Multiple logistic regression and receiver operating characteristic curve were conducted to determine the discriminative capacity., Results: Mean age was 62.3 ± 11.7 years and median baseline NIHSS was 12[IQR 8.0-18.0]. HT was detected in 30(27%) patients. Biomarker levels at 12 h were elevated with median MMP-9 concentration of 153.9 ng/mL[IQR 110.6-309 ng/mL] indicating a trend toward significant positive correlation with HT(P = 0.05). Claudin-5 levels at 12 h was elevated but was not statistically significant (43.1 pg/mL[IQR:26.7-72.6 pg/mL] vs 59.4 pg/mL[IQR:24.5-100.8 pg/mL];P = 0.4). Multiple logistic regression indicated Claudin-5 levels at 12 h (OR 9.46;95% CI:1.97-64.6;P = 0.010) and baseline low ASPECTS score(OR 20.3;95% CI:3.46-193; P = 0.003) independently predicted HT. MMP-9 at 12 h was significantly elevated in patients with moderate to severe strokes (P = 0.04)., Conclusions: Claudin-5 and low ASPECTS independently predicted HT. MMP-9 was positively correlated with baseline stroke severity., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Hemorrhagic transformation (HT) is a common complication of intravenous thrombolysis (IVT) in patients with acute ischemic stroke (AIS) and may lead to neurological deterioration. This article discusses whether monocyte count to high-density lipoprotein ratio (MHR) level is associated with HT in AIS patients. Materials and methods: The clinical data of AIS patients who underwent rt-PA IVT treatment were continuously collected. According to whether HT occurred, patients were divided into HT group and non-HT group. Potential association between MHR and HT in different subtypes AIS was explored by using logistic regression. Results: A total of 444 AIS patients were retrospective analyzed. The MHR level was lower in HT group compared with the non-HT group in all AIS patients (0.28 vs 0.36, P  = .031) and in large-artery atherosclerosis (LAA) type AIS patients (0.31 vs 0.37, P  = .032). Low MHR was independently related to HT (OR:0.035, 95%CI:0.003-0.390, P  = .006). Among all TOAST subtypes, low MHR was only independently associated with HT in patients of LAA-type AIS after adjusting for confounding factors (OR:0.01, 95%CI:0.00-0.62, P  = .031), with an optimal cut-off value of 0.41, sensitivity of 85.7%, and specificity of 43.1%. MHR was not correlated with SVO, VE, and CE subtype AIS. Conclusion: Low MHR may be an independent predictor of HT in patients with AIS and this conclusion only existed in LAA-type AIS.

Background: Magnesium (Mg) is a neuroprotectant in preclinical models. Lower serum Mg levels have been associated with symptomatic hemorrhagic transformation (HT) in patients with ischemic stroke. Early treatment of acute ischemic stroke with Mg may reduce rates of symptomatic HT., Methods: In this post hoc study of the Field Administration of Stroke Therapy Magnesium (FAST-MAG) trial, 1,245 participants with a diagnosis of cerebral ischemia received 20 g of Mg or placebo initiated in the prehospital setting. Posttreatment serum Mg level was measured for 809 participants. Cases of clinical deterioration, defined as worsening by ≥4 points on the National Institute of Health Stroke Scale (NIHSS), were imaged and evaluated for etiology. Symptomatic HT was defined as deterioration with imaging showing new hemorrhage., Results: Clinical deterioration occurred in 187 and symptomatic HT in 46 of 1,245 cases of cerebral ischemia. Rates of deterioration and symptomatic HT were not significantly lower in those who received Mg (15.7% vs. 14.4%, p = 0.591; 2.8% vs. 4.6%, p = 0.281). In cases where serum Mg level was obtained posttreatment, lower serum Mg level (<1.7 mg/dL) was associated with significantly higher rates of deterioration and symptomatic HT (27.5% vs. 15.5%, p = 0.0261; 11.6% vs. 3.65%, p = 0.00819)., Conclusions: Treatment with Mg did not significantly reduce rates of clinical deterioration or symptomatic HT. Future analysis should address whether treatment with Mg could have influenced the subgroup with low serum Mg at baseline., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Background: At least one-third of Alzheimer's disease (AD) patients have cerebrovascular abnormalities, micro- and macro-infarctions, and ischemic white matter alterations. Stroke prognosis impacts AD development due to vascular disease. Hyperglycemia can readily produce vascular lesions and atherosclerosis, increasing the risk of cerebral ischemia. Our previous research has demonstrated that protein O-GlcNAcylation, a dynamic and reversible post-translational modification, provides protection against ischemic stroke. However, the role of O-GlcNAcylation in the exacerbation of cerebral ischemia injury due to hyperglycemia remains to be elucidated., Objective: In this study, we explored the role and underlying mechanism of protein O-GlcNAcylation in the exacerbation of cerebral ischemia injury caused by hyperglycemia., Methods: High glucose-cultured brain microvascular endothelial (bEnd3) cells were injured by oxygen-glucose deprivation. Cell viability was used as the assay result. Stroke outcomes and hemorrhagic transformation incidence were assessed in mice after middle cerebral artery occlusion under high glucose and streptozotocin-induced hyperglycemic conditions. Western blot estimated that O-GlcNAcylation influenced apoptosis levels in vitro and in vivo., Results: In in vitro analyses showed that Thiamet-G induces upregulation of protein O-GlcNAcylation, which attenuates oxygen-glucose deprivation/R-induce injury in bEnd3 cells cultured under normal glucose conditions, while aggravated it under high glucose conditions. In in vivo analyses, Thiamet-G exacerbated cerebral ischemic injury and induced hemorrhagic transformation, accompanied by increased apoptosis. While blocking protein O-GlcNAcylation with 6-diazo-5-oxo-L-norleucine alleviated cerebral injury of ischemic stroke in different hyperglycemic mice., Conclusion: Overall, our study highlights the crucial role of O-GlcNAcylation in exacerbating cerebral ischemia injury under conditions of hyperglycemia. O-GlcNAcylation could potentially serve as a therapeutic target for ischemic stroke associated with AD.

Introduction: Hemorrhagic transformation (HT) is a severe but frequent complication of acute ischemic stroke (AIS). This study aimed to evaluate the relationship between serum lactate dehydrogenase (LDH) levels and HT., Methods: We retrospectively included 542 AIS patients with HT and 1,091 age- and gender-matched patients without HT. Demographic and clinical data were obtained from medical records, and blood samples were obtained within 24 h after admission. The characteristics of the groups were compared. With the receiver operating characteristic (ROC) curve analysis, we assessed the discriminating capacity of LDH levels in predicting HT in patients with AIS. The logistic regression model was used to determine the connection between LDH and HT., Results: The HT group had considerably higher LDH levels than the non-HT group (263.0 [216.0-323.3] U/L versus 178.0 [162.0-195.0] U/L, p < 0.001). We also observed that the levels of LDH in the parenchymal hemorrhage subgroup were significantly higher than those in the hemorrhagic infarction subgroup (281.0 [230.0-340.0] U/L versus 258.0 [209.0-311.0] U/L, p < 0.001). The area under the ROC curve of LDH was 0.890 (95% confidence level [CI] 0.874-0.905, p < 0.001). Besides, logistic regression revealed that high LDH levels (LDH >215 U/L) showed a higher risk of HT (odds ratio = 10.958, 95% CI 7.964-15.078, p < 0.001)., Conclusion: High LDH levels were linked with an increased risk of HT in AIS patients. Practical measures should be considered in patients with increased LDH levels (LDH >215 U/L)., (© 2023 S. Karger AG, Basel.)

Objective: The study aimed to assess effects of the simultaneous use of Cerebrolysin and intravenous thrombolysis (Alteplase) on hemorrhagic transformation (HT) and functional outcome as well as to analyze the treatment safety in acute stroke patients., Material and Methods: It was a prospective, randomized, open-label, multicenter, parallel-group, active-controlled pilot study (Trial Registration Number: ISRCTN87656744, https://doi.org/10.1186/ISRCTN87656744, Trial registration date: 16/02/2021). The intervention group ( n =126) was treated with Cerebrolysin infusion (30 mL) started simultaneously with Alteplase (0.9 mg/kg) via a separate IV line. The Cerebrolysin treatment continued for 14 consecutive days with the baseline therapy along. The control group ( n =215) received only Alteplase and the baseline therapy. The primary endpoints were the rate of any and symptomatic hemorrhagic transformation (HT) from admission to day 14. Secondary endpoints were treatment safety and functional outcome measured with the National Institutes of Health stroke scale (NIHSS) in 24 h and on day 14, and with the modified Rankin scale (mRS) on day 90., Results: Treatment with Cerebrolysin resulted in a significant reduction of the symptomatic HT rate with an odds ratio of 0.248 (95% CI: 0.072-0.851; p =0.019). No serious adverse events related to Cerebrolysin were observed. On day 14, the intervention group showed a significant reduction in the NIHSS score ( p =0.045). However, no difference in the mRS score was observed on day 90, but there was a trend towards its improvement., Conclusion: The combination of Cerebrolysin and Alteplase was safe and significantly reduced the rate of symptomatic HT and improved early neurological deficit. However, no difference in functional outcome was found on day 90, but there was a trend towards favorable functional outcome.

Background: Endovascular thrombectomy has changed the management of ischemic stroke. The reperfusion can however lead to a hemorrhagic transformation (HT). Decompressive craniectomy (DC) is a surgical procedure used for malignant ischemic stroke. However, its efficacy was demonstrated before the era of endovascular thrombectomy trials. Here, we hypothesized that DC for ischemic stroke after thrombectomy could lead to a higher risk of HT. We thus evaluated this hypothesis in a mouse model of stroke induced by occlusion of the middle cerebral artery (MCAO) with or without mechanical reperfusion., Methods: Ninety mice subjected to MCAO were divided into 6 groups: permanent MCAO with or without DC; MCAO followed by a mechanical reperfusion with or without DC and MCAO with a mechanical reperfusion followed by r-tPA (recombinant tissue-type plasminogen activator)-induced reperfusion with or without DC. Mice were evaluated by magnetic resonance imaging 24 hours after the MCAO to assess ischemic lesion volumes, and the rate, type, and volume of HTs., Results: The ischemic volume was higher in the 2 groups without reperfusion than in the 4 groups with reperfusion independently of r-tPA treatment and DC. The distribution of HT types was different between the 6 groups. The HT volumes and HT scores was smaller in the 2 groups without reperfusion and in the reperfusion group without r-tPA and without DC. In mice having reperfusion, the mean HT score was higher in mice who had DC without r-tPA (HT score 5; P =0.048) or with r-tPA (HT score 8; P =0.02), than in mice without DC (HT score 1)., Conclusions: DC for a malignant stroke, after reperfusion, corresponding to an endovascular thrombectomy failure, increases the risk of severe hemorrhagic transformations in a model of ischemic stroke in mice. This result support the need of clinical studies to evaluate the added value of DC at the era of endovascular thrombectomy.

Background: Essential thrombocythemia (ET) is a rare cause of stroke. The V617F mutation in the Janus kinase 2 (JAK2) gene is one of the most typical mutations in ET and has been shown to be a risk factor for stroke, especially in younger people. However, to date, there have been few reports of intracranial thrombotic and hemorrhagic complications in patients with ET. Herein, we present a case of JAK2 gene mutation-associated ET in a patient who developed both ischemic and hemorrhagic stroke, and discuss potential underlying mechanisms., Case Presentation: A 45-year-old Chinese male presented to our center with gradually developing weakness of the right limbs for 3 months. A computed tomography scan of the brain showed an area of infarction with hemorrhage in the left subcortical and corona radiata regions. High-resolution magnetic resonance imaging revealed a thrombosis on the surface of the atherosclerotic plaque. Digital subtraction angiography revealed an insect bite-like change in the C1 branch of the left internal carotid artery, which caused up to 50% stenosis. Blood tests showed continued elevation of the platelet and white blood cell counts. After consultation with a hematologist, a bone marrow biopsy was performed, which revealed proliferative bone marrow changes with numerous megakaryocytes and proliferative but mature granulocytes. Further genetic testing revealed a positive JAK2-V617F mutation. Therefore, the diagnosis of ET was confirmed according to the World Health Organization (WHO) 2016 diagnostic criteria. Finally, we decided to administer aspirin and hydroxyurea. The patient remained stroke free and the platelet levels were normal throughout the 1-year follow-up period., Conclusions: JAK2 mutations affect the proliferation and differentiation of blood cells through the JAK, signal transducer and activator of transcription pathway, which leads to changes in platelets and macrophages, and an increase in neutrophil extracellular traps, which may explain the patient's ischemic and hemorrhagic changes. Further investigation of the underlying mechanisms may change the treatment strategy for such patients in the future., (© 2022. The Author(s).)

Background: Hemorrhagic transformation (HT) is a common complication of ischemic stroke. A growing number of studies have found that serum calcium levels are lower in HT groups than in control groups. However, the relationship between serum calcium and HT remains controversial. We performed a meta-analysis to assess the relationship between serum calcium levels and HT., Methods and Results: Electronic databases were searched for studies on serum calcium and HT from inception to November 6, 2021. Ten studies included in present meta-analysis with a total of 3212 participants. Due to the high heterogeneity (I 2  = 81%), we chose the random effects model. The results showed that the serum calcium level in the HT group was significantly lower than that in the control group (pooled mean difference, -0.05; 95% confidence interval (CI), (-0.09, -0.02); P = 0.001). Whether thrombolytic or not the results were applied (pooled mean difference, -0.07; 95% CI, (-0.13, -0.01); P = 0.02 and pooled mean difference, -0.03; 95% CI, (-0.06, -0.01); P = 0.007)., Conclusions: Serum calcium was related to HT and may be one of the risk factors for HT., 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 © 2022 Elsevier Ltd. All rights reserved.)

Background: Cardiovascular diseases like stroke cause changes to sphingolipid mediators like sphingosine 1-phosphate (S1P) or its ceramide analogs, which bear the potential to either alleviate or exacerbate the neurological damage. Therefore, the precise identification of alterations within the sphingolipidome during ischemic stroke (IS) and hemorrhagic transformation (HT) harbors a putative therapeutic potential to orchestrate local and systemic immunomodulatory processes. Due to the scarcity of research in this field, we aimed to characterize the sphingolipidome in IS and HT., Methods: C57BL/6 mice underwent middle cerebral artery occlusion (MCAO) and specimens of the peri-infarct tissue were taken for sphingolipid profiling., Results: Ischemic stroke resulted in reduced S1P whilst ceramides were elevated six hours post ischemia onset. However, these differences were nearly revoked at 24 hours post ischemia onset. Moreover, the topmost S1P and ceramide levels were linked to the presence of HT after MCAO. In this study we show the characterization of the sphingolipidomic landscape of the peri-infarct tissue after ischemic stroke and HT. Especially, highest values of S1P, C 18 lactosylceramide, C 18 glucosylceramide, and C 24:1 ceramide were nearly entirely expressed by mice with HT., Conclusions: Our results warrant further investigations into the immunomodulatory consequences of altered sphingolipid species for the development of HT after IS., Competing Interests: The authors declare no conflict of interest., (© 2022 The Author(s). Published by IMR Press.)

Objectives: The neutrophil-to-lymphocyte ratio (NLR) is a known marker of systemic inflammation. Recent studies demonstrated its applicability as a marker of poor prognosis for stroke patients. In this study, we evaluated the relationship between dynamic changes in the NLR and sICH in patients with successful recanalization following ERT., Materials and Methods: This study included 128 patients with acute ischemic stroke who underwent successful ERT between January 2013 and November 2019. We evaluated the NLR pre-ERT (at admission) and post-ERT (at 24-36 h after ERT). The symptomatic ICH and miserable outcomes at 3 months after ERT were analyzed as outcomes. sICH was defined as type-2 parenchymal hematoma with neurological deterioration (defined as National Institute of Health Stroke Scale score ≥4). Moreover, a modified Rankin Scale score of 5-6 at 3 months was considered a miserable outcome., Results: Among the included patients, sICH occurred in 12 (9.4%). The sICH group had significantly higher post-ERT NLR (P < 0.001) and ∆NLR (calculated as the difference between pre-ERT NLR and post-ERT NLR) (P = 0.004). In the multivariate analysis, the post-ERT NLR was independently associated with sICH (odds ratio [OR], 1.166; 95% confidence interval [CI], 1.041-1.306; P = 0.008) and miserable outcome at 3 months (OR, 1.101; 95% CI, 1.002-1.210; P = 0.045)., Conclusions: This study demonstrated that temporal elevation of the NLR is associated with sICH events after successful ERT in patients with acute ischemic stroke. The temporal variation in NLR may help to identify high-risk patients with sICH after ERT., Competing Interests: Declaration of Competing Interests None., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: Posterior Circulation (PC) stroke represents one-fifth of all ischemic strokes, with peculiar physiological characteristics. Hemorrhagic Transformation (HT) is a dreaded complication among stroke patients. Many predictive scores of this complication have been proposed, but none is designed specifically for PC stroke patients - therefore, patients who are not eligible for reperfusion therapies (RT) represent about 80% of hospitalized cases. We propose a scoring system to assess the HT risk in PC stroke patients not submitted to RT., Methods: We retrospectively evaluated data of patients diagnosed with PC stroke not treated with RT from 5 Comprehensive Stroke Centers (four in Brazil, 1 in the US) from 2015 to 2018. All patients underwent CT scan or MRI at admission and a follow-up neuroimaging within seven days. Independent variables identified in a logistic regression analysis were used to produce a predictive grading score., Results: We included 952 patients in the final analysis. The overall incidence of HT was 8.7%. Male gender (1 point), NIH Stroke Scale at admission ≥ 5 points (1), blood glucose at admission ≥ 160 mg/dL (1), and cardioembolism (2) were independently associated with HT. The AUC of the grading score (0 to 5 points) was 0.713 (95% CI 0.65-0.78). Subjects with a score ≥ 3 points had an OR of 4.8 (95% CI 2.9-7.9, p < 0.001) for HT., Conclusions: Our score has good accuracy in identifying patients at higher risk of HT. This score may be useful for evaluating secondary prevention and stratifying patients in the context of even clinical trials., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objectives: The purpose of this study is to investigate the relationship between the timing of starting direct oral anticoagulants (DOACs) and subsequent clinical outcomes in patients with hemorrhagic transformation (HT) after endovascular treatment (EVT)., Materials and Methods: The subjects were patients with acute cardioembolic stroke who underwent EVT and received DOACs in our department from February 2017 to August 2021. Based on CT at 24 h after EVT, the patients were classified using European Collaborative Acute Stroke Study criteria into three groups: no HT, hemorrhagic infarction (HI), and parenchymal hematoma (PH). Outcomes were assessed for incidence of recurrent ischemic stroke (RIS), new intracranial hemorrhage (ICH), and worsened HT associated with DOACs., Results: Of 111 patients, 29 (26.1%) had HT, including 16 (14.4%) with HI and 13 (11.7%) with PH. The start of DOACs was significantly delayed in the PH group (no HT: 1.0 (1.0-3.0) days vs. HI: 3.0 (2.0-5.0) days vs. PH: 7.0 (7.0-10.0) days, P < 0.01). The incidence of RIS did not differ significantly among the three groups, but tended to be higher in the PH group (no HT: 3.7% vs. HI: 6.3% vs. PH: 15.4%, p = 0.12). There were no cases of new symptomatic ICH. New asymptomatic ICH occurred in 2 cases in the no HT group. Worsened HT after initiation of DOACs did not occur in the HI or PH group., Conclusions: The timing of starting DOACs in patients with HT after EVT may be divided by subtypes of HI and PH. In patients with HI, early initiation of DOACs can prevent RIS and is unlikely to cause new ICH or worsened HI. In PH, initiation of DOACs within 14 days appears to be safe and does not exacerbate PH. The later the start of DOACs, the higher the frequency of RIS, so early initiation of DOACs is desirable., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2022. Published by Elsevier Inc.)

Background: Hemorrhagic transformation (HT) is a dreaded complication in stroke patients who were treated or not with recombinant tissue plasminogen activator (tPA). There are many predictive scores of HT, but all of them included patients treated with tPA. Molecular effects of tPA and clinical aspects of eligible patients for tPA therapy may imply specific HT's risk factors. We aimed to describe HT's characteristics and risk factors in patients treated or not with tPA., Methods: We included 1565 consecutive stroke patients admitted to a Comprehensive Stroke Center, from 2015 to 2017. All included patients underwent a follow-up neuroimaging within seven days after admission. From a logistic regression model, we derived a score based on the beta-coefficients. The accuracy of the models was attested by Receiver Operating Characteristic analysis., Results: Low ASPECTS, blood glucose ≥ 180 mg/dL, tPA treatment, and cardio-aortic embolism were predictors of HT. Male sex, leukoaraiosis, and hyperdense MCA sign were associated with HT in non-treated patients. Diastolic blood pressure ≥ 105 mmHg was a risk factor only in non-treated patients. The cutoff of our predictive score of HT was higher in patients not treated with tPA (5 vs 2 points)., Conclusions: High arterial blood pressure was associated with HT only in patients treated with tPA. Different cutoffs and accuracy measurements suggest that scoring systems derived from patients treated with tPA may not be efficient to predict HT in non-treated patients. Further directions indicate considering the use of reperfusion therapies to select the most accurate predictive variables of HT., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objectives: Hemorrhagic transformation (HT) is a frequent and severe complication of ischemic stroke. This study aimed to evaluate the factors associated with the occurrence of HT in patients with acute cerebellar infarction., Materials and Methods: A total of 190 patients, 141 male (74.2%) and 49 female (25.8%) with mean age 61.84 ± 12.16 years, who were admitted within 72 h of acute cerebellar infarction onset from January 2017 to March 2021 were retrospectively recruited. The multivariate logistic regression analysis was used to evaluate the independent influent factors for HT and receiver-operating characteristic (ROC) curve was applied to calculate the predictive value of those factors for HT in patients with acute cerebellar infarction., Results: 37 out of 190 recruited patients (19.47%) had HT within 14 days after acute cerebellar infarction onset. The incidence rates of HT occurring within 3 days, 3-7 days and 7-14 days were 13.5%, 40.5% and 45.9%, respectively. Results of the multivariable logistic regression analysis indicated that atrial fibrillation (AF) (OR 6.196, 95% CI 1.357-28.302, P = 0.019), infarct diameter (OR 5.813, 95% CI 2.932-11.526, P < 0.001), white matter hyperintensity (WMH) (OR 2.44, 95% CI 1.134-5.252, P = 0.023) were independent risk factors for HT in acute cerebellar infarction, while lymphocyte count (OR 0.319, 95% CI 0.142-0.716, P = 0.006) showed an independently protective effect., Conclusions: Infarct diameter, AF and WMH are independent risk factors for HT in patients with acute cerebellar infarction, while the lymphocyte count is a protective factor., Competing Interests: Declaration competing of interest The authors declare that they have no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Tissue plasminogen activator (tPA) is recommended by the FDA to dissolve intravascular clots after acute ischemic stroke (AIS). However, it may contribute to hemorrhagic transformation (HT). The Wnt/β-catenin signaling pathway plays an important role in regulating the blood-brain barrier (BBB) formation in the central nervous system. We explored whether glucagon-like peptide-1 receptor (GLP-1R) agonist exendin-4 (EX-4) reduces the risk of HT after rtPA treatment via the Wnt/β-catenin pathway by using a rat transient middle cerebral artery occlusion (MCAO) model in vivo and an oxygen-glucose deprivation plus reoxygenation (OGD/R) model in vitro. Our results showed that EX-4 attenuated neurological deficits, brain edema, infarct volume, BBB disruption, and rtPA-induced HT in ischemic stroke. EX-4 suppressed the production of ROS and the activation of MMP-9 to protect the integrity of the BBB by activating the Wnt/β-catenin signaling pathway. PRI-724, a selective inhibitor of β-catenin, was able to reverse the therapeutic effect of EX-4 in vivo and in vitro. Therefore, our results indicate that the GLP-1R agonist may be a potential therapeutic agent to decrease the risk of rtPA-induced HT after ischemic stroke via the Wnt/β-catenin signaling pathway., (© 2022. The Author(s).)

Purpose: Hemorrhagic transformation (HT) following cerebral endovascular thrombectomy (EVT) for large vessel occlusion (LVO) in acute ischemic stroke is associated with poor outcome. Recent studies have shown that EVT can be efficacious in imaging-selected patients as late as 6-24 h from onset (late time window; LTW). We sought to determine predictors and prognostic implications of HT following EVT in LTW., Methods: Consecutive patients undergoing EVT for LVO were recruited into a prospective multicenter database. HT was divided into petechial hemorrhagic-infarction and parenchymal hematoma (PH) type 1 or 2 defined as confluent hemorrhage covering < or > than 1/3 of the infarct volume, respectively. Multivariate analyses were performed to determine variables associated with HT subtypes., Results: Among 611 patients included (mean age 70.5 ± 12.5 years; median NIHSS 16), 115 (18.8%) had HT and 33 of them (5.4%) had PH2. Independent PH2 predictors included failed recanalization (OR 7.0, 95% CI 2.3-21.6), longer time from symptom onset to admission (OR 1.002 per minute 95% CI 1.001-1.003) and hyperlipidemia (OR 3.12; 95%CI 1.12-8.7). HT was not associated with outcome. In contrast, PH2 patients had lower favorable outcome rates (14.3 vs 41.6%, p = 0.004) and higher mortality rates (39 vs 17%, p = 0.001). Patients who underwent EVT in the late versus early window had similar PH2 rates (4.5 vs 6.7%, p = 0.27). In multivariate models, PH2 tripled the odds of both 90-day poor outcome (OR 3.1, 95% CI 1.01-9.5) and 90-day mortality (OR 3.2, 95% CI 1.4-7.3)., Conclusions: PH2 following EVT is associated with increased mortality and unfavorable outcome rates. Rates of PH2 are not different between LTW patients and those treated < 6 h from symptom onset., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE).)