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

BACKGROUND: A 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). METHODS: We 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. RESULTS: A 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. CONCLUSIONS: This 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.

High serum sICAM-1 is correlated with cerebral microbleeds and hemorrhagic transformation in ischemic stroke patients.

Object: Intercellular adhesion molecule 1 (ICAM-1) is an adhesive protein involved in inflammatory responses and endothelial dysfunction. ICAM-1 expression is upregulated in cerebrovascular tissue affected by stroke. We investigated whether serum soluble ICAM-1 (sICAM-1) levels are associated with cerebral microbleeds (CMBs) and risk of hemorrhagic transformation (HT).Methods: 148 patients with acute ischemic stroke were enrolled. Serum sICAM-1 levels were measured and compared between patients and healthy controls. Multivariate logistic regression analysis was performed to estimate the relationship between serum sICAM-1 levels and the HT risk.Results: Serum sICAM-1 levels were significantly higher in ischemic stroke patients compared with healthy controls (p < .001), and higher in patients with CMBs (n = 81) compared with patients without CMBs (n = 67) (p < .001). Patients with high sICAM-1 levels (≥250.5 ng/mL) were more likely to have hypertension, diabetes mellitus, previous stroke, and CMBs compared with patients with low sICAM-1 levels. In stroke patients with CMBs, higher serum sICAM-1 levels were independently associated with increased HT risk.Conclusion: Serum sICAM-1 levels are associated with presence of CMBs and increased risk of HT in ischemic stroke patients.

Predictors of acute post-thrombectomy intracranial hemorrhage expansion in anterior circulation infarcts.

BACKGROUND: Post-mechanical thrombectomy (MT) intracranial hemorrhage (ICH) is a major source of morbidity in treated acute ischemic stroke patients with large vessel occlusion. ICH expansion may further contribute to morbidity. We sought to identify factors associated with ICH expansion on imaging evaluation post-MT. METHODS: We performed a retrospective cohort study of patients undergoing MT at a single comprehensive stroke center. Per protocol, patients underwent dual-energy head CT (DEHCT) post-MT followed by a 24-h interval non-contrast enhanced MRI. ICH expansion was defined as any increase in blood volume between the two studies if identified on the DEHCT. Univariate and multivariable analyses were performed to identify risk factors for ICH expansion. RESULTS: ICH was identified on DEHCT in 13% of patients (n = 35/262), with 20% (7/35) demonstrating expansion on interval MRI. The average increase in blood volume was 11.4 ml (SD 6.9). Univariate analysis identified anticoagulant usage (57% vs 14%, p = 0.03), petechial hemorrhage inside the infarct margins or intraparenchymal hematoma on DEHCT (ECASS-II HI2/PH1/PH2) (71% vs 14%, p < 0.01), basal ganglia hemorrhage (71% vs 21%, p = 0.02), and basal ganglia infarction (86% vs 32%, p = 0.03) as factors associated with ICH expansion. Multivariate regression demonstrated that anticoagulant usage (OR 20.3, 95% C.I. 2.43-446, p < 0.05) and ECASS II scores of HI2/PH1/PH2 (OR 11.7, 95% C.I. 1.24-264, p < 0.05) were significantly predictive of ICH expansion. CONCLUSION: Expansion of post-MT ICH on 24-h interval MRI relative to immediate post-thrombectomy DEHCT is significantly associated with baseline anticoagulant usage and petechial hemorrhage inside the infarct margins or presence of intraparenchymal hematoma (ECASS-II HI2/PH1/PH2).

Low-to-moderate dose statins improve the functional outcome of acute ischemic stroke with conventional medication treatment.

Background: Low-to-moderate dose statins (LMDSs) are more commonly used among Asian acute ischemic stroke (AIS) patients in clinical practice. However, the correlation between the LMDS use and prognosis has not been evaluated in AIS patients with conventional medication treatment alone. This study aimed to investigate the influence of LMDS on the prognosis of AIS patients and how prognosis and potential prognostic factors interact with different statin doses. Methods: This retrospective cohort study included AIS patients who were admitted within 7 days after symptom onset and received conventional medication treatment alone from November 2019 to November 2020 in the Neurology, Department of West China Hospital, Sichuan University. From a total of 782 initial patients, a final cohort of 327 patients was included in the study. These patients were divided into three groups based on statin doses: non-statin (48 patients), LMDS (152 patients), and high-dose statin (HDS) (127 patients). The follow-up period was 3 months after the onset of stroke and the primary outcome was defined as a modified Rankin scale (mRS) score of 0 to 2 at 3 months, secondary outcomes were hemorrhagic transformation (HT) and death within 3 months. Stratified analysis was also conducted to test the robustness of the relationship between the use of different statin doses and functional outcomes in various subgroups. Results: Compared with non-statin therapy, both LMDS therapy and HDS therapy were associated with good functional outcomes [odds ratio (OR) =3.68, 95% confidence interval (CI): 1.13-12.01, P=0.0309; OR =3.45, 95% CI: 1.06-11.26, P=0.0402, respectively] and a lower risk of HT (OR =0.30, 95% CI: 0.11-0.86, P=0.0253; OR =0.36, 95% CI: 0.13-0.99, P=0.0488, respectively). However, there was no significant difference in all-cause death within 3 months among the three groups (OR =0.84, 95% CI: 0.29-2.46, P=0.7468; OR =0.76, 95% CI: 0.26-2.22, P=0.6104). Additionally, no significant differences were observed between LMDS therapy and HDS therapy regarding good functional outcomes at 3 months (OR =0.94, 95% CI: 0.50-1.77, P=0.8411) and the occurrence of HT (OR =1.19, 95% CI: 0.47-3.02, P=0.7093). The results of the relationship between different statin doses and 3-month good functional outcome were consistent after interaction tests. Conclusions: Our findings provide evidence for the benefit and safety of LMDS therapy in AIS patients with medication treatment alone. LMDS therapy is associated with favorable impacts on 3-month functional outcomes and a reduced risk of HT compared to non-statin therapy. There were no significant differences in achieving 3-month good functional outcome, the risk of HT or death within 3 months were observed between LMDS and HDS therapy in our study. Further studies with prospective design and larger sample sizes are necessary to validate our results.

Angong Niuhuang Wan reduces hemorrhagic transformation and mortality in ischemic stroke rats with delayed thrombolysis: involvement of peroxynitrite-mediated MMP-9 activation.

BACKGROUND: Hemorrhagic transformation (HT) is a common complication of delayed tissue plasminogen activator (t-PA) treatment for ischemic stroke. Peroxynitrite plays an important role in the breakdown of blood-brain barrier (BBB) and the development of HT. We tested the hypothesis that Angong Niuhuang Wan (AGNHW), a traditional Chinese medicinal formula, could be used in conjunction with t-PA to protect the BBB, minimize HT, and improve neurological function by suppressing peroxynitrite-mediated matrix metalloproteinase-9 (MMP-9) activation. METHODS: We first performed quality control study and chemical identification of AGNHW by using UPLC. In animal experiments, male Sprague-Dawley rats were subjected to 5 h of middle cerebral artery occlusion (MCAO) followed by 19 h of reperfusion plus t-PA infusion (10 mg/kg) at 5 h of cerebral ischemia. AGNHW (257 mg/kg) was given orally at 2 h after MCAO. Hemorrhagic transformation was measured using hemorrhagic scores and hemoglobin levels in ischemic brains. Evans blue leakage was utilized to assess the severity of the blood-brain barrier (BBB) damage. The modified neurologic severity score (mNSS) test was used to assess neurological functions. Peroxynitrite and superoxide was detected by using fluorescent probes. MMP-9 activity and expression were examined by gelatin zymography and immunostaining. The antioxidant effects were also studied by using brain microvascular endothelial b.End3 cells exposed to 5 h of oxygen and glucose deprivation (OGD) plus 5 h of reoxygenation with t-PA treatment (20 µg/ml). RESULTS: AGNHW significantly reduced the BBB damage, brain edema, reduced hemorrhagic transformation, enhanced neurological function, and reduced mortality rate in the ischemic stroke rats with t-PA treatment. AGNHW reduced peroxynitrite and superoxide in vivo and in vitro and six active chemical compounds were identified from AGNHW with peroxynitrite scavenging activity. Furthermore, AGNHW inhibited MMP-9 activity, and preserved tight junction protein claudin-5 and collagen IV in the ischemic brains. CONCLUSION: AGNHW could be a potential adjuvant therapy with t-PA to protect the BBB integrity, reduce HT, and improve therapeutic outcome in ischemic stroke treatment via inhibiting peroxynitrite-mediated MMP-9 activation.

Predictive accuracy of an ADC map for hemorrhagic transformation in acute ischemic stroke patients after successful recanalization with endovascular therapy.

Background: Hemorrhagic transformation (HT) of acute ischemic stroke (AIS) is associated with poor outcome. Previous studies only reported the association of mean ischemic severity or total infarct volume with HT after endovascular therapy (EVT). We aimed to investigate the predictive value of preoperative apparent diffusion coefficient (ADC) map for HT by combinated ischemic severity and corresponding volume in AIS after successful recanalization with EVT. Methods: We retrospectively analyzed 119 consecutive cases of AIS with large vessel occlusion of anterior circulation within 24 hours after symptom onset and successful recanalization after EVT. All cases had baseline magnetic resonance imaging (MRI), follow-up computed tomography (CT), and magnetic resonance angiography (MRA) or computed tomography angiography (CTA). Volumes of ADC <0.6×10-3, 0.5×10-3, 0.4×10-3, and 0.3×10-3 mm2/s, baseline characteristics and outcomes of patients with and without HT identified by European Collaborative Acute Stroke Study (ECASS) were compared. The optimal ADC and volume threshold for predicting HT were analyzed using receiver operating characteristic (ROC) curve, and multivariate logistic regression analysis were performed with clinical characteristics and volumes of optimal ADC threshold to determine risk factors for HT. Results: Among 119 patients, 42 patients had HT on follow-up CT, including 24 hemorrhagic infarct (HI) cases and 18 parenchymal hematoma (PH) cases. The optimal volumes were 6.46 mL with ADC <0.4×10-3 mm2/s for predicting both HT and PH, with a larger area under curve (AUC) of 83.3% for HT than that for PH of 80%. In logistic regression analysis, intravenous tissue plasminogen activator (IV tPA) treatment, atrial fibrillation, and volume of ADC <0.4×10-3 mm2/s were identified as independent predictors for HT and volume of ADC <0.4×10-3 mm2/s had the highest odds ratio (OR) value. Conclusions: The combination of ischemic severity and corresponding volume in ADC map may predict HT after thrombectomy. In addition to the total infarct volume, volume with severe ischemia should be taken into consideration in preoperative patient selection.

Hemorrhagic Transformation After Ischemic Stroke: Mechanisms and Management.

Symptomatic hemorrhagic transformation (HT) is one of the complications most likely to lead to death in patients with acute ischemic stroke. HT after acute ischemic stroke is diagnosed when certain areas of cerebral infarction appear as cerebral hemorrhage on radiological images. Its mechanisms are usually explained by disruption of the blood-brain barrier and reperfusion injury that causes leakage of peripheral blood cells. In ischemic infarction, HT may be a natural progression of acute ischemic stroke and can be facilitated or enhanced by reperfusion therapy. Therefore, to balance risks and benefits, HT occurrence in acute stroke settings is an important factor to be considered by physicians to determine whether recanalization therapy should be performed. This review aims to illustrate the pathophysiological mechanisms of HT, outline most HT-related factors after reperfusion therapy, and describe prevention strategies for the occurrence and enlargement of HT, such as blood pressure control. Finally, we propose a promising therapeutic approach based on biological research studies that would help clinicians treat such catastrophic complications.

Anticoagulation Resumption in a Patient With Mechanical Heart Valves, Antithrombin Deficiency, and Hemorrhagic Transformation Following Thrombectomy After Ischemic Stroke.

Anticoagulation is essential for patients undergoing mechanical heart valve replacement; however, the timing to reinitiate the anticoagulant could be a dilemma that imposes increased risk for bleeding events in patients suffering from the life-threatening hemorrhagic transformation (HT) after ischemic stroke. Such a situation was presented in this case report. A 71-year-old woman was transferred directly to the Neurocritical Care Unit because of a HT that occurred following the mechanical thrombectomy for ischemic stroke. Since she had a history of prosthetic metallic valve replacement, how the anticoagulating therapy could balance the hemorrhagic and thrombotic risks was carefully evaluated. On day 6 after the onset of hemorrhage transformation, the laboratory results of coagulation and fibrinolysis strongly suggested thrombosis as well as antithrombin deficiency. The short-acting and titratable anticoagulant argatroban was immediately initiated at low dose, and thrombosis was temporarily terminated. On day 3 of anticoagulation resumption, argatroban was discontinued for one dose when the prothrombin time and activated partial thromboplastin time significantly prolonged after argatroban infusion. Aortic valve thrombosis was detected the next day. The anticoagulation was then strengthened by dose adjustment to keep mitral valve intact, to stabilize the aortic valve thrombosis, and to decrease the aortic flow rate. The intravenous argatroban was transited to oral warfarin before the patient was discharged. This study is the first report of administering argatroban and titrating to its appropriate dose in the patient with valve thrombosis, antithrombin deficiency, and HT after mechanical thrombectomy for acute ischemic stroke. Notably, the fluctuations argatroban brings to the coagulation test results might not be interpreted as increased bleeding risk. This case also suggested that the reported timing (day 6 to day 14 after hemorrhage) of anticoagulant resumption in primary intracerebral hemorrhage with mechanical valves might be late for some patients with HT.

Identification of Predictors for Hemorrhagic Transformation in Patients with Acute Ischemic Stroke After Endovascular Therapy Using the Decision Tree Model.

PURPOSE: This study aimed to identify independent predictors for the risk of hemorrhagic transformation (HT) in arterial ischemic stroke (AIS) patients. METHODS: Consecutive patients with AIS due to large artery occlusion in the anterior circulation treated with mechanical thrombectomy (MT) were enrolled in a tertiary stroke center. Demographic and medical history data, admission lab results, and Circle of Willis (CoW) variations were collected from all patients. RESULTS: Altogether, 90 patients were included in this study; among them, 34 (37.8%) had HT after MT. The final pruned decision tree (DT) model consisted of collateral score and platelet to lymphocyte ratios (PLR) as predictors. Confusion matrix analysis showed that 82.2% (74/90) were correctly classified by the model (sensitivity, 79.4%; specificity, 83.9%). The area under the ROC curve (AUC) was 81.7%. The DT model demonstrated that participants with collateral scores of 2-4 had a 75.0% probability of HT. For participants with collateral scores of 0-1, if PLR at admission was <302, participants had a 13.0% probability of HT; otherwise, participants had an 75.0% probability of HT. The final adjusted multivariate logistic regression analysis indicated that collateral score 0-1 (OR, 10.186; 95% CI, 3.029-34.248; p < 0.001), PLR (OR, 1.005; 95% CI, 1.001-1.010; p = 0.040), and NIHSS at admission (OR, 1.106; 95% CI, 1.014-1.205; p = 0.022) could be used to predict HT. The AUC for the model was 0.855, with 83.3% (75/90) were correctly classified (sensitivity, 79.4%; specificity, 87.3%). Less patients with HT achieved independent outcomes (mRS, 0-2) in 90 days (20.6% vs. 64.3%, p < 0.001). Rate of poor outcomes (mRS, 4-6) was significantly higher in patients with HT (73.5% vs. 19.6%; p < 0.001). CONCLUSION: Both the DT model and multivariate logistic regression model confirmed that the lower collateral status and the higher PLR were significantly associated with an increased risk for HT in AIS patients after MT. PLR may be one of the cost-effective and practical predictors for HT. Further prospective multicenter studies are needed to validate our findings.

The Role of Dual Energy CT in Evaluating Hemorrhagic Complications at Different Stages After Thrombectomy.

Background: Contrast media extravasation can mimic hemorrhage after endovascular thrombectomy (EVT). Dual energy CT (DECT) has the potential to distinguish hemorrhage from iodine contrast. Methods: We retrospectively examined clinical and radiological data from 106 consecutive acute ischemic stroke patients who received EVT and underwent DECT immediately and 24 h after EVT. Iodine overlay map, virtual non-contrast, and mixed images are reconstructed. Results: With the use of DECT, the proportion of all patients diagnosed with hemorrhagic transformation on mixed images immediately after EVT was reduced from 74.5% (79 of 106) to 10.4% (11 of 106), with a very poor consistency (κ = 0.076, p = 0.041). Correspondingly, hemorrhagic transformation on mixed images 24 h after EVT was reduced from 41.5% (44 of 106) to 30.2% (32 of 106), with a moderate consistency (κ = 0.757, p < 0.001). Conclusions: The use of DECT both immediately and 24 h after EVT changes the diagnosis of hemorrhagic transformation in a considerable proportion of acute ischemic stroke patients with EVT. This could affect decision making with respect to antithrombotic strategy.

Reperfusion Into Severely Damaged Brain Tissue Is Associated With Occurrence of Parenchymal Hemorrhage for Acute Ischemic Stroke.

Background and Purpose: This study aims to quantify the reperfusion status within severely damaged brain tissue and to evaluate its relationship with high grade of hemorrhagic transformation (HT). Methods: Pseudo-continuous ASL was performed along with DWI in 102 patients within 24 h post-treatments. The infarction core was identified using ADC values <550 × 10-6 mm2/s. CBF within the infarction core and its contralateral counterpart were acquired. CBF at the 25th, median, and 75th percentiles of the contralateral counterpart were used as thresholds and the ASL reperfusion volume above the threshold was labeled as vol-25, -50, and -75, respectively. Recanalization was defined according to Thrombolysis in Myocardial Infarction (TIMI) criteria. Results: Quantified reperfusion within the infarction core differed significantly in patients with complete and incomplete recanalization. In the ROC analysis for the prediction of parenchymal hematoma (PH), ASL reperfusion vol-25 had the highest area under the curve (AUC) when compared with ASL vol-50 and ASL vol-75. ASL reperfusion vol-25 had significantly higher AUC compared with ADC threshold volume in the prediction of PH (0.783 vs. 0.685, P = 0.0036) and PH-2 (0.844 vs. 0.754, P = 0.0035). In stepwise multivariate logistic regression analysis, only ASL reperfusion vol-25 emerged as an independent predictor of PH (OR = 3.51, 95% CI: 1.65-7.45, P < 0.001) and PH-2 (OR = 2.32, 95% CI: 1.13-4.76, P = 0.022). Conclusions: Increased reperfusion volume within severely damaged brain tissue is associated with the occurrence of higher grade of HT.

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.

Blood-Brain Barrier Disruption and Hemorrhagic Transformation in Acute Ischemic Stroke: Systematic Review and Meta-Analysis.

Introduction: Hemorrhagic transformation (HT) is a complication of reperfusion therapy for acute ischemic stroke. Blood-brain barrier (BBB) disruption is a crucial step toward HT; however, in clinical studies, there is still uncertainty about this relation. Hence, we conducted a systematic review and meta-analysis to summarize the current evidence. Methods: We performed systematic review and meta-analysis of observational studies from January 1990 to March 2020 about the relation between BBB disruption and HT in patients with acute ischemic stroke with both computed tomography (CT) and magnetic resonance (MR) assessment of BBB. The outcome of interest was HT at follow-up imaging evaluation (within 48 h from symptom onset). We pooled data from available univariate odds ratios (ORs) in random-effects models with DerSimonian-Laird weights and extracted cumulative ORs. Results: We included 30 eligible studies (14 with CT and 16 with MR), N = 2,609 patients, with 88% and 70% of patients included in CT and MR studies treated with acute stroke therapy, respectively. The majority of studies were retrospective and had high or unclear risk of bias. BBB disruption was measured with consistent methodology in CT studies, whereas in MR studies, there was more variability. All CT studies provided a BBB disruption cutoff predictive of HT. Four CT and 10 MR studies were included in the quantitative analysis. We found that BBB disruption was associated with HT with both CT (OR = 3.42; 95%CI = 1.62-7.23) and MR (OR = 9.34; 95%CI = 3.16-27.59). There was a likely publication bias particularly for MR studies. Conclusion: Our results confirm that BBB disruption is associated with HT in both CT and MR studies. Compared with MR, CT has been more uniformly applied in the literature and has resulted in more consistent results. However, more efforts are needed for harmonization of protocols and methodology for implementation of BBB disruption as a neuroradiological marker in clinical practice.

Added Prognostic Value of Hemorrhagic Transformation Quantification in Patients With Acute Ischemic Stroke.

Introduction and Aim: Hemorrhagic transformation (HT) frequently occurs after acute ischemic stroke and negatively influences the functional outcome. Usually, HT is classified by its radiological appearance. Discriminating between the subtypes can be complicated, and interobserver variation is considerable. Therefore, we aim to quantify rather than classify hemorrhage volumes and determine the association of hemorrhage volume with functional outcome in comparison with the European Cooperative Acute Stroke Study II classification. Patients and Methods: We included patients from the MR CLEAN trial with follow-up imaging. Hemorrhage volume was estimated by manual delineation of the lesion, and HT was classified according to the European Cooperative Acute Stroke Study II classification [petechial hemorrhagic infarction types 1 (HI1) and 2 (HI2) and parenchymal hematoma types 1 (PH1) and 2 (PH2)] on follow-up CT 24 h to 2 weeks after treatment. We assessed functional outcome using the modified Rankin Scale 90 days after stroke onset. Ordinal logistic regression with and without adjustment for potential confounders was used to describe the association of hemorrhage volume with functional outcome. We created regression models including and excluding total lesion volume as a confounder. Results: We included 478 patients. Of these patients, 222 had HT. Median hemorrhage volume was 3.37 ml (0.80-12.6) and per HT subgroup; HI1: 0.2 (0.0-1.7), HI2: 3.2 (1.7-6.1), PH1: 6.3 (4.2-13), and PH2: 47 (19-101). Hemorrhage volume was associated with functional outcome [adjusted common odds ratio (acOR): 0.83, 95% CI: 0.73-0.95] but not anymore after adjustment for total lesion volume (acOR: 0.99, 95% CI: 0.86-1.15, per 10 ml). Hemorrhage volume in patients with PH2 was significantly associated with functional outcome after adjusting total lesion volume (acOR: 0.70, 95% CI: 0.50-0.98). Conclusion: HT volume is associated with functional outcomes in patients with acute ischemic stroke but not independent of total lesion volume. The extent of a PH2 was associated with outcome, suggesting that measuring hemorrhage volume only provides an additional benefit in the prediction of the outcome when a PH2 is present.

Glycyrrhizin Prevents Hemorrhagic Transformation and Improves Neurological Outcome in Ischemic Stroke with Delayed Thrombolysis Through Targeting Peroxynitrite-Mediated HMGB1 Signaling.

Peroxynitrite (ONOO-) and high mobility group box 1 protein (HMGB1) are important cytotoxic factors contributing to cerebral ischemia-reperfusion injury. However, the roles of ONOO- in mediating HMGB1 expression and its impacts on hemorrhagic transformation (HT) in ischemic brain injury with delayed t-PA treatment remain unclear. In the present study, we tested the hypothesis that ONOO- could directly mediate the activation and release of HMGB1 in ischemic brains with delayed t-PA treatment. With clinical studies, we found that plasma nitrotyrosine (NT, a surrogate marker of ONOO-) was positively correlated with HMGB1 level in acute ischemic stroke patients. Hemorrhagic transformation and t-PA-treated ischemic stroke patients had increased levels of nitrotyrosine and HMGB1 in plasma. In animal experiments, we found that FeTmPyP, a representative ONOO- decomposition catalyst (PDC), significantly reduced the expression of HMGB1 and its receptor TLR2, and inhibited MMP-9 activation, preserved collagen IV and tight junction claudin-5 in ischemic rat brains with delayed t-PA treatment. ONOO- donor SIN-1 directly induced expression of HMGB1 and its receptor TLR2 in naive rat brains in vivo and induced HMGB1 in brain microvascular endothelial b.End3 cells in vitro. Those results suggest that ONOO- could activate HMGB1/TLR2/MMP-9 signaling. We then addressed whether glycyrrhizin, a natural HMGB1 inhibitor, could inhibit ONOO- production and the antioxidant properties of glycyrrhizin contribute to the inhibition of HMGB1 and the neuroprotective effects on attenuating hemorrhagic transformation in ischemic stroke with delayed t-PA treatment. Glycyrrhizin treatment downregulated the expressions of NADPH oxidase p47 phox and p67 phox and iNOS, inhibited superoxide and ONOO- production, reduced the expression of HMGB1, TLR2, MMP-9, preserved type IV collagen and claudin-5 in ischemic brains. Furthermore, glycyrrhizin significantly decreased the mortality rate, attenuated hemorrhagic transformation, brain swelling, blood-brain barrier damage, neuronal apoptosis, and improved neurological outcomes in the ischemic stroke rat model with delayed t-PA treatment. In conclusion, peroxynitrite-mediated HMGB1/TLR2 signaling contributes to hemorrhagic transformation, and glycyrrhizin could be a potential adjuvant therapy to attenuate hemorrhagic transformation, possibly through inhibiting the ONOO-/HMGB1/TLR2 signaling cascades.

There Is No Association Between the Number of Stent Retriever Passes and the Incidence of Hemorrhagic Transformation for Patients Undergoing Mechanical Thrombectomy.

Background: Previous research has focused on the association between hemorrhagic transformation (HT) incidence and pre-procedural variables (i.e., baseline variables) rather than the association between HT incidence and endovascular treatment (EVT) procedural variables (e.g., stent retriever passes). Objective: To assess the association, if any, that exists between the number of stent retriever passes per procedure and the incidence of HT for patients undergoing mechanical thrombectomy. Methods: An endovascular database from a comprehensive stroke center was used to collect data on EVT patients treated with Trevo, Solitaire, or Penumbra stent retrievers from the years 2012 to 2017. Statistical analyses were conducted on the stent retriever passes, demographics, morbidities, medication usage, and outcomes and their association with HT. Results: Of the 329 total patients, 46 (14%) had HT. The HT group had an average [SD] of 1.65 [0.67] and range of [1-3] passes per procedure while the non-HT group had an average [SD] of 1.63 [0.86] and range of [1-5] passes per procedure. Admission NIHSS score (p = 0.0003) and the incidence of diabetes mellitus (DM) (p = 0.05) were significantly higher in the HT group. Subdividing HT into symptomatic and asymptomatic ICH groups failed to display significant differences in the distribution of the stent retriever passes (p = 0.969). The number of passes failed to show any association with HT (p = 0.804) while admission NIHSS score was found to have an OR of 1.07 (95%CI: 1.029-1.121, p = 0.001) with HT incidence. Conclusion: No significant association was found between HT incidence and the stent retriever passes. Further multicenter studies are warranted to corroborate our results.

Reduction in the Ratio of Low-density Lipoprotein Cholesterol to Highdensity Lipoprotein Cholesterol is Associated with Increased Risks of Hemorrhagic Transformation in Patients with Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: Hemorrhagic transformation (HT) is a potentially serious complication in patients with acute ischemic stroke (AIS). Whether the ratio of low-density lipoprotein cholesterol to high-density lipoprotein cholesterol (LDL-C/HDL-C) is associated with HT remains unclear. METHODS: Ischemic stroke patients within 7 days of stroke onset from January 2016 to November 2017 were included in this study. Lipid profiles were measured within 24h after admission. HT was determined by a second computed tomography or magnetic resonance imaging within 7 days after admission. Univariate and multivariate logistic regression analysis was used to assess the association between LDL-C/HDL-C and HT. RESULTS: We enrolled 1239 patients with AIS (788 males; mean age, 64 ± 15 years), of whom 129 (10.4%) developed HT. LDL-C/HDL-C was significantly lower on admission in patients with HT than those without HT (2.00 ± 0.89 vs. 2.25 ± 1.02, P=0.009). The unadjusted odds ratio (OR) of low LDL-C/HDL-C for HT was 2.07 (95% confidence interval [CI] 1.42-3.01, P＜0.001). After adjustment for possible confounders, lower LDL-C/HDL-C (≤1.52) was significantly associated with HT (OR 1.53, 95% CI: 1.02-2.31, P=0.046). Similar results were observed between lower LDL-C (≤ 4 mmol/L) and HT (OR 4.17, 95% CI: 1.25-13.90, P=0.02). However, no significant association was found between HT and high HDL-C, low triglycerides or low total cholesterol. CONCLUSION: Lower LDL-C/HDL-C and LDL-C were significantly associated with increased risk of HT after AIS. Further investigations are warranted to confirm these findings and then optimize lipid management in stroke patients with lower LDL/HDL-C or LDL-C.

Hemorrhagic transformation after cerebral infarction: current concepts and challenges.

Hemorrhagic transformation (HT) is a frequent complication of acute ischemic stroke that is especially common after thrombolytic therapy. The risk of HT limits the applicability of tissue plasminogen activator (tPA). Here, we sought to review the rate, classification, predictors, possible mechanism, and clinical outcomes of HT, as well as existing therapeutic approaches, in order to call attention to the current challenges in the treatment of this complication.