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Microvascular Research Nov 2021Several studies have reported that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can directly infect endothelial cells, and endothelial dysfunction is... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Several studies have reported that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can directly infect endothelial cells, and endothelial dysfunction is often found in severe cases of coronavirus disease 2019 (COVID-19). To better understand the prognostic values of endothelial dysfunction in COVID-19-associated coagulopathy, we conducted a systematic review and meta-analysis to assess biomarkers of endothelial cells in patients with COVID-19.
METHODS
A literature search was conducted on online databases for observational studies evaluating biomarkers of endothelial dysfunction and composite poor outcomes in COVID-19 patients.
RESULTS
A total of 1187 patients from 17 studies were included in this analysis. The estimated pooled means for von Willebrand Factor (VWF) antigen levels in COVID-19 patients was higher compared to healthy control (306.42 [95% confidence interval (CI) 291.37-321.48], p < 0.001; I:86%), with the highest VWF antigen levels was found in deceased COVID-19 patients (448.57 [95% CI 407.20-489.93], p < 0.001; I:0%). Meta-analysis showed that higher plasma levels of VWF antigen, tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor-1 antigen (PAI-1) antigen, and soluble thrombomodulin (sTM) were associated with composite poor outcome in COVID-19 patients ([standardized mean difference (SMD) 0.74 [0.33-1.16], p < 0.001; I:80.4%], [SMD 0.55 [0.19-0.92], p = 0.003; I:6.4%], [SMD 0.33 [0.04-0.62], p = 0.025; I:7.9%], and [SMD 0.55 [0.10-0.99], p = 0.015; I:23.6%], respectively).
CONCLUSION
The estimated pooled means show increased levels of VWF antigen in COVID-19 patients. Several biomarkers of endothelial dysfunction, including VFW antigen, t-PA, PAI-1, and sTM, are significantly associated with increased composite poor outcomes in patients with COVID-19.
PROSPERO REGISTRATION NUMBER
CRD42021228821.
Topics: Adult; Aged; Aged, 80 and over; Biomarkers; COVID-19; Endothelium, Vascular; Female; Humans; Male; Middle Aged; Plasminogen Activator Inhibitor 1; Predictive Value of Tests; Prognosis; Thrombomodulin; Tissue Plasminogen Activator; von Willebrand Factor
PubMed: 34273359
DOI: 10.1016/j.mvr.2021.104224 -
Neurology Aug 2021To provide a critical appraisal on the evidence from randomized controlled clinical trials (RCTs) on the utility of direct endovascular treatment (dEVT) compared to the... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To provide a critical appraisal on the evidence from randomized controlled clinical trials (RCTs) on the utility of direct endovascular treatment (dEVT) compared to the combination of endovascular treatment preceded by IV thrombolysis (bridging therapy [BT]) for patients with acute large vessel occlusion (LVO).
METHODS
Eligible RCTs were identified by searching Medline and Scopus. We calculated the corresponding odds ratios (ORs) and 95% confidence intervals (CIs) and pooled estimates using random-effects models. The primary outcome was the probability of modified Rankin scale (mRS) score of 0 to 2 at 3 months.
RESULTS
We included 3 studies comprising 1,092 patients. No difference between the dEVT and BT groups was detected for the outcomes of mRS score of 0 to 2 (OR 1.08, 95% CI 0.85-1.38; adjusted OR 1.11, 95% CI 0.76-1.63), mRS score of 0 to 1 (OR 1.10, 95% CI 0.84-1.43; adjusted OR 1.16, 95% CI 0.84-1.61), and functional improvement at 3 months (common OR 1.08, 95% CI 0.88-1.34; adjusted common OR 1.09, 95% CI 0.86-1.37). Patients receiving dEVT had significantly lower likelihood of successful recanalization before the endovascular procedure compared to those receiving BT (OR 0.37, 95% CI 0.18-0.77). Patients receiving dEVT had lower intracranial bleeding rates compared to those receiving BT (OR 0.67, 95% CI 0.49-0.92) but without a significant difference in the probability of symptomatic intracranial hemorrhage. No differences in all-cause mortality, serious adverse events, or procedural complications between the 2 groups were uncovered.
CONCLUSIONS
We detected no differences in functional outcomes of IV thrombolysis-eligible patients with an acute LVO receiving dEVT compared to BT. Because uncertainty for most endpoints remains large and the available data are not able to exclude the possibility of overall benefit or harm, further RCTs are needed.
Topics: Combined Modality Therapy; Endovascular Procedures; Fibrinolytic Agents; Humans; Ischemic Stroke; Outcome Assessment, Health Care; Randomized Controlled Trials as Topic; Tissue Plasminogen Activator
PubMed: 34144996
DOI: 10.1212/WNL.0000000000012390 -
The Cochrane Database of Systematic... Jun 2021Most disabling strokes are due to a blockage of a large artery in the brain by a blood clot. Prompt removal of the clot with intra-arterial thrombolytic drugs or... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Most disabling strokes are due to a blockage of a large artery in the brain by a blood clot. Prompt removal of the clot with intra-arterial thrombolytic drugs or mechanical devices, or both, can restore blood flow before major brain damage has occurred, leading to improved recovery. However, these so-called endovascular interventions can cause bleeding in the brain. This is a review of randomised controlled trials of endovascular thrombectomy or intra-arterial thrombolysis, or both, for acute ischaemic stroke.
OBJECTIVES
To assess whether endovascular thrombectomy or intra-arterial interventions, or both, plus medical treatment are superior to medical treatment alone in people with acute ischaemic stroke.
SEARCH METHODS
We searched the Trials Registers of the Cochrane Stroke Group and Cochrane Vascular Group (last searched 1 September 2020), CENTRAL (the Cochrane Library, 1 September 2020), MEDLINE (May 2010 to 1 September 2020), and Embase (May 2010 to 1 September 2020). We also searched trials registers, screened reference lists, and contacted researchers.
SELECTION CRITERIA
Randomised controlled trials (RCTs) of any endovascular intervention plus medical treatment compared with medical treatment alone in people with definite ischaemic stroke.
DATA COLLECTION AND ANALYSIS
Two review authors (MBR and MJ) applied the inclusion criteria, extracted data, and assessed trial quality. Two review authors (MBR and HL) assessed risk of bias, and the certainty of the evidence using GRADE. We obtained both published and unpublished data if available. Our primary outcome was favourable functional outcome at the end of the scheduled follow-up period, defined as a modified Rankin Scale score of 0 to 2. Eighteen trials (i.e. all but one included trial) reported their outcome at 90 days. Secondary outcomes were death from all causes at in the acute phase and by the end of follow-up, symptomatic intracranial haemorrhage in the acute phase and by the end of follow-up, neurological status at the end of follow-up, and degree of recanalisation.
MAIN RESULTS
We included 19 studies with a total of 3793 participants. The majority of participants had large artery occlusion in the anterior circulation, and were treated within six hours of symptom onset with endovascular thrombectomy. Treatment increased the chance of achieving a good functional outcome, defined as a modified Rankin Scale score of 0 to 2: risk ratio (RR) 1.50 (95% confidence interval (CI) 1.37 to 1.63; 3715 participants, 18 RCTs; high-certainty evidence). Treatment also reduced the risk of death at end of follow-up: RR 0.85 (95% CI 0.75 to 0.97; 3793 participants, 19 RCTs; high-certainty evidence) without increasing the risk of symptomatic intracranial haemorrhage in the acute phase: RR 1.46 (95% CI 0.91 to 2.36; 1559 participants, 6 RCTs; high-certainty evidence) or by end of follow-up: RR 1.05 (95% CI 0.72 to 1.52; 1752 participants, 10 RCTs; high-certainty evidence); however, the wide confidence intervals preclude any firm conclusion. Neurological recovery to National Institutes of Health Stroke Scale (NIHSS) score 0 to 1 and degree of recanalisation rates were better in the treatment group: RR 2.03 (95% CI 1.21 to 3.40; 334 participants, 3 RCTs; high-certainty evidence) and RR 3.11 (95% CI 2.18 to 4.42; 268 participants, 3 RCTs; high-certainty evidence), respectively.
AUTHORS' CONCLUSIONS
In individuals with acute ischaemic stroke due to large artery occlusion in the anterior circulation, endovascular thrombectomy can increase the chance of survival with a good functional outcome without increasing the risk of intracerebral haemorrhage or death.
Topics: Aged; Bias; Cause of Death; Female; Fibrinolytic Agents; Humans; Infarction, Middle Cerebral Artery; Intracranial Hemorrhages; Ischemic Stroke; Male; Mechanical Thrombolysis; Middle Aged; Randomized Controlled Trials as Topic; Thrombolytic Therapy; Urokinase-Type Plasminogen Activator
PubMed: 34125952
DOI: 10.1002/14651858.CD007574.pub3 -
The American Journal of Emergency... May 2022
Meta-Analysis
Topics: Brain Ischemia; Fibrinolytic Agents; Humans; Stroke; Tenecteplase; Thrombolytic Therapy; Tissue Plasminogen Activator; Treatment Outcome
PubMed: 34116894
DOI: 10.1016/j.ajem.2021.05.079 -
Frontiers in Neurology 2021The indications for mechanical thrombectomy in acute ischemic stroke continue to broaden, leading neurointerventionalists to treat vessel occlusions at increasingly...
The indications for mechanical thrombectomy in acute ischemic stroke continue to broaden, leading neurointerventionalists to treat vessel occlusions at increasingly distal locations farther in time from stroke onset. Accessing these smaller vessels raises the concern of iatrogenic subarachnoid hemorrhage (SAH) owing to increasing complexity in device navigation and retrieval. This study aims to determine the prevalence of SAH following mechanical thrombectomy, associated predictors, and resulting functional outcomes using a multicenter registry and compare this with a systematic review and meta-analysis of the literature. Data from STRATIS (The Systematic Evaluation of Patients Treated with Neurothrombectomy Devices for Acute Ischemic Stroke) registry were analyzed dichotomized by the presence or absence of SAH after thrombectomy. Only patients with 24-h post-procedural neuroimaging were included ( = 841). Multivariable logistic regression was performed to identify significant predictors of SAH. A systematic review and random-effects meta-analysis was also conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) protocol. The prevalence of post-thrombectomy SAH was 5.23% in STRATIS with 15.9% (1.84% overall) experiencing neurological decline. Distal location of vessel occlusion (OR 3.41 [95% CI: 1.75-6.63], < 0.001) and more than 3 device passes (OR 1.34 [95% CI: 1.09-1.64], = 0.01) were associated with a higher probability of SAH in contrast to a reduction with administration of intravenous tissue plasminogen activator (tPA) (OR 0.48 [95% CI: 0.26-0.89], = 0.02). There was a trend toward a higher discharge NIHSS (8.3 ± 8.7 vs. 5.3 ± 6.6, = 0.07) with a significantly reduced proportion achieving functional independence at 90 days (modified Rankin Score 0-2: 32.5% vs. 57.8%, = 0.002) in SAH patients. Pooled analysis of 10,126 patients from 6 randomized controlled trials and 64 observational studies demonstrated a prevalence of 5.85% [95% CI: 4.51-7.34%, : 85.2%]. Only location of vessel occlusion was significant for increased odds of SAH at distal sites (OR 2.89 [95% CI: 1.14, 7.35]). Iatrogenic SAH related to mechanical thrombectomy is more common with treatment of distally-situated occlusions and multiple device passes. While low in overall prevalence, its effect is not benign with fewer patients reaching post-procedural functional independence, particularly if symptomatic.
PubMed: 34113310
DOI: 10.3389/fneur.2021.663058 -
Journal of Clinical Medicine Apr 2021Infection by SARS-CoV-2 is associated with a high risk of thrombosis. The laboratory documentation of hypercoagulability and impaired fibrinolysis remains a challenge.... (Review)
Review
Infection by SARS-CoV-2 is associated with a high risk of thrombosis. The laboratory documentation of hypercoagulability and impaired fibrinolysis remains a challenge. Our aim was to assess the potential usefulness of viscoelastometric testing (VET) to predict thrombotic events in COVID-19 patients according to the literature. We also (i) analyzed the impact of anticoagulation and the methods used to neutralize heparin, (ii) analyzed whether maximal clot mechanical strength brings more information than Clauss fibrinogen, and (iii) critically scrutinized the diagnosis of hypofibrinolysis. We performed a systematic search in PubMed and Scopus databases until 31st December 2020. VET methods and parameters, and patients' features and outcomes were extracted. VET was performed for 1063 patients (893 intensive care unit (ICU) and 170 non-ICU, 44 studies). There was extensive heterogeneity concerning study design, VET device used (ROTEM, TEG, Quantra and ClotPro) and reagents (with non-systematic use of heparin neutralization), timing of assay, and definition of hypercoagulable state. Notably, only 4 out of 25 studies using ROTEM reported data with heparinase (HEPTEM). The common findings were increased clot mechanical strength mainly due to excessive fibrinogen component and impaired to absent fibrinolysis, more conspicuous in the presence of an added plasminogen activator. Only 4 studies out of the 16 that addressed the point found an association of VETs with thrombotic events. So-called functional fibrinogen assessed by VETs showed a variable correlation with Clauss fibrinogen. Abnormal VET pattern, often evidenced despite standard prophylactic anticoagulation, tended to normalize after increased dosing. VET studies reported heterogeneity, and small sample sizes do not support an association between the poorly defined prothrombotic phenotype of COVID-19 and thrombotic events.
PubMed: 33923851
DOI: 10.3390/jcm10081740 -
International Wound Journal Oct 2021Livedoid vasculopathy (LV) is considered a disease of hypercoagulability. Association of LV with genetic variants is poorly characterised and large-scale genetic...
Livedoid vasculopathy (LV) is considered a disease of hypercoagulability. Association of LV with genetic variants is poorly characterised and large-scale genetic association studies have not been performed. The aim of the study was to systematically review variants in LV patients and to analyse the available clinical data. A systematic search of the literature in PubMed and Embase databases was performed to identify articles investigating genetic variation in LV patients. Thirty studies or case reports were identified that reported 265 LV patients tested for at least one out of six genetic variations. Among them, PAI-1 -675 4G/5G was the most common, accounting for 85.26% (81/95). Heterozygous 4G/5G was the major genotype. PAI-1 A844G, MTHFR C677T, and MTHFR A1298C were the second, third, and fourth most common variants in LV patients. Prothrombin G20210A and Factor V G1691A were mainly present in LV patients from Europe, North America, and South America. This review highlights the associations between LV and genetic variants. The distribution of variants may be geographically or ethnicity dependent; however, large sample case-control studies are needed to clarify associations.
Topics: Case-Control Studies; Factor V; Genotype; Homocystinuria; Humans; Methylenetetrahydrofolate Reductase (NADPH2); Prothrombin
PubMed: 33686673
DOI: 10.1111/iwj.13563 -
Frontiers in Systems Neuroscience 2020This comprehensive meta-analysis aimed to assess whether an increased homocysteine (Hcy) level is an independent predictor of unfavorable outcomes in acute ischemic...
This comprehensive meta-analysis aimed to assess whether an increased homocysteine (Hcy) level is an independent predictor of unfavorable outcomes in acute ischemic stroke (AIS) patients. A comprehensive literature search was conducted up to August 1, 2020 to collect studies reporting Hcy levels in AIS patients. We analyzed all the data using Review Manager 5.3 software. Seventeen studies with 15,636 AIS patients were selected for evaluation. A higher Hcy level was associated with a poorer survival outcome (OR 1.43, 95% CI: 1.25-1.63). Compared with the AIS group, Hcy levels were significantly lower in the healthy control patients, with an SMD of 5.11 and 95% CI (1.87-8.35). Analysis of the different subgroups of AIS demonstrated significant associations between high Hcy levels and survival outcomes only in Caucasian and Asian patients. Moreover, whereas high Hcy levels were closely associated with gender, B12 deficiency, smoking, and patients who received tissue plasminogen activator treatment, no significant difference was found between increased Hcy levels and age, drinking, hypertension, diabetes mellitus, and hyperlipidemia. In addition, the cut-off value (20.0 μmol/L) might be an optimum cut-off index for AIS patients in clinical practice. This meta-analysis reveals that the Hcy level may serve as an independent predictor for unfavorable survival outcomes in AIS patients, particularly in Caucasian and Asian AIS patients. Further studies can be conducted to clarify this relationship.
PubMed: 33643003
DOI: 10.3389/fnsys.2020.600582 -
Translational Stroke Research Jun 2021Intravenous recombinant tissue plasminogen activator (iv-rtPA) has been routinely used to treat ischemic stroke for 25 years, following large clinical trials. However,... (Meta-Analysis)
Meta-Analysis
Intravenous recombinant tissue plasminogen activator (iv-rtPA) has been routinely used to treat ischemic stroke for 25 years, following large clinical trials. However, there are few prospective studies on the efficacy and safety of this therapy in strokes attributed to cerebral small vessel disease (SVD). We evaluated functional outcome (modified Rankin scale, mRS) and symptomatic intracerebral hemorrhage (sICH) using all available data on the effects of iv-rtPA in SVD-related ischemic stroke (defined either using neuroimaging, clinical features, or both). Using fixed-effect and random-effects models, we calculated the pooled effect estimates with regard to excellent and favorable outcomes (mRS=0-1 and 0-2 respectively, at 3 months), and the rate of sICH. Twenty-three studies fulfilled the eligibility criteria, 11 of which were comparative, and there were only 3 randomized clinical trials. In adjusted analyses, there was an increased odds of excellent outcome (adjusted OR=1.53, 95% CI: 1.29-1.82, I2: 0%) or favorable outcome (adjusted OR=1.68, 95% CI: 1.31-2.15,I2: 0%) in patients who received iv-rtPA compared with placebo. Across the six studies which reported it, the incidence of sICH was higher in the treatment group (M-H RR = 8.83, 95% CI: 2.76-28.27). The pooled rate of sICH in patients with SVD administered iv-rtPA was only 0.72% (95% CI: 0.12%-1.64%). We conclude that when ischemic stroke attributed to SVD is considered separately, available data on the effects of iv-rtPA therapy are insufficient for the highest level of recommendation, but it seems to be safe. Although further therapeutic trials in SVD-related ischemic stroke appear to be justified, our findings should not prevent its continued use for this group of patients in clinical practice.
Topics: Brain Ischemia; Fibrinolytic Agents; Humans; Ischemic Stroke; Prospective Studies; Stroke; Thrombolytic Therapy; Tissue Plasminogen Activator; Treatment Outcome
PubMed: 33641037
DOI: 10.1007/s12975-021-00890-9 -
Frontiers in Pediatrics 2021Worldwide neonatal hypoxic-ischemic encephalopathy (HIE) is a common cause of mortality and neurologic disability, despite the implementation of therapeutic hypothermia...
Worldwide neonatal hypoxic-ischemic encephalopathy (HIE) is a common cause of mortality and neurologic disability, despite the implementation of therapeutic hypothermia treatment. Advances toward new neuroprotective interventions have been limited by incomplete knowledge about secondary injurious processes such as cerebral hyperperfusion commonly observed during the first 1-5 days after asphyxia. Cerebral hyperperfusion is correlated with adverse neurodevelopmental outcome and it is a process that remains poorly understood. In order to provide an overview of the existing knowledge on the pathophysiology and highlight the gaps in current understanding of cerebral hyperperfusion in term animals and neonates with HIE, we performed a systematic research. We included papers scoping for study design, population, number of participants, study technique and relevant findings. Methodological quality was assessed using the checklist for cohort studies from The Joanna Briggs Institute. Out of 2,690 results, 34 studies were included in the final review-all prospective cohort studies. There were 14 studies of high, 17 moderate and 3 of low methodological quality. Data from the literature were analyzed in two main subjects: (1) Hemodynamic Changes subdivided into macro- and microscopic hemodynamic changes, and (2) Endogenous Pathways which was subdivided into N-methyl-D-aspartate/Mitogen activated protein kinase (NDMA/MAPK), Nitric Oxide (NO), prostanoids and other endogenous studies. Cerebral hyperperfusion in term neonates with HIE was found to be present 10-30 min after the hypoxic-ischemic event and was still present around day 10 and up to 1 month after birth. Cerebral hyperperfusion was also characterized by angiogenesis and cerebral vasodilation. Additionally, cerebral vasodilation was mediated by endogenous pathways such as MAPK through urokinase Plasminogen Activator (uPA), by neuronal NO synthase following NMDA and by prostanoid synthesis. Future research should elucidate the precise role of NMDA, MAPK and prostanoids in cerebral hyperperfusion. Moreover, research should focus on possible interventions and the effect of hypothermia on hyperperfusion. These findings should be taken into account simultaneously with brain imagining techniques, becoming a valuable asset in assessing the impact in neurodevelopmental outcome.
PubMed: 33604320
DOI: 10.3389/fped.2021.631258