Risk Of Hemorrhagic Transformation Research Articles

Blood-brain barrier leakage and hemorrhagic transformation: The Reperfusion Injury in Ischemic StroKe (RISK) study.

In patients with acute ischemic stroke treated with reperfusion therapy we aimed to evaluate whether pretreatment blood-brain barrier (BBB) leakage is associated with subsequent hemorrhagic transformation (HT). We prospectively screened patients with acute ischemic stroke treated with intravenous thrombolysis and/or endovascular treatment. Before treatment, each patient received computed tomography (CT), CT angiography, and CT perfusion. We assessed pretreatment BBB leakage within the ischemic area using the volume transfer constant (Ktrans ) value. Our primary outcome was relevant HT, defined as hemorrhagic infarction type 2 or parenchymal hemorrhage type 1 or 2. We evaluated independent associations between BBB leakage and HT using logistic regression, adjusting for age, sex, baseline stroke severity, Alberta Stroke Program Early CT Score (ASPECTS)≥6, treatment type, and onset-to-treatment time. We enrolled 171 patients with available assessment of BBB leakage. The patients' mean (±SD) age was 75.5 (±11.8) years, 86 (50%) were men, and the median (interquartile range) National Institutes of Health Stroke Scale score was 18 (12-23). A total of 32 patients (18%) received intravenous thrombolysis, 102 (60%) underwent direct endovascular treatment, and 37 (22%) underwent both. Patients with relevant HT (N=31;18%) had greater mean BBB leakage (Ktrans 0.77 vs. 0.60; p=0.027). After adjustment in the logistic regression model, we found that BBB leakage was associated both with a more than twofold risk of relevant HT (odds ratio [OR]2.50; 95% confidence interval [CI]1.03-6.03 per Ktrans point increase; OR2.34; 95% CI1.06-5.17 for Ktrans values>0.63 [mean BBB leakage value]) and with symptomatic intracerebral hemorrhage (OR4.30; 95% CI1.13-13.77 per Ktrans point increase). Pretreatment BBB leakage before reperfusion therapy was associated with HT, and may help to identify patients at risk of HT.

Factors associated with the presence of cerebral microbleeds and its influence on outcomes of stroke not treated with alteplase

ObjectivesCerebral microbleeds (CMB) are associated with increased risk of hemorrhagic transformation (HT) of ischemic stroke with alteplase. Whether the presence of CMB influences the risk of HT and discharge outcomes of stroke patients not receiving alteplase is unclear. We evaluated the factors associated with the presence of CMB, and if the rates of HT and discharge outcomes were modified by the presence of CMB among stroke patients not treated with alteplase. MethodsIschemic stroke patients who had MRI and did not receive alteplase were included in the study. CMB, HT and white matter hyperintensity (WMH) were evaluated using Microbleed Anatomical Rating Scale, Heidelberg bleeding classification, and Fazekas scales, respectively. Multivariate regression analysis was performed to evaluate factors associated with the presence of CMB. ResultsAmong 196 patients in the study, 58 (30%) patients had CMB. Nine patients had ≥ 10 CMBs. Median National Institutes of Health stroke scale score was 4. In multivariate analysis, age (OR=1.07;95%CI=1.01–1.12), history of stroke (OR=3.10;95%CI=1.08–8.92), congestive heart failure (OR=7.26;95%CI=1.58–33.42), admission diastolic blood pressure (OR=1.03;95%CI=1.003–1.06) and severe WMH defined as Fazekas score 4–6 (OR=4.69;95%CI=1.80–12.23) were significantly associated with the presence of CMB. There was no difference in HT (10% vs 12%, p = 0.80) or discharge outcomes (modified Rankin Scale 0–2: 53% vs 57%, p = 0.62) of patients with CMB compared to those without CMB. ConclusionCMB are associated with severe WMH and higher diastolic blood pressure. CMB are not associated with the HT occurrence or discharge outcome of mild ischemic stroke in the absence of alteplase.

Disruptions of Circadian Rhythms and Thrombolytic Therapy During Ischemic Stroke Intervention.

Several endogenous and exogenous factors interact to influence stroke occurrence, in turn contributing to discernable daily distribution patterns in the frequency and severity of cerebrovascular events. Specifically, strokes that occur during the morning tend to be more severe and are associated with elevated diastolic blood pressure, increased hospital stay, and worse outcomes, including mortality, compared to strokes that occur later in the day. Furthermore, disrupted circadian rhythms are linked to higher risk for stroke and play a role in stroke outcome. In this review, we discuss the interrelation among core clock genes and several factors contributing to ischemic outcomes, sources of disrupted circadian rhythms, the implications of disrupted circadian rhythms in foundational stroke scientific literature, followed by a review of clinical implications. In addition to highlighting the distinct daily pattern of onset, several aspects of physiology including immune response, endothelial/vascular and blood brain barrier function, and fibrinolysis are under circadian clock regulation; disrupted core clock gene expression patterns can adversely affect these physiological processes, leading to a prothrombotic state. Lastly, we discuss how the timing of ischemic onset increases morning resistance to thrombolytic therapy and the risk of hemorrhagic transformation.

Prediction of Hemorrhagic Transformation After Ischemic Stroke: Development and Validation Study of a Novel Multi-biomarker Model.

Objectives: We aimed to develop and validate a novel multi-biomarker model for predicting hemorrhagic transformation (HT) risk after acute ischemic stroke (AIS).Methods: We prospectively included patients with AIS admitted within 24 h of stroke from January 1st 2016 to January 31st 2019. A panel of 17 circulating biomarkers was measured and analyzed in this cohort. We assessed the ability of individual circulating biomarkers and the combination of multiple biomarkers to predict any HT, symptomatic HT (sHT) and parenchymal hematoma (PH) after AIS. The strategy of multiple biomarkers in combination was then externally validated in an independent cohort of 288 Chinese patients.Results: A total of 1207 patients with AIS (727 males; mean age, 67.2 ± 13.9 years) were included as a derivation cohort, of whom 179 patients (14.8%) developed HT. The final multi-biomarker model included three biomarkers [platelets, neutrophil-to-lymphocyte ratios (NLR), and high-density lipoprotein (HDL)] from different pathways, showing a good performance for predicting HT in both the derivation cohort (c statistic = 0·64, 95% CI 0·60–0·69), and validation cohort (c statistic = 0·70, 95% CI 0·58–0·82). Adding these three biomarkers simultaneously to the basic model with conventional risk factors improved the ability of HT reclassification [net reclassification improvement (NRI) 65.6%, P < 0.001], PH (NRI 64.7%, P < 0.001), and sHT (NRI 71.3%, P < 0.001).Conclusion: This easily applied multi-biomarker model had a good performance for predicting HT in both the derivation and external validation cohorts. Incorporation of biomarkers into clinical decision making may help to identify patients at high risk of HT after AIS and warrants further consideration.

Hemorrhagic Transformation in Ischemic Stroke and the Role of Inflammation.

Hemorrhagic transformation (HT) is a common complication in patients with acute ischemic stroke. It occurs when peripheral blood extravasates across a disrupted blood brain barrier (BBB) into the brain following ischemic stroke. Preventing HT is important as it worsens stroke outcome and increases mortality. Factors associated with increased risk of HT include stroke severity, reperfusion therapy (thrombolysis and thrombectomy), hypertension, hyperglycemia, and age. Inflammation and the immune system are important contributors to BBB disruption and HT and are associated with many of the risk factors for HT. In this review, we present the relationship of inflammation and immune activation to HT in the context of reperfusion therapy, hypertension, hyperglycemia, and age. Differences in inflammatory pathways relating to HT are discussed. The role of inflammation to stratify the risk of HT and therapies targeting the immune system to reduce the risk of HT are presented.

Prognostic value of the neutrophil-to-lymphocyte ratio in acute ischemic stroke patients treated with intravenous thrombolysis: a systematic review and meta-analysis

BackgroundThe relationship between the neutrophil-to-lymphocyte ratio (NLR) and poor prognostics in acute ischemic stroke (AIS) patients who receive intravenous thrombolysis (IVT) remains controversial. The purpose of this systematic review and meta-analysis was to evaluate the association between the NLR and poor prognosis after IVT. Furthermore, we aimed to determine whether the NLR at admission or post-IVT plays a role in AIS patients who received IVT.MethodsThe PubMed, Embase, Web of Science and China National Knowledge Infrastructure databases were searched for relevant articles until October 7, 2020. Cohort and case-control studies were included if they were related to the NLR in AIS patients treated with IVT. Odds ratios (ORs) and 95 % confidence intervals (95 % CIs) were pooled to estimate the relationship between NLR and poor prognosis after IVT. A random effects model was used to calculate the pooled data.ResultsTwelve studies, including 3641 patients, met the predefined inclusion criteria. Higher NLRs were associated with an increased risk of hemorrhagic transformation (HT) (OR = 1.33, 95 % CI = 1.14–1.56, P < 0.001) and a poor 3-month functional outcome (OR = 1.64, 95 % CI = 1.38–1.94, P < 0.001) in AIS patients who received IVT. Subgroup analysis suggested that the NLR at admission rather than post-IVT was associated with a higher risk of HT (OR = 1.33, 95 % CI = 1.01–1.75, P = 0.039). There was no statistically significant difference between higher NLRs and 3-month mortality (OR = 1.14, 95 % CI = 0.97–1.35, P = 0.120).ConclusionsA high NLR can predict HT and poor 3-month functional outcomes in AIS patients who receive IVT. The NLR at admission rather than the post-IVT NLR was an independent risk factor for an increased risk of HT after IVT.

Protocol for LASER: A Randomized Evaluation and an Associated Registry of Early Anticoagulation With Edoxaban After Ischemic Stroke in Patients With Atrial Fibrillation.

Background: The optimal timing of anticoagulation after stroke in patients with atrial fibrillation (AF) is unknown.Aim and Hypothesis: Our primary aim is to demonstrate the safety of edoxaban initiation within 5 days of AF related stroke. Our secondary aim is to determine predictors of hemorrhagic transformation (HT) after AF related stroke. We hypothesize that the rate of radiological HT will not be increased in patients starting edoxaban within 5 days of AF related stroke, relative to those in whom initiation is delayed. We hypothesize that the risk of HT in patients treated with edoxaban can be predicted using RNA expressed in leukocytes at time of stroke.Methods and Design: LASER (Lixiana Acute Stroke Evaluation Registry) is a randomized controlled trial with an associated registry (clinicaltrials.gov NCT03494530). One hundred and fifty patients with ischemic stroke and AF will undergo baseline Computed Tomography (CT) scan and will be randomized 2:1 within 5 days of symptom onset to early (≤5 days, n = 100) or delayed (6–14 days, n = 50) edoxaban initiation. Participants will undergo clinical assessment and repeat CT at 7 days and clinical assessment at 90 days.Study Outcomes: The primary outcome is the rate of incident radiological HT. Secondary outcomes include symptomatic HT, recurrent ischemic stroke, recurrent sub-clinical infarcts on follow up CT, systemic hemorrhagic complication rate, National Institute of Health Stroke Scale and modified Rankin Scale at day 7 and 90, mortality within 90 days, quality of life assessments at day 90, and predictors of HT, including RNA expression by 6 pre-selected candidate genes.Discussion: Event rates for both HT and recurrent ischemic events, in patients treated with early vs. delayed edoxaban initiation are unknown. The primary study endpoint of LASER is an objective performance criterion relevant to clinical decision making in patients with AF related stroke. This study will provide data required for a definitive safety/efficacy study sample size power calculation.

Abstract P12: Alteplase Reduces Mortality in Patients With Ischemic Stroke and Atrial Fibrillation: Analysis of the IAC Study

Background and Purpose: Multiple studies have established that intravenous thrombolysis with alteplase improves outcome after acute ischemic stroke. However, assessment of thrombolysis’ efficacy in stroke patients with atrial fibrillation (AF) has yielded mixed results. We sought to determine the association of alteplase with mortality, hemorrhagic transformation (HT), infarct volume, and mortality in patients with AF and acute ischemic stroke. Methods: We retrospectively analyzed consecutive acute ischemic stroke patients with AF included in the Initiation of Anticoagulation after Cardioembolic stroke (IAC) study, which pooled data from 8 comprehensive stroke centers in the United States. 1889 (90.6%) had available 90-day follow up data and were included. For our primary analysis we used a cohort of 1367/1889 (72.4%) patients who did not undergo mechanical thrombectomy (MT). Secondary analyses were repeated in the patients that underwent MT (n=522). Binary logistic regression was used to determine whether alteplase use was independently associated with risk of HT, final infarct volume, and 90-day mortality, respectively, adjusting for potential confounders. Results: In our primary analyses we found that alteplase use was independently associated with an increased risk for HT (adjusted OR 2.14, 95% CI 1.49 - 3.07, p &lt;0.001) but overall reduced risk of 90-day mortality (adjusted OR 0.58, 95% CI 0.39 - 0.87, p = 0.009). Among patients undergoing MT, alteplase use was associated with a trend towards a reduction in 90-day mortality (adjusted OR 0.68 95% CI 0.45 - 1.04, p = 0.077). In the subgroup of patients prescribed DOAC treatment (n = 327; 24 received alteplase), alteplase treatment was associated with a trend towards smaller infarct size (&lt; 10 mL), (adjusted OR 0.40, 95% CI 0.15 - 1.12, p = 0.082) without a significant difference in the odds of 90-day mortality (adjusted OR 0.51, 95% CI 0.12 - 2.13, p = 0.357) or hemorrhagic transformation (adjusted OR 0.27, 95% CI 0.03 - 2.07, p = 0.206). Conclusion: Thrombolysis with intravenous alteplase was associated with reduced 90-day mortality in AF patients with acute ischemic stroke not undergoing MT. Further study is required to assess the safety and efficacy of alteplase in AF patients undergoing MT and those on DOACs.

Abstract MP33: Association Between Neurologic Outcomes and Temporal Profile of Systolic Blood Pressure Variability After Endovascular Thrombectomy

Introduction: Higher systolic blood pressure variability (BPV) after endovascular thrombectomy (EVT) has been associated with an increased risk of hemorrhagic transformation and worse functional outcomes. However, the time-varying behavior of BPV after EVT and its effects on functional outcome have not been well characterized. Methods: We analyzed data from an international cohort of patients with acute large-vessel occlusion stroke who underwent EVT at 11 centers across North America, Europe, and Asia. Repeated time-stamped blood pressure data were recorded for the first 72 hours after thrombectomy. Parameters of BPV were calculated in 12-hour epochs using five established methodologies: standard deviation (SD), coefficient of variation (CV), average real variability (ARV), successive variation (SV), and residual SD (rSD). Patients’ overall mean BPV was then used to assign patients into tertiles for regression analysis: low BPV, intermediate BPV, and high BPV. Functional outcome was measured with the modified Rankin Scale (mRS) at 90 days. Results: Of the 1,791 patients (age 69 ± 14, NIHSS 15 ± 6) included in our analysis, 1,085 (60.6%) had a poor 90-day outcome (mRS &gt;3). Patients with poor outcome had significantly higher systolic BPV (p&lt;0.05) measured as standard deviation (SBP SD) at each epoch (Figure 1B). Compared to patients with low BPV, those in the highest tertile group had significantly greater odds of a poor functional outcome after adjusting for age, sex, hypertension, NIHSS, ASPECT, tPA, time to reperfusion, and TICI score (OR 1.5; 95% CI 1.2-2; p=0.001). Patients in the highest tertile of BPV demonstrated time-dependent variability with the highest SBP SD during the first 24 hours after thrombectomy (Figure 1A). Conclusions: Higher BPV measured by SBP SD appears to be associated with poor 90-day outcome in EVT-treated stroke patients. Early treatment strategies targeting early high BPV warrant further prospective investigation.

Effects of ML351 and tissue plasminogen activator combination therapy in a rat model of focal embolic stroke.

Thrombolytic stroke therapy with tissue plasminogen activator (tPA) is limited by risks of hemorrhagic transformation (HT). We have reported that a new 12/15-lipoxygenase (12/15-LOX) inhibitor ML351 reduced tPA related HT in mice subjected to experimental stroke under anticoagulation. In this study, we asked whether ML351 can ameliorate tPA induced HT in an embolic stroke model. Rats were subjected to embolic middle cerebral artery occlusion with 2 or 3hr ischemia and tPA infusion, with or without ML351. Regional cerebral blood flow was monitored 2hr after ischemia and continuously monitored for 1hr after treatment for determining reperfusion. Hemoglobin was determined in brain homogenates and infarct volume was quantified at 24hr after stroke.12/15-LOX, cluster of differentiation 68(CD68), immunoglobulin G (IgG), and tight junction proteins expression was detected by immunohistochemistry. ML351 significantly reduced tPA related hemorrhage after stroke without affecting its thrombolytic efficacy. ML351 also reduced blood-brain barrier disruption and improved preservation of junction proteins. ML351 and tPA combination improved neurological deficit of rats even though ML351 did not further reduce the infarct volume compared to tPA alone treated animals. Pro-inflammatory cytokines were suppressed by ML351 both in vivo and in vitro experiments. We further showed that ML351 suppressed the expression of c-Jun-N-terminal kinase (JNK) in brains and microglia cultures, whereas exogenous 12-HETE attenuated this effect in vitro. In conclusion, ML351 and tPA combination therapy is beneficial in ameliorating HT after ischemic stroke. This protective effect is probably because of 12/15-LOX inhibition and suppression of JNK-mediated microglia/macrophage activation.

Association of Non-Traditional Lipid Parameters with Hemorrhagic Transformation and Clinical Outcome After Thrombolysis in Ischemic Stroke Patients.

Recently, a few studies have shown that non-traditional lipid parameters are associated with the hemorrhagic transformation (HT) and the clinical outcome of ischemic stroke. However, the role of non-traditional lipid parameters in ischemic stroke patients treated with intravenous thrombolysis remains unclear. Thus, we aimed to assess the associations of non-traditional lipid parameters with HT and clinical outcome after thrombolysis in ischemic stroke patients. This study consecutively included 763 ischemic stroke patients treated with intravenous thrombolysis. Non-traditional lipid parameters included non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol to HDL-C ratio (TC/HDL-C), triglyceride to HDL-C ratio (TG/ HDL-C), and low-density lipoprotein cholesterol to HDL-C ratio (LDL-C/HDL-C). Receiver operating characteristic (ROC) curves and multivariate logistic regression analyses were used to investigate the associations between the four non-traditional lipid parameters and HT and poor outcome after thrombolysis. Of 763 patients, 78 (10.2%) had HT and 281 (36.8%) had poor outcome. The ROC curves showed that the optimum cut-off points of the non-HDL-C, TC/HDL-C, TG/HDL-C, and LDL/HDL-C for predicting HT and poor outcome were 2.99 and 2.01, 4.05 and 3.66, 0.82 and 1.02, as well as 2.67 and 2.71, respectively. Multivariate logistic regression analyses showed that the TC/HDL-C <4.05 (adjusted odds ratio [OR]=1.727, 95% confidence interval [CI]: 1.008-2.960), TG/HDL-C <0.82 (adjusted OR=2.064, 95% CI: 1.241-3.432), and LDL/HDL-C <2.67 (adjusted OR=1.935, 95% CI: 1.070-3.501) were positively associated with the risk of HT, while the non-HDL-C <2.99 (adjusted OR=0.990, 95% CI: 0.583-1.680) was not related to the risk of HT. In addition, the non-HDL-C <2.01, TC/HDL-C <3.66, TG/HDL-C <1.02, and LDL/HDL-C <2.71 were associated with an increased risk of poor outcome, with adjusted ORs of 2.340 (95% CI: 1.150-4.764), 1.423 (95% CI: 1.025-1.977), 1.539 (95% CI: 1.102-2.151), and 1.608 (95% CI: 1.133-2.283). Low TC/HDL-C, TG/HDL-C, and LDL/HDL-C, but not non-HDL-C, were associated with an increased risk of HT after thrombolysis. In addition, low non-HDL-C, TC/HDL-C, TG/HDL-C, and LDL/HDL-C were associated with an increased risk of poor outcome in ischemic stroke patients with intravenous thrombolysis.

The prognostic significance of large vessel occlusion in stroke patients treated by intravenous thrombolysis

PurposeAccording to guidelines, to shorten the treatment window, acute ischaemic stroke (AIS) treatment by intravenous thrombolysis (IVT) can be done based on the results of head computed tomography (CT) without contrast. The impact of large vessel occlusion (LVO) on computed tomography angiography (CTA) in stroke prognosis in patients treated IVT or IVT and mechanical thrombectomy (MT), where indicated, has not yet been studied systematically. We investigated the influence of LVO in consecutive AIS patients on haemorrhagic transformation (HT) on CT 24 h after treatment, mRS < 2 on discharge (unfavourable outcome), and in-hospital mortality.Material and methodsWe analysed several parameters within 24 h after AIS: demographics, risk factors, mRS score pre-stroke, NIHSS upon admission and 24 h later, several clinical and biochemical parameters, and chronic treatment.ResultsWe registered 1209 patients, of whom 362 (29.9%) received IVT and 108 had MT, where indicated. Admission CTA showed LVO in 197 patients (54.4%). Multivariate regression analysis showed that the presence of LVO and lower delta NIHSS (NIHSS on admission minus NIHSS 24 hours later) were independent parameters affecting HT risk. Multivariate analysis showed that the presence LVO and also older age, female sex, lower delta NIHSS, HT, stroke-associated infection, CRP levels ≥ 10 mg/L, and higher WBC count affected unfavourable outcome on discharge. LVO did not affect in-hospital mortality.ConclusionsLVO in AIS patients treated by IVT or IVT and MT affects the risk of HT and unfavourable short-term outcome but not in-hospital mortality.

Association Between Plasma Total Homocysteine Levels and Risk of Early Hemorrhagic Transformation in Patients with Acute Ischemic Stroke: A Hospital-Based Study

ObjectsIn this study, we investigated the association between plasma total homocysteine(tHcy) levels and the risk of early hemorrhagic transformation(HT) in patients with acute ischemic stroke(AIS). MethodsConsecutive hospitalized participants who met the inclusion criteria were enrolled and grouped according to plasma tHcy levels. Participants were divided into a low homocysteine level(L-tHcy) group (<12 µmol/L) and a high homocysteine level group(H-tHcy) (≥ 12 µmol/L). Baseline computed tomography (CT) examination was performed. HT was determined via CT or magnetic resonance imaging within 1 to 3 days after admission. ResultsA total of 1858 patients were screened and 1378 patients completed the this study(797 patients in the H-tHcy group and 581 patients in the L-tHcy group). HT incidence was 5.2% (30/581,) in the L-tHcy group and 11.2% (90/797) in the H-tHcy group(P<0.05). Binary logistic regression analysis showed that initial NIHSS score, tHcy levels, treatment with recombinant tissue plasminogen activator thrombolysis, systolic blood pressure on admission, glucose level on admission, smoking status and estimated glomerular filtration rate were independent risk factors for HT. Receiver operating characteristic analysis showed that tHcy level was a moderately sensitive and specific index to predict the incidence of HT, and the optimal cutoff was 16.56 μmol/L (sensitivity 63.3%, specificity 41.3%). ConclusionOur study findings reveal that high plasma tHcy level is one independent risk factor associated with increased risk of early HT in patients with AIS.

Pathophysiology of Blood-Brain Barrier Permeability Throughout the Different Stages of Ischemic Stroke and Its Implication on Hemorrhagic Transformation and Recovery.

The blood–brain barrier (BBB) is a dynamic interface responsible for maintaining the central nervous system homeostasis. Its unique characteristics allow protecting the brain from unwanted compounds, but its impairment is involved in a vast number of pathological conditions. Disruption of the BBB and increase in its permeability are key in the development of several neurological diseases and have been extensively studied in stroke. Ischemic stroke is the most prevalent type of stroke and is characterized by a myriad of pathological events triggered by an arterial occlusion that can eventually lead to fatal outcomes such as hemorrhagic transformation (HT). BBB permeability seems to follow a multiphasic pattern throughout the different stroke stages that have been associated with distinct biological substrates. In the hyperacute stage, sudden hypoxia damages the BBB, leading to cytotoxic edema and increased permeability; in the acute stage, the neuroinflammatory response aggravates the BBB injury, leading to higher permeability and a consequent risk of HT that can be motivated by reperfusion therapy; in the subacute stage (1–3 weeks), repair mechanisms take place, especially neoangiogenesis. Immature vessels show leaky BBB, but this permeability has been associated with improved clinical recovery. In the chronic stage (>6 weeks), an increase of BBB restoration factors leads the barrier to start decreasing its permeability. Nonetheless, permeability will persist to some degree several weeks after injury. Understanding the mechanisms behind BBB dysregulation and HT pathophysiology could potentially help guide acute stroke care decisions and the development of new therapeutic targets; however, effective translation into clinical practice is still lacking. In this review, we will address the different pathological and physiological repair mechanisms involved in BBB permeability through the different stages of ischemic stroke and their role in the development of HT and stroke recovery.

A new nomogram for individualized prediction of the probability of hemorrhagic transformation after intravenous thrombolysis for ischemic stroke patients

BackgroundA reliable scoring tool to detect the risk of intracerebral hemorrhage (ICH) after intravenous thrombolysis for ischemic stroke is warranted. The present study was designed to develop and validate a new nomogram for individualized prediction of the probability of hemorrhagic transformation (HT) in patients treated with intravenous (IV) recombinant tissue plasminogen activator (rt-PA).MethodsWe enrolled patients who suffered from acute ischemic stroke (AIS) with IV rt-PA treatment in our emergency green channel between August 2016 and July 2018. The main outcome was defined as any type of intracerebral hemorrhage according to the European Cooperative Acute Stroke Study II (ECASS II). All patients were randomly divided into two cohorts: the primary cohort and the validation cohort. On the basis of multivariate logistic model, the predictive nomogram was generated. The performance of the nomogram was evaluated by Harrell’s concordance index (C-index) and calibration plot.ResultsA total of 194 patients with complete data were enrolled, of whom 131 comprised the primary cohort and 63 comprised the validation cohort, with HT rate 12.2, 9.5% respectively. The score of chronic disease scale (CDS), the global burden of cerebral small vascular disease (CSVD), National Institutes of Health Stroke Scale (NIHSS) score ≥ 13, and onset-to-treatment time (OTT) ≥ 180 were detected important determinants of ICH and included to construct the nomogram. The nomogram derived from the primary cohort for HT had C- Statistics of 0.9562 and the calibration plot revealed generally fit in predicting the risk of HT. Furthermore, we made a comparison between our new nomogram and several other risk-assessed scales for HT with receiver operating characteristic (ROC) curve analysis, and the results showed the nomogram model gave an area under curve of 0.9562 (95%CI, 0.9221–0.9904, P < 0.01) greater than HAT (Hemorrhage After Thrombolysis), SEDAN (blood Sugar, Early infarct and hyper Dense cerebral artery sign on non-contrast computed tomography, Age, and NIHSS) and SPAN-100 (Stroke Prognostication using Age and NIHSS) scores.ConclusionsThis proposed nomogram based on the score of CDS, the global burden of CSVD, NIHSS score ≥ 13, and OTT ≥ 180 gives rise to a more accurate and more comprehensive prediction for HT in patients with ischemic stroke receiving IV rt-PA treatment.

Predictive Factors of Hemorrhage After Thrombolysis in Patients With Acute Ischemic Stroke.

Background: Ischemic stroke has a poor prognosis and brings a ponderous burden on families and society. Hemorrhagic transformation (HT) after intravenous thrombolysis can increase the mortality of patients with ischemic stroke. Thus, finding new HT biomarkers to be applicable in clinical practice is of great importance.Methods: The related risk factors were recruited for analysis, including smoking, drinking, hyperlipidemia, diabetes, anamnesis, and pathological indicators. Moreover, the relationship between serum levels of caveolin-1, caveolin-2, and HT after rt-PA treatment were also studied.Results: We studied 306 patients with acute ischemic stroke treated with recombinant tissue type plasminogen activator (rt-PA) within 4.5 h of symptom onset. The results showed that Age ≥68 years, smoking, Atrial fibrillation, NIHSS score before thrombolysis ≥17, and systolic pressure 2 h after thrombolysis (mmHg) ≥149 increased the risks of HT after rt-PA administration. Remarkably, the concentration of caveolin-1 (ng/mL) ≤ 0.12 and caveolin-2 (ng/mL) ≤ 0.43 in serum increased the risks of HT after rt-PA administration.Conclusion: Knowledge on the risk factors associated with HT after rt-PA treatment may help develop treatment strategies and reduce the risk of HT. Caveolin-1 and caveolin-2 can be predictors of HT after rt-PA administration. These findings provide evidence for future further investigations aimed to validate these biomarkers.

Hemorrhagic Transformation After Tissue Plasminogen Activator Treatment in Acute Ischemic Stroke.

Hemorrhagic transformation (HT) is a common complication after thrombolysis with recombinant tissue-type plasminogen activator (rt-PA) in ischemic stroke. In this article, recent research progress of HT in vivo and in vitro studies was reviewed. We have discussed new potential mechanisms and possible experimental models of HT development, as well as possible biomarkers and treatment methods. Meanwhile, we compared and analyzed rodent models, large animal models and in vitro BBB models of HT, and the limitations of these models were discussed. The molecular mechanism of HT was investigated in terms of BBB disruption, rt-PA neurotoxicity and the effect of neuroinflammation, matrix metalloproteinases, reactive oxygen species. The clinical features to predict HT were represented including blood biomarkers and clinical factors. Recent progress in neuroprotective strategies to improve HT after stroke treated with rt-PA is outlined. Further efforts need to be made to reduce the risk of HT after rt-PA therapy and improve the clinical prognosis of patients with ischemic stroke.

COVID-19 Severity and Stroke: Correlation of Imaging and Laboratory Markers.

Coronavirus disease 2019 (COVID-19) appears to be an independent risk factor for stroke. We hypothesize that patients who develop stroke while hospitalized for severe COVID-19 will have higher inflammatory markers and distinct stroke imaging patterns compared with patients positive for COVID-19 with out-of-hospital stroke onset and milder or no COVID-19 symptoms. This is a retrospective case series of patients positive for COVID-19 on polymerase chain reaction testing with imaging-confirmed stroke treated within a large health care network in New York City and Long Island between March 14 and April 26, 2020. Clinical and laboratory data collected retrospectively included complete blood counts and creatinine, alanine aminotransferase, lactate dehydrogenase, C-reactive protein, ferritin, and D-dimer levels. All CT and MR imaging studies were independently reviewed by 2 neuroradiologists who recorded stroke subtype and patterns of infarction and intracranial hemorrhage. Compared with patients with COVID-19 with outside-of-hospital stroke onset and milder or no COVID-19 symptoms (n = 45, 52.3%), patients with stroke already hospitalized for severe COVID-19 (n = 41, 47.7%) had significantly more frequent infarctions (95.1% versus 73.3%, P = .006), with multivascular distributions (56.4% versus 33.3%, P = .022) and associated hemorrhage (31.7% versus 4.4%, P = .001). Patients with stroke admitted with more severe COVID-19 had significantly higher C-reactive protein and ferritin levels, elevated D-dimer levels, and more frequent lymphopenia and renal and hepatic injury (all, P < .003). Patients with stroke hospitalized with severe COVID-19 are characterized by higher inflammatory, coagulopathy, and tissue-damage biomarkers, supporting proposed pathogenic mechanisms of hyperinflammation activating a prothrombotic state. Cautious balancing of thrombosis and the risk of hemorrhagic transformation is warranted when considering anticoagulation.

Liver Fibrosis Is Associated With Hemorrhagic Transformation in Patients With Acute Ischemic Stroke

Background: Hemorrhagic transformation (HT) is a frequent, often asymptomatic event that occurs after acute ischemic stroke (AIS). Liver fibrosis, usually subclinical, is common and crucial in the development of liver disease. We aimed to investigate the association between liver fibrosis and HT in patients with AIS.Methods: We performed a single-center and retrospective study. A total of 185 consecutive participants with HT and 199 age- and sex-matched stroke patients without HT were enrolled in this study. We calculated one validated fibrosis index—Fibrosis-4 (FIB-4) score—to assess the extent of liver fibrosis. HT was detected by routine CT or MRI and was radiologically classified as hemorrhagic infarction type 1 or 2 or parenchymal hematoma type 1 or 2. HT was also classified into asymptomatic or symptomatic. We used logistic regression models adjusted for previously established risk factors to assess the risks for HT.Results: The median FIB-4 score was significantly higher among patients who developed HT than among those without HT, whereas standard hepatic assays were largely normal. Patients were assigned to groups of high FIB-4 score and low FIB-4 score based on the optimal cutoff value. Compared with the subjects in the low-FIB-4-score group, incidence of HT for the high-FIB-4-score group was significantly higher. After adjustment for potential confounders, the patients with high FIB-4 score had 3.461-fold risk of HT in AIS compared to the patients with low FIB-4 score [odds ratio, 3.461 (95% CI, 1.404–8.531)].Conclusion: Liver fibrosis, measured by FIB-4 score, was independently associated with the risk of HT in AIS patients.

Low Serum Magnesium Levels Are Associated With Hemorrhagic Transformation After Thrombolysis in Acute Ischemic Stroke.

Background: In patients with acute ischemic stroke, hemorrhagic transformation is a major complication after intravenous thrombolysis. This study aimed to investigate the relationship between serum magnesium levels and hemorrhagic transformation (HT) after thrombolytic therapy.Methods: We retrospectively analyzed data from 242 patients who received thrombolytic therapy at the Second Affiliated Hospital of the Wenzhou Medical University in China. Baseline serum magnesium levels were measured before intravenous thrombolysis, and the occurrence of HT was evaluated using computed tomography images reviewed within 24–36 h after therapy. The relationship between serum magnesium levels and HT was examined using multivariate logistic regression, subgroup analysis, and restricted cubic spline models.Results: Of the 242 included patients, 43 (17.8%) developed HT. Patients with HT had significant lower serum magnesium levels than those without HT (0.81 ± 0.08 vs. 0.85 ± 0.08 mmol/L, p = 0.007). Multivariable logistic regression analysis indicated that patients with higher serum magnesium levels had lower risk of HT (OR per 0.1-mmol/L increase 0.43, 95% CI 0.27–0.73, p = 0.002). However, this association did not persist when baseline levels of serum magnesium were higher than the median value (0.85 mmol/L) in subgroup analysis (OR per 0.1-mmol/L increase 0.58, 95% CI 0.14–2.51, p = 0.47). This threshold effect was also observed in the restricted cubic spline model when serum magnesium levels were above 0.88 mmol/L. No association between symptomatic HT and serum magnesium levels was observed in our study (OR per 0.1-mmol/L increase 0.52, 95% CI 0.25–1.11, p = 0.092).Conclusions: Lower serum magnesium levels in patients with ischemic stroke are associated with an increased risk of HT after intravenous thrombolysis, but perhaps only when serum magnesium is below a certain minimal concentration.