Platelet Receptor Glycoprotein VI-Dimer Is Overexpressed in Patients with Atrial Fibrillation at High Risk of Ischemic Stroke
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SUBMITTER: Induruwa I
PROVIDER: S-EPMC10643047 | biostudies-literature | 2023 Oct
REPOSITORIES: biostudies-literature
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Project description:ObjectivesPlatelet activation underpins thrombus formation in ischemic stroke. The active, dimeric form of platelet receptor glycoprotein (GP) VI plays key roles by binding platelet ligands collagen and fibrin, leading to platelet activation. We investigated whether patients presenting with stroke expressed more GPVI on their platelet surface and had more active circulating platelets as measured by platelet P-selectin exposure.Methods129 ischemic or hemorrhagic stroke patients were recruited within 8h of symptom onset. Whole blood was analyzed for platelet-surface expression of total GPVI, GPVI-dimer, and P-selectin by flow cytometry at admission and day-90 post-stroke. Results were compared against a healthy control population (n = 301).ResultsThe platelets of stroke patients expressed significantly higher total GPVI and GPVI-dimer (P<0.0001) as well as demonstrating higher resting P-selectin exposure (P<0.0001), a measure of platelet activity, compared to the control group, suggesting increased circulating platelet activation. GPVI-dimer expression was strongly correlated circulating platelet activation [r2 = 0.88, P<0.0001] in stroke patients. Furthermore, higher platelet surface GPVI expression was associated with increased stroke severity at admission. At day-90 post-stroke, GPVI-dimer expression and was further raised compared to the level at admission (P<0.0001) despite anti-thrombotic therapy. All ischemic stroke subtypes and hemorrhagic strokes expressed significantly higher GPVI-dimer compared to controls (P<0.0001).ConclusionsStroke patients express more GPVI-dimer on their platelet surface at presentation, lasting at least until day-90 post-stroke. Small molecule GPVI-dimer inhibitors are currently in development and the results of this study validate that GPVI-dimer as an anti-thrombotic target in ischemic stroke.
| S-EPMC8765640 | biostudies-literature
Project description:Essentials Glycoprotein VI (GPVI) binds collagen, starting thrombogenesis, and fibrin, stabilizing thrombi. GPVI-dimers, not monomers, recognize immobilized fibrinogen and fibrin through their D-domains. Collagen, D-fragment and D-dimer may share a common or proximate binding site(s) on GPVI-dimer. GPVI-dimer-fibrin interaction supports spreading, activation and adhesion involving αIIbβ3.SummaryBackground Platelet collagen receptor Glycoprotein VI (GPVI) binds collagen, initiating thrombogenesis, and stabilizes thrombi by binding fibrin. Objectives To determine if GPVI-dimer, GPVI-monomer, or both bind to fibrinogen substrates, and which region common to these substrates contains the interaction site. Methods Recombinant GPVI monomeric extracellular domain (GPVIex ) or dimeric Fc-fusion protein (GPVI-Fc2 ) binding to immobilized fibrinogen derivatives was measured by ELISA, including competition assays involving collagenous substrates and fibrinogen derivatives. Flow adhesion was performed with normal or Glanzmann thrombasthenic (GT) platelets over immobilized fibrinogen, with or without anti-GPVI-dimer or anti-αIIbβ3. Results Under static conditions, GPVIex did not bind to any fibrinogen substrate. GPVI-Fc2 exhibited specific, saturable binding to both D-fragment and D-dimer, which was inhibited by mFab-F (anti-GPVI-dimer), but showed low binding to fibrinogen and fibrin under our conditions. GPVI-Fc2 binding to D-fragment or D-dimer was abrogated by collagen type III, Horm collagen or CRP-XL (crosslinked collagen-related peptide), suggesting proximity between the D-domain and collagen binding sites on GPVI-dimer. Under low shear, adhesion of normal platelets to D-fragment, D-dimer, fibrinogen and fibrin was inhibited by mFab-F (inhibitor of GPVI-dimer) and abolished by Eptifibatide (inhibitor of αIIbβ3), suggesting that both receptors contribute to thrombus formation on these substrates, but αIIbβ3 makes a greater contribution. Notably, thrombasthenic platelets showed limited adhesion to fibrinogen substrates under flow, which was further reduced by mFab-F, supporting some independent GPVI-dimer involvement in this interaction. Conclusion Only dimeric GPVI interacts with fibrinogen D-domain, at a site proximate to its collagen binding site, to support platelet adhesion/activation/aggregate formation on immobilized fibrinogen and polymerized fibrin.
| S-EPMC5838801 | biostudies-literature
Project description:Platelets are essential to physiological hemostasis or pathological thrombus formation. Current antiplatelet agents inhibit platelet aggregation but leave patients at risk of systemic side-effects such as hemorrhage. Newer therapeutic strategies could involve targeting this cascade earlier during platelet adhesion or activation via inhibitory effects on specific glycoproteins, the thrombogenic collagen receptors found on the platelet surface.Glycoprotein VI (GPVI) is increasingly being recognized as the main platelet-collagen receptor involved in arterial thrombosis. This review summarizes the crucial role GPVI plays in ischemic stroke as well as the current strategies used to attempt to inhibit its activity.In this review, we discuss the normal hemostatic process, and the role GPVI plays at sites of atherosclerotic plaque rupture. We discuss how the unique structure of GPVI allows for its interaction with collagen and creates downstream signaling that leads to thrombus formation. We summarize the current strategies used to inhibit GPVI activity and how this could translate to a clinically viable entity that may compete with current antiplatelet therapy.From animal models, it is clear that GPVI inhibition leads to an abolished platelet response to collagen and reduced platelet aggregation, culminating in smaller arterial thrombi. There is now an increasing body of evidence that these findings can be translated into the development of a bleeding free pharmacological entity specific to sites of plaque rupture in humans.
| S-EPMC5390959 | biostudies-other
Project description:Background To clarify differences in clinical significance of intracardiac thrombi in nonvalvular atrial fibrillation-associated stroke as identified by transesophageal echocardiography (TEE) and transthoracic echocardiography (TTE). Methods and Results Using patient data on nonvalvular atrial fibrillation-associated ischemic stroke between 2011 and 2014 from 15 South Korean stroke centers (n=4841) and 18 Japanese centers (n=1192), implementation rates of TEE/TTE, and detection rates of intracardiac thrombi at each center were correlated. The primary outcome was recurrent ischemic stroke at 1 year after the onset. A total of 5648 patients (median age, 75 years; 2650 women) were analyzed. Intracardiac thrombi were detected in 75 patients (1.3%) overall. Thrombi were detected in 7.8% of patients with TEE (either TEE alone or TEE+TTE: n=679) and in 0.6% of those with TTE alone (n=3572). Thrombus detection rates varied between 0% and 14.3% among centers. As TEE implementation rates at each center increased from 0% to 56.7%, thrombus detection rates increased linearly (detection rate [%]=0.11×TEE rate [%]+1.09 [linear regression], P<0.01). TTE implementation rates (32.3%-100%) were not associated with thrombus detection rates (P=0.53). Intracardiac thrombi were associated with risk of recurrent ischemic stroke overall (adjusted hazard ratio [aHR] 2.35, 95% CI, 1.07-5.16). Thrombus-associated ischemic stroke risk was high in patients with TEE (aHR, 3.13; 95% CI, 1.17-8.35), but not in those with TTE alone (aHR, 0.89; 95% CI, 0.12-6.51). Conclusions Our data suggest clinical relevance of TEE for accurate detection and risk stratification of intracardiac thrombi in nonvalvular atrial fibrillation-associated stroke. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01581502.
| S-EPMC8751927 | biostudies-literature
Project description:Patients with atrial fibrillation (AF) experiencing ischemic stroke despite oral anticoagulation (OAC), i.e., breakthrough strokes, are not uncommon, and represent an important clinical subgroup in view of the consistently high risk of stroke recurrence and mortality. The understanding of the heterogenous potential mechanism underlying OAC failure is essential in order to implement specific therapeutic measures aimed at reducing the risk of recurrent ischemic stroke. However, due to the incomplete comprehension of this phenomenon and the limited available data, secondary stroke prevention in such high-risk patients represents a clinical dilemma. There are several available strategies to prevent ischemic stroke recurrence in AF patients with breakthrough stroke in the absence of competing causes unrelated to AF, and these include continuation or change in the type of OAC, addition of antiplatelet therapy, left atrial appendage closure, or any combination of the above options. However, due to the limited available data, the latest guidelines do not provide any specific recommendations about which of the above strategies may be preferred. This review describes the incidence, the clinical impact and the potential mechanisms underlying OAC failure in AF patients. Furthermore, the evidence supporting each of the above therapeutic options for secondary stroke prevention and the potential future directions will be discussed.
| S-EPMC10532406 | biostudies-literature
Project description:Background and purposeAtrial fibrillation (AF) is a leading cause of cardioembolic stroke, but the relationship between AF and noncardioembolic stroke subtypes are unclear. Because AF may be unrecognized, and because AF has a substantial genetic basis, we assessed for predisposition to AF across ischemic stroke subtypes.MethodsWe examined associations between AF genetic risk and Trial of Org 10172 in Acute Stroke Treatment stroke subtypes in 2374 ambulatory individuals with ischemic stroke and 5175 without from the Wellcome Trust Case-Control Consortium 2 using logistic regression. We calculated AF genetic risk scores using single-nucleotide polymorphisms associated with AF in a previous independent analysis across a range of preselected significance thresholds.ResultsThere were 460 (19.4%) individuals with cardioembolic stroke, 498 (21.0%) with large vessel, 474 (20.0%) with small vessel, and 814 (32.3%) individuals with strokes of undetermined cause. Most AF genetic risk scores were associated with stroke, with the strongest association (P=6×10-4) attributed to scores of 944 single-nucleotide polymorphisms (each associated with AF at P<1×10-3 in a previous analysis). Associations between AF genetic risk and stroke were enriched in the cardioembolic stroke subset (strongest P=1.2×10-9, 944 single-nucleotide polymorphism score). In contrast, AF genetic risk was not significantly associated with noncardioembolic stroke subtypes.ConclusionsComprehensive AF genetic risk scores were specific for cardioembolic stroke. Incomplete workups and subtype misclassification may have limited the power to detect associations with strokes of undetermined pathogenesis. Future studies are warranted to determine whether AF genetic risk is a useful biomarker to enhance clinical discrimination of stroke pathogeneses.
| S-EPMC7438180 | biostudies-literature
Project description:The outcome of early intravenous thrombolysis for ischemic stroke in patients with atrial fibrillation (AF) is worse than that without thrombosis. How to increase the efficacy of intravenous thrombolysis for AF-related ischemic stroke remains largely unknown. In this study, we investigated factors that influence the effect of intravenous thrombolysis in these patients. Our results showed that thrombolysis was independently associated with a favorable outcome (P < 0.001) and did not influence the mortality of AF-related ischemic stroke, although it increased the risk of hemorrhage within 24 h after treatment. Risk factors for a poor outcome at admission were: heart failure (P = 0.045); high systolic pressure (P = 0.039); high blood glucose (P = 0.030); and a high National Institutes of Health Stroke Scale (NIHSS) score (P < 0.001). Moreover, high systolic pressure at admission (P = 0.007), high blood glucose (P = 0.027), and a high NIHSS score (P < 0.001) were independent risk factors for mortality at 3 months. Besides thrombolysis, a high NIHSS score (P = 0.006) and warfarin taken within 48 h before stroke onset (P = 0.032) were also independent risk factors for symptomatic hemorrhage within 24 h after treatment. Ischemic stroke patients with AF benefited from intravenous thrombolysis with recombinant tissue plasminogen activator within 4.5 h after stroke.
| S-EPMC5563741 | biostudies-other
Project description:IntroductionAtrial fibrillation (AF) is the most common cardiac arrhythmia in the general population, and stroke is the most severe complication of AF. Exosomal miRNAs have been reported to be candidates as biomarkers for cardiovascular diseases, including AF and stroke. This study aimed to identify differentially expressed miRNAs (DEMs) in serum exosomes of AF and AF-associated ischemic stroke (AF-IS) patients and evaluate their potential in distinguishing AF and AF-IS patients.MethodsSerum exosomes were isolated from 8 healthy individuals with sinus rhythm (SR controls), 8 AF patients, and 8 AF-IS patients. miRNA-seq was performed to identify DEMs, and qRT-PCR analysis was performed to confirm the sequencing results. A support vector machine (SVM) model was developed using Python to distinguish AF and AF-IS patients.Results68 and 86 DEMs were identified in serum exosomes of AF patients compared to AF-IS patients and SR controls, respectively. Levels of miR-641 and miR-30e-5p were found significantly higher in AF-IS patients. The SVM model achieved an accuracy of 100%, with an area under curve of 1.ConclusionsThe results indicated that miRNA expression profiles of serum exosomes in AF patients were distinct from those in AF-IS patients, and based on the distinction, AF and AF-IS patients can be distinguished.
| S-EPMC10273881 | biostudies-literature
Project description:Background Atrial fibrillation (AF) is a major, often undetected, cardiac cause of stroke. Markers of atrial cardiopathy, including left atrial enlargement (LAE) or excessive atrial ectopy (EAE) increase the risk of AF and have shown associations with stroke. We sought to determine whether these markers improve stroke risk prediction beyond traditional vascular risk factors (eg CHA2DS2-VASc score). Methods and Results Retrospective longitudinal cohort of 32 454 consecutive community-dwelling adults aged ≥65 years referred for outpatient echocardiogram or Holter in Ontario, Canada (2010-2017). Moderate-severe LAE was defined as men >47 mm and women >43 mm, and EAE was defined as >30 APBs per hour. Cause-specific competing risks Cox proportional hazards used to estimate risk of ischemic stroke (primary), incident AF, and death (secondary). C-statistics, incremental discrimination improvement and net reclassification were used to compare CHA2DS2-VASc with LAE and EAE to CHA2DS2-VASc alone. Each 10 mm increase in left atrial diameter increased 2- and 5-year adjusted cause-specific stroke hazard almost 2-fold (LAE: 2-year hazard ratio (HR), 1.72; P=0.007; 5-year HR, 1.87; P<0.0001), while EAE showed no significant associations with stroke (2-year HR, 1.00; P=0.99; 5-year HR, 1.08, P=0.70), adjusting for incident AF. Stroke risk estimation improved significantly at 2 (C-statistics=0.68-0.75, P=0.008) and 5 years (C-statistics=0.70-0.76, P=0.003) with LAE and EAE. Conclusions LAE was independently associated with an increased risk of ischemic stroke in the absence of AF and both LAE and EAE improved stroke risk prediction. These findings have implications for stroke risk stratification, AF screening, and stroke prevention before the onset of AF.
| S-EPMC7428995 | biostudies-literature
Project description:ObjectiveThe aim was to evaluate, in patients with atrial fibrillation (AF) and acute ischemic stroke, the association of prior anticoagulation with vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs) with stroke severity, utilization of intravenous thrombolysis (IVT), safety of IVT, and 3-month outcomes.MethodsThis was a cohort study of consecutive patients (2014-2019) on anticoagulation versus those without (controls) with regard to stroke severity, rates of IVT/mechanical thrombectomy, symptomatic intracranial hemorrhage (sICH), and favorable outcome (modified Rankin Scale score 0-2) at 3 months.ResultsOf 8,179 patients (mean [SD] age, 79.8 [9.6] years; 49% women), 1,486 (18%) were on VKA treatment, 1,634 (20%) on DOAC treatment at stroke onset, and 5,059 controls. Stroke severity was lower in patients on DOACs (median National Institutes of Health Stroke Scale 4, [interquartile range 2-11]) compared with VKA (6, [2-14]) and controls (7, [3-15], p < 0.001; quantile regression: β -2.1, 95% confidence interval [CI] -2.6 to -1.7). The IVT rate in potentially eligible patients was significantly lower in patients on VKA (156 of 247 [63%]; adjusted odds ratio [aOR] 0.67; 95% CI 0.50-0.90) and particularly in patients on DOACs (69 of 464 [15%]; aOR 0.06; 95% CI 0.05-0.08) compared with controls (1,544 of 2,504 [74%]). sICH after IVT occurred in 3.6% (2.6-4.7%) of controls, 9 of 195 (4.6%; 1.9-9.2%; aOR 0.93; 95% CI 0.46-1.90) patients on VKA and 2 of 65 (3.1%; 0.4-10.8%, aOR 0.56; 95% CI 0.28-1.12) of those on DOACs. After adjustments for prognostic confounders, DOAC pretreatment was associated with a favorable 3-month outcome (aOR 1.24; 1.01-1.51).InterpretationPrior DOAC therapy in patients with AF was associated with decreased admission stroke severity at onset and a remarkably low rate of IVT. Overall, patients on DOAC might have better functional outcome at 3 months. Further research is needed to overcome potential restrictions for IVT in patients taking DOACs. ANN NEUROL 2021;89:42-53.
| S-EPMC7756294 | biostudies-literature