Tissue Plasminogen Activator Research Articles

Impact of COVID-19 on cardiology and neurology services in a peripheral hospital in Northern Israel

Abstract Background The indirect impact of COVID-19 pandemic on clinical services remains incompletely described in secondary care hospitals outside major urban centers. We compared clinical outcomes before and during the pandemic in a disrupted service (Neurology) and a non-disrupted one (Cardiology) in a peripheral hospital in Israel, using Cerebral Vascular Accident (CVA) and ST-elevation myocardial infarction (STEMI) as clinical indicators, respectively. Methods We compared demographics, treatment and outcomes from CVA and STEMI patients who attended Ziv Medical Center, Israel, during the pandemic (15/3/2020-15/4/2022) and before (1/1/2018-14/3/2020), Using chi-square, t-test and Wilcoxon-Mann-Whitney tests. Results 1029 CVA and 497 STEMI patients were included. Those who arrived during the pandemic were demographically comparable to those arriving before. Compared to pre-pandemic, intra-pandemic median time for CVA patients from arrival to imaging was longer (23 vs. 19 minutes, p = 0.001). However, timing from arrival to tissue Plasminogen Activator administration was similar (49 vs. 45 min, p = 0.61). The likelihood of transfer to another hospital was higher (20.3% vs. 14.4% p = 0.01) and median length of stay (LOS) was shorter (3 vs. 4 days, p < 0.05). Among STEMI patients, median time from arrival to percutaneous coronary intervention during the pandemic was shorter than before (45 vs. 50 minutes p = 0.02) and median ejection fraction at discharge was higher (50% vs. 45% p = 0.02). Mean LOS was shorter (3.86 vs. 4.48 p = 0.01), and unplanned re-admission to the ED was less frequent (7.8% vs. 14.6% p = 0.01). No significant changes in mortality were observed. Conclusions Our data shows no major negative impact of the COVID-19 pandemic on CVA and STEMI outcomes, and possibly improved care in the less disrupted department. Follow-up qualitative studies with neurology and cardiology staff already in action to comprehend how quality of care was maintained during the crises. Key messages • In peripheral setting, COVID-19 hadn’t negatively impact Neurology or Cardiology acute clinical outcomes. • The consequences of maintaining clinical performance when working under adverse conditions requires further research.

Relationship between lipoprotein(a) and endogenous fibrinolytic status in patients with STEMI

Abstract Background The risk of myocardial infarction is at least doubled in individuals with lipoprotein(a) (Lp[a]) levels >90th percentile.[1] Lp(a) may exert pro-thrombotic effects by impairing fibrinolysis. Lp(a) has a high degree of homology to plasminogen and can competitively inhibit tissue plasminogen activator (tPA)-mediated plasminogen activation and tPA-mediated clot lysis.[2] Furthermore, Lp(a) stimulates the activity of plasminogen activator inhibitor-1, the major inhibitor of the fibrinolytic system. In patients with ST-segment elevation myocardial infarction (STEMI), impaired endogenous fibrinolysis is a strong, independent risk factor for recurrent cardiovascular events,[3] but the drivers of this are not fully understood. Whether impaired endogenous fibrinolysis is related to increased Lp(a) levels in patients with STEMI, is not known. Purpose We aimed to assess the relationship between Lp(a) and endogenous fibrinolysis in patients with STEMI. Methods In a prospective, observational study, venous blood samples were drawn from patients presenting with STEMI immediately before revascularisation, after dual antiplatelet therapy but before heparin administration. Endogenous fibrinolysis was measured immediately in non-anticoagulated whole blood using the point-of-care Global Thrombosis Test, which measures the time for occlusive thrombus formation under high shear (occlusion time) and the time for spontaneous lysis of the thrombus (lysis time).[3] Assessment of Lp(a) levels, measured by particle enhanced immunoturbidimetric assay, was performed with paired plasma samples, standardized against the International Federation of Clinical Chemistry reference material SRM2B for nmol/L. Lp(a) >32 nmol/L is associated with increased risk of ischaemic heart disease. Results A total of 80 patients were included (age 64±14y, 25% females and 86% Caucasian). There was a positive correlation between Lp(a) level and lysis time (r = 0.330, P = 0.003) (Figure 1). Lysis time was significantly longer in patients with Lp(a) >32 nmol/L (2782 [1626-3683] vs. 1725 [1259-2955] s, P = 0.044). Using a cut-point of lysis time ≥2500 s previously associated with a significantly increased cardiovascular risk in patients with STEMI, we showed that Lp(a) was significantly higher in patients with lysis time ≥2500 s (40 (22-111) vs. 18 (7-73) nmol/L, P = 0.045). Table 1 shows the relationship between clinical characteristics and Lp(a) and lysis time. Lp(a) level was higher in non-Caucasian patients. There was no correlation between Lp(a) and occlusion time (r = 0.156, P = 0.168). Conclusion In patients with STEMI, longer endogenous fibrinolysis time is related to higher Lp(a) level. Raised Lp(a) levels may, in part, contribute to impaired endogenous fibrinolysis. Future studies are required to assess whether reduction in Lp(a) with novel therapies currently in phase 3 trials can favourably modulate fibrinolysis and improve clinical outcomes.Figure 1

Tissue Plasminogen Activator (tPA) Use in Persistent Loculated Ascites

Tissue Plasminogen Activator (tPA) Use in Persistent Loculated Ascites

Iodine-Based Dual-Energy Computed Tomography After Mechanical Thrombectomy Predicts Secondary Neurologic Decline from Cerebral Edema After Severe Stroke.

Patients with severe stroke are at high risk of secondary neurologic decline (ND) from the development of malignant cerebral edema (MCE). However, early infarcts are hard to diagnose on conventional head computed tomography (CT). We hypothesize that high-energy (190keV) virtual monochromatic imaging (VMI) from dual-energy CT (DECT) imaging enables earlier detection of ND from MCE. Consecutive patients with severe stroke with National Institute of Health Stroke Scale (NIHSS) scores > 15 and DECT within 10h of mechanical thrombectomy from May 2020 to March 2022 were included. We excluded patients with parenchymal hematoma type 2 transformation. Retrospective analysis of clinical and novel variables included the VMI Alberta Stroke Program Early CT Score (ASPECTS), total iodine content, and VMI infarct volume. The primary outcome was secondary ND, defined using a composite outcome variable of clinical worsening (increase in NIHSS score ≥ 4 or decrease in Glasgow Coma Scale score > 2) or malignant radiographical edema (midline shift ≥ 5mm at the level of the septum pellucidum). Fisher's exact test and Wilcoxon's test were used for univariate analysis. Logistic regression was used to develop prediction models for categorical outcomes. Eighty-four patients with severe stroke with a median age of 67.5 (interquartile range [IQR] 57-78) years and an NIHSS score of 22 (IQR 18-25) were included. Twenty-nine patients had ND. The VMI ASPECTS, total iodine content, and VMI infarct volume were associated with ND. The VMI ASPECTS, VMI infarct volume, and total iodine content were predictors of ND after adjusting for age, sex, initial NIHSS score, and tissue plasminogen activator administration, with areas under the receiver operating characteristic curve (AUROC) of 0.691 (95% confidence interval [CI] 0.572-0.810), 0.877 (95% CI 0.800-0.954), and 0.845 (95% CI 0.750-0.940). By including all three predictors, the model achieved an AUROC of 0.903 (95% CI 0.84-0.97) and was cross-validated by the leave one out method, with an AUROC of 0.827. The VMI ASPECTS and VMI infarct volume from DECT are superior to the conventional CT ASPECTS and are novel predictors for secondary ND due to MCE after severe stroke. Clinical trial registration ClinicalTrials.gov identifier: NCT04189471.

The impact of sex differences on stroke risk factors and 3-month outcomes in patients receiving thrombolytic therapy for acute ischemic stroke

BackgroundAcute ischemic stroke (AIS) is a major public health issue, and women have a disproportionate share of stroke-related disability and mortality, which is poorly understood. This study aimed to determine the effect of sex differences on AIS treated by thrombolysis using recombinant tissue plasminogen activator (rTPA). The study included 134 AIS patients eligible for rTPA. Risk factors, clinical presentation, thrombolysis response, complications, and outcomes were recorded. The outcomes were measured using the National Institute of Health Stroke Scale (NIHSS) and the modified Rankin Scale (mRS) 3 months after stroke. The incidence of intracranial haemorrhage was also determined.ResultsAmong 134 AIS patients treated with rTPA (59% male, 41% female), females had higher rates of hypertension (67.3% versus 49.4%, p = 0.040) and atrial fibrillation (AF) (12.7% versus 2.5%, p = 0.020), while smoking was more prevalent in males (31.6% versus 0%, p < 0.0001). Cardioembolism was more frequent in females than in males (23.6% versus 6.3%, p = 0.004). Females also had shorter onset-to-door (110.7 ± 63 versus 131.1 ± 50.2 min, p = 0.035) and onset-to-needle times (151.6 ± 66.5 versus 173.7 ± 50.6 min, p = 0.046). Both sexes showed significant improvements in NIHSS (males: 11.58 ± 3.7 to 6.05 ± 5.6; females: 11.64 ± 4.7 to 6.9 ± 5.9; p < 0.0001) and mRS scores (males: 3.34 ± 1.05 to 2.03 ± 2; females: 3.53 ± 1 to 2.02 ± 2; p < 0.0001) over 3 months, with no significant differences between sexes. Predictors of poor outcome (mRS 3–6) differed: diabetes mellitus (DM) (OR 7.79, p = 0.002) and longer door-to-needle time (OR 1.04, p = 0.008) for males, and hemorrhage (OR 9.41, p = 0.048) for females. Hemorrhage predicted mortality in males (OR 27.08, p < 0.0001), while AF was associated with increased mortality in females (OR 8.06, p = 0.024).ConclusionsThis study revealed sex-specific differences in AIS risk factors, aetiology, and rTPA treatment timelines, although post-treatment improvements were comparable between sexes. Notably, outcome predictors and mortality factors differed by sex. These findings emphasize the need for sex-specific considerations in AIS management and risk assessment.

Tissue Plasminogen Activator or Perfluoropropane for Submacular Hemorrhage in Age-Related Macular Degeneration

Evidence is limited to support therapies to treat submacular hemorrhage (SMH) secondary to neovascular age-related macular degeneration (AMD) as an adjunct to anti-vascular endothelial growth factor therapy (anti-VEGF). To determine if intravitreal tissue plasminogen activator (TPA) or gas improves visual acuity or promotes resolution of SMH secondary to neovascular AMD in eyes treated with ranibizumab. This was a double-masked, sham-controlled, factorial randomized clinical trial and feasibility study that recruited participants from June 2014 to March 2019, with 12 months' follow-up. Included in the trial were patients from 4 UK vitreoretinal units who had fovea-involving SMH of at least 1 disc area secondary to neovascular AMD and were evaluated within 14 days of onset. Study eyes received baseline ranibizumab and were then randomized 2:1:1:1 to 1 of 4 intravitreal treatments: sham injection, perfluoropropane (C3F8), TPA, or combined C3F8 and TPA (C3F8 + TPA). All eyes received monthly pro re nata ranibizumab therapy over 12 months. Outcome assessors were masked to intervention assignment. Best-corrected visual acuity (BCVA) at month 3. Fifty-three of 56 participants (95%; mean [SD] age, 81.5 [8.1] years; 33 female [59%]) reached the primary end point. Study eyes were randomized to the following intravitreal treatments: sham injection (n = 23), C3F8 (n = 11), TPA (n = 11), or C3F8 + TPA (n = 11). On factorial analysis, the combined TPA groups had significantly better month 3 mean logMAR BCVA than those not receiving TPA: 0.66 vs 0.98 (μd = -0.32; 95% CI, -0.58 to -0.07; P = .02). There was no statistically significant difference comparing groups that did vs did not receive C3F8: 0.80 vs 0.90 (μd = -0.11; 95% CI, -0.37 to 0.16; P = .43). The combined TPA groups were less likely to have SMH present at month 1 (10 of 18 [55.6%] vs 21 of 24 [87.5%]; P = .03), a benefit not evident in the combined gas groups. The mean logMAR BCVA at 3 months was not significantly different between the groups: monotherapy control, 0.99; C3F8, 0.97 (vs control μd = -0.02; 95% CI, -0.48 to 0.44); TPA, 0.70 (vs control μd = -0.29; 95% CI, -0.79 to 0.21); combined C3F8 and TPA, 0.71 (vs control μd = -0.36; 95% CI, -0.82 to 0.11); P = .11. No safety differences were identified across the treatment groups. Results of this randomized clinical trial suggest that TPA may increase the chance of visual acuity gain when added to ranibizumab therapy for neovascular AMD in eyes with SMH, warranting consideration of additional clinical trials. ClinicalTrials.gov Identifier: NCT01835067.

Anterior circulation acute ischemic stroke due to vertebral artery ostial stenosis in a patient with congenital internal carotid artery agenesis: a case report

BackgroundCongenital agenesis of internal carotid artery (ICA) is a rare cerebrovascular variation entity. Most cases of congenital ICA agenesis are asymptomatic and discovered incidentally. Congenital ICA agenesis presenting as ischemic stroke is even rare.Case presentationAn 80-year-old male patient was admitted to our hospital due to sudden dysarthria and left limb weakness for 3.5 h. Based on emergency physical examination and head computed tomography (CT) scan results, acute ischemic stroke (AIS) of right cerebral hemisphere was suspected. Following intravenous thrombolysis with recombinant tissue plasminogen activator, right congenital agenesis of ICA was confirmed by CT and digital subtraction angiography. Additionally, there was a severe right vertebral artery ostial (VAO) stenosis. After ruling out common causes of AIS such as haematological diseases, arterial dissection, organic heart disease, immunological abnormality and underlying possible malignancies, we hypothesize that the severe stenosis of the right VAO may have contributed to the development of AIS in this case.ConclusionsWe present a case of right congenital ICA agenesis in which severe stenosis of the right VAO may have played a role in the development of AIS. This case underscores a rare scenario where a lesion in the posterior circulation leads to an infarction in the anterior circulation in the setting of congenital ICA agenesis.

Neuropsychological outcomes following endovascular clot retrieval and intravenous thrombolysis in ischemic stroke.

Cognitive impairment, anxiety, depression, fatigue, and dependence in instrumental activities of daily living (ADL) are common after stroke; however, little is known about how these outcomes may differ following treatment with endovascular clot retrieval (ECR), intravenous tissue plasminogen activator (t-PA), or conservative management. Patients were recruited after acute treatment and invited to participate in an outcome assessment 90-120 days post-stroke. The assessment included a cognitive test battery and several questionnaires. The COVID-19 pandemic led to significant disruptions in recruitment and data collection, and the t-PA and conservative management groups were combined into a standard medical care (SMC) group. Sixty-two participants were included in the study (ECR = 31, SMC = 31). Mean age was 66.5 (20-86) years, and 35 (56.5%) participants were male. Participants treated with ECR had significantly higher National Institutes of Health Stroke Scale scores at presentation and significantly lower education. After adjusting for stroke severity, premorbid intellectual ability, and age, treatment with ECR was associated with significantly better performances on measures of cognitive screening, visual working memory, and verbal learning and memory. Participants treated with ECR also experienced less fatigue and were more likely to achieve independence in basic and instrumental ADLs. Despite this, cognitive impairment and fatigue were still common among participants treated with ECR and anxiety and depression symptoms were experienced similarly by both groups. Cognitive impairment and fatigue were less common but still prevalent following treatment with ECR. This has important practical implications for stroke rehabilitation, and routine assessment of cognition, emotion, and fatigue is recommended for all stroke survivors regardless of stroke treatment and functional outcome.

Recombinant Plasminogen Activator of the Sandworm (Perinereis aibuhitensis) Expression in Escherichia coli.

As an essential thrombolytic agent, the tissue plasminogen activator receives increasing attention due to its longer half-life, lower immunogenicity, and easier administration, which are superior to other thrombolytic agents. In this study, the isolated and purified plasminogen activator from the sandworm (Perinereis aibuhitensis) was expressed in E. coli (Escherichia coli) to investigate its potential for simplifying the development process. The sandworm plasminogen activator was previously successfully cloned and expressed in E. coli with low yield and activity in the culture supernatant. This low yield and activity prompted us to optimize its DNA sequence. Furthermore, to raise the efficiency in the separation of the target protein, the protein's solubility was enhanced by fusing it with maltose-binding protein (MBP) tags. Eventually, the fibrinolytic activity was successfully restored after digestion with tobacco etch virus (TEV) protease. This study provides an innovative method of efficiently expressing and purifying plasminogen activators from sandworm in E. coli and broadens its applications in therapeutic treatment of cardiovascular diseases, including thrombosis, stroke, and coronary atherosclerotic heart disease.

Mechanical thrombectomy for internal carotid artery occlusion beyond a large paraclinoid aneurysm

BackgroundWith the launch of mechanical thrombectomy (MT), the prognosis of patients with cerebral infarction associated with large-vessel occlusion has improved. However, good outcomes are still not achieved in a few patients because of technical difficulties.Case presentationA 79-year-old Japanese woman was admitted with sudden-onset left hemiplegia. Tissue plasminogen activator was administered and MT was performed for internal carotid artery occlusion distal to a large paraclinoid aneurysm. Some technical difficulties were unique, including contrast agent retention, difficulty in guiding the system, and avoidance of rupture of the aneurysm. Here, we discuss the technical issues and solutions of the MT procedure employed in this case.ConclusionsThe procedure used in flow-diverter devices should be referenced and a stent-retrieving into an aspiration catheter with proximal balloon technique may be the most appropriate method.

Comprehensive analysis of the impact of procedure time and the ‘golden hour’ in subpopulations of stroke thrombectomy patients

ObjectiveTo evaluate the effect of procedure time on thrombectomy outcomes in different subpopulations of patients undergoing endovascular thrombectomy (EVT), given the recently expanded indications for EVT.MethodsThis multicenter study included patients...

Thrombolysis exacerbates cerebrovascular injury after ischemic stroke via a VEGF-B dependent effect on adipose lipolysis.

Cerebrovascular injuries leading to edema and hemorrhage after ischemic stroke are common. The mechanisms underlying these events and how they are connected to known risk factors for poor outcome, like obesity and diabetes, is relatively unknown. Herein we demonstrate that increased adipose tissue lipolysis is a dominating risk factor for the development of a compromised cerebrovasculature in ischemic stroke. Reducing adipose lipolysis by VEGF-B antagonism improved vascular integrity by reducing ectopic cerebrovascular lipid deposition. Thrombolytic therapy in ischemic stroke using tissue plasminogen activator (tPA) leads to increased risk of hemorrhagic complications, substantially limiting the use of thrombolytic therapy. We provide evidence that thrombolysis with tPA promotes adipose tissue lipolysis, leading to a rise in plasma fatty acids and lipid accumulation in the ischemic cerebrovasculature after stroke. VEGF-B blockade improved the efficacy and safety of thrombolysis suggesting the potential use of anti-VEGF-B therapy to extend the therapeutic window for stroke management.

Multimodal imaging-based treatment recommendations for managing submacular hemorrhage.

Submacular haemorrhage (SMH) is an emergency, and the most important immediate action in the treatment of SMH is the early displacement or evacuation of subretinal heme from below the fovea, followed by simultaneous or sequential treatment of the underlying cause. Photoreceptor damage can occur immediately after the onset of SMH for a variety of reasons, including toxins released from the blood, the diffusion barrier created by the blood for oxygen delivery and nutrition to the outer retinal layers, and shearing forces on the outer retinal layers, resulting in permanent visual deterioration. A clinician's decision to treat SMH is influenced by a number of factors, including presenting visual acuity, duration of visual symptoms, SMH aetiology and characteristics, availability of intraocular gases and tissue plasminogen activator, and pars plana vitrectomy facilities. For many clinicians, the duration of visual symptoms is the most important and first consideration when planning SMH treatment. Very little emphasis is given to the SMH's imaging characteristics. Currently, there are several treatment options for SMH removal. There is a need to develop a simplified treatment algorithm for SMH that is less reliant on the patient's visual complaints, considers heme characteristics on basic retinal imaging, and has the potential to achieve uniform and predictable treatment outcomes in real-world situations. In this short article, we discuss the various factors that can assist clinicians in the management of SMH and present a simplified treatment algorithm based on the SMH's retinal imaging characteristics.

Effect of intravenous thrombolysis with butylphthalide, edaravone and recombinant tissue plasminogen activator (rt-PA) on serum inflammatory factors in patients with ischemic stroke

Purpose: To study the impact of edaravone in combination with edaravone and recombinant tissue plasminogen activator (rt-PA) intravenous thrombolysis on serum inflammatory factors in ischemic stroke subjects. Methods: Eighty ischemic stroke patients in the First Affiliated Hospital of Xi'an Medical University, Xi’an, China were randomly assigned to study and control cohorts, each with 40 subjects. Patients in control cohort were administered edaravone and rt-PA intravenous thrombolysis. The study cohort received butylphthalide in combination with edaravone and rt-PA intravenous thrombolysis. Treatment effectiveness/efficacy, neurological function, self-care ability, inflammatory indicator levels, and blood cell levels were compared between the 2 cohorts. Results: Efficacy was significantly better in the study cohort than in the control cohort (p &lt; 0.05). After treatment, NIHSS score was significantly lower in the study cohort than in control cohort, while ADL score was significantly higher in the study cohort (p &lt; 0.05). After medication, CRP level was decreased significantly in both cohorts, but was significantly lower level in the study cohort (p &lt; 0.05). Treatment led to significant reductions in white blood cell count, neutrophil count, and NLR ratio in the study cohort, relative to the control cohort (p &lt; 0.05). Conclusion: The use of butylphthalide in combination with edaravone and rt-PA intravenous thrombolysis produces significant and beneficial effects on ischemic stroke subjects by regulating abnormal levels of inflammatory cells, improving coagulation status and decreasing inflammation. Moreover, it ameliorates neurological defects and improves activities of daily living. There is, however, a need to determine the mechanisms of action of this combination therapy and the influence of other cofounding factors on the activities of the combination therapy.

Clinical characteristics, in-hospital management, and outcomes among patients hospitalized for acute ischemic stroke in rural versus urban hospitals in China: A nationwide hospital-based study.

Efforts to improve rural stroke care have intensified in China. However, high-quality comprehensive data on the differences in care and outcomes between rural and urban hospitals are limited. We analyzed data on patients with acute ischemic stroke hospitalized in the China Stroke Center Alliance hospitals from 2015 to 2022. The in-hospital management measures assessed included nine acute and five discharge management measures. Outcomes evaluated included death or discharge against medical advice (DAMA), major adverse cardiovascular events (MACE), disability at discharge, and in-hospital complications. We enrolled 1,583,271 patients with acute ischemic stroke from 1930 hospitals, comprising 1086 (56.3%) rural sites with 735,452 patients and 844 (43.7%) urban sites with 847,891 patients. Patients in rural hospitals demonstrate suboptimal management measures compared to those in urban hospitals, including lower rates of intravenous recombinant tissue plasminogen activator within 4.5 h (26.0% vs 28.3%; difference: -2.3% (-2.5% to -2.0%)), endovascular treatment (0.6% vs 1.9%; difference: -1.3% (-1.3% to -1.2%)), vessel assessment (88.5% vs 92.0%; difference: -3.5% (95% confidence interval (CI): -3.6% to -3.4%)), and anticoagulants for atrial fibrillation at discharge (42.9% vs 47.7%; difference: -4.8% (95% CI: -5.4% to -4.2%)). Overall, the rural-urban disparity in in-hospital outcomes was small. Rural patients had a slightly higher rate of in-hospital death/DAMA (9.0% vs 8.0%; adjusted odds ratio (OR): 1.22 (95% CI: 1.20-1.23); adjusted risk difference (aRD): 1.3% (95% CI: 1.2%-1.4%)) and a slightly lower rate of complications (10.9% vs 13.0%; aOR: 0.83 (95% CI: 0.82-0.84); aRD: -1.3% (95% CI: -1.3% to -1.3%)). No notable rural-urban differences were observed in MACE and disability at discharge. Patients in rural hospitals demonstrated suboptimal management measures and had higher rates of in-hospital death/DAMA compared to those in urban hospitals. Prioritizing the allocation of health resources to rural hospitals is essential to improve healthcare quality and outcomes. The data supporting the findings of this study are available from the corresponding author upon reasonable request.

Successful nonsurgical therapeutic management in a case of early mechanical aortic prosthetic thrombosis and coronary embolism after a modified Bentall procedure.

Prosthetic valve thrombosis, although rare, is a life-threatening complication of valve replacement surgery. The authors present an atypical case of a modified Bentall procedure with the CarboSeal Valsalva™ conduit complicated by an early mechanical prosthetic aortic valve thrombosis and coronary embolism. The patient was successfully treated with an emergency percutaneous coronary angioplasty and intracoronary thrombus aspiration of the left anterior descending artery, followed by a systemic 10mg bolus of tissue plasminogen activator followed by ultraslow (25 h) infusion of low-dose (25mg), while supported with venoarterial extracorporeal membrane oxygenation.

SARS-CoV-2 Spike Protein Exacerbates Thromboembolic Cerebrovascular Complications in Humanized ACE2 Mouse Model.

COVID-19 increases the risk for acute ischemic stroke, yet the molecular mechanisms are unclear and remain unresolved medical challenges. We hypothesize that the SARS-CoV-2 spike protein exacerbates stroke and cerebrovascular complications by increasing coagulation and decreasing fibrinolysis by disrupting the renin-angiotensin-aldosterone system (RAAS). A thromboembolic model was induced in humanized ACE2 knock-in mice after one week of SARS-CoV-2 spike protein injection. hACE2 mice were treated with Losartan, an angiotensin receptor (AT1R) blocker, immediately after spike protein injection. Cerebral blood flow and infarct size were compared between groups. Vascular-contributes to cognitive impairments and dementia was assessed using a Novel object recognition test. Tissue factor-III and plasminogen activator inhibitor-1 were measured using immunoblotting to assess coagulation and fibrinolysis. Human brain microvascular endothelial cells (HBMEC) were exposed to hypoxia with/without SARS-CoV-2 spike protein to mimic ischemic conditions and assessed for inflammation, RAAS balance, coagulation, and fibrinolysis. Our results showed that the SARS-CoV-2 spike protein caused an imbalance in the RAAS that increased the inflammatory signal and decreased the RAAS protective arm. SARS-CoV-2 spike protein increased coagulation and decreased fibrinolysis when coincident with ischemic insult, which was accompanied by a decrease in cerebral blood flow, an increase in neuronal death, and a decline in cognitive function. Losartan treatment restored RAAS balance and reduced spike protein-induced effects. SARS-CoV-2 spike protein exacerbates inflammation and hypercoagulation, leading to increased neurovascular damage and cognitive dysfunction. However, the AT1R blocker, Losartan, restored the RAAS balance and reduced COVID-19-induced thromboembolic cerebrovascular complications.

Visual and anatomical outcomes following vitrectomy with subretinal tPA injection in patients with submacular haemorrhages secondary to wet AMD

Purpose: Submacular haemorrhages (SMHs) are most commonly associated with wet age-related macular degeneration (AMD) and their size and duration are strong prognostic factors for visual outcome. The aim of this audit was to evaluate outcomes of direct injection of submacular tissue plasminogen activator (t-PA) into these lesions during pars plana vitrectomy (PPV). Methods: All patients presenting to the Mater Misericordiae Hospital from January 2017 to December 2019 with large SMHs secondary to wet AMD who underwent this treatment were included for review. All ten patients underwent complete PPV, injection of 0.2ml (50µg) subretinal t-PA and air tamponade. Pre-operative and post-operative evaluations included visual acuity testing (VA), optical coherence tomography (OCT) and slit lamp examination. Results: Eight patients (80%) showed improvement of their VA, with 4 patients achieving a VA of ≤0.4 LogMAR (20/50). Six patients had a total clearing of the macular haemorrhage, with a further 2 having sub-total clearance. One patient subsequently developed a retinal detachment requiring oil tamponade. Conclusions: SMH secondary to wet AMD is a sight threatening event with a varied prognosis but in most cases, vitrectomy with subretinal t-PA injection results in improved anatomical and visual outcomes.

Evaluating the Role of Silymarin in Coordinating the Relationship between Inflammation and Thrombosis by Affecting Endothelial Cells

Background: A widespread crosstalk between inflammation and coagulation has been shown in numerous studies. This suggests that coagulation can trigger an inflammatory response which ultimately leads to coagulation activation. Previous research has shown that polyphenols can affect blood pressure and endothelial dysfunction, resulting in reduced risk of cardiovascular diseases. This study aimed to investigate whether Silymarin, a flavonolignans, could play a role in the interaction between inflammation and coagulation by influencing endothelial cells. Materials and Methods: In this experimental study, human umbilical vein endothelial cells (HUVECs) were seeded with and without various concentrations of silymarin. In vivo, treatment with silymarin was also carried out. Coagulative and fibrinolytic factors, including Von Willebrand factor (VWF) and Factor VIII (FVIII), tissue plasminogen activator-1 (TPA-1), and inflammatory factors, including interleukin 8 (IL-8) and tumor necrosis factor-alpha (TNF-α), were evaluated by flow cytometry, Real-Time Polymerase Chain Reaction (qPCR), Enzyme-Linked Immunosorbent Assay (ELISA) and Immunocytochemistry (ICC). Results: Silymarin increased the gene expression, release, and storage of VWF while diminishing the gene expression, release, and storage of TPA-1 (P ˂ 0.05). The activity of FVIII was dramatically increased, and IL-8 and TNF-α levels were augmented. The in vivo study also indicated an elevated plasma level of VWF and IL-8 by silymarin administration. Conclusion: The results showed that, although silymarin reduces inflammatory factors, it can affect coagulation factors by increasing the levels of VWF and FVIII activity and inhibiting TPA-1 production, thereby making thrombosis probable. Consequently, it is advisable to prescribe this medication with caution for individuals who are susceptible to thrombotic events.

Prognostic Value of Fibrosis-4 in Acute Ischemic Stroke Patients Undergoing Intravenous Thrombolysis.

Although recombinant tissue plasminogen activator (rt-PA) treatment is efficient in patients with acute ischemic stroke (AIS), a significant percentage of patients who received rt-PA intravenous thrombolysis (IVT) do not achieve a good prognosis. Therefore, the factors that affect the poor prognosis of patients with IVT are needed. The Fibrosis-4 (FIB-4) index has been used as a liver fibrosis biomarker. We aimed to investigate the relationship between the FIB-4 index and functional outcomes in patients with AIS receiving IVT. This study prospectively included consecutive patients with AIS receiving IVT between April 2015 and May 2022. We collected clinical and laboratory data and calculated the FIB-4 index. Clinical outcome was poor functional outcome (mRS ≥3) at 3 months after IVT. Multivariate logistic regression analysis was used to analyze the association between FIB-4 and outcome. We explored the interactive effect of FIB-4 and dyslipidemia on poor outcomes, and subgroup analysis was performed. Furthermore, an individualized prediction model based on the FIB-4 for functional outcome was established in the dyslipidemia group. A total of 1135 patients were included, and 41.50% had poor 3-month outcomes. After adjusted by other variants that P value <0.05 in univariable analysis, FIB-4 was independently associated with poor outcomes (OR=1.420; 95% CI: 1.113-1.812; P=0.004). There was a significant interaction between FIB-4 and dyslipidemia on poor outcome (P=0.036), and the independent association between FIB-4 and poor outcome was maintained in the dyslipidemia subgroup (OR=1.646; 95% CI: 1.228-2.206; P=0.001). Furthermore, in the dyslipidemia group, the FIB-4-based prediction model had good predictive value (the AUC of the training and validation sets were 0.767 and 0.708, respectively), good calibration (P-values for the Hosmer-Lemeshow test >0.05), and clinical usefulness. FIB-4 is an independent risk factor for poor outcomes in IVT patients with dyslipidemia, which can be used as a simple predictor of their prognosis.