Targeted Thrombolysis with Magnetic Nanotherapeutics: A Translational Assessment.

Plasminogen activators, such as recombinant tissue-type plasminogen activators (rtPAs), while effective in treating thromboembolic diseases, often induce hemorrhagic complications due to non-specific enzyme activities in the systemic circulation. This study evaluated the targeting efficiency, efficacy, biodistribution, and potential toxicity of a rtPA covalently attached to chitosan-coated magnetic nanoparticles (chitosan-MNP-rtPA). The thrombolytic activity of a chitosan-MNP-rtPA was preserved by protection from an endogenous plasminogen activator inhibitor-1 (PAI-1) in whole blood and after circulation in vivo, as examined by thromboelastometry. Single-photon emission computed tomography (SPECT) demonstrated real-time retention of a 99mTc-MNP-rtPA induced by magnet application in a rat embolic model; an 80% reduction in rtPA dosage for a chitosan-MNP-rtPA with magnetic guidance was shown to restore blood flow. After treatment, iron deposition was observed in the reticuloendothelial systems, with portal edema and neutrophil infiltration in the liver at a ten-fold higher dose but not the regular dose. Nevertheless, no liver or renal toxicity was observed at this higher dose. In conclusion, the liver may still be the major deposit site of rtPA nanocomposites after targeted delivery; chitosan-coated MNPs are potentially amenable to target therapeutics with parenteral administration.

Intravenous Thrombolysis Before Thrombectomy Improves Functional Outcome After Stroke Independent of Reperfusion Grade.

BACKGROUND: We studied the association of bridging intravenous thrombolysis (IVT) before thrombectomy for anterior circulation large-vessel occlusion and functional outcome and scrutinized its dependence on grade of reperfusion and distal thrombus migration. METHODS AND RESULTS: We included consecutive patients with anterior circulation large-vessel occlusion from our prospective registry of thrombectomy-eligible patients treated from January 1, 2017 to January 1, 2023 at a tertiary stroke center in Germany in this retrospective cohort study. To evaluate the association of bridging IVT and functional outcome quantified via modified Rankin Scale score at 90 days we used multivariable logistic and lasso regression including interaction terms with grade of reperfusion quantified via modified Thrombolysis in Cerebral Infarction (mTICI) scale and distal thrombus migration adjusted for demographic and cardiovascular risk profiles, clinical and imaging stroke characteristics, onset-to-recanalization time and distal thrombus migration. We performed sensitivity analysis using propensity score matching. In our study population of 1000 thrombectomy-eligible patients (513 women; median age, 77 years [interquartile range, 67-84]), IVT emerged as a predictor of favorable functional outcome (modified Rankin Scale score, 0-2) independent of modified mTICI score (adjusted odds ratio, 0.49 [95% CI, 0.32-0.75]; P=0.001). In those who underwent thrombectomy (n=812), the association of IVT and favorable functional outcome was reproduced (adjusted odds ratio, 0.49 [95% CI, 0.31-0.74]; P=0.001) and was further confirmed on propensity score analysis, where IVT led to a 0.35-point decrease in 90-day modified Rankin Scale score (ß=-0.35 [95 CI%, -0.68 to 0.01]; P=0.04). The additive benefit of IVT remained independent of modified mTICI score (ß=-1.79 [95% CI, -3.43 to -0.15]; P=0.03) and distal thrombus migration (ß=-0.41 [95% CI, -0.69 to -0.13]; P=0.004) on interaction analysis. Consequently, IVT showed an additive association with functional outcome in the subpopulation of patients undergoing thrombectomy who achieved successful reperfusion (mTICI ≥2b; ß=-0.46 [95% CI, -0.74 to -0.17]; P=0.002) and remained beneficial in those with unsuccessful reperfusion (mTICI ≤2a; ß=-0.47 [95% CI, -0.96 to 0.01]; P=0.05). CONCLUSIONS: In thrombectomy-eligible patients with anterior circulation large-vessel occlusion, IVT improves functional outcome independent of grade of reperfusion and distal thrombus migration.

New Wine in an Old Bottle: tPA for Ischemic Stroke Management.

As the only clinical thrombolytic drug approved by the FDA, tissue-type plasminogen activator (tPA) is the good standard acute treatment against ischemic stroke (IS) during the super-early stage. tPA forms the active principle of alteplase, a recombinant tissue-type plasminogen activator (rtPA), which is well known for its intravascular thrombolytic activity. However, the multifaceted functions of tPA in the central nervous system (CNS) hold untapped potential. Currently, increasing studies have explored the neuroprotective function of tPA in neurological diseases, particularly in acute ischemic stroke (AIS). A series of studies have indicated that tPA has anti-excitotoxic, neurotrophic, and anti-apoptotic effects on neurons; it is also involved in neuronal plasticity, axonal regeneration, and cerebral inflammatory processes, but how to deeply understand the underlying mechanism and take maximum advantage of tPA seems to be urgent. Therefore, more work is needed to illuminate how tPA performs with more diverse functions after stroke onset. In this comment, we focus on possible hypotheses about why and how tPA promotes ischemic neuronal survival in a comprehensive view. The text provides a holistic picture of the functions of tPA and enlists the considerations for the future, which might attract more attention toward the therapeutic potential of tPA in AIS.

Effect of microbubbles on transcranial doppler ultrasound-assisted intracranial recombinant tissue-type plasminogen activator thrombolysis.

OBJECTIVES: The aim of this study was to evaluate the effect of microbubbles on the efficacy of transcranial doppler (TCD) ultrasound-assisted thrombolytic therapy of recombinant tissue-type plasminogen activator (rt-PA). METHODS: Male New Zealand white rabbits (n = 36) were randomly divided into an rt-PA group (n = 18) and an rt-PA plus microbubble group (n = 18). After the cerebral infarction model was constructed with autologous blood clots, rt-PA and rt-PA plus microbubble intervention were performed, respectively. The hemodynamic changes and infarct size of the two groups were recorded. In addition, the ELISA method was used to detect the level of nitric oxide (NO), superoxide dismutase (SOD), and malondialdehyde (MDA) in the brain tissue of the two-group graph model and high-sensitivity C-reactive protein (hs-CRP) in the serum. RESULTS: In the rt-PA group, the recanalization rate was 38.9% and the average infarct size was 11.8%. In the rt-PA plus microbubble group, the recanalization rate was 66.7% and the average infarct size was 8.2%. In addition, the average values for NO, SOD, MDA, and hs-CRP were 16.48 ± 5.39 µmol/L, 730.2 ± 9.86 U/mg, 0.92 ± 0.43 nmol/mg, and 8.56 ± 1.64 mg/L in the rt-PA group, respectively, and the average values were 9.18 ± 3.37 µmol/L, 426.2 ± 6.39 U/mg, 0.73 ± 0.44 nmol/mg, and 5.23 ± 0.94 mg/L in the rt-PA plus microbubble group, respectively. CONCLUSIONS: The addition of microbubbles enhanced the effects of TCD-assisted rrt-PA thrombolysis.

Analysis of influencing factors of early neurological improvement after intravenous rt-PA thrombolysis in acute anterior circulation ischemic stroke.

Background and objective: It has been widely reported that Early neurological improvement (ENI) after rt-PA intravenous thrombolysis contributes to a good long-term prognosis in patients experiencing acute ischemic stroke (AIS). However, which clinical factors influence after intravenous administration of recombinant tissue-type plasminogen activator (IV-rt PA) in AIS patients ENI is still unclear. This study aimed to evaluate the impact of influencing factors on the benefit of ENI after intravenous thrombolysis neurological improvement after IV-rt PA. Methods: The data of 73 patients with acute anterior circulation ischemic stroke who received intravenous thrombolysis with rt-PA in Chongqing University Jiangjin Hospital from January 2021 to July 2022 were retrospectively studied. According to the change rate of 24 h NISHH score, the research subjects were divided into the recovery group, the significant curative effect group, the curative effect group and the no curative effect group, the ENI after intravenous thrombolysis with rt-PA was defined as the improvement rate of National Institutes of Health Stroke Scale (NIHSS)score >46% at 24 h after IV-rt PA, and univariate factor analysis was used Clinical factors associated with ENI after intravenous thrombolysis. Results: According to the 24-h NIHSS improvement rate of rt-PA intravenous thrombolysis in patients with acute anterior circulation ischemic stroke, 35 cases (47.95%) of the study population had ENI. There was no statistical difference between the improvement and non-improvement group in general demographic data, stroke TOAST classification, stroke risk factors (history of stroke, heart disease, hyperlipidemia, hypertension), and laboratory test data. There was a statistically significant difference in the random blood glucose levels between the two groups (p < 0.001, t = 3.511). Conclusion: The effect of rt-PA intravenous thrombolysis within the time window of patients with acute anterior circulation ischemic stroke is significant, but the ENI after thrombolysis is easily affected by the level of blood glucose; diabetes is the most important factor affecting the acute anterior circulation ischemic stroke patients Clinical factors of ENI after intravenous thrombolysis with rt-PA.

In vitro study about prevention of vascular reocclusion by low intensity ultrasonic irradiation.

For the treatment of acute ischemic stroke, the current standard of care is thrombolysis by the administration of intravenous (IV) recombinant tissue-type plasminogen activator (rt-PA). Although this approach is proven to be effective, reocclusion within 24 hours occurs in about 20% of patients who receive recanalization by rt-PA. In addition, the administration of anticoagulants within 24 hours after IV rt-PA increases the risk of intracranial hemorrhage; therefore, treatment with anticoagulants is contraindicated in this population. To address the need for an approach to sustain the effects of thrombolysis prevent blood vessel reocclusion without the use of anticoagulants, this study proposes a novel method using a low-intensity ultrasound (US) irradiation. An in vitro thrombus-growth model, in a latex rubber container was developed to study the effect of thrombus-growth suppression by US irradiation at 500 kHz in a 37°C water bath. The US acoustic intensity was set at or below 0.72 W/cm2, which is the maximum allowed for noninvasive acoustic irradiation. Low-intensity US irradiation of the thrombus-growth model resulted in a remarkable suppression of thrombus growth (100.22 ± 10.1 mg vs. 50.22 ± 5.3 mg, p < 0.0001), and the clot-growth inhibition depended logarithmically on acoustic intensity. Thrombus growth can be suppressed by low-intensity US irradiation, opening a new way to combat vascular reocclusion after rt-PA treatment of acute ischemic stroke.

Initial medical protocol efforts using both CT and MRI/MRA for acute cerebral infarction.

BACKGROUND: Earlier administration of intravenous recombinant tissue-type plasminogen activator (rtPA) and mechanical thrombectomy (MT) improves the neurological prognosis of patients with acute ischemic stroke (AIS). We introduced a new protocol that includes head and chest computed tomography (CT) and magnetic resonance imaging (MRI)/ magnetic resonance angiography (MRA) for all patients, which is quite different from previously evaluated protocols. This study aimed to examine whether this protocol could contribute to the prompt therapeutic intervention of AIS. METHODS: This is a retrospective observational study analyzing patients with AIS who were transported to our hospital by ambulance between January 2015 and November 2021. An AIS initial treatment protocol was introduced in April 2020, under which, CT and MRI/MRA imaging were performed in all patients, and the indication for rtPA and MT were determined. The participants were divided into those who were treated before and after the protocol introduction (conventional treatment and protocol groups, respectively). The time from hospital arrival to the start of rtPA administration (door-to-needle time: DNT) and the time from hospital arrival to the start of endovascular treatment (door-to-puncture time: DPT) were compared between the groups. RESULT: A total of 121 patients were analyzed, wherein 63 patients received rtPA (18 in the conventional treatment group and 45 in the protocol group) and 98 patients received MT (32 in the conventional treatment group and 66 in the protocol group). The median DNT was 97.0 (IQR 49.0-138.0) min vs. 56.5 (IQR 41.0-72.0) min (p < 0.001) for the conventional treatment and the protocol groups, respectively. The median DPT was 129.0 (IQR 62.0-196.0) min vs. 55.0 (IQR 40.5-69.5) min (p < 0.001), respectively. Moreover, DNT was achieved within 60 min in 5.6% vs. 69.9% (p < 0.001) and DPT within 90 min in 25.0% vs. 85.7% (p < 0.001), respectively. CONCLUSION: The introduction of a protocol, including CT/MRI imaging, significantly shortened DNT and DPT.

Impact of Stress Hyperglycemia on Early Neurological Deterioration in Acute Ischemic Stroke Patients Treated With Intravenous Thrombolysis.

Background and Purpose: It has been widely reported that stress hyperglycemia contributes to poor prognosis in patients experiencing acute ischemic stroke (AIS). However, its predictive value for early neurological deterioration (END) after intravenous administration of recombinant tissue-type plasminogen activator (IV-rtPA) in AIS patients is still unclear. The aim of this study was to evaluate the impact of stress hyperglycemia on the risk of END after IV-rtPA. Methods: A total of 798 consecutive patients treated with IV-rtPA were included in this study. The stress hyperglycemia ratio (SHR) was calculated as fasting plasma glucose level at admission (mg/dl)/glycosylated hemoglobin (HbAlc) (%). END was defined as a National Institutes of Health Stroke Scale Score (NIHSS) ≥ 4 points 24 h after IV-rtPA, and poor functional outcome at discharge was defined as a modified Rankin Scale (mRS) score of 3-6 at discharge. Patients with a prior history of diabetes or HbAlc ≥ 6.5% were considered to have diabetes mellitus. Patients were grouped according to SHR values. Multivariate logistical regression was used to evaluate the risk of END for patients within specific SHR categories. Results: In total, 139 (17.4%) patients had END. After adjusting for confounders, the highest tertile group had higher risks of END and poor functional outcome at discharge than those of patients in the lowest tertile group (OR, 1.95; 95% CI, 1.21-3.15; p = 0.006) (OR, 1.85; 95% CI, 1.163-2.941; p = 0.009), and the predictive value of high SHR for END was also significant in patients with diabetes mellitus (OR, 3.05; 95% CI, 1.29-7.21; p = 0.011). However, a significant association of high SHR and poor functional outcome was only found in patients without diabetes (OR, 1.85; 95% CI, 1.002-3.399; p = 0.045). Conclusion: A higher SHR predicted that patients with severe stress hyperglycemia had higher risks of END and poor functional outcome at discharge after IV-rtPA.

Efficacy and Safety of Different Dosage of Recombinant Tissue-type Plasminogen Activator (rt-PA) in the Treatment of Acute Pulmonary Embolism: A Systematic Review and Meta-analysis.

Reperfusion therapies are recommended for patients with hemodynamic instability or high-risk acute pulmonary embolism (PE). Lower doses of tissue plasminogen activator (rt-PA) could be considered to improve bleeding complications. The aim of this study was to evaluate the efficacy and safety of a reduced dose of rt-PA for the treatment of acute PE, compared with anticoagulation and standard dose. PubMed Central, Scopus, Web of Science and Embase were searched for all relevant randomized studies and prospective observational studies that compared reduced dose of rt-PA with anticoagulation alone or standard dose of rt-PA in patients with acute PE. The risk ratios (RR, with 95% CI) were calculated according to the value of I2. Outcomes were described as bleeding events, all-cause death, and recurrence of PE. Thirteen articles, including four observational studies (4223 patients) and nine RCTs (780 patients), were included. In comparing reduced dose of rt-PA with anticoagulant, a greater incidence of total bleeding events in low dose was showed (RR, 5.08 (95% CI, (1.39-18.6), I2 = 0.0%). In the standard dose rt-PA vs. reduced dose, there was a greater incidence of total bleeding events in the standard dose of rt-PA, RR 1.48 (95% CI, (1.00-2.19), I2 = 0.0%) was shown. There were no statistical differences in recurrent PE or all-cause mortality. It concluded that in the absence of the benefit of a standard dose of rt-PA in comparison with dose reduction, a reduced dose of rt-PA showed a lower rate of total bleeding events and similar efficacy regarding mortality and PE recurrence rate.

Iodinated Contrast Agents Reduce the Efficacy of Intravenous Recombinant Tissue-Type Plasminogen Activator in Acute Ischemic Stroke Patients: a Multicenter Cohort Study.

This study aimed to investigate whether the application of iodinated contrast agents before intravenous (IV) recombinant tissue plasminogen activator (rt-PA) reduces the efficacy in acute ischemic stroke (AIS) patients. To determine whether the application of iodinated contrast agents before intravenous rt-PA reduces the efficacy in AIS patients. We analyzed our prospectively collected data of consecutive AIS patients receiving IV rt-PA treatment in the MISSION CHINA study. Clinical outcome at 3 months was assessed with modified Rankin Scale (mRS) score and dichotomized into good outcome (0-2) and poor outcome (3-6). Symptomatic intracerebral hemorrhage (sICH) was defined as cerebral hemorrhagic transformation in combination with clinical deterioration of National Institutes of Health Stroke Scale (NIHSS) score ≥ 4 points at 24-h. We performed logistic regression analysis and propensity score matching analysis to investigate the impact of iodinated contrast agents before IV rt-PA on poor outcome and sICH, respectively. A total of 3593 patients were finally included, and iodinated contrast agents were used before IV rt-PA among 859 (23.9%) patients. Patients in the iodinated contrast group were more likely to result in poor outcome (39.9% vs 33.4%, P = 0.001) and sICH (3.4% vs 1.5%, P < 0.001), compared with non-contrast group. Binary logistic regression analysis revealed that the application of iodinated contrast agents was independently associated with poor outcome (OR 1.342; 95% CI 1.103-1.631; P = 0.003) and sICH (OR 1.929; 95% CI 1.153-3.230; P = 0.012), respectively. After propensity score matching, the application of iodinated contrast agents was still independently associated with poor outcome (OR 1.246; 95% CI 1.016-1.531; P = 0.034) and sICH (OR 1.965; 95% CI 1.118-3.456; P = 0.019). Applying iodinated contrast agents before IV rt-PA may reduce the thrombolytic efficacy in AIS patients. Further benefit-risk analysis might be needed when iodinated contrast-used imaging is considered before intravenous thrombolysis.

Successful free flap salvage surgery with off-label use of Alteplase: A case report, review of the literature and our free flap salvage algorithm.

INTRODUCTION: Microvascular free tissue transfer is a technique for reconstruction of large defects in head and neck surgery. Failure due to microvascular thrombosis can lead to microvascular damage or flap loss. Recombinant tissue-type plasminogen activator (Alteplase) is still an off-label use but it can help to rescue free flaps when embedded in a salvage algorithm. PRESENTATION OF CASE: A 39-year-old patient with received a tumor resection and reconstruction by a radial forearm flap of the left palate. Postoperatively a venous flap thrombosis occurred and immediate surgical revision was done. Initially eperfusion of the flap could not be achieved even after mechanical removal of the thrombus. Then a thrombolysis with Alteplase, which was applied directly into the radial artery, was done. The flap was salvaged and is now completely integrated into the mucosa. Flap salvage procedure was performed according to our free flap salvage algorithm. DISCUSSION: Thrombolysis with Alteplase for free flap salvage is not a common method. Pedicle thrombosis cannot be predicted. Important procedures during surgical intervention when thrombosis occurs are careful reopening, removal of thrombus, flushing with heparin. Since these procedures failed, surgeons decided to employ Alteplase to optimally rescue the flap. CONCLUSION: The present case shows that pharmacological thrombolysis with Alteplase is an effective ultima ratio in free flap salvage with venous thrombosis, although it is still considered offlabel use. Early detection of flap failure and a clear salvage algorithm are important for successful surgical revisions.

Alteplase for Acute Ischemic Stroke in Patients Aged >80 Years: Pooled Analyses of Individual Patient Data.

BACKGROUND/PURPOSE: Expert guidelines specify no upper age limit for alteplase for thrombolysis of acute ischemic stroke (AIS) but, until recently, European regulatory criteria restricted its use to patients aged 18 to 80 years. We performed pooled analyses of randomized controlled trial (RCT) and registry data to evaluate the benefit-risk profile of alteplase for AIS among patients aged >80 years to support a regulatory application to lift the upper age restriction. METHODS: Individual patient data were evaluated from 7 randomized trials of alteplase (0.9 mg/kg) versus placebo or open control for AIS, and the European SITS-UTMOST registry database. Clinical outcomes, including good functional outcome (score 0-1, modified Rankin Scale day 90 or Oxford Handicap Score day 180), were evaluated in the full RCT and registry populations, and specified age-based subgroups (≤80 or >80 years) who met existing European regulatory criteria for alteplase, excluding upper age restriction. RESULTS: Regardless of treatment allocation, 90-day mortality was lower among RCT patients aged ≤80 versus >80 years who otherwise met existing European regulatory criteria (246/2405 [10.2%] versus 307/1028 [29.9%], respectively). Among patients aged >80 years, alteplase versus placebo was associated with a higher proportion of good stroke outcome (modified Rankin Scale score 0-1; 99/518 [19.1%] versus 67/510 [13.1%]; P=0.0109) and similar 90-day mortality (153/518 [29.5%] versus 154/510 [30.2%]; P=0.8382). The odds of a good stroke outcome following alteplase allocation in the full RCT population were independent of age (P=0.7383). Good stroke outcome was reported for almost half (4821/11 169 [43.2%]) of the patients who received alteplase in routine practice. Outcomes in routine practice supported those achieved in RCTs. CONCLUSIONS: Alteplase for AIS has a positive benefit-risk profile among patients aged >80 years when administered according to other regulatory criteria. Alteplase for AIS should be evaluated on an individual benefit-risk basis.

Opalski Syndrome Treated with Intravenous Recombinant Tissue Type Plasminogen Activator-Case Report and Review of Literature.

A 65-year-old man with a history of Wallenberg syndrome caused by vertebral artery dissection at 62 years old was admitted to our hospital with nausea, vertigo, right facial dysesthesia, right hemiplegia, crossed sensory disturbance (sensory loss and numbness in the right face and left body below the neck), and right limb ataxia. Magnetic resonance imaging (MRI) performed 80 minutes after onset revealed no acute ischemic stroke lesions, but magnetic resonance angiography (MRA) demonstrated complete occlusion of the right vertebral artery. Based on these neurological and MRA findings, atypical lateral medullary infarction was suggested, and intravenous tissue plasminogen activator (IV-tPA) was started 178 minutes after onset. Right hemiplegia improved immediately after IV-tPA administration. MRI performed on hospital day 2 showed an acute ischemic lesion on the right side of the medulla oblongata, resulting in a diagnosis of Opalski syndrome. Opalski syndrome is a rare subtype of Wallenberg syndrome accompanied by hemiplegia of the side ipsilateral to the lesion, and expansion of the stroke lesion to the corticospinal tract below the pyramidal decussation is considered to cause ipsilateral hemiplegia. Based on this case and previous reports, Opalski syndrome should be considered when limb ataxia and crossed sensory deficit are observed among patients with hyperacute-onset hemiplegia, and IV t-PA therapy should be considered even in the absence of neurological findings such as dysphagia, dysarthria, and Horner's signs and radiological evidence of acute ischemic stroke.

In acute ischemic stroke patients with smoking incidence, are more women than men more likely to be included or excluded from thrombolysis therapy?

BACKGROUND: Clinical factors associated with exclusion from recombinant tissue plasminogen activator in both men and women are not completely understood. The aim of this study is to determine whether there is a gender difference in clinical risk factors that excluded ischemic stroke patients with a history of smoking from recombinant tissue plasminogen activator. METHODS: Retrospective data from a stroke registry were analyzed, and multivariable linear regression models were used to determine gender differences. Logistic regression models determined exclusion clinical risk factors for thrombolysis in male and female acute ischemic stroke patients with a history of smoking, while sequentially adjusting for sociodemographic, clinical, and stroke-related variables. The Kaplan-Meier survival analysis was used to determine the exclusion probabilities of men and women with a history of smoking within the stroke population. RESULTS: Of the 1,446 acute ischemic stroke patients eligible for recombinant tissue plasminogen activator, 379 patients with a history of smoking were examined, of which 181 received recombinant tissue plasminogen activator while 198 were excluded from receiving recombinant tissue plasminogen activator. Of the 198 patients, 75 females and 123 males were excluded from receiving recombinant tissue plasminogen activator. After multivariable adjustment for age, National Institutes of Health scores, and stroke-related factors, females who present with weakness/paresis on initial examination (OR = 0.117, 95% CI, 0.025-0.548) and men who present with a history of previous transient ischemic attack (OR = 0.169, 95% CI, 0.044-0.655), antiplatelet medication use (OR = 0.456, 95% CI, 0.230-0.906), and weakness/paresis on initial examination (OR = 0.171, 95% CI, 0.056-0.521) were less likely to be excluded from recombinant tissue plasminogen activator (thrombolysis therapy). CONCLUSIONS: In an ischemic stroke population with a history of smoking, female smokers are more likely to be excluded from thrombolysis therapy in comparison to men, even after adjustment for confounding variables.

Clinical outcomes of mechanical thrombectomy following intravenous administration of recombinant tissue-type plasminogen activator for basilar artery occlusion.

OBJECTIVE: Mechanical thrombectomy (MT) following intravenous administration of recombinant tissue-type plasminogen activator (IV-rt-PA) is considered an effective treatment for the occlusion of the internal carotid artery or the M1 segment of the middle cerebral artery. However, its efficacy in treating basilar artery (BA) occlusion is still unclear. In order to evaluate the efficacy of MT in treating BA occlusion, we aimed to analyzed the clinical outcomes of those patients who had undergone MT following IV-rt-PA administration. PATIENTS AND METHODS: We retrospectively analyzed the clinical outcomes of 11 patients with BA occlusion who had undergone MT following IV-rt-PA administration between January 1, 2015, and March 31, 2019. RESULTS: The patients consisted of 8 men and 3 women. The mean (±standard deviation) age was 73 ±â€¯9.4 years. Stroke subtypes were found to be atherothrombosis in 2 patients, cardiogenic embolism in 6, arterial dissection in 1, and an unknown cause in 2. The median pretreatment scores were 9 on the Glasgow Coma Scale (GCS) and 25 on the National Institutes of Health Stroke Scale. The time elapsed from onset of the stroke to reperfusion was 281 min. Successful reperfusion, characterized by a modified Thrombolysis in Cerebral Infarction grade ≥ 2b, was achieved in all patients. The 3-month outcomes were good [modified Rankin Scale (mRS) 0-2] in 5 patients and poor (mRS 3-6) in 6 patients. The pretreatment median GCS scores were significantly higher in patients with a good outcome compared to that in those with a poor outcome with scores of 11 and 7.5, respectively (P =  0.044). The receiver operating characteristic (ROC) curve analysis showed that the optimal cut-off score on the GCS was 9.5 [area under the curve (AUC), 0.867; sensitivity, 0.8; specificity, 1.0]. Complications occurred in 1 patient with arterial dissection who had developed a subarachnoid hemorrhage and later died. CONCLUSION: The results of the present study suggests that the pretreatment GCS score might affect the clinical outcomes in patients with BA occlusion who underwent MT following IV-rt-PA therapy.

Prevalence of a Multiple Territory Stroke Pattern After Intravenous Thrombolysis.

BACKGROUND: It has been proposed that the presence of a multiple territory stroke pattern (MTSP) on brain imaging may aid identification of patients with covert atrial fibrillation (AF). However, it is uncertain whether this association holds true among patients treated with intravenous recombinant tissue plasminogen activator (rtPA) because clot fragmentation may affect MTSP prevalence. METHODS/DESIGN: Retrospective analysis of 149 acute ischemic stroke patients treated with intravenous rtPA who underwent brain MRI. Presence of multiple acute infarctions on brain MRI that involved more than one vascular territory was considered to denote MTSP. Stroke etiology was categorized as nonembolic, cardioembolic (CES), and embolic stroke of undetermined source (ESUS). RESULTS: In the entire cohort, subjects with CES and ESUS had significantly more often an MTSP than subjects with other determined stroke mechanism (P= .007). Although numerically relatively more patients had an MTSP as compared to a non-MTSP among subjects with CES (52% versus 33.9%) and ESUS (44% versus 34.7%), this difference did not reach significance after Bonferroni-adjustment for multiple comparisons (P> .05, each). There was no difference in the prevalence of an MTSP among subjects with known (n = 11/51; 21.6%) versus subsequently diagnosed (n = 1/3; 33.3%) AF (P= .54). CONCLUSIONS: Our findings indicate that the known association of multiterritory infarct with AF and ESUS is maintained after thrombolysis. In light of its high specificity, MTSP represents a good marker for AF-related stroke etiology; nevertheless, overall sensitivity for AF was low highlighting that an absent MTSP does not rule out AF.

Safety and Efficacy of Repeated Thrombolysis with Alteplase in Early Recurrent Ischemic Stroke: A Systematic Review.

BACKGROUND AND AIM: The current American Heart Association guidelines for the management of acute ischemic stroke advise against the use of intravenous (IV) alteplase in patients with recurrent stroke occurring within 90 days of their index event. Following these guidelines strictly, patients having early recurrent ischemic stroke would be unable to avail of this reperfusion strategy that has been proven to confer superior clinical outcomes. While some registry-based studies have demonstrated the safety of IV alteplase in this subgroup of patients, data on the repeated use of the drug are lacking. Thus, we aim to determine the safety and efficacy of repeated thrombolysis in patients with early recurrent ischemic strokes. METHODS: The following electronic databases were searched for relevant studies: the Cochrane Central Register for Controlled Trials by The Cochrane Library, MEDLINE by PubMed, Health Research and Development Information Network, Scopus, and ClinicalTrials.gov. Data on symptomatic intracranial hemorrhage, 90-day clinical outcomes, systemic hemorrhage and allergic reactionswere synthesized. RESULTS: Ten articles with 33 patients in total were included in our review. One patient developed symptomatic intracranial hemorrhage after the second reperfusion attempt and subsequently died from pneumonia. Another died from spontaneous rupture of previously unidentified infrarenal aortic aneurysm. Six of the 13 patients with available follow-up data had good clinical outcomes (Modified Rankin Score 0-2). There were no allergic reactions and other drug-related adverse events noted. CONCLUSIONS: Repeated IV alteplase can be safe and efficacious in patients who have early recurrent ischemic stroke. Larger studies, trials, or registry-based data are needed to ascertain the encouraging findings of our review.

Thrombolysis induced by intravenous administration of plasminogen activator in magnetoliposomes: dual targeting by magnetic and thermal manipulation.

In previously published studies, intra-arterial (i.a.), but not intravenous (i.v.) delivery of recombinant tissue-type plasminogen activator (rtPA) immobilized on the surface of magnetic nanoparticles induces thrombolysis by magnetic targeting. We asked whether i.v. delivery of protected rtPA in a thermosensitive magnetoliposome (TML@rtPA) may achieve target thrombolysis. PEGylated TML@rtPA was optimized and characterized; controlled release of rtPA was achieved by thermodynamic and magnetic manipulation in vitro. The lysis index of TML@rtPA incubated with blood at 43 °C vs. 37 °C was 53 ±â€¯11% vs. 81 ±â€¯3% in thromboelastograms, suggesting thermosensitive thrombolysis of TML@rtPA. In a rat embolic model with superfusion of 43 °C saline on a focal spot on the iliac artery with clot lodging, release of rtPA equivalent to 20% regular dose from TML@rtPA administered i.a. vs. i.v. significantly restored iliac blood flow 15 vs. 55 min after clot lodging, respectively. TML@rtPA with magnetic guiding and focal hyperthermia may be potentially amendable to target thrombolysis.

Targeting Platelet GPVI Plus rt-PA Administration but Not α2ß1-Mediated Collagen Binding Protects against Ischemic Brain Damage in Mice.

Platelet collagen interactions at sites of vascular injuries predominantly involve glycoprotein VI (GPVI) and the integrin α2ß1. Both proteins are primarily expressed on platelets and megakaryocytes whereas GPVI expression is also shown on endothelial and integrin α2ß1 expression on epithelial cells. We recently showed that depletion of GPVI improves stroke outcome without increasing the risk of cerebral hemorrhage. Genetic variants associated with higher platelet surface integrin α2 (ITGA2) receptor levels have frequently been found to correlate with an increased risk of ischemic stroke in patients. However until now, no preclinical stroke study has addressed whether platelet integrin α2ß1 contributes to the pathophysiology of ischemia/reperfusion (I/R) injury. Focal cerebral ischemia was induced in C57BL/6 and Itga2-/- mice by a 60 min transient middle cerebral artery occlusion (tMCAO). Additionally, wild-type animals were pretreated with anti-GPVI antibody (JAQ1) or Fab fragments of a function blocking antibody against integrin α2ß1 (LEN/B). In anti-GPVI treated animals, intravenous (IV) recombinant tissue plasminogen activator (rt-PA) treatment was applied immediately prior to reperfusion. Stroke outcome, including infarct size and neurological scoring was determined on day 1 after tMCAO. We demonstrate that targeting the integrin α2ß1 (pharmacologic; genetic) did neither reduce stroke size nor improve functional outcome on day 1 after tMCAO. In contrast, depletion of platelet GPVI prior to stroke was safe and effective, even when combined with rt-PA treatment. Our results underscore that GPVI, but not ITGA2, is a promising and safe target in the setting of ischemic stroke.

Correlation of Changes in Leukocytes Levels 24 Hours after Intravenous Thrombolysis With Prognosis in Patients With Acute Ischemic Stroke.

OBJECTIVE: Leukocytes play a crucial role in inflammation and immune response. This study aims to demonstrate the value of changes in leukocytes levels 24 hours after intravenous thrombolysis to predict prognosis in acute ischemic stroke (AIS). METHODS: From Jan 2016 to Oct 2017, the patients who suffered AIS to our center within 4.5 hours of symptom onset were all treated with recombinant tissue-type plasminogen activator. Data from 213 AIS patients were analyzed. Patients were divided into 4 groups: persistent leukocytosis (PL), transient leukocytosis (TL), leukocytosis 24 hours (L24H) and no leukocytosis (NL). By comparison, the factors with statistically significant were selected in pairwise multiple comparisons. Good clinical outcome was defined as the Modified Rankin Scale score of 2 or lower. Multivariate logistic regression was used to assess the association of the indicators with clinical outcome. RESULTS: By pairwise multiple comparisons, PL and L24H had higher baseline National Institutes of Health Stroke Scale (NIHSS) score than NL and were likely to lead poor clinical outcomes. TL had a better prognosis than L24H. As the results of multivariable analyses shown, PL and L24H were risk factors to poor functional outcomes (odds ratio [OR] = 2.668, 95% confidence interval [CI] = 1.139-6.249, P = .024; OR = 6.648, 95%CI = 2.048-21.584, P = .002). CONCLUSION: Persistent leukocytosis and leukocytosis 24 hours both had higher baseline NIHSS scores, more serious stroke and were more likely to lead to unfavorable outcome. Therefore, changes in leukocytes levels 24 hours after intravenous thrombolysis could be predicted the short-term functional outcome of AIS patients.