Recombinant Tissue-type Plasminogen Activator Research Articles

Correlations of 2 Novel Inflammation Indexes With the Risk for Early Neurological Deterioration in Acute Ischemic Stroke Patients After Intravenous Thrombolytic Therapy.

Elevation of the systemic immune inflammation (SII) index and system inflammation response index (SIRI) is known to be associated with higher risk of stroke and all-cause death. However, no study has reported their correlation with early neurological deterioration (END) following recombinant tissue-type plasminogen activator (IV-rtPA) in acute ischemic stroke patients. The aim of this study was to explore the correlation of SII and SIRI with the risk of END after IV-rtPA. Included in this study were 466 consecutive patients treated with IV-rtPA. SII and SIRI were calculated according to blood cell counts before IV-rtPA. Patients were divided into 3 groups based on trisectional quantiles according to SII and SIRI values. The risk of END was assessed by multivariate regression. The overall discriminative ability of SII and SIRI in predicting END was assessed by receiver operating characteristic curve analysis. Of the 466 included patients, 62 (13.3%) were identified as having END. Compared with the first tertile of SII, multivariable regression analysis demonstrated that patients were more likely to have END (odds ratio 2.54; 95% CI: 1.23-5.23) and poor outcome at 90 days (odds ratio 2.02; 95% CI: 1.06-3.86) in third tertile after adjustment for potential confounders. In addition, a cutoff value of 591.63 for SII was detected in predicting post-thrombolysis END with a sensitivity of 58.1% and a specificity of 64.6% (area under the curve 0.61; 95% CI: 0.54-0.69). Higher SII but not SIRI may prove to be a predictor for high risk of END and a poor functional outcome at 90 days after IV-rtPA.

Acupuncture Extended the Thrombolysis Window by Suppressing Blood-Brain Barrier Disruption and Regulating Autophagy-Apoptosis Balance after Ischemic Stroke.

Ischemic stroke (IS) is one of the leading causes of death and disability worldwide. The narrow therapeutic window (within 4.5 h) and severe hemorrhagic potential limits therapeutic efficacy of recombinant tissue type plasminogen activator (rt-PA) intravenous thrombolysis for patients. Xingnao Kaiqiao (XNKQ) acupuncture is an integral part of traditional Chinese medicine, specifically designed to address acute ischemic stroke by targeting key acupoints such as Shuigou (GV26) and Neiguan (PC6). In this study, we explored the therapeutic potential of XNKQ acupuncture in extending the time window for thrombolysis and interrogated the molecular mechanisms responsible for this effect. The effect of extending the thrombolysis window by acupuncture was evaluated via TTC staining, neuronal score evaluation, hemorrhagic transformation assay, and H&E staining. RNA sequencing (RNA-seq) technology was performed to identify the therapeutic targets and intervention mechanisms of acupuncture. Evans blue staining and transmission electron microscopy were used to assess blood-brain barrier (BBB) integrity. Immunofluorescence staining and co-immunoprecipitation were performed to evaluate the level of autophagy and apoptosis and validate their interactions with BBB endothelial cells. Acupuncture alleviated infarction and neurological deficits and extended the thrombolysis window to 6 h. The RNA-seq revealed 16 potential therapeutic predictors for acupuncture intervention, which related to suppressing inflammation and restoring the function of BBB and blood vessels. Furthermore, acupuncture suppressed BBB leakage and preserved tight junction protein expression. The protective effect was associated with regulation of the autophagy-apoptosis balance in BBB endothelial cells. Acupuncture intervention dissociated the Beclin1/Bcl-2 complex, thereby promoting autophagy and reducing apoptosis. XNKQ acupuncture could serve as an adjunctive therapy for rt-PA thrombolysis, aiming to extend the therapeutic time window and mitigate ischemia-reperfusion injury. Acupuncture suppressed BBB disruption by regulating the autophagy-apoptosis balance, which in turn extended the therapeutic window of rt-PA in IS. These findings provide a rationale for further exploration of acupuncture as a complementary candidate co-administered with rt-PA.

The Janus face of endogenous neuronal tPA: promoting self-protection and worsening the death of neighboring neurons

Recombinant tissue-type plasminogen activator (r-tPA/Actilyse) stands as the prevailing pharmacological solution for treating ischemic stroke patients, of whom because their endogenous circulating tPA alone is not sufficient to rescue reperfusion and to promote favorable outcome. Beyond the tPA contributed by circulating endothelial cells and hepatocytes, neurons also express tPA, sparking debates regarding its impact on neuronal fate ranging from pro-survival to neurotoxic properties. In order to investigate the role of neuronal tPA during brain injuries, we developed models leading to its conditional deletion in neurons, employing AAV9-pPlat-GFP and AAV9-pPlat-Cre-GFP along with tPA floxed mice. These models were subjected to N-methyl-D-aspartate (NMDA)-induced excitotoxicity or thromboembolic ischemic stroke in mice. Initially, we established that our AAV9 constructs selectively transduce neurons, bypassing other brain cell types. Subsequently, we demonstrated that tPA-expressing neurons exhibit greater resistance against NMDA-induced excitotoxicity compared to tPA negative neurons. The targeted removal of tPA in neurons heightened the susceptibility of these neurons to cell death and prevented a paracrine neurotoxic effect on tPA non-expressing neurons. Under ischemic conditions, the self-neuroprotective influence of tPA encompassed both excitatory (GFP+/Tbr1+) and inhibitory (GFP+/GABA+) neurons. Our data indicate that endogenous neuronal tPA is a protective or deleterious factor against neuronal death in an excitotoxic/ischemic context, depending on whether it acts as an autocrine or a paracrine mediator.

Impact of a novel pre-hospital stroke notification programme on acute stroke care key performance indicators in Hong Kong: a multicentre prospective cohort study with historical controls.

Early identification and initiation of reperfusion therapy is essential for suspected acute ischaemic stroke. A pre-hospital stroke notification (PSN) protocol using FASE (facial drooping, arm weakness, speech difficulties, and eye palsy) was implemented to improve key performance indicators (KPIs) in acute stroke care delivery. We assessed KPIs and clinical outcomes before and after PSN implementation in Hong Kong. This prospective cohort study with historical controls was conducted in the Accident and Emergency Departments of four public hospitals in Hong Kong. Patients were screened using the PSN protocol between August 2021 and February 2022. Suspected stroke patients between August 2020 and February 2021 were included as historical controls. Door-to-needle (DTN) and door-to-computed tomography (DTC) times before and after PSN implementation were compared. Clinical outcomes including National Institutes of Health Stroke Scale score at 24 hours and modified Rankin Scale score at 3 months after intravenous recombinant tissue-type plasminogen activator (IV-rtPA) were also assessed. Among the 715 patients (266 PSN and 449 non-PSN) included, 50.8% of PSN patients and 37.7% of non-PSN patients had a DTC time within 25 minutes (P<0.001). For the 58 PSN and 134 non-PSN patients given IV-rtPA, median DTN times were 67 and 75.5 minutes, respectively (P=0.007). The percentage of patients with a DTN time within 60 minutes was higher in the PSN group than in the non-PSN group (37.9% vs 21.6%; P=0.019). No statistically significant differences in clinical outcomes were observed. Although the PSN protocol shortened DTC and DTN times, clinical outcomes did not significantly differ.

Impact of Off-Hour Admission on In-Hospital Outcomes for Patients With Stroke Receiving Reperfusion Therapy in China.

The structure and staffing of hospitals greatly impact patient outcomes, with frequent changes occurring during nights and weekends. This retrospective cohort study assessed the impact of admission timing on in-hospital management and outcomes for patients with stroke receiving reperfusion therapy in China using data from a nationwide registry. Data from patients receiving reperfusion therapy were extracted from the Chinese Stroke Center Alliance. Hospital admission time was categorized according to day/evening versus night and weekday versus weekend. Primary outcomes were in-hospital death or discharge against medical advice, hemorrhage transformation, early neurological deterioration, and major adverse cardiovascular events. Logistic regression was performed to compare in-hospital management performance and outcomes based on admission time categories. Overall, 42 381 patients received recombinant tissue-type plasminogen activator (r-tPA) therapy, and 5224 underwent endovascular treatment (EVT). Patients admitted during nighttime had a higher probability of receiving r-tPA therapy within 4.5 hours from onset or undergoing EVT within 6 hours from onset compared with those admitted during day/evening hours (adjusted odds ratio, 1.04 [95% CI, 1.01-1.08]; P=0.021; adjusted odds ratio, 1.72 [95% CI, 1.59-1.86]; P<0.001, respectively). However, no significant difference was observed between weekend and weekday admissions for either treatment. No notable differences were noted between weekends and weekdays or nighttime and daytime periods in door-to-needle time for r-tPA or door-to-puncture time for EVT initiation. Furthermore, weekend or nighttime admission did not have a significant effect on the primary outcomes of r-tPA therapy or EVT. Nevertheless, in patients undergoing EVT, a higher incidence of pneumonia was observed among those admitted at night compared with those admitted during day/evening hours (adjusted odds ratio, 1.22 [95% CI, 1.05-1.42]; P=0.011). Patients admitted at nighttime were more likely to receive r-tPA therapy or EVT within the time window recommended in the guidelines. However, patients receiving EVT admitted at night had an increased risk of pneumonia.

R-tPA Resistance Is Specific for Platelet-Rich Stroke Thrombi and Can Be Overcome by Targeting Nonfibrin Components.

Resistance to r-tPA (recombinant tissue-type plasminogen activator) is a well-known but poorly understood phenomenon that hampers successful recanalization in patients with acute ischemic stroke. Using clinically relevant thrombi from patients with acute ischemic stroke, we investigated if and how thrombus composition impacts r-tPA-mediated lysis. In addition, we explored strategies to overcome r-tPA resistance. Thrombi were split into 2 parts, 1 of which was used for thrombolysis and the other for detailed histological analysis. Thrombolysis was performed in normal human plasma using r-tPA alone, using r-tPA in combination with DNase-1 or using r-tPA in combination with N,N'-diacetyl-l-cystine. Thrombus lysis was calculated as the percentage of residual thrombus weight compared with its initial weight and the degree of lysis was linked to thrombus composition determined via histology. Interestingly, we found that the efficacy of r-tPA-mediated thrombolysis was strongly correlated with the composition of the thrombi. Thrombi containing high amounts of red blood cells and low amounts of DNA and von Willebrand Factor were efficiently degraded by r-tPA, whereas thrombi containing low amounts of red blood cells and higher amounts of DNA and von Willebrand Factor were resistant to r-tPA. Importantly, combination of r-tPA with DNase-1 or N,N'-diacetyl-l-cystine significantly and specifically improved the lysis of these r-tPA-resistant thrombi. Using patient thrombus material, our results for the first time show that the composition of stroke thrombi largely determines their susceptibility to r-tPA-mediated thrombolysis. Red blood cell-poor thrombi have a specific resistance to r-tPA, which can be overcome by targeting nonfibrin components using DNase-1 or N,N'-diacetyl-l-cystine.

LOX-1 and MMP-9 Inhibition Attenuates the Detrimental Effects of Delayed rt-PA Therapy and Improves Outcomes After Acute Ischemic Stroke.

Acute ischemic stroke triggers endothelial activation that disrupts vascular integrity and increases hemorrhagic transformation leading to worsened stroke outcomes. rt-PA (recombinant tissue-type plasminogen activator) is an effective treatment; however, its use is limited due to a restricted time window and hemorrhagic transformation risk, which in part may involve activation of MMPs (matrix metalloproteinases) mediated through LOX-1 (lectin-like oxLDL [oxidized low-density lipoprotein] receptor 1). This study's overall aim was to evaluate the therapeutic potential of novel MMP-9 (matrix metalloproteinase 9) ± LOX-1 inhibitors in combination with rt-PA to improve stroke outcomes. A rat thromboembolic stroke model was utilized to investigate the impact of rt-PA delivered 4 hours poststroke onset as well as selective MMP-9 (JNJ0966) ±LOX-1 (BI-0115) inhibitors given before rt-PA administration. Infarct size, perfusion, and hemorrhagic transformation were evaluated by 9.4-T magnetic resonance imaging, vascular and parenchymal MMP-9 activity via zymography, and neurological function was assessed using sensorimotor function testing. Human brain microvascular endothelial cells were exposed to hypoxia plus glucose deprivation/reperfusion (hypoxia plus glucose deprivation 3 hours/R 24 hours) and treated with ±tPA and ±MMP-9 ±LOX-1 inhibitors. Barrier function was assessed via transendothelial electrical resistance, MMP-9 activity was determined with zymography, and LOX-1 and barrier gene expression/levels were measured using qRT-PCR (quantitative reverse transcription PCR) and Western blot. Stroke and subsequent rt-PA treatment increased edema, hemorrhage, MMP-9 activity, LOX-1 expression, and worsened neurological outcomes. LOX-1 inhibition improved neurological function, reduced edema, and improved endothelial barrier integrity. Elevated MMP-9 activity correlated with increased edema, infarct volume, and decreased neurological function. MMP-9 inhibition reduced MMP-9 activity and LOX-1 expression. In human brain microvascular endothelial cells, LOX-1/MMP-9 inhibition differentially attenuated MMP-9 levels, inflammation, and activation following hypoxia plus glucose deprivation/R. Our findings indicate that LOX-1 inhibition and ± MMP-9 inhibition attenuate negative aspects of ischemic stroke with rt-PA therapy, thus resulting in improved neurological function. While no synergistic effect was observed with simultaneous LOX-1 and MMP-9 inhibition, a distinct interaction is evident.

A Study of Factors Affecting Functional Outcomes in Patients With Successful Recanalization by Mechanical Thrombectomy.

Reperfusion therapy is typically performed in cases with acute cerebral infarction. Mechanical thrombectomy (MT) achieves superior recanalization and favorable outcomes. However, some patients have poor functional prognosis despite successful recanalization. We investigated factors affecting functional prognosis after MT with good reperfusion. Among the 205 consecutive cases with ischemic stroke treated with MT at our center from January 1, 2019 to March 31, 2021, 168 with successful recanalization were included. Factors affecting early neurological improvement (ENI) and modified Rankin Scale (mRS) scores were reviewed retrospectively. There were 93 (55%) cases with ENI and 75 (45%) without ENI. The times from onset to recombinant tissue-type plasminogen activator administration and recanalization in ENI cases were shorter than those in non-ENI cases. However, non-ENI cases had significantly higher Fazekas grades for white matter lesions. In multivariate analysis, the Fazekas grade was related to ENI (odds ratio [OR]=0.572, 95% confidence interval [CI]=0.345-0.948). The mRS score at discharge was 0-2 in 64 cases (good outcome) and 3-6 in 104 cases (poor outcome). Patients with a poor outcome had a significantly higher age, National Institutes of Health Stroke Scale (NIHSS) score, and Fazekas grade. Multivariate analysis revealed that the NIHSS score (OR=1.073, 95% CI=1.020-1.129) and Fazekas grade (OR=2.162, 95% CI=1.458-3.205) at hospitalization affected the mRS score at discharge. There is a correlation of greater severity of white matter lesions with poorer ENI and clinical outcomes at discharge post-MT.

Improving stroke outcomes in hyperglycemic mice by modulating tPA/NMDAR signaling to reduce inflammation and hemorrhages

AbstractThe pharmacological intervention for ischemic stroke hinges on intravenous administration of the recombinant tissue-type plasminogen activator (rtPA, Alteplase/Actilyse) either as a standalone treatment or in conjunction with thrombectomy. However, despite its clinical significance, broader use of rtPA is constrained because of the risk of hemorrhagic transformations (HTs). Furthermore, the presence of diabetes or chronic hyperglycemia is associated with an elevated risk of HT subsequent to thrombolysis. This detrimental impact of tPA on the neurovascular unit in patients with hyperglycemia has been ascribed to its capacity to induce endothelial N-methyl-D-aspartate receptor (NMDAR) signaling, contributing to compromised blood-brain barrier integrity and neuroinflammatory processes. In a mouse model of thromboembolic stroke with chronic hyperglycemia, we assessed the effectiveness of rtPA and N-acetylcysteine (NAC) as thrombolytic agents. We also tested the effect of blocking tPA/NMDAR signaling using a monoclonal antibody, Glunomab. Magnetic resonance imaging, speckle contrast imaging, flow cytometry, and behavioral tasks were used to evaluate stroke outcomes. In hyperglycemic animals, treatment with rtPA resulted in lower recanalization rates and increased HTs. Conversely, NAC treatment reduced lesion sizes while mitigating HTs. After a single administration, either in standalone or combined with rtPA-induced thrombolysis, Glunomab reduced brain lesion volumes, HTs, and neuroinflammation after stroke, translating into improved neurological outcomes. Additionally, we demonstrated the therapeutic efficacy of Glunomab in combination with NAC or as a standalone strategy in chronic hyperglycemic animals. Counteracting tPA-dependent endothelial NMDAR signaling limits ischemic damages induced by both endogenous and exogenous tPA, including HTs and inflammatory processes after ischemic stroke in hyperglycemic animals.

Efficacy and Safety of Human Urinary Kallidinogenase for Acute Ischemic Stroke: A Retrospective Single-Center Study.

The aim of this study was to investigate the outcomes of human urinary kallidinogenase (HUK) after recombinant tissue-type plasminogen activator treatment in patients with acute ischemic stroke (AIS). In this retrospective study conducted from December 2018 to August 2020, 313 patients with AIS patients who received recombinant tissue-type plasminogen activator treatment were enrolled. Among them, 148 patients received basic therapy, and 165 patients received HUK treatment. Demographics and clinical characteristics were analyzed after treatment, and patients were monitored for stroke recurrence for 12 months. National Institute of Health Stroke Scale (NIHSS) and modified Rankin Scale scores were used to assess the efficacy of treatment. Logistic regression analysis was used to identify risk factors for recurrence. There were no differences in baseline clinical characteristics between the 2 groups in the database. After 14 days of treatment, the HUK group had significantly lower NIHSS and modified Rankin Scale scores than the control group ( P <0.01). The recurrence rates in the HUK and control groups were 12.84% and 21.82%, respectively, with patients treated with HUK having better outcomes ( P <0.001). Logistic analysis indicated that high homocysteine levels and high NIHSS scores at diagnosis were risk factors for AIS recurrence. In addition, HUK treatment was found to reduce the risk of recurrence. Treatment with HUK after intravenous thrombolysis can significantly improve the neurological function of AIS patients and reduce stroke recurrence.

An Automatic DWI/FLAIR Mismatch Assessment of Stroke Patients.

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

Pulmonary Embolism Successfully Treated with Tenecteplase: A case report

Acute pulmonary embolism is a life-threatening situation when presenting with hypotension is called high-risk (massive) pulmonary embolism (PE) which is associated with mortality, especially if there is hemodynamic instability, right ventricular dysfunction with thrombus. Thrombolytic therapy can be lifesaving and leads faster improvement in hemodynamics in patients with acute pulmonary embolism and cardiogenic shock which accelerates the resolution of thrombus, reduction of RV dilatation, mortality and recurrent PE. Only three fibrinolytic agents namely Recombinant tissue-type plasminogen activator (rtPA), Streptokinase and Urokinase have been approved in the treatment of PE. We report the case of a 64 years old Bangladeshi female with a history of immobilization due to unilateral cut injury of foot, who presented with shortness of breath and intermittent chest pain for a duration of 7 days during OPD visit. ECG showed sinus tachycardia (HR-120bpm, regular) and poor progression of R wave. Echocardiography revealed dilated RV, PA with RV dysfunction, presence of McConnell’s sign, RV apical &amp; PA thrombus, flattened IVS, PHT, and minimal pericardial effusion, normal LV systolic function which was reported as suspected pulmonary embolism. Urgent hospitalization and CT pulmonary angiogram (CTPA) was done for confirmatory diagnosis which revealed large pulmonary thrombus in both right and left pulmonary artery. Thrombolysis with Tenecteplase (100ml) over 2 hours was started immediately along with intravenous normal saline and norepinephrine for hypotension, although, it was not recommended by the European Society of Cardiology (ESC) guideline, resulting a successful resolution of the PA thrombus and clinical improvement. She was discharged with oral anticoagulant Rivaroxaban. Bangladesh Heart Journal 2023; 38(2): 148-154

Association of Atrial Fibrillation with Remote Intracerebral Hemorrhage After Intravenous Thrombolysis: Results from a Multicenter Study in China.

This study aimed to investigate the association between atrial fibrillation (AF), particularly newly diagnosed AF, and remote intracerebral hemorrhage (rICH) in patients with ischemic stroke who were treated with intravenous thrombolysis (IVT). This observational study was conducted on patients with ischemic stroke who received IVT with recombinant tissue-type plasminogen activator. The data were taken from a multicenter prospective registry of a Chinese population. rICH was defined as any extraischemic hemorrhage detected on computerized tomography (CT) 24h after intravenous thrombolysis. We collected and compared the demographic data and clinical characteristics of all the patients with rICH to those of patients without any type of hemorrhagic transformation. The association between AF and rICH was analyzed using univariate analysis and binary logistic regression. A total of 20,697 patients were included in the study, with 1566 (7.6%) experiencing intracerebral hemorrhage (ICH), 586 (2.8%) experiencing rICH, and 19,131 (92.4%) not experiencing any form of hemorrhagic transformation. Univariate analysis revealed significant differences in age, pre-thrombolysis systolic blood pressure, baseline National Institute of Health Stroke Scale score, previously known AF, newly diagnosed AF, coronary heart disease, congestive heart failure, hyperhomocysteinemia, and history of thrombolysis between the rICH and control groups (P < 0.05). Further multivariate logistic regression analysis indicated that total AF (OR 1.821, 95%CI 1.082-3.065, P < 0.05), previously known AF (OR 1.470, 95%CI 1.170-1.847), and newly diagnosed AF (OR 1.920, 95%CI 1.304-2.825) were independently associated with rICH. This study suggests that AF, regardless of whether it is newly diagnosed or previously known, may be associated with the occurrence of rICH following intravenous thrombolysis. Interestingly, our findings suggest that newly diagnosed AF may have a stronger impact on rICH than previously known AF, although confirmation from more studies is needed.

Seizures at stroke onset: A case-control study

PurposeSeizures occurring at the immediate onset of a stroke, abbreviated "seizures at onset" (SaO), pose a diagnostic and therapeutic challenge for physicians. In this study, we report on the current clinical practice in managing stroke patients with SaO from a large tertiary stroke center in Germany. MethodsWe selected all patients with SaO and acute ischemic or hemorrhagic stroke admitted to the Department of Neurology at the University Hospital of Cologne between 2019 and 01–01 and 2020–12–31. SaO patients were then compared to patients with acute ischemic or hemorrhagic stroke without SaO from the local stroke registry. Further, we compared SaO patients who received intravenous recombinant tissue-type plasminogen activator (rt-PA) and/or mechanical thrombectomy with matched controls. ResultsOverall, 54 out of 2312 stroke patients (2.3 %) in the examined period presented with SaO. The most prevalent SaO semiology was focal to bilateral tonic-clonic (42.6 %). SaO was associated with hemorrhagic strokes and higher in-hospital mortality in all stroke patients. The rate of acute stroke therapy was not influenced by the occurrence of SaO. In patients that received acute stroke therapy, patients with SaO had higher scores on the National Institutes of Health Stroke Scale (NIHSS) and the modified Rankin Scale (mRS) at admission, and longer door-to-needle times for the administration of rt-PA, while none of the examined outcome parameters revealed a difference between patients with and without SaO after adjusting for potential confounders. ConclusionData show that SaO is rare in stroke patients but associated with more extensive strokes.

Augmented Glycemic Gap is a Marker for Predicting the Early Neurological Outcomes in Acute Ischemic Stroke Patients Treated with Intravenous Thrombolysis

Background and Purpose: Glycemic Gap (GG) as an index reflecting the acute fluctuation of glycemia, has been proved to be associated with poor functional outcomes in Acute Ischemic Stroke (AIS) patients. However, it predictive value on post-thrombolysis Early Neurological Outcomes (ENOs) are still controversial. This study aimed to use GG to evaluate the influence of pretreatment relative glucose changes on post-thrombolysis ENOs, and we further explored the predictive value of GG in different glycemic control status. Methods: Early Neurological Deterioration (END) was defined as a National Institutes of Health Stroke Scale Score (NIHSS) =4, Early Neurological Improvement (ENI) was defined as a =4-point decrease in NIHSS score or a complete resolution of neurological deficits, between the time of admission and 24 hours after intravenous recombinant tissue-type plasminogen activator (IV-rtPA). GG was calculated as Admission Blood Glucose level (ABG)- estimated average blood glucose level (eAG), eAG could be derived from HbAlc according to the equation eAG=28.7*HbAlc-46.7 Results: Increased GG was significantly associated with post-thrombolysis END and poor functional outcome at discharge (OR, 1.982; 95% CI, 1.213-3.238; P=0.006) (OR, 2.079; 95% CI, 1.305-3.312; P=0.002). Its predictive value on END was more pronounce in diabetic patients (OR, 2.434; 95% CI, 1.079-5.491; P=0.032), after dichotomizing glycemic control status, its significance was only maintained in diabetic patients with good previous glucose control (OR, 6.946; 95% CI, 1.217-39.636; P=0.029). Conclusion: An evaluated GG was associated with high risk of post-thrombolysis END and poor functional outcome at discharge in AIS patients, and the previous glucose control should be considered when predicting ENOs.

71-year Old Male Patient with 20 Hour Onset of Infarct Stroke that was Performed with Intra-Arterial Thrombolysis, Mechanical Thrombectomy, Balloon Angioplasty, and Carotid Stenting: A Case Report

Introduction: For above 2 decades, the definitive management for acute ischemic stroke is intravenous or intra-arterial thrombolysis (IAT), using recombinant tissue-type plasminogen activator. Recently mechanical thrombectomy (MT) was developed to overcome the problem that intravenous thrombolysis is only effective in removing large artery occlusions in the range of 10-30%. Early treatment with intra-arterial thrombolysis, permanent stent insertion and clot extraction devices evolved into the stent-retriever device used in most of the important trials and, recently, emerged aspiration tool. This case report presented 71-year-old male patient with infarct stroke who performed with MT. Case presentation: This case report presented 71-year-old male patient with the main complaint of right limbs weakness. A non-contrast head CT scan found infarction in the cortical-subcortical left parietal lobe, posterior pericornu of the right lateral ventricle and right temporal cornu periventricular; lacunar infarction in the right and left paramedian pons; old lacunar infarction in the left and right centrum semiovale, left corona radiata, right internal capsule, right parietal lobe white matter, left lentiform nucleus, left posterior crus of the internal capsule-thalamus, right thalamus, right lateral ventricular pericornu and left paramedian pons. The patient underwent cerebral digital substraction angiography (DSA), as well as IAT, MT, balloon angioplasty, and carotid stenting with good clinical outcome. Conclusion: With the overwhelming positive results of studies evaluating the safety, efficiency, and efficacy of mechanical thrombectomy; the standard of care for the treatment of patients with anterior circulation vessel occlusion is becoming clear.

Diagnosis and treatment of venous thromboembolism and clinical application of inferior vena cava filter in China

ObjectiveThis study investigated the trend of venous thromboembolism (VTE) in China during the past 10 years and assessed the clinical application of inferior vena cava filters (IVCFs). MethodsA survey designed to investigate the diagnosis and management of VTE, specifically the application of IVCFs, was distributed nationally from January 2009 to December 2019. The respondents were mainly designated medical professionals and were asked to complete 4 major and 61 minor items in the survey. ResultsA total of 53 medical centers, including 27 radiologic and 26 vascular surgery centers, from 21 provinces in China participated in the study. These centers had diagnosed and treated 171,310 patients with VTE; 83,969 were inpatients (49%). During a 10-year period, an increasing trend of VTE diagnosis and inpatient management, 3.8-fold and 4.8-fold, respectively, was observed. The characteristics of the inpatients were as follows: 15% bilateral lower extremity deep vein thrombosis (DVT), 27% right lower extremity DVT, and 58% left lower extremity DVT. Anticoagulation therapy included unfractionated heparin with vitamin K antagonists (8%), low-molecular-weight heparin (LMWH) with vitamin K antagonists (21%), LMWH with transition to rivaroxaban (34.2%), LMWH with transition to dabigatran (2.4%), rivaroxaban alone (33.4%), and dabigatran alone (1.0%). The percentage of patients continuing anticoagulation therapy at 3, 6, 12, 24, and >24 months was 36%, 35%, 18%, 6.0%, and 5%, respectively. The in-hospital mortality for the patients with VTE was 3.2%, with DVT and pulmonary embolism responsible for 5.2% and DVT alone for 2.7%. Thrombolytic therapy was initiated for 39,046 of 83,969 patients (46.5%), including catheter-directed thrombolysis for 33,189 of the 39,046 patients (85%) and evaluation of the iliac vein using ultrasound and/or venography for 63,816 patients (76%). Urokinase was the main thrombolytic drug used (98%), followed by recombinant tissue-type plasminogen activator. Complete and partial thrombolysis was achieved in 70% and 30% of the patients, respectively. Bleeding complications were observed in 3.5% of patients, and 20% of the patients with bleeding complications required intervention. Between 2009 and 2019, 40,478 IVCFs (76% retrievable) were implanted in hospitalized VTE patients. During the enrollment period, the total number of IVCFs implanted increased by 3.8-fold, with a 4.8-fold increase in retrievable IVCFs and 7.5-fold decline in permanent IVCFs. The removal rate for the retrievable IVCFs was 72%. After IVCF implantation, 94.8% of patients received anticoagulation therapy for an average of 9.1 ± 8.6 months. The overall complication rate associated with IVCF placement was 15.5% (n = 6274 of 40,478 IVCFs), including tilting (54%), vena cava thrombosis (26.1%), caval penetration (12.6%), and migration (7.3%). No IVCF placement-related mortality occurred. ConclusionsA significant increase occurred in VTE diagnosis in China during the past decade. Anticoagulation therapy was the mainstay treatment, and catheter-directed thrombolysis was widely used. Most IVCFs placed were retrievable, and the use of permanent IVCFs has largely been discarded.

Influencing factors of early dramatic recovery of neurological function after intravenous thrombolysis in patients with branch atheromatous disease.

Intravenous thrombolysis can significantly improve the neurological function of patients with acute ischemic stroke. However, the expected early dramatic recovery (EDR) of neurological function after thrombolysis is not achieved in some patients with branch atheromatous disease (BAD). Here we evaluated the factors associated with EDR after thrombolysis in BAD patients. We conducted a retrospective study on 580 consecutive BAD patients. All patients met the diagnostic criteria of BAD and received intravenous recombinant tissue-type plasminogen activator (rt-PA). EDR was defined when the improvement of National Institutes of Health Stroke Scale (NIHSS) score was >8 points within 2 or 24 hours after rt-PA, or the total NIHSS score was 0 or 1. The factors associated with EDR were analyzed with multivariate logistic regression analysis. Among 580 patients, the incidence of EDR was 35.2% (204 cases). Compared with patients without EDR, patients with EDR had lower incidence of diabetes (15.7% vs 29.3%, P < .001), lower NIHSS scores at 2 and 24 hours after rt-PA (P < .001), less cerebral hemorrhage (0% vs 5.3%, P = .001), and shorter onset to treatment time (OTT) (P < .001). Multivariate logistic regression analysis in propensity score-matched cohort showed that EDR was associated with OTT (adjusted OR = 0.994; 95% CI, 0.989-0.999) and NIHSS score after rt-PA (adjusted OR = 0.768; 95% CI, 0.663-0.890). Notably, diabetes (adjusted OR = 0.477, 95% CI, 0.234-0.972) was an independent factor related to EDR of neurological function in BAD patients. In the subgroup analysis, a lower incidence of diabetes (adjusted OR = 0.205, 95% CI: 0.059-0.714, P = .013) and a lower NIHSS score after thrombolysis in patients with paramedian pontine infarction (adjusted OR = 0.809, 95% CI: 0.656-0.997, P = .047) were significantly associated with EDR. Diabetes is not conducive to EDR of neurological function in patients with BAD, especially in patients with paramedian pontine infraction. Low NIHSS score and short OTT after thrombolysis may be closely related to EDR after intravenous thrombolysis.

Acute Outflow Graft Occlusion-A Novel Predictable Complication of Lysis Therapy for the Treatment of Left Ventricular Assist Device Intra-Pump Thrombosis.

Lysis therapy is an established treatment option for intra-pump thrombosis of left ventricular assist devices (LVADs). In clinical routine, we observed repeated cases of acute outflow graft occlusions (OGO) associated with lysis therapy with need for urgent intervention. The aim of this investigation was to gain understanding of this observation. We screened data of 962 HeartWare ventricular assist device (HVAD) patients. One hundred twenty (13.8%) had intra-pump thromboses; 58 were treated with recombinant tissue-type plasminogen activator (rtPA). Mean age was 53.0 ± 11.1 years; 84.9% were male. In 13 (24.5%) patients, OGO occurred following rtPA-lysis. These patients showed an increase in left ventricular function (18.45% ± 12.62% to 27.73% ± 10.57%; p = 0.056), more frequent 1:1 aortic valve opening (OGO+: +36.4%; OGO-: +7.4%; p = 0.026), a decrease in LVAD pulsatility within 12 months prior intra-pump thrombosis (OGO+: -0.8 L/min [interquartile range {IQR}, -1.4 to -0.4 L/min]; OGO-: -0.3 L/min [IQR, -0.9 to 0.1 L/min]; p = 0.038) and lower HVAD flows at admission (OGO+: 6.7 L/min [IQR, 6.1-7.4 L/min]; OGO-: 8.3 L/min [IQR, 6.9-9.3 L/min]; p = 0.013), indicating a subclinical OGO prior intra-pump thrombosis. There were no differences in implantation techniques, blood parameters, and lysis strategy. Subclinical OGO represented a major risk factor for acute OGO following rtPA lysis therapy. We here propose an algorithm for risk stratification and dealing with patients presenting this first-described complication. Further research is required to confirm our results and decipher the underlying pathomechanism. http://links.lww.com/ASAIO/B97.

Spatial Proteomics Analysis of Soft and Stiff Regions in Human Acute Arterial Thrombus.

The soft regions of a thrombus tend to be more susceptible to r-tPA (recombinant tissue-type plasminogen activator)-mediated thrombolysis and are more easily removed by mechanical thrombectomy than the stiff counterpart. This study aimed to understand the molecular pathological differences between the soft and stiff regions of human arterial thrombus. We developed a spatial proteomic workflow combining proteomics with laser-captured microdissection to analyze human arterial thrombi with Masson trichrome staining to identify stiff and soft regions from 2 independent cohorts of patients with acute myocardial or cerebral infarction. Dysregulated proteins in a C57BL6/J male mouse model of arterial thrombosis were identified by pathway enrichment and pairwise analyses from the common gene ontology enrichment and dysregulated proteins between carotid and coronary arterial thrombi, and validated by immunohistochemistry. Spatial proteomics of the coronary arterial thrombi collected from 7 patients with myocardial infarct revealed 7 common dysregulated proteins in 2 cohorts of patients, and upregulation of TGF-β1 (transforming growth factor β1) was the most prominent fibrosis-related protein. Inhibition of TGF-β1 resulted in delayed arterial thrombosis and accelerated blood flow restoration in mouse model. We further expanded the spatial proteomic workflow to the carotid artery thrombi collected from 11 patients with cerebral infarction. Pairwise proteomic analysis of stiff and soft regions between carotid and coronary arterial thrombi further revealed 5 common gene ontology clusters including features of platelet activation, and a common dysregulated protein COL1A1 (collagen type 1 alpha 1) that was reported to be influenced by TGF-β1. We also verified the expression in human and mice carotid arterial thrombi. This study demonstrates the spatially distinct composition of proteins in the stiff and soft regions of human arterial thrombi, and suggests that TGF-β1 is a key therapeutic target for promoting arterial thrombolysis.