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Duan ZW, Li ZN, Zhai YJ, Liu TF, Zhang CC, Hu T, Wei XE, Rong LQ, Liu HY. Effects of glycemic indicators on early neurological outcomes in patients with acute ischemic stroke treated with intravenous thrombolysis. World J Diabetes 2025; 16:94491. [PMID: 40093278 PMCID: PMC11885979 DOI: 10.4239/wjd.v16.i3.94491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 10/01/2024] [Accepted: 12/09/2024] [Indexed: 01/21/2025] Open
Abstract
BACKGROUND Stress hyperglycemia (SH) is a common phenomenon that is present in about 50% of patients with acute ischemic stroke (AIS). It is thought to be a main risk factor for poor functional outcome among patients with AIS undergoing intravenous thrombolysis (IVT). AIM To investigate the predictive value of glycemic indicators for early neurological outcomes (ENOs) in patients with AIS treated with IVT. METHODS We retrospectively reviewed a prospectively collected database of patients with AIS who underwent IVT at the Department of Neurology, Second Affiliated Hospital of Xuzhou Medical University, between January 2017 and June 2022. ENO included early neurological improvement (ENI) and early neurological deterioration (END), defined as a decrease or increase in the National Institutes of Health Stroke Scale (NIHSS) score between baseline and 24 hours after IVT. We analyzed the associations between glycemic indicators [including admission hyperglycemia (AH), fasting blood glucose (FBG), and SH ratio (SHR)] and ENO in all patients and in subgroups stratified by diabetes mellitus (DM). RESULTS A total of 819 patients with AIS treated with IVT were included. Among these, AH was observed in 329 patients (40.2%). Compared with patients without AH, those with AH were more likely to have a higher prevalence of DM (P < 0.001) and hypertension (P = 0.031) and presented with higher admission NIHSS scores (P < 0.001). During the first 24 hours after IVT, END occurred in 208 patients (25.4%) and ENI occurred in 156 patients (19.0%). Multivariate mixed logistic regression analyses indicated that END was independently associated with AH [odds ratio (OR): 1.744, 95% confidence interval (CI): 1.236-2.463; P = 0.002]. Subjects were classified into four groups representing quartiles. Compared with Q1, patients in the higher quartiles of SHR (Q2: OR: 2.306, 95%CI: 1.342-3.960; P = 0.002) (Q3: OR: 2.284, 95%CI: 1.346-3.876; P = 0.002) (Q4: OR: 3.486, 95%CI: 2.088-5.820; P = 0.001) and FBG (Q3: OR: 1.746, 95%CI: 1.045-2.917; P = 0.033) (Q4: OR: 2.436, 95%CI: 1.476-4.022; P = 0.001) had a significantly higher risk of END in the overall population. However, none of the glycemic indicators were found to be associated with ENI in patients with or without DM. CONCLUSION Our study demonstrated that glycemic indicators in patients with stroke treated with IVT were associated with the presence of END rather than ENI during the first 24 hours after admission.
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Affiliation(s)
- Zuo-Wei Duan
- Department of Neurology, The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou 221006, Jiangsu Province, China
| | - Zhi-Ning Li
- Department of Neurology, The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou 221006, Jiangsu Province, China
| | - Yu-Jia Zhai
- Department of Neurology, The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou 221006, Jiangsu Province, China
| | - Teng-Fei Liu
- Department of Neurology, The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou 221006, Jiangsu Province, China
| | - Cui-Cui Zhang
- Department of Neurology, The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou 221006, Jiangsu Province, China
| | - Ting Hu
- Department of Neurology, Medical School of Nanjing University, Xuzhou 221006, Jiangsu Province, China
| | - Xiu-E Wei
- Department of Neurology, The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou 221006, Jiangsu Province, China
| | - Liang-Qun Rong
- Department of Neurology, The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou 221006, Jiangsu Province, China
| | - Hai-Yan Liu
- Department of Neurology, The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou 221006, Jiangsu Province, China
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Marta-Enguita J, Machado FJD, Orbe J, Muñoz R. Thrombus composition and its implication in ischemic stroke assessment and revascularization treatments. Neurologia 2025; 40:77-88. [PMID: 39716574 DOI: 10.1016/j.nrleng.2024.12.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 11/01/2022] [Indexed: 12/25/2024] Open
Abstract
INTRODUCTION Since mechanical thrombectomy has allowed ischaemic stroke thrombus retrieval, the exhaustive study of this material has enabled better understanding of the potential physiopathological processes involved in thrombus formation. DEVELOPMENT Thrombotic pathways involved in the different vascular beds share common mechanisms, causing difficulties in the identification of specific patterns associated with stroke aetiology. However, other factors such as clot formation time, associated inflammatory status, or activation of additional immune and coagulation pathways (neutrophil extracellular trap [NET] delivery, platelet aggregation, endothelial activation, and von Willebrand Factor release) have been described as determinants in thrombus characteristics. Thus, variable proportions of fibrin-/platelet-rich and erythrocyte-rich areas are closely interrelated within the thrombus, frequently associated with a protective outer shell with high concentrations of fibrin, NETs, and von Willebrand Factor. The presence of these components, as well as their distribution and interrelationships, have been shown to have effects on the thrombus' resistance to revascularisation treatments. Understanding of these pathways has enabled the development of adjuvant therapies capable of enhancing current fibrinolytic drugs and/or increasing the efficacy of endovascular treatments. CONCLUSION Understanding of thrombus components and mechanisms involved in thrombus formation represent a potential pathway for the development of ischaemic stroke therapeutics with promising perspectives.
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Affiliation(s)
- Juan Marta-Enguita
- Servicio de Neurología, Hospital Universitario Navarra, Pamplona, Navarra, Spain; Servicio de Neurología, Hospital Universitario Donostia, San Sebastián, Guipúzcoa, Spain; Laboratorio Aterotrombosis, CIMA-Universidad de Navarra, IdiSNA, Pamplona, Navarra, Spain; RICORS-ICTUS, ISCIII, Madrid, Spain.
| | - Florencio J D Machado
- Laboratorio Aterotrombosis, CIMA-Universidad de Navarra, IdiSNA, Pamplona, Navarra, Spain
| | - Josune Orbe
- Laboratorio Aterotrombosis, CIMA-Universidad de Navarra, IdiSNA, Pamplona, Navarra, Spain; RICORS-ICTUS, ISCIII, Madrid, Spain
| | - Roberto Muñoz
- Servicio de Neurología, Hospital Universitario Navarra, Pamplona, Navarra, Spain; RICORS-ICTUS, ISCIII, Madrid, Spain
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Riddell A, Flynn A, Bergugnat H, Dowsett L, Miller A. SDMA as a marker and mediator in cerebrovascular disease. Clin Sci (Lond) 2024; 138:1305-1323. [PMID: 39391895 PMCID: PMC11479986 DOI: 10.1042/cs20241021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Revised: 09/11/2024] [Accepted: 09/16/2024] [Indexed: 10/12/2024]
Abstract
Symmetric dimethylarginine (SDMA) is a methylated derivative of arginine, generated by all cells as a by-product of cellular metabolism and eliminated via the kidney. For many years SDMA has been considered inert and of little biological significance. However, a growing body of evidence now suggests this view is outdated and that circulating SDMA levels may, in fact, be intricately linked to endothelial dysfunction and vascular risk. In this review, we specifically examine SDMA within the context of cerebrovascular disease, with a particular focus on ischaemic stroke. We first discuss pre-clinical evidence supporting the notion that SDMA has effects on nitric oxide signalling, inflammation, oxidative stress, and HDL function. We then appraise the most recent clinical studies that explore the relationship between circulating SDMA and cerebrovascular risk factors, such as chronic kidney disease, hypertension, atrial fibrillation, and atherosclerosis, exploring whether any associations may arise due to the existence of shared risk factors. Finally, we consider the evidence that elevated circulating SDMA is linked to poor outcomes following ischaemic and haemorrhagic stroke. We draw upon pre-clinical insights into SDMA function to speculate how SDMA may not only be a marker of cerebrovascular disease but could also directly influence cerebrovascular pathology, and we highlight the pressing need for more mechanistic pre-clinical studies alongside adequately powered, longitudinal clinical studies to fully evaluate SDMA as a marker/mediator of disease.
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Affiliation(s)
- Alexandra Riddell
- British Heart Foundation Glasgow Cardiovascular Research Centre, School of Cardiovascular and Metabolic Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Arun Flynn
- British Heart Foundation Glasgow Cardiovascular Research Centre, School of Cardiovascular and Metabolic Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Hugo Bergugnat
- British Heart Foundation Glasgow Cardiovascular Research Centre, School of Cardiovascular and Metabolic Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Laura B. Dowsett
- British Heart Foundation Glasgow Cardiovascular Research Centre, School of Cardiovascular and Metabolic Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Alyson A. Miller
- British Heart Foundation Glasgow Cardiovascular Research Centre, School of Cardiovascular and Metabolic Sciences, University of Glasgow, Glasgow, United Kingdom
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Ceulemans A, Spronk HMH, Ten Cate H, van Zwam WH, van Oostenbrugge RJ, Nagy M. Current and potentially novel antithrombotic treatment in acute ischemic stroke. Thromb Res 2024; 236:74-84. [PMID: 38402645 DOI: 10.1016/j.thromres.2024.02.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 01/22/2024] [Accepted: 02/12/2024] [Indexed: 02/27/2024]
Abstract
Acute ischemic stroke (AIS) is the most common type of stroke and requires immediate reperfusion. Current acute reperfusion therapies comprise the administration of intravenous thrombolysis and/or endovascular thrombectomy. Although these acute reperfusion therapies are increasingly successful, optimized secondary antithrombotic treatment remains warranted, specifically to reduce the risk of major bleeding complications. In the development of AIS, coagulation and platelet activation play crucial roles by driving occlusive clot formation. Recent studies implicated that the intrinsic route of coagulation plays a more prominent role in this development, however, this is not fully understood yet. Next to the acute treatments, antithrombotic therapy, consisting of anticoagulants and/or antiplatelet therapy, is successfully used for primary and secondary prevention of AIS but at the cost of increased bleeding complications. Therefore, better understanding the interplay between the different pathways involved in the pathophysiology of AIS might provide new insights that could lead to novel treatment strategies. This narrative review focuses on the processes of platelet activation and coagulation in AIS, and the most common antithrombotic agents in primary and secondary prevention of AIS. Furthermore, we provide an overview of promising novel antithrombotic agents that could be used to improve in both acute treatment and stroke prevention.
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Affiliation(s)
- Angelique Ceulemans
- Department of Neurology, Maastricht University Medical Center+, Maastricht, the Netherlands; School for Cardiovascular Diseases (CARIM), Maastricht University, Maastricht, the Netherlands
| | - Henri M H Spronk
- School for Cardiovascular Diseases (CARIM), Maastricht University, Maastricht, the Netherlands; Department of Biochemistry, Maastricht University Medical Center+, Maastricht, the Netherlands; Thrombosis Expertise Center, Heart & Vascular Center, Maastricht University Medical Center+, Maastricht, the Netherlands
| | - Hugo Ten Cate
- School for Cardiovascular Diseases (CARIM), Maastricht University, Maastricht, the Netherlands; Department of internal medicine, Maastricht University Medical Center+, Maastricht, the Netherlands; Thrombosis Expertise Center, Heart & Vascular Center, Maastricht University Medical Center+, Maastricht, the Netherlands
| | - Wim H van Zwam
- School for Cardiovascular Diseases (CARIM), Maastricht University, Maastricht, the Netherlands; Department of Radiology and Nuclear Medicine, Maastricht University Medical Center+, Maastricht, the Netherlands
| | - Robert J van Oostenbrugge
- Department of Neurology, Maastricht University Medical Center+, Maastricht, the Netherlands; School for Cardiovascular Diseases (CARIM), Maastricht University, Maastricht, the Netherlands
| | - Magdolna Nagy
- School for Cardiovascular Diseases (CARIM), Maastricht University, Maastricht, the Netherlands; Department of Biochemistry, Maastricht University Medical Center+, Maastricht, the Netherlands; Thrombosis Expertise Center, Heart & Vascular Center, Maastricht University Medical Center+, Maastricht, the Netherlands.
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Grosse GM, Leotescu A, Sieweke JT, Schneppenheim S, Budde U, Ziegler NL, Biber S, Gabriel MM, Ernst J, Schuppner R, Lichtinghagen R, Bavendiek U, Widder J, Weissenborn K. ADAMTS-13 activity in stroke of known and unknown cause: Relation to vascular risk factor burden. Front Neurol 2023; 13:1045478. [PMID: 36703637 PMCID: PMC9871749 DOI: 10.3389/fneur.2022.1045478] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Accepted: 12/13/2022] [Indexed: 01/11/2023] Open
Abstract
Background The identification of the underlying mechanism in ischemic stroke has important implications for secondary prevention. A disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13 (ADAMTS-13) has antithrombotic properties and was repeatedly implicated in the pathophysiology of stroke. In this study, we, therefore, aimed to investigate whether ADAMTS-13 is associated with stroke etiology and the burden of vascular risk factors. Methods We determined ADAMTS-13 activity in two prospectively recruited stroke cohorts in the long-term course after the event. Cohort 1 (n = 88) consisted of patients who suffered a stroke due to embolic stroke of undetermined source (ESUS), cardioembolic stroke due to atrial fibrillation (AF), large-artery atherosclerosis, or small vessel disease. In cohort 2, patients with cryptogenic stroke and patent foramen ovale (PFO) scheduled for PFO closure (n = 38) were enrolled. As measures of vascular risk factor burden, the CHA2DS2VASC score, the Essen Stroke Risk Score (ESRS), and the Risk of Paradoxical Embolism (RoPE) score were calculated, as appropriate. Results ADAMTS-13 activity was lower in patients with AF-related stroke compared to patients with ESUS (p = 0.0227), which was, however, due to confounding by vascular risk factors. ADAMTS-13 activity inversely correlated with the ESRS (r = -0.452, p < 0.001) and CHA2DS2VASC (r = -0.375, p < 0.001) in cohort 1. In accordance with these findings, we found a positive correlation between ADAMTS-13 activity and the RoPE score in cohort 2 (r = 0.413, p = 0.010). Conclusion ADAMTS-13 activity is inversely correlated with the number of vascular risk factors across different stroke etiologies. Further study is warranted to establish ADAMTS-13 as a mediator of cerebrovascular risk.
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Affiliation(s)
- Gerrit M. Grosse
- 1Department of Neurology, Hannover Medical School, Hannover, Germany,*Correspondence: Gerrit M. Grosse ✉
| | - Andrei Leotescu
- 1Department of Neurology, Hannover Medical School, Hannover, Germany
| | | | | | - Ulrich Budde
- 3Medilys Laboratory, Asklepios Klinik Altona, Hamburg, Germany
| | - Nora L. Ziegler
- 1Department of Neurology, Hannover Medical School, Hannover, Germany
| | - Saskia Biber
- 1Department of Neurology, Hannover Medical School, Hannover, Germany
| | - Maria M. Gabriel
- 1Department of Neurology, Hannover Medical School, Hannover, Germany
| | - Johanna Ernst
- 1Department of Neurology, Hannover Medical School, Hannover, Germany
| | - Ramona Schuppner
- 1Department of Neurology, Hannover Medical School, Hannover, Germany
| | - Ralf Lichtinghagen
- 4Institute of Clinical Chemistry, Hannover Medical School, Hannover, Germany
| | - Udo Bavendiek
- 2Department of Cardiology, Hannover Medical School, Hannover, Germany
| | - Julian Widder
- 2Department of Cardiology, Hannover Medical School, Hannover, Germany,5Medizinische Klinik VI, Kardiologie, Angiologie und Internistische Intensivmedizin, Städtisches Klinikum Karlsruhe, Karlsruhe, Germany
| | - Karin Weissenborn
- 1Department of Neurology, Hannover Medical School, Hannover, Germany
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Cui Y, Wang XH, Zhao Y, Chen SY, Sheng BY, Wang LH, Chen HS. Association of serum biomarkers with early neurologic improvement after intravenous thrombolysis in ischemic stroke. PLoS One 2022; 17:e0277020. [PMID: 36315566 PMCID: PMC9621449 DOI: 10.1371/journal.pone.0277020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Accepted: 10/17/2022] [Indexed: 11/15/2022] Open
Abstract
BACKGROUND Early neurologic improvement (ENI) after intravenous thrombolysis is associated with favorable outcome, but associated serum biomarkers were not fully determined. We aimed to investigate the issue based on a prospective cohort. METHODS In INTRECIS study, five centers were designed to consecutively collect blood sample from enrolled patients. The patients with ENI and without ENI were matched by propensity score matching with a ratio of 1:1. Preset 49 biomarkers were measured through microarray analysis. Enrichment of gene ontology and pathway, and protein-protein interaction network were analyzed in the identified biomarkers. RESULTS Of 358 patients, 19 patients with ENI were assigned to ENI group, while 19 matched patients without ENI were assigned to Non ENI group. A total of nine biomarkers were found different between two groups, in which serum levels of chemokine (C-C motif) ligand (CCL)-23, chemokine (C-X-C motif) ligand (CXCL)-12, insulin-like growth factor binding protein (IGFBP)-6, interleukin (IL)-5, lymphatic vessel endothelial hyaluronan receptor (LYVE)-1, plasminogen activator inhibitor (PAI)-1, platelet-derived growth factor (PDGF)-AA, suppression of tumorigenicity (ST)-2, and tumor necrosis factor (TNF)-α were higher in the ENI group, compared with those in the Non ENI group. CONCLUSIONS We found that serum levels of CCL-23, CXCL-12, IGFBP-6, IL-5, LYVE-1, PAI-1, PDGF-AA, ST-2, and TNF-α at admission were associated with post-thrombolytic ENI in stroke. The role of biomarkers warrants further investigation. TRIAL REGISTRATION Clinical Trial Registration: https://www.clinicaltrials.gov; identifier: NCT02854592.
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Affiliation(s)
- Yu Cui
- Department of Neurology, General Hospital of Northern Theatre Command, Shenyang, China
| | - Xin-Hong Wang
- Department of Neurology, General Hospital of Northern Theatre Command, Shenyang, China
| | - Yong Zhao
- Department of Neurology, Haicheng Hospital of Traditional Chinese Medicine, Haicheng, China
| | - Shao-Yuan Chen
- Department of Neurology, Chinese People’s Liberation Army 321 Hospital, Baicheng, China
| | - Bao-Ying Sheng
- Department of Neurology, Jiamusi University First Affiliated Hospital, Jiamusi, China
| | - Li-Hua Wang
- Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Hui-Sheng Chen
- Department of Neurology, General Hospital of Northern Theatre Command, Shenyang, China
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Meta-Analysis of Predictive Role of Early Neurological Deterioration after Intravenous Thrombolysis. Emerg Med Int 2022; 2022:2894426. [PMID: 35912390 PMCID: PMC9337960 DOI: 10.1155/2022/2894426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 05/25/2022] [Accepted: 06/02/2022] [Indexed: 11/17/2022] Open
Abstract
With the popularization of intravenous thrombolysis, more and more people use intravenous thrombolysis to treat related diseases, but problems also arise. There are still a considerable number of patients with early disease after thrombolytic therapy not only not significantly improving, but also progressing, that is, early neurological deterioration (END). In view of this problem, the prediction of END after intravenous thrombolysis becomes very important. With the development of medical technology, research on the prediction of END after intravenous thrombolysis has gradually been carried out. Effective prediction is of great significance for the prevention and treatment of END after intravenous thrombolysis. This article aimed to carry out a meta-analysis of the predictive role of END after intravenous thrombolysis. Through an informed analysis of all studies of this type in this field, this article determines a method for predicting END after intravenous thrombolysis. The actual effect of its role is revealed in this paper, and its purpose is to promote the development of this field. This article addresses the same type of study on the predictive role of neurological deterioration after intravenous thrombolysis. The article performs test and meta-analysis of its role by conditionally searching for literature studies. It is explained using the relevant theoretical formulas. The analysis results show that the prediction of END after intravenous thrombolysis in this paper can effectively help make a preliminary judgment on the possible later neurological deterioration. Although there is an error between the predicted curve and the actual curve, the difference between the two is between 1% and 5%. It can basically effectively predict the occurrence of END. Therefore, the prediction of END after intravenous thrombolysis has a very large preventive effect on the END after intravenous thrombolysis.
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Grosse GM, Werlein C, Blume N, Abu-Fares O, Götz F, Gabriel MM, Ernst J, Leotescu A, Worthmann H, Kühnel MP, Jonigk DD, Falk CS, Weissenborn K, Schuppner R. Circulating Cytokines and Growth Factors in Acute Cerebral Large Vessel Occlusion-Association with Success of Endovascular Treatment. Thromb Haemost 2021; 122:623-632. [PMID: 34225367 PMCID: PMC9142215 DOI: 10.1055/a-1544-5431] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Mechanical thrombectomy (MT) is a highly efficient treatment in patients with acute ischemic stroke due to large vessel occlusion (LVO). However, in a relevant proportion of LVO, no sufficient recanalization can be achieved. The composition of cerebral thrombi is highly heterogeneous and may constitute a relevant factor for insufficient reperfusion. We hypothesized that circulating cytokines and growth factors involved in thromboinflammation and platelet activation may be associated with reperfusion status and thrombus composition in patients undergoing MT. An according biomarker panel was measured in plasma specimens taken prior to MT and at a 7-day follow-up. The reperfusion status was categorized into sufficient or insufficient. The composition of retrieved thrombi was histologically analyzed. Differences of baseline biomarker concentrations between insufficient and sufficient reperfusions were highest for interferon (IFN)-γ, epidermal growth factor, platelet-derived growth factor (PDGF)-AB/BB, and IFN-γ-induced protein 10 (IP-10/CXCL10). After applying correction for multiple comparisons and logistic regression analysis adjusting for stroke etiology, intravenous thrombolysis, and vascular risk factors, PDGF-AB/BB was identified as an independent predictor of reperfusion status (odds ratio: 0.403; 95% confidence interval: 0.199-0.819). Histological analysis revealed that the majority of thrombi had a mixed composition. In conclusion, this study provides the first evidence that cytokines and growth factors are potential effectors in patients undergoing MT for the treatment of acute ischemic stroke.
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Affiliation(s)
- Gerrit M. Grosse
- Department of Neurology, Hannover Medical School, Hannover, Germany,Address for correspondence Gerrit M. Grosse, MD Department of Neurology, Hannover Medical SchoolCarl-Neuberg-Str. 1, 30625 HannoverGermany
| | | | - Nicole Blume
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | - Omar Abu-Fares
- Institute of Diagnostic and Interventional Neuroradiology, Hannover Medical School, Hannover, Germany
| | - Friedrich Götz
- Institute of Diagnostic and Interventional Neuroradiology, Hannover Medical School, Hannover, Germany
| | - Maria M. Gabriel
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | - Johanna Ernst
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | - Andrei Leotescu
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | - Hans Worthmann
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | - Mark P. Kühnel
- Institute of Pathology, Hannover Medical School, Hannover, Germany,Member of the German Center for Lung Research (DZL), Biomedical Research in End-stage and Obstructive Lung Disease Hannover (BREATH), Hannover, Germany
| | - Danny D. Jonigk
- Institute of Pathology, Hannover Medical School, Hannover, Germany,Member of the German Center for Lung Research (DZL), Biomedical Research in End-stage and Obstructive Lung Disease Hannover (BREATH), Hannover, Germany
| | - Christine S. Falk
- Institute of Transplant Immunology, Hannover Medical School, Hannover, Germany
| | | | - Ramona Schuppner
- Department of Neurology, Hannover Medical School, Hannover, Germany
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Weiland J, Beez A, Westermaier T, Kunze E, Sirén AL, Lilla N. Neuroprotective Strategies in Aneurysmal Subarachnoid Hemorrhage (aSAH). Int J Mol Sci 2021; 22:5442. [PMID: 34064048 PMCID: PMC8196706 DOI: 10.3390/ijms22115442] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 04/30/2021] [Accepted: 05/18/2021] [Indexed: 12/19/2022] Open
Abstract
Aneurysmal subarachnoid hemorrhage (aSAH) remains a disease with high mortality and morbidity. Since treating vasospasm has not inevitably led to an improvement in outcome, the actual emphasis is on finding neuroprotective therapies in the early phase following aSAH to prevent secondary brain injury in the later phase of disease. Within the early phase, neuroinflammation, thromboinflammation, disturbances in brain metabolism and early neuroprotective therapies directed against delayed cerebral ischemia (DCI) came into focus. Herein, the role of neuroinflammation, thromboinflammation and metabolism in aSAH is depicted. Potential neuroprotective strategies regarding neuroinflammation target microglia activation, metalloproteases, autophagy and the pathway via Toll-like receptor 4 (TLR4), high mobility group box 1 (HMGB1), NF-κB and finally the release of cytokines like TNFα or IL-1. Following the link to thromboinflammation, potential neuroprotective therapies try to target microthrombus formation, platelets and platelet receptors as well as clot clearance and immune cell infiltration. Potential neuroprotective strategies regarding metabolism try to re-balance the mismatch of energy need and supply following aSAH, for example, in restoring fuel to the TCA cycle or bypassing distinct energy pathways. Overall, this review addresses current neuroprotective strategies in aSAH, hopefully leading to future translational therapy options to prevent secondary brain injury.
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Affiliation(s)
- Judith Weiland
- Department of Neurosurgery, University Hospital Würzburg, Josef-Schneider Str. 11, 97080 Würzburg, Germany; (A.B.); (T.W.); (E.K.); (A.-L.S.)
| | - Alexandra Beez
- Department of Neurosurgery, University Hospital Würzburg, Josef-Schneider Str. 11, 97080 Würzburg, Germany; (A.B.); (T.W.); (E.K.); (A.-L.S.)
| | - Thomas Westermaier
- Department of Neurosurgery, University Hospital Würzburg, Josef-Schneider Str. 11, 97080 Würzburg, Germany; (A.B.); (T.W.); (E.K.); (A.-L.S.)
- Department of Neurosurgery, Helios-Amper Klinikum Dachau, Krankenhausstr. 15, 85221 Dachau, Germany
| | - Ekkehard Kunze
- Department of Neurosurgery, University Hospital Würzburg, Josef-Schneider Str. 11, 97080 Würzburg, Germany; (A.B.); (T.W.); (E.K.); (A.-L.S.)
| | - Anna-Leena Sirén
- Department of Neurosurgery, University Hospital Würzburg, Josef-Schneider Str. 11, 97080 Würzburg, Germany; (A.B.); (T.W.); (E.K.); (A.-L.S.)
| | - Nadine Lilla
- Department of Neurosurgery, University Hospital Würzburg, Josef-Schneider Str. 11, 97080 Würzburg, Germany; (A.B.); (T.W.); (E.K.); (A.-L.S.)
- Department of Neurosurgery, University Hospital Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany
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Yang J, Wu Z, Long Q, Huang J, Hong T, Liu W, Lin J. Insights Into Immunothrombosis: The Interplay Among Neutrophil Extracellular Trap, von Willebrand Factor, and ADAMTS13. Front Immunol 2020; 11:610696. [PMID: 33343584 PMCID: PMC7738460 DOI: 10.3389/fimmu.2020.610696] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2020] [Accepted: 11/02/2020] [Indexed: 12/24/2022] Open
Abstract
Both neutrophil extracellular traps (NETs) and von Willebrand factor (VWF) are essential for thrombosis and inflammation. During these processes, a complex series of events, including endothelial activation, NET formation, VWF secretion, and blood cell adhesion, aggregation and activation, occurs in an ordered manner in the vasculature. The adhesive activity of VWF multimers is regulated by a specific metalloprotease ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motifs, member 13). Increasing evidence indicates that the interaction between NETs and VWF contributes to arterial and venous thrombosis as well as inflammation. Furthermore, contents released from activated neutrophils or NETs induce the reduction of ADAMTS13 activity, which may occur in both thrombotic microangiopathies (TMAs) and acute ischemic stroke (AIS). Recently, NET is considered as a driver of endothelial damage and immunothrombosis in COVID-19. In addition, the levels of VWF and ADAMTS13 can predict the mortality of COVID-19. In this review, we summarize the biological characteristics and interactions of NETs, VWF, and ADAMTS13, and discuss their roles in TMAs, AIS, and COVID-19. Targeting the NET-VWF axis may be a novel therapeutic strategy for inflammation-associated TMAs, AIS, and COVID-19.
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Affiliation(s)
- Junxian Yang
- Research Department of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.,Institute of Biomechanics/School of Bioscience and Bioengineering, South China University of Technology, Guangzhou, China
| | - Zhiwei Wu
- Research Department of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.,Institute of Biomechanics/School of Bioscience and Bioengineering, South China University of Technology, Guangzhou, China
| | - Quan Long
- Institute of Biomechanics/School of Bioscience and Bioengineering, South China University of Technology, Guangzhou, China
| | - Jiaqi Huang
- Institute of Biomechanics/School of Bioscience and Bioengineering, South China University of Technology, Guangzhou, China
| | - Tiantian Hong
- Research Department of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.,Institute of Biomechanics/School of Bioscience and Bioengineering, South China University of Technology, Guangzhou, China
| | - Wang Liu
- Institute of Biomechanics/School of Bioscience and Bioengineering, South China University of Technology, Guangzhou, China
| | - Jiangguo Lin
- Research Department of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.,Institute of Biomechanics/School of Bioscience and Bioengineering, South China University of Technology, Guangzhou, China
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Su Y, Chen X, Ye X, Sun H, Wu F, Dong Q, Cheng X, Wu D. The Value of ADAMTS13 in Predicting Clinical Outcomes in Patients With Acute Ischemic Stroke Receiving Thrombolysis. Front Neurol 2020; 11:799. [PMID: 32849241 PMCID: PMC7412597 DOI: 10.3389/fneur.2020.00799] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2020] [Accepted: 06/25/2020] [Indexed: 01/01/2023] Open
Abstract
Objective: To determine the association between baseline ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) antigen level and 90-days clinical outcome in patients with acute ischemic stroke (AIS) receiving recombinant tissue plasminogen activator (rt-PA) thrombolysis. Methods: AIS patients receiving rt-PA thrombolytic therapy from Huashan Hospital and Fifth People's Hospital of Shanghai, China in 2014–2017 were consecutively enrolled. Blood samples for ADAMTS13 tests were drawn before intravenous rt-PA administration. The primary outcome was defined as the poor functional outcome of modified Rankin Scale (mRS) >2 at 90-days follow-up. Secondary outcome was hemorrhagic transformation after rt-PA therapy. Moreover, for AIS patients with large vessel occlusion from Huashan Hospital, the association between baseline ADAMTS13 level and cerebral collateral flow was also assessed. Results: A total of 163 AIS patients (median age 66.2 years, 63.8% male) were included. Baseline ADAMTS13 level was marginally decreased in patients with 90-days mRS >2 than in those with mRS ≤ 2 (mean ± SD, 1458.4 ± 323.3 vs. 1578.3 ± 395.4 ng/mL, p = 0.046). However, no difference of ADAMTS13 level was found after adjusting for age, history of atrial fibrillation, glycemia, baseline NIHSS score and TOAST classification (p = 0.43). We found no difference in ADAMTS13 level between patients with parenchymal hemorrhage after rt-PA therapy and those without (p = 0.44). Among 66 patients with large vessel occlusion, there was also no association between ADAMTS13 level and cerebral collateral flow in multivariable analyses. Conclusion: In our cohort, blood ADAMTS13 antigen level before rt-PA therapy could not be used as an independent biomarker in predicting clinical outcomes of AIS patients at 90 days.
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Affiliation(s)
- Ya Su
- State Key Laboratory of Medical Neurobiology, Department of Neurology, National Clinical Research Centre for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Xin Chen
- Department of Neurology, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China
| | - Xiaofei Ye
- Department of Health Statistics, Second Military Medical University, Shanghai, China
| | - Haiyan Sun
- Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences, Tianjin, China
| | - Fei Wu
- State Key Laboratory of Medical Neurobiology, Department of Neurology, National Clinical Research Centre for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Qiang Dong
- State Key Laboratory of Medical Neurobiology, Department of Neurology, National Clinical Research Centre for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Xin Cheng
- State Key Laboratory of Medical Neurobiology, Department of Neurology, National Clinical Research Centre for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Danhong Wu
- Department of Neurology, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China
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12
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von Willebrand factor/ADAMTS13 ratio at presentation of acute ischemic brain injury is predictive of outcome. Blood Adv 2020; 4:398-407. [PMID: 31990334 DOI: 10.1182/bloodadvances.2019000979] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Accepted: 12/20/2019] [Indexed: 12/31/2022] Open
Abstract
Acute ischemic stroke (IS) and transient ischemic attack (TIA) are associated with raised von Willebrand factor (VWF) and decreased ADAMTS13 activity (ADAMTS13Ac). Their impact on mortality and morbidity is unclear. We conducted a prospective investigation of the VWF-ADAMTS13 axis in 292 adults (acute IS, n = 103; TIA, n = 80; controls, n = 109) serially from presentation until >6 weeks. The National Institutes of Health Stroke Score (NIHSS) and modified Rankin scale (mRS) were used to assess stroke severity. Presenting median VWF antigen (VWF:Ag)/ADAMTS13Ac ratios were: IS, 2.42 (range, 0.78-9.53); TIA, 1.89 (range, 0.41-8.14); and controls, 1.69 (range, 0.25-15.63). Longitudinally, the median VWF:Ag/ADAMTS13Ac ratio decreased (IS, 2.42 to 1.66; P = .0008; TIA, 1.89 to 0.65; P < .0001). The VWF:Ag/ADAMTS13Ac ratio was higher at presentation in IS patients who died (3.683 vs 2.014; P < .0001). A presenting VWF:Ag/ADAMTS13Ac ratio >2.6 predicted mortality (odds ratio, 6.33; range, 2.22-18.1). Those with a VWF:Ag/ADAMTS13Ac ratio in the highest quartile (>3.091) had 31% increased risk mortality. VWF:Ag/ADAMTS13Ac ratio at presentation of ischemic brain injury was associated with higher mRS (P = .021) and NIHSS scores (P = .029) at follow-up. Thrombolysis resulted in prompt reduction of the VWF:Ag/ADAMTS13Ac ratio and significant improvement in mRS on follow-up. A raised VWF:Ag/ADAMTS13Ac ratio at presentation of acute IS or TIA is associated with increased mortality and poorer functional outcome. A ratio of 2.6 seems to differentiate outcome. Prompt reduction in the ratio in thrombolysed patients was associated with decreased mortality and morbidity. The VWF:Ag/ADAMTS13Ac ratio is a biomarker for the acute impact of an ischemic event and longer-term outcome.
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13
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Grosse GM, Schwedhelm E, Worthmann H, Choe CU. Arginine Derivatives in Cerebrovascular Diseases: Mechanisms and Clinical Implications. Int J Mol Sci 2020; 21:ijms21051798. [PMID: 32150996 PMCID: PMC7084464 DOI: 10.3390/ijms21051798] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Revised: 02/27/2020] [Accepted: 03/01/2020] [Indexed: 02/07/2023] Open
Abstract
The amino acid L-arginine serves as substrate for the nitric oxide synthase which is crucial in vascular function and disease. Derivatives of arginine, such as asymmetric (ADMA) and symmetric dimethylarginine (SDMA), are regarded as markers of endothelial dysfunction and have been implicated in vascular disorders. While there is a variety of studies consolidating ADMA as biomarker of cerebrovascular risk, morbidity and mortality, SDMA is currently emerging as an interesting metabolite with distinct characteristics in ischemic stroke. In contrast to dimethylarginines, homoarginine is inversely associated with adverse events and mortality in cerebrovascular diseases and might constitute a modifiable protective risk factor. This review aims to provide an overview of the current evidence for the pathophysiological role of arginine derivatives in cerebrovascular ischemic diseases. We discuss the complex mechanisms of arginine metabolism in health and disease and its potential clinical implications in diverse aspects of ischemic stroke.
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Affiliation(s)
- Gerrit M. Grosse
- Department of Neurology, Hannover Medical School, 30625 Hannover, Germany;
- Correspondence:
| | - Edzard Schwedhelm
- Institute of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, 20249 Hamburg, Germany;
- DZHK (Deutsches Zentrum für Herz-Kreislauf-Forschung e.V.), partner site Hamburg/Kiel/Lübeck, 20249 Hamburg, Germany
| | - Hans Worthmann
- Department of Neurology, Hannover Medical School, 30625 Hannover, Germany;
| | - Chi-un Choe
- Department of Neurology, University Medical Center Hamburg-Eppendorf, 20249 Hamburg, Germany;
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