scholarly journals Platelet-Mediated NET Formation Exacerbates Ischemic Stroke Brain Injury

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 437-437
Author(s):  
Frederik Denorme ◽  
Irina Portier ◽  
Mark Cody ◽  
Ramesh Grandhi ◽  
Matthew D Neal ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Brain Injury ◽  
Board Of Directors ◽  
Motor Function ◽  
Platelet Activation ◽  
Research Funding ◽  
Stroke Patients ◽  
Dna Complexes ◽  
Advisory Committees ◽  
Stroke Outcomes

Abstract Background: Ischemic stroke provokes a strong inflammatory response which has been shown to exacerbate ischemic stroke brain injury in mice and is associated with worse outcomes in ischemic stroke patients. Classic anti-inflammatory strategies have been unsuccessful in clinical trials for ischemic stroke, implying other mechanisms contribute to injurious inflammation in ischemic stroke. Immunothrombosis is the interplay between coagulation, platelet activation and the innate immune system leading to thrombosis. A critical component of immunothrombosis is the formation of neutrophil extracellular traps (NETs). In this study, we investigated mechanistic regulators of NET formation in stroke and if they contribute to ischemic stroke outcomes. Methods: Markers of immunothrombosis were assessed in plasma from ischemic stroke patients and healthy matched donors. Flow cytometry was used to characterize platelet and neutrophil function. For murine studies, we used male and female C57Bl/6 mice that were subjected to transient middle cerebral artery occlusion. Stroke outcomes were assessed 24 hours or 7 days after stroke using neurological and motor function testing as well as brain infarct size analysis. Results: Ischemic stroke patients had significantly increased plasma biomarkers of immunothrombosis including D-Dimers (coagulation), platelet factor 4 (platelet activation) and calprotectin (neutrophil activation). Moreover, specific markers of NET formation including citrullinated histone H3 (H3cit) and MPO-DNA complexes were significantly elevated in ischemic stroke patients. Interestingly, H3cit and MPO-DNA complexes positively correlated with worse stroke outcomes at discharge while they did not correlate with stroke severity at admission. Next, we observed increased plasma and platelet surface expressed high mobility group box 1 (HMGB1) in ischemic stroke patients compared to matched healthy controls. NETs were found in platelet-rich areas in ischemic stroke thrombi, and HMGB1 colocalized with platelets in ischemic stroke thrombi. Blocking platelet-derived HMGB1 in vitro prevented platelet-induced NET formation. Mechanistically, depleting platelets in mice reduced plasma HMGB1 levels as well as NET formation and improved outcomes after ischemic stroke. In contrast, depleting neutrophils did not affect plasma HMGB1 levels, but reduced plasma NETs and improved stroke outcomes. Treatment of mice with a competitive HMGB1 inhibitor (BoxA) reduced NET formation and improved stroke outcomes. Combined, these results imply a causative role for platelet-derived HMGB1 in mediating detrimental NET formation after ischemic stroke. Finally, as NETs appeared injurious in ischemic stroke, we investigated the therapeutic potential of a recently discovered neonatal NET inhibitory factor (nNIF). nNIF is a cleavage fragment of alpha-1-antitrypsin and specifically blocks NET formation in human and murine neutrophils without affecting other critical neutrophil functions such as chemotaxis or phagocytosis. Mice treated with nNIF had reduced brain and plasma NETs after stroke while cerebral neutrophil recruitment remained unaffected. The reduction in NET formation after stroke was associated with reduced neuronal apoptosis and smaller brain infarcts. Furthermore, nNIF treated mice had improved neurological and motor function and enhanced 7-day survival after ischemic stroke. Conclusions: These results support a pathological role for NETs in acute ischemic stroke and warrant further investigation into nNIF as a therapeutic to improve stroke outcomes. Disclosures Neal: Instrumentation Laboratories: Research Funding; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Haima Therapeutics: Membership on an entity's Board of Directors or advisory committees; Haemonetics: Honoraria, Research Funding.

The Pan Histone Deacetylase Inhibitor Panobinostat and the Iso-Selective Inhibitor Romidepsin Reduce Glycoprotein VI Expression and Inhibit Platelet Activation in Response to Collagen Related Peptide

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1154-1154
Author(s):  
Mark J Bishton ◽  
Miles Prince ◽  
Ricky W Johnstone ◽  
Simon J. Harrison ◽  
Benjamin T. Kile
Keyword(s):  
Board Of Directors ◽  
Histone Deacetylase ◽  
Platelet Activation ◽  
Western Blotting ◽  
Research Funding ◽  
Histone Deacetylase Inhibitors ◽  
Surface Expression ◽  
Selective Inhibitor ◽  
Advisory Committees ◽  
Related Peptide

Abstract Abstract 1154 Histone deacetylase inhibitors (HDACi) are anti-cancer drugs able to induce chromatin remodelling, alter gene expression and affect function of non-histone proteins. We recently reported that the pan-HDACi panobinostat and the iso-selective inhibitor romidepsin induce thrombocytopenia by reducing megakaryocyte proplatelet number, without effects on platelet half life (Bishton et al Blood 2011). The effect of HDACis on platelet function remains unknown, and we postulated possible interference with the expression or function of key platelet activating proteins. Platelet Glycoprotein (GP) VI is a member of the immunoglobulin superfamily, expressed exclusively on the surface of platelets and megakaryocytes, complexed with FcR g-chain dimers, predominantly responsible for adhesion of platelets to collagen. Following interaction with sub-endothelial collagen, the Src family kinases Fyn and Lyn mediate the recruitment and autophosphorylation of Syk kinase and thereby downstream signalling and platelet activation. Following the treatment of C57BL/6 mice with 10mg/kg panobinostat or 1mg/kg romidepsin intraperitoneally (IP) daily for three days, we isolated washed murine platelets for function testing. Following stimulation with thrombin, a dose-dependant increase was seen in platelet surface expression of CD62P (P-selectin), and also the conformationally active form of the integrin αIIbbIIIa, with no difference seen between groups. When collagen related peptide (CRP) was used as a platelet agonist, and activation assessed by p-selectin and activated αIIbbIIIa expression, platelets from cohorts of mice treated with panobinostat or romidepsin failed to increase the expression of either molecule in response to CRP, compared to vehicle treated mice. Co-treatment of mice with the murine thrombopoietin mimetic, AMP-4, or the proteasome inhibitor bortezomib did not alter effects of the HDACi. Ex vivo addition of panobinostat or romidepsin to naïve platelets did not however affect platelet activation, suggesting megakaryocytes rather than platelets to be the target cell responsible for these effects. Flow cytometric analysis of the expression of GPVI on platelets showed a consistent and statistically significant decrease in the median fluorescent intensity (MFI) of staining seen in both HDACi treated groups. No equivalent changes in the surface expression of the other collagen receptor integrin α2b1 were seen. Western blotting of murine platelets confirmed this reduction in GPVI and a ∼17kDa fragment was also seen with HDACi treated platelets, suggesting GPVI degradation. Following stimulation with CRP, Western blotting of platelets with a phospho-syk antibody showed a reduction in phospho-syk levels in platelets from mice treated with HDACi, consistent with decreased downstream signalling from the GPVI receptor. Western blotting of murine megakaryocytes differentiated from murine fetal liver cells by TPO, also demonstrated a reduction in GPVI expression following HDACi exposure, again suggesting an intrinsic megakaryocyte process to be responsible. qRT-PCR on HDACi treated megakaryocytes demonstrated a mild increase in GPVI mRNA levels post romidepsin, but no changes post panobinostat compared to vehicle treated cells, confirming transcriptional repression not to be responsible for these changes. We show that HDACi cause a reduction in surface expression of GPVI expression by inducing its degradation and thus inhibiting murine platelet responses to CRP. There was no evidence of an effect on gene transcription. Our work suggests a potential beneficial anti-thrombotic effect of HDACi, mediated by reduction in both platelet number and function. These findings support the need to investigate the role of HDACi and their effect on GPVI in myeloproliferative neoplasms particularly with respect to their impact on thrombotic complications. Disclosures: Off Label Use: Panobinostat and romidepsin are histone deacetylase inhibitors. We show that both reduce platelet response to collagen and therefore may have an anti-thrombotic effect. Prince:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Johnstone:N: Research Funding. Harrison:Cellgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding.

Transcriptome Profiling of Pediatric Myeloproliferative Neoplasms Demonstrates Dysregulation of Platelet-Relevant Genes and Enrichment of Inflammatory and JAK2 Mediated Complement Pathways

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4203-4203
Author(s):  
Nicole Kucine ◽  
Amanda R. Leonti ◽  
Aishwarya Krishnan ◽  
Rhonda E. Ries ◽  
Ross L. Levine ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Board Of Directors ◽  
Platelet Activation ◽  
Research Funding ◽  
Mononuclear Cells ◽  
Myeloproliferative Neoplasms ◽  
Differentially Expressed ◽  
Rna Seq ◽  
Advisory Committees ◽  
Normal Controls

Introduction : Myeloproliferative neoplasms (MPNs) are rare clonal bone marrow disorders in children characterized by high blood counts, predisposition to clotting events, and the potential to transform to myelofibrosis or acute myeloid leukemia (AML). Children with MPNs have lower rates of the known driver mutations (in JAK2, MPL, and CALR) than adult patients, and the underlying pathways and molecular derangements in young patients remain unknown. Given the lack of knowledge about pediatric MPNs, it is critical that we gain a better understanding of the dysregulated pathways in these diseases, which is necessary for improving disease understanding and broadening treatment options in children. Therefore, the objective of this work was to identify differentially expressed genes and pathways between children with MPNs and healthy controls, as well as children with AML, to guide further study. Methods : Mononuclear cells were extracted from peripheral blood of pediatric MPN patients (n=20) and pediatric and young adult AML patients (n=1410), and bone marrow of normal controls (NC, n=68). AML patient samples were being evaluated as part of a Children's Oncology Group planned analysis. To identify an expression profile unique to MPNs, transcriptome data from MPN patients was contrasted against NC and AML patients. All samples were ribodepleted and underwent Illumina RNA-Seq to generate transcriptome expression data. All analyses were performed in R. Differentially expressed genes were identified using the voom function from the limma package (v. 3.38.3), and enriched pathways were identified using the pathfindR package (v. 1.3.1). Unsupervised hierarchical clustering and heatmap generation was performed using the ComplexHeatmap package (v. 1.20.0). Results : MPN patient samples showed a unique expression signature, distinct from both AML patients and normal controls. Unsupervised PCA plot (Figure 1A) and heatmaps (Figure 1B) show that MPN samples cluster together. There were 4,012 differentially expressed (DE) genes in MPNs compared to NC and 6,743 DE genes in MPNs compared to AML patients. There were 2,493 shared genes between the 2 groups (Figure 1C.) Significantly DE genes between MPNs and other groups included multiple platelet-relevant genes including PF4 (CXCL4), PF4V1, P2RY12, and PPBP (CXCL7). Interestingly, PF4V1 was the most DE gene in MPNs compared to AML, and third highest versus NC. Dysregulation of some of these genes has been seen in adult MPNs, as well as thrombosis. Further comparison of transcriptome profiles between children with (n=13) and without (n=7)JAK2 mutations showed upregulation of three genes, CFB, C2, and SERPING1, which are all known complement genes, implicating complement activation in JAK2-mutated MPN patients. Complement activation has previously been reported in adult MPNs. Pathway enrichment analysis shows a number of immune and inflammatory pathways as enriched in MPN patients compared to both AML and NC. There were 179 enriched pathways in MPNs compared to AML and 142 compared to NC, with 134 common pathways (Figure 1D.) The systemic lupus erythematosus pathway was the most heavily enriched pathway in MPNs compared to both AML and NC. Additional pathways with significant enrichment include hematopoietic cell lineage, cytokine-cytokine interactions, DNA replication, and various infection-relevant pathways. The JAK-STAT signaling pathway was also enriched in MPNs compared to both AML and NC, as was the platelet activation pathway. Conclusion: Transcriptome evaluation of childhood MPNs shows enrichment of numerous inflammatory and immune pathways, highlighting that, as in adult MPNs, inflammation is implicated in pediatric MPNs. Furthermore, specific complement genes were upregulated in JAK2-mutant MPN. Upregulation of platelet-specific genes implies potential insights into disease mechanisms and warrants more study. Variations in the cell populations may account for some of the differences seen, however all samples were largely mononuclear cells, making their comparisons reasonable. Further analysis of this early data is needed to better assess inflammatory changes and platelet activation in pediatric MPNs, as are larger sample sizes. Individual cells may have differential expression of various genes, and future experiments with single-cell RNA-seq would be helpful to further elucidate differences. Disclosures Levine: Novartis: Consultancy; Loxo: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; Gilead: Consultancy; Roche: Consultancy, Research Funding; Lilly: Honoraria; Amgen: Honoraria; Qiagen: Membership on an entity's Board of Directors or advisory committees; Imago Biosciences: Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Membership on an entity's Board of Directors or advisory committees; Prelude Therapeutics: Research Funding; Isoplexis: Membership on an entity's Board of Directors or advisory committees.

Warfarin Resumption after Intracranial Hemorrhage: A Systematic Review and Meta-Analysis

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3821-3821
Author(s):  
Chatree Chai-Adisaksopha ◽  
Christopher M Hillis ◽  
Daniel M. Witt ◽  
Sam Schulman ◽  
Mark Crowther ◽  
...  
Keyword(s):  
Systematic Review ◽  
Ischemic Stroke ◽  
Board Of Directors ◽  
Intracranial Hemorrhage ◽  
Research Funding ◽  
Meta Analysis ◽  
Forest Plot ◽  
Thromboembolic Events ◽  
Advisory Committees ◽  
All Cause Mortality

Abstract Objective: To assess the effect of warfarin resumption in patients who experienced warfarin-associated intracranial hemorrhage. Study design: Systematic review and meta-analysis Data sources:We searched MEDLINE (1966 to July 2016), EMBASE (1980 to July 2016) and Cochrane Library electronic database (up to July 2016). Inclusion criteria:Studies were eligible for inclusion if (1) they were randomized controlled trials, prospective cohort or retrospective cohort studies, (2) studies that included adult patients (≥18 years), (3) studies that investigated the patients who experienced warfarin-associated intracranial bleeding, (4) studies that evaluated incidence of recurrent intracranial hemorrhage, thromboembolic events, and all-cause mortality, and (5) studies that reported on patients with warfarin resumption compared to controls (those who did not resume warfarin). Main outcome and measures: Primary outcome was all-cause mortality. Secondary outcomes were ischemic stroke, thromboembolic events, recurrent intracranial hemorrhage and any bleeding. Pooled relative risks (RRs) were calculated using random-effects model. Results: Seven studies were included in the meta-analysis, involving 623 patients who resumed warfarin and 1851 patients who did not resume warfarin after warfarin-associated intracranial hemorrhage. Majority of patients were anticoagulated due to atrial fibrillation, prosthetic heart valve and venous thrombosis. Median time to resume warfarin ranged form 11 days to 39.2 days. Warfarin resumption significantly reduced risk of all-cause mortality (17.06% vs 35.71%), RR 0.50, 95% confidence interval [CI];0.33-0.77, I-square=58.7%, Figure 1. Lower ischemic stroke was observed in patients who resumed warfarin (4.89% vs 7.64%), RR 0.67, 95%CI; 0.45-0.99, I-square=0%, Figure 2. Composite outcome of thromboembolic event was lower but not significant in patients who resumed warfarin (7.35% vs 11.48%), RR 0.61, 95%CI; 0.39-1.07, I-square=50.7%. Recurrent intracranial hemorrhage was not significantly different between patients who resumed and those who did not resume warfarin (7.33% vs 7.39%), RR 1.14, 95%CI; 0.57-2.27, I-square=51.0%, Figure 3. Any bleeding was not significantly different between 2 groups (8.23% vs 8.31%), RR 1.03, 95%CI; 0.73-1.43, I-square=50.4%. Conclusions: Major limitation of this meta-analysis included potential selection bias of the original studies, specifically, patients with better prognosis tended be selected to restart warfarin. In summary, , warfarin resumption after warfarin-associated intracranial hemorrhage was associated with lower risk of all-cause mortality and ischemic stroke without a significant increase in recurrent intracranial hemorrhage. Figure 1 Forest plot of all-cause mortality comparing patients who do and do not resume warfarin. Figure 1. Forest plot of all-cause mortality comparing patients who do and do not resume warfarin. Figure 2 Forest plot of ischemic stroke comparing between patients who do and do not resume warfarin. Figure 2. Forest plot of ischemic stroke comparing between patients who do and do not resume warfarin. Figure 3 Forest plot of recurrent intracranial hemorrhage comparing between patients who resume warfarin versus those who did not resume. Figure 3. Forest plot of recurrent intracranial hemorrhage comparing between patients who resume warfarin versus those who did not resume. Disclosures Hillis: Celgene: Consultancy; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria. Crowther:AKP America: Membership on an entity's Board of Directors or advisory committees; Alexion: Consultancy, Speakers Bureau; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Celgene: Honoraria; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daichii: Honoraria; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ortho Clinical Diagnostics: Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees.

The Impact of Atrial Fibrillation on Subsequent Survival of Patients Receiving Ibrutinib As Treatment of Chronic Lymphocytic Leukemia (CLL): An International Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3242-3242 ◽  
Author(s):  
Philip A Thompson ◽  
Vincent Levy ◽  
Constantine S. Tam ◽  
Chadi al Nawakil ◽  
Francois Xavier Goudot ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Overall Survival ◽  
Ischemic Stroke ◽  
Board Of Directors ◽  
Cardiac Failure ◽  
Research Funding ◽  
Pulmonary Hemorrhage ◽  
Bleeding Events ◽  
Advisory Committees

Abstract Introduction Atrial fibrillation (AF) occurs in 5-9% of patients treated with ibrutinib for CLL. We previously reported on the clinical characteristics and management outcomes of 56 patients with ibrutinib-associated AF (n=52) or atrial flutter (n=4) retrospectively identified from centers of the FILO group (French Innovative Leukemia Organization, France/Belgium, n=29), MD Anderson Cancer Center (USA, n=21), and Peter MacCallum Cancer Centre (Australia, n=6) (Thompson et al BJH 2016). We found that (1) the median time from the initiation of ibrutinib to AF was 3.8 months (range: 6 - 1410 days); (2) AF recurred or became persistent in 63% despite medical management; (3) AF and its management was associated with serious sequelae including severe cardiac failure (n=3, 1 fatal), ischemic stroke (n=3) and severe bleeding events (n=8); (4) immediate cessation of ibrutinib therapy was required in 22/56 (39%). Given the reported poor outcomes for patients who discontinue ibrutinib for toxicity, we update the results of this cohort with respect to CLL outcomes and survival. Aim To describe long term overall and disease-specific outcomes in patients who develop ibrutinib-associated AF. Methods This is an update of an international, retrospective cohort of patients who developed ibrutinib-associated AF. Patients are managed according to local best standard practice. The median follow-up from onset of AF is 21 months. Results The median overall survival after development of AF is 43 months. Twenty-two (39%) patients stopped ibrutinib at the time of AF. Among these patients, 7 (32%) eventually died from CLL progression (n=3), infection (1), cardiac failure (1), pulmonary hemorrhage (1) and colon cancer (1). Of the 34 patients who initially continued ibrutinib, 5 (15%) died; causes of death were: Richter transformation (RT) (n=2), septic shock (1), CLL progression (1), and stroke in the context of AF (1). In order to gain insight into disease control in relationship to AF and its management, we examined PFS from the time of AF onset. The following features had no impact on PFS: single AF episode vs paroxysmal/permanent AF or time from ibrutinib initiation to onset of AF. However, patients who had ibrutinib interrupted at the time of AF onset (n=22) had a significantly inferior PFS (median 19 months) compared with those who had dose reduction without interruption (n=13) or those who continued full dose ibrutinib (n=21, median 27 months, p=0.023, Figure 1). There was a trend toward inferior overall survival in those who interrupted ibrutinib (62% at 3 years) compared with those who continued without interruption (74% at 3 years, p=0.10), but this did not reach statistical significance at the time of analysis. Only 3 of 22 (14%) patients who had initial interruption of ibrutinib successfully restarted ibrutinib following control of AF; all 3 remain in continuous partial remission. Four other patients restarted ibrutinib, but subsequently discontinued due to pulmonary hemorrhage (n=1), stroke (1), CLL progression (1) and RT (1). Among patients who discontinued Ibrutinib permanently, only 9 did so solely because of uncomplicated AF. The others discontinued because of: (a) complications of AF or its management such as cardiac failure (n=1), recurrent AF (n=5) and bleeding events (n=4; one each of hemopericardium, pulmonary hemorrhage, subdural hematoma and gastrointestinal hemorrhage); (b) complications related to CLL such as CLL progression (n=1) and RT (n=2); or (c) other causes such as lung cancer (n=1) or unknown reasons (n=2). Altogether, 21 patients were still on Ibrutinib among 44 patients alive at last follow-up. Conclusion Occurrence of AF at any time during ibrutinib treatment was associated with an initial discontinuation rate of 39%, and only 37.5% of patients remain alive and on drug after a median of 21 months follow-up. Patients who interrupted ibrutinib at the time of AF onset have an inferior PFS compared to those who continued ibrutinib or were managed with dose reductions. This inferior outcome in CLL control is likely related to the low rate of patients (14%) who subsequently successfully restarted ibrutinib. Development of AF was associated with serious complications, including hemorrhage, ischemic stroke and cardiac failure. Management of ibrutinib-associated AF is complex and requires international consensus guidelines and a multidisciplinary approach. Figure 1 Figure 1. Disclosures Thompson: Pharmacyclics: Consultancy, Honoraria. Levy:Abbive: Honoraria; Roche: Honoraria; Janssen: Honoraria; Gilead: Honoraria. Tam:janssen: Honoraria, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Quinquenel:janssen: Honoraria, Research Funding. Dupuis:ABBVIE: Membership on an entity's Board of Directors or advisory committees; janssen: Honoraria. Cymbalista:Roche: Honoraria; Abbvie: Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Research Funding.

scholarly journals Characterization of Platelet Activation in Patients with Eisenmenger Syndrome

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4973-4973
Author(s):  
Gordon Haire ◽  
Karl Egan ◽  
Barry Kevane ◽  
Michael Fay ◽  
Anne Fortune ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Board Of Directors ◽  
Platelet Activation ◽  
Research Funding ◽  
Congenital Heart ◽  
Plasma Concentrations ◽  
Published Data ◽  
Healthy Controls ◽  
Eisenmenger Syndrome ◽  
Advisory Committees

Abstract Background Eisenmenger Syndrome (ES) is an extremely rare and serious complication of congenital heart disease in which pulmonary vascular resistance overcomes that of the systemic circulation causing bidirectional or reversed flow across an intracardiac shunt. Patients with ES have an increased incidence of both thrombotic and bleeding complications which occur through poorly understood mechanisms. We have recently demonstrated a critical mechanistic role for platelets in supporting abnormal hypercoagulability in patients with ES using calibrated automated thrombography (Kevane & Ní Áinle et al., J Thromb Haemost 2018). Aims Based upon our published data, we further hypothesized that patients with ES would have higher plasma concentrations of platelet activation markers. Therefore, the aim of this study was to measure plamsa levels of soluble P-Selectin (sP-Selectin) and soluble glycoprotein VI (sGPVI) in patients with ES and in matched healthy controls. Methods Patients over the age of 18 with Eisenmenger Syndrome and healthy controls were recruited from the cardiology service at a large tertiary referral centre (Mater Misericordiae University Hospital) incorporating the Irish national congenital heart disease service. Platelet poor plasma (PPP) was generated from participants' blood by centrifugation at 2000xg for 10 minutes at room temperature. Commercially available ELISA assays employing quantitative sandwich immunoassay techniques were performed according to manufacturer protocol to measure plasma sP-Selectin and sGPVI levels. All experiments were performed in duplicate with results expressed as mean +/- standard error of mean. Comparisons between groups were made utilising the Student's t-test with a p-value < 0.05 deemed to represent statistical significance. Results During the study period, >14,000 patients attended the MMUH cardiology service. Of these, 14 consecutive patients with a diagnosis of ES and 10 matched healthy controls were recruited. Patients with ES had significantly elevated plasma concentrations of both soluble P-Selectin [38.5 +/- 8.3 vs. 11.3 +/- 4.2 ng/ml (p < 0.05)] and soluble GPVI [10.5 +/- 2.4 vs. 1.5 +/- 1.4 ng/ml (p < 0.01)] compared to healthy controls. Conclusion Building upon our recently published data in this population, a large cohort given the extreme rarity of this condition, increased concentrations of markers of platelet activation in individuals with ES further suggest a mechanistic role for platelets in ES-mediated hypercoagulability. This phenotype may be a consequence of vascular pathology associated with pulmonary hypertension in these patients. As such, therapies targeted at underlying vascular pathologies may act to ameliorate prothrombotic tendencies and we aim to characterize response to therapy during this ongoing study. Disclosures Ni Ainle: Leo Pharma: Research Funding; Actelion: Research Funding; Bayer: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Boehringer: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Increased Soluble GPVI Levels in Cirrhosis: Evidence for Collagen Induced Platelet Activation In Vivo

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1114-1114
Author(s):  
Karl Egan ◽  
Eimear Dunne ◽  
Audrey Dillon ◽  
Barry Kevane ◽  
Zita Galvin ◽  
...  
Keyword(s):  
Liver Disease ◽  
Board Of Directors ◽  
Platelet Activation ◽  
Research Funding ◽  
Decompensated Cirrhosis ◽  
Dependent Manner ◽  
Healthy Controls ◽  
Advisory Committees ◽  
Significant Difference

Abstract Background Cirrhosis is a consequence of prolonged inflammation arising from chronic liver disease of different aetiologies. It is characterised by tissue fibrosis, the deposition of collagen-rich extracellular matrix tissue within the liver. Glycoprotein VI (GPVI) is platelet-specific collagen receptor that is shed from the platelet surface in a metalloproteinase-dependent manner in response to GPVI ligation. The shed extracellular region of GPVI can be detected in plasma and used as a measure of GPVI-dependent platelet activation in vivo. Several lines of evidence suggest that GPVI-dependent platelet activation occurs in cirrhosis. Platelets have been shown to accumulate at sites of collagen-rich fibrotic tissue. Circulating levels of collagen are increased in cirrhosis. Collagen-induced platelet aggregation responses are reduced in vitro with cirrhosis. Based on these results, we hypothesised that soluble GPVI (sGPVI) levels are increased in patients with cirrhosis. As such, the aim of this study was to quantify sGPVI levels in patients with cirrhosis and compare to healthy controls. Methods Compensated cirrhotic patients were recruited at the Mater Misericordiae University Hospital, Dublin, Ireland. The diagnosis of cirrhosis was based on clinical examination, blood tests, and radiological examination (nodular surface, larger right lobe, coarse echotexture). Exclusion criteria were decompensated cirrhosis, recent thrombotic events, and antiplatelet and/or anticoagulant therapies. Healthy controls were recruited at the Royal College of Surgeons in Ireland and Beaumont Hospital, Dublin, Ireland. Blood samples were collected into vacutainers containing 3.2 % sodium citrate as anticoagulant. sGPVI levels in platelet poor plasma were measured using an in house custom ELISA. Results 57 patients with mixed aetiology cirrhosis and 55 healthy controls were recruited. In the patient group, 42% of patients had alcoholic liver disease (ALD), 30% had hepatitis C (HCV), 7% had non alcoholic fatty liver disease (NAFLD), 5% had Hepatitis B (HBV), 5% had autoimmune hepatitis (AIH), 5% had cryptogenic liver disease, 4% had hereditary haemochromatosis (HH), and 2% had primary biliary cholangitis (PBC). sGPVI levels were significantly increased in patients with cirrhosis (5.8 ± 0.6 ng/ml, n = 57) compared to healthy controls (3.2 ± 0.4 ng/ml, n = 55, p < 0.0001). There was no significant difference between sGPVI levels in AIH (4 ± 1 ng/ml, n = 3), ALD (5.6 ± 1 ng/ml, n = 24), cryptogenic (12 ± 5 ng/ml, n = 3), HBV (3.1 ± 1 ng/ml, n = 3), HCV (5 ± 0.6 ng/ml), or NAFLD (5.3 ± 1.1 ng/ml, n = 4). sGPVI levels did not correlate with platelet count (r = 0.12, p = 0.3) or parameters of liver cell function (albumin, bilirubin, prothrombin time, and liver stiffness measurements). Conclusion sGPVI levels are significantly increased in patients with mixed aetiology cirrhosis. This indicates collagen induced platelet activation is occurring in vivo and suggests the presence of an underlying coagulopathy in patients with cirrhosis. Disclosures Ní Áinle: Actelion Pharma: Research Funding; Leo Pharma: Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Inherited Thrombophilia and the Risk of Arterial Ischemic Stroke: A Systematic Review and Meta-Analysis

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2518-2518
Author(s):  
Thita Chiasakul ◽  
Elizabeth De Jesus ◽  
Jiayi Tong ◽  
Yong Chen ◽  
Mark Crowther ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Board Of Directors ◽  
Research Funding ◽  
Meta Analysis ◽  
Cryptogenic Stroke ◽  
Young Patients ◽  
Case Control Studies ◽  
Arterial Ischemic Stroke ◽  
Advisory Committees ◽  
Inherited Thrombophilia

Abstract Introduction:The inherited thrombophilias Factor V Leiden (FVL), the Prothrombin G20210A mutation (PTM), Protein C deficiency (PCD), Protein S deficiency (PSD), and Antithrombin deficiency (ATD) are well-established predisposing factors for venous thromboembolism, but their role in arterial thrombosis such as arterial ischemic stroke remains uncertain. The 2018 American Heart Association/American Stroke Association clinical practice guideline recommends against thrombophilia testing in patients with ischemic stroke, though such testing remains common in clinical practice. We conducted a systematic review and meta-analysis to evaluate the association of inherited thrombophilias and risk of arterial ischemic stroke in adults. Methods:A systematic literature search was performed using MEDLINE, EMBASE, and Cochrane Library Databases from inception to December 31, 2017 without language restrictions. Manual reviews of conference abstracts and bibliographies of included studies were performed to identify additional eligible studies. We included case-control studies of adults age ≥15 years that reported the prevalence of at least one of the inherited thrombophilias of interest (FVL, PTM, PCD, PSD, ATD) in both subjects with a history of arterial ischemic stroke (cases) and subjects without arterial ischemic stroke (controls). Studies were required to have ≥10 subjects in each group. Studies that enrolled patients with transient ischemic attack, hemorrhagic stroke, cerebral venous sinus thrombosis, and other arterial thromboses were excluded. Two reviewers (T.C. and E.D.) independently searched the literature and extracted data from eligible studies. Disagreements were resolved by consensus or a third reviewer (A.C.) when necessary. Methodological quality of included studies was appraised using the NIH Quality Assessment of Case-Control Studies assessment tool. Data analysis was performed using R version 3.4.4. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random-effects model. Inter-study heterogeneity was evaluated using Cochran's Q test and I2statistics. Prespecified subgroup analyses were performed in young patients (<65 years), patients with a patent foramen ovale (PFO), and patients with cryptogenic stroke. Funnel plots and Egger's test were used to assess for the presence of publication bias. The study protocol is available on PROSPERO (CRD42018090020). Results:A total of 1,730 records were retrieved from the literature search. After screening by title and abstract, 1527 records were excluded. The remaining 203 references underwent full text review, 71 of which met eligibility criteria and were included in the analysis. These 71 studies collectively enrolled 13,347 stroke patients and 31,676 controls. The number of studies that reported on FVL, PTM, PCD, PSD, and ATD were 59, 47, 14, 15, and 11, respectively. Heterogeneity among studies was low. Compared with controls, inherited thrombophilia was significantly more common in patients with arterial ischemic stroke for the following defects: homozygous FVL (OR 2.24; 95%CI, 1.24-4.07; I2=0%), heterozygous FVL (OR 1.32; 95%CI, 1.11-1.57; I2=33%), homozygous PTM (OR 7.19; 95%CI 2.47-20.95; I2=0%), heterozygous PTM (OR 1.53; 95%CI, 1.27-1.84; I2=2%), PCD (OR 2.70; 95%CI, 1.44-5.04; I2=0%), and PSD (OR 2.75; 95%CI, 1.56-4.85; I2=34%) (Figure 1). Statistical significance was not reached for ATD (OR 1.84; 95%CI, 0.92-3.71; I2=11%). Subgroup analyses showed a higher magnitude of stroke risk in young patients across all thrombophilias. The associations were non-significant for patients with PFO and cryptogenic stroke (Table 1). Funnel plots were symmetrical and Egger's test was non-significant (p>0.05), suggesting absence of publication bias, for all thrombophilias except heterozygous FVL (p=0.003). Conclusions: Our results suggest that inherited thrombophilias including FVL, PTM, PCD, and PSD are associated with an increased risk of arterial ischemic stroke, particularly in young patients. The association with FVL and PTM is stronger in the homozygous than in the heterozygous state, suggesting a potential dose-response relationship and causal role for inherited thrombophilias. The implications of these findings with respect to the evaluation and management of patients with ischemic stroke require further investigation. Disclosures Crowther: Alnylam: Equity Ownership; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Shinogi: Consultancy; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Leo Pharma: Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion: Speakers Bureau. Garcia:Bristol Meyers Squibb: Consultancy; Daiichi Sankyo: Research Funding; Janssen: Consultancy, Research Funding; Pfizer: Consultancy; Portola: Research Funding; Incyte: Research Funding; Retham Technologies LLC: Consultancy; Shingoi: Consultancy; Boehringer Ingelheim: Consultancy. Cuker:Kedrion: Membership on an entity's Board of Directors or advisory committees; Spark Therapeutics: Research Funding; Synergy: Consultancy; Genzyme: Consultancy.

scholarly journals The Population of Circulating Extracellular Vesicles Dramatically Alters after Very Premature Delivery- a Previously Unrecognised Postnatal Adaptation Process?

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1129-1129 ◽  
Author(s):  
Daniel O'Reilly ◽  
Karl Egan ◽  
Oscar Burke ◽  
Angharad Griffiths ◽  
Elaine Neary ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Board Of Directors ◽  
Extracellular Vesicles ◽  
Platelet Activation ◽  
Research Funding ◽  
Transition Period ◽  
Annexin V ◽  
Mass Spectrometry Analysis ◽  
Preterm Neonates ◽  
Advisory Committees

Abstract Introduction Following birth, the transition from intrauterine to extrauterine life is associated with major physiological changes. Many pathological processes linked with mortality and morbidity in preterm infants start at this time. Extracellular vesicles (EVs) are subcellular particles released by all known cell types and readily detectable in large numbers in all biological fluids. EVs are heterogeneous in size and origin, consisting of exosomes (endosomal origin, 30-150 nm), microvesicles (plasma membrane-derived, 50-1000nm), and apoptotic bodies (500-2000 nm). They are linked with a wide variety of processes including coagulation and cell-cell communication, and it has been hypothesized that they may affect preterm morbidities. It is unknown whether circulating EVs can change during this extrauterine transition period. Aim Here we investigate if the population of circulating EVs is altered in premature neonates during the extrauterine transition period Patients and Methods Preterm neonates were recruited through the Department of Neonatology at the Rotunda Hospital, Dublin, Ireland. Written informed consent was obtained from the parents of all participants. Blood collection was performed during routine phlebotomy. Platelet free plasma was prepared by double centrifugation at 3000g for 10 minutes. 15x Day 1 of life and 14x days 3 of life plasma samples were available from preterm neonates, 8 of which were matched Day 1 and Day 3 samples. EVs were quantified and characterised by both nanoparticle tracking analysis (NTA with a Malvern NanoSight 3000) and flow cytometry (Beckman Coulter CytoFLEX LX). Results The extrauterine transition period is characterised by a shift in plasma EVs profile. Using NTA, we observed an increase in the levels of plasma EVs (0-200nm) from Day 1 to Day 3 (Day 1; 4.0 ± 2.5 x 107/µl vs. Day 3; 7.2 ± 4.4 x 107/µl; p = 0.03). This increase in EV levels (0-200nm) was supported by flow cytometry, which also demonstrated an increase in EVs (100-900nm) from day 1 to Day 3 (Day 1; 1.1 ± 0.3 X 106/µl vs. Day 3; 4.2 ± 3.2 x 106/µl, p = 0.0009). There was a highly significant correlation between EV levels measured by NTA and flow cytometry (Spearmann rank correlation coefficient, r = 0.69, p < 0.0001), suggesting simultaneous increases in small and large EVs during the extrauterine transition period. Using flow cytometry, we also observed a change in the composition of plasma EVs during the extrauterine transition period. Flow cytometry data from Day 3 samples were characterised by the presence of a homogenous population of EVs of ~100-300nm in size, which was not observed on Day 1. The presence of this population caused a significant increase in the median side scatter height (SSC-H) value of the plasma EV population (Day 1; 1800 ± 746 vs. Day 3; 3832 ± 1633, p = 0.0013), as well as reduction in the percentage of 100nm EVs (Day 1; 73.9 ± 9.2 % vs. Day 3; 57.4 ± 12.6 %, p = 0.0005) and an increase in the percentage of 100-300nm EVs (Day 1; 19.7 ± 7.7 % vs. Day 3; 38.0 ± 12.9%, p = 0.001). EVs from Day 3 samples were characterised by higher median Red SSC-H values (Day 1; 1688 ± 2902 vs. Day 3; 3641 ± 6247, p = 0.0004) and Violet SSC-H values (Day 1; 42641 ± 21131 vs. Day 3; 97133 ± 38311, p < 0.0001), suggesting a potential change in the membrane or internal composition of EVs in the extrauterine transition period. We also observed a change in protein expression on EVs during the extrauterine transition period. Platelets and platelet activation play a physiological role in the closure of the ductus arteriosus . As such, we assessed the levels of platelet EVs (CD41+/Annexin V+), an established marker of platelet activation in vivo. The percentage of CD41+/Annexin V-EVs significantly decreased from Day 1 to Day 3 (Day 1; 6.5 ± 4.9 % vs. Day 3; 2.4 ± 1.9 %, p = 0.007), suggestive of a platelet activation event early in the extrauterine transition period. Proteomic differences between day 1 and day 3 were analysed using mass spectrometry analysis Conclusion In this study, we clearly demonstrate that the extrauterine transition period is characterised by major changes in plasma EVs. These changes include an increase in the levels of EVs, a change in the composition of EVs, and a reduction in the percentage of platelet-derived EVs. The physiological or pathophysiological causes of the changes require further elucidation. In addition, the role of this change of EV profile in the pathogenesis of important preterm morbidities needs to be clarified. Disclosures Ni Ainle: Leo Pharma: Research Funding; Actelion: Research Funding; Bayer: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Boehringer: Membership on an entity's Board of Directors or advisory committees.

Terminal Complement Inhibitor Eculizumab Improves Complement-Mediated Platelet Consumption and Thrombocytopenia in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4030-4030 ◽  
Author(s):  
Gerard Socie ◽  
Petra Muus ◽  
Hubert Schrezenmeier ◽  
Britta Höchsmann ◽  
Jaroslaw P. Maciejewski ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Platelet Activation ◽  
Complement Activation ◽  
Research Funding ◽  
Advisory Committees ◽  
Thrombotic Risk ◽  
Complement Inhibition ◽  
Platelet Counts ◽  
History Of ◽  
Terminal Complement

Abstract Abstract 4030 Poster Board III-966 PNH is a hematopoietic stem cell disorder in which unregulated activation of the complement system leads to significant morbidities with shortened lifespan. Life threatening thromboembolism (TE) is the most feared complication of PNH, accounting for 45% of patient deaths. Approximately 40% of PNH patients experience a clinically evident TE and 60% of patients without clinically diagnosed TE demonstrate TE by high-sensitivity MRI, indicating the ongoing thrombotic risk in PNH patients. Thrombocytopenia is found in 25-50% of PNH patients at presentation. PNH platelets are extremely sensitive to terminal complement activation, and circulating platelets are activated in thrombocytopenic PNH patients without clinically diagnosed TE. Eculizumab, a monoclonal antibody targeted to complement C5, blocks the production of both C5a and C5b-9, and has been demonstrated to reduce TE events by up to 92% in PNH patients. Eculizumab has also been shown to beneficially impact several prothrombotic processes in PNH patients including hemolysis, nitric oxide consumption, thrombin generation, tissue factor pathways, and inflammation. We hypothesized that terminal complement activation of PNH platelets contributes to ongoing platelet activation, which is reflected by platelet consumption, contributing to chronic thrombocytopenia defined as platelets <100×109/L. This hypothesis was tested by examining whether chronic inhibition of terminal complement activation with eculizumab increases platelet counts in thrombocytopenic PNH patients. The study population was comprised of the 49 thrombocytopenic PNH patients identified from the total 195 patients in the SHEPHERD, TRIUMPH, and Phase 2 eculizumab trials. Platelet counts were measured at baseline, 26 and 52 weeks of eculizumab treatment. At baseline the median platelet count in the thrombocytopenic group was 68×109/L (range 23 to 97). Patients with thrombocytopenia were more likely to have a history of TE than patients with normal platelet counts (45% vs 27%; P<0.022). Treatment with eculizumab markedly inhibited terminal complement activity in all thrombocytopenic patients, as measured by a significant reduction in LDH at 26 and 52 weeks (median values at baseline, 26 weeks, and 52 weeks: 1746 IU/L, 290 IU/L, 286 IU/L, respectively, UNL 220 U/L); P<0.00001 for each time point vs. baseline). Chronic terminal complement inhibition with eculizumab significantly increased platelet counts to a non-thrombocytopenic level in 33% (95% CI: 20-48%) and 36% (95% CI: 22-51%) of thrombocytopenic patients at 26 and 52 weeks, respectively, of treatment. By inhibiting C5 activity, the median platelet counts significantly increased in thrombocytopenic patients from 68×109/L at baseline to 80 and 85×109/L (P<0.001) at 26 and 52 weeks, respectively. Eculizumab treatment significantly increased platelet counts in both thrombocytopenic patients with a history of TE and no history of TE (P<0.05 vs baseline in both groups). Treatment with eculizumab significantly increased platelet counts at 52 weeks in this thrombocytopenic patient population irrespective of a history of bone marrow failure (P<0.05 vs baseline for each group). As expected, there was no apparent impact of terminal complement inhibition on marrow blood cell production as measured by no change in absolute neutrophil count at 26 and 52 weeks. This suggests that the mechanism of platelet increase may be due to inhibition of terminal complement-mediated consumption of platelets in thrombocytopenic patients with PNH. The present study indicates that thrombosis in PNH patients is more frequent in patients with thrombocytopenia. Terminal complement deposition on PNH platelets results in platelet activation which in turn would be expected to result in platelet consumption, suggestive of a chronic prothrombotic state, in PNH patients. Earlier studies have shown that chronic terminal complement inhibition with eculizumab reduces thrombotic risk in patients with PNH. The current study shows that chronic terminal complement inhibition with eculizumab treatment improves pre-existing thrombocytopenia in a significant proportion of patients with PNH. These clinical findings warrant further investigation and suggest that terminal complement C5 activity contributes to platelet activation and consumption with subsequent thrombocytopenia and an increased thrombotic risk in patients with PNH. Disclosures: Socie: Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees. Muus:Alexion Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Schrezenmeier:Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Höchsmann:Alexion: Honoraria. Hill:Alexion: Honoraria. Bessler:Alexion: Membership on an entity's Board of Directors or advisory committees. Risitano:Alexion Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Dysphagia in Patients with Acute Ischemic Stroke: Early Dysphagia Screening May Reduce Stroke-Related Pneumonia and Improve Stroke Outcomes

2016 ◽  
Vol 42 (1-2) ◽  
pp. 81-89 ◽  
Author(s):  
Mohamed Al-Khaled ◽  
Christine Matthis ◽  
Andreas Binder ◽  
Jonas Mudter ◽  
Joern Schattschneider ◽  
...  
Keyword(s):  
Logistic Regression ◽  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Case Fatality ◽  
National Institutes Of Health ◽  
Modified Rankin Scale ◽  
Stroke Patients ◽  
Stroke Outcomes ◽  
Increased Risk ◽  
Reduced Risk

Background: Dysphagia is associated with poor outcome in stroke patients. Studies investigating the association of dysphagia and early dysphagia screening (EDS) with outcomes in patients with acute ischemic stroke (AIS) are rare. The aims of our study are to investigate the association of dysphagia and EDS within 24 h with stroke-related pneumonia and outcomes. Methods: Over a 4.5-year period (starting November 2007), all consecutive AIS patients from 15 hospitals in Schleswig-Holstein, Germany, were prospectively evaluated. The primary outcomes were stroke-related pneumonia during hospitalization, mortality, and disability measured on the modified Rankin Scale ≥2-5, in which 2 indicates an independence/slight disability to 5 severe disability. Results: Of 12,276 patients (mean age 73 ± 13; 49% women), 9,164 patients (74%) underwent dysphagia screening; of these patients, 55, 39, 4.7, and 1.5% of patients had been screened for dysphagia within 3, 3 to <24, 24 to ≤72, and >72 h following admission. Patients who underwent dysphagia screening were likely to be older, more affected on the National Institutes of Health Stroke Scale score, and to have higher rates of neurological symptoms and risk factors than patients who were not screened. A total of 3,083 patients (25.1%; 95% CI 24.4-25.8) had dysphagia. The frequency of dysphagia was higher in patients who had undergone dysphagia screening than in those who had not (30 vs. 11.1%; p < 0.001). During hospitalization (mean 9 days), 1,271 patients (10.2%; 95% CI 9.7-10.8) suffered from stroke-related pneumonia. Patients with dysphagia had a higher rate of pneumonia than those without dysphagia (29.7 vs. 3.7%; p < 0.001). Logistic regression revealed that dysphagia was associated with increased risk of stroke-related pneumonia (OR 3.4; 95% CI 2.8-4.2; p < 0.001), case fatality during hospitalization (OR 2.8; 95% CI 2.1-3.7; p < 0.001) and disability at discharge (OR 2.0; 95% CI 1.6-2.3; p < 0.001). EDS within 24 h of admission appeared to be associated with decreased risk of stroke-related pneumonia (OR 0.68; 95% CI 0.52-0.89; p = 0.006) and disability at discharge (OR 0.60; 95% CI 0.46-0.77; p < 0.001). Furthermore, dysphagia was independently correlated with an increase in mortality (OR 3.2; 95% CI 2.4-4.2; p < 0.001) and disability (OR 2.3; 95% CI 1.8-3.0; p < 0.001) at 3 months after stroke. The rate of 3-month disability was lower in patients who had received EDS (52 vs. 40.7%; p = 0.003), albeit an association in the logistic regression was not found (OR 0.78; 95% CI 0.51-1.2; p = 0.2). Conclusions: Dysphagia exposes stroke patients to a higher risk of pneumonia, disability, and death, whereas an EDS seems to be associated with reduced risk of stroke-related pneumonia and disability.

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