Thrombin generation parameters, relationship with cerebral micro-embolic signal status, and a systematic review of the literature on platelet biomarkers in patients with symptomatic and asymptomatic carotid stenosis
Citation:
Subramanian, Arun, Thrombin generation parameters, relationship with cerebral micro-embolic signal status, and a systematic review of the literature on platelet biomarkers in patients with symptomatic and asymptomatic carotid stenosis, Trinity College Dublin.School of Medicine, 2022Download Item:
Abstract:
Background:?Activation of platelets and the coagulation system are integrally involved in acute thrombus formation and distal thrombo-embolism. A better understanding of these complex thrombotic and haemostatic pathways could improve primary and secondary prevention in patients with atherosclerotic carotid stenosis.
Aims I:?One of the main aims of this thesis was to perform innovative preliminary experiments to assess coagulation system potential in patients with moderate or severe asymptomatic and symptomatic carotid artery stenosis and to assess the relationship between these biomarkers and cerebral micro-embolic signals (MES).
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Aims II:?The co-primary aim of this thesis was to conduct a systematic review to enhance our understanding of the role of platelet biomarkers in the pathogenesis of vascular events and risk stratification in patients with asymptomatic and symptomatic atherosclerotic carotid stenosis.
Methods I:?An observational analytical study, with longitudinal follow-up in the symptomatic cohort, was performed to assess thrombin generation potential parameters in patients with moderate or severe (≥50-99%) asymptomatic?vs. early (≤4 weeks) and late phase symptomatic (≥3 months after TIA or stroke) carotid stenosis. Coagulation system/thrombin generation potential was assessed in platelet poor plasma in patients who had been recruited to the?HaEmostasis?In carotid?STenosis (HEIST) study. Transcranial Doppler ultrasound was performed to evaluate for the presence of cerebral MES in both study groups.
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Methods II:?A Systematic review was conducted in accordance with the current Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement to collate all available data from 1975-2020 on?ex vivo?platelet activation and platelet function/reactivity in patients with atherosclerotic carotid stenosis.
Results I:?Data from 34 asymptomatic, 39 'early symptomatic' and 31 'late symptomatic' patients were analysed. Peak thrombin production (365.1 vs. 327.2 nM, P = 0.003) and endogenous thrombin potential ETP (2242.6 vs. 2078.4 nM*min, P = 0.048) significantly decreased between the early and late phase after symptom onset in symptomatic patients with 'matched data' at each time point, regardless of whether or not they underwent carotid interventional treatment. Of note, peak thrombin levels only decreased in the symptomatic subgroup who underwent carotid intervention between the early phase and late post-intervention phase (P = 0.007) but did not change significantly over time in the symptomatic subgroup who did not have carotid interventional treatment and who were treated with best medical therapy alone. There were no differences in any other thrombin generation parameters over time within subgroups of symptomatic patients who did or did not undergo carotid intervention. Transcranial Doppler ultrasound data were available in 28 asymptomatic, 30 early symptomatic, and 26 late symptomatic patients. In our nested longitudinal study, peak thrombin generation also significantly decreased between the early and late phase after symptom onset in the subgroup of MES-ve symptomatic patients who had matched data at each time point (376.8nM vs. 325.4nM; P = 0.029)
Results II:?For our systematic review, 43 manuscripts met inclusion criteria; the majority included patients on antiplatelet therapy. Five studies showed increased platelet biomarkers in patients with ≥30% asymptomatic carotid stenosis?vs. controls, with one neutral study. Preliminary data from one study suggest that quantification of 'coated platelets' in combination with stenosis severity may aid risk stratification in patients with ≥50-99% asymptomatic stenosis. Platelets are excessively activated in patients with ≥30% symptomatic carotid stenosis compared with controls (≥11 positive studies and one neutral study). Antiplatelet-High on-Treatment Platelet Reactivity (HTPR), previously called 'antiplatelet-resistance,' was observed in 23 - 57% on aspirin (N = 7/30 - 17/30), with clopidogrel-HTPR in 25-100% (N= 1/4 - 4/4) of patients with ≥50-99% asymptomatic stenosis in the literature. Aspirin-HTPR was noted in 9.5-64% (N = 4/42 - 7/11) and clopidogrel-HTPR in 0-83% (N = 0/6 - 5/6) of patients with ≥50% symptomatic stenosis. Platelets are excessively activated (N=5), with increased platelet counts (N=3) in recently symptomatic?vs. asymptomatic carotid stenosis patients, including those without micro-emboli on transcranial Doppler monitoring (N=2). Most available studies (7/13) showed that platelets might become more reactive or activated following carotid endarterectomy or stenting, either as an acute phase response to intervention or peri-procedural treatment.
Discussion and Conclusions:?Thrombin generation potential decreased over time following TIA or stroke associated with recently symptomatic carotid stenosis, especially in patients who underwent intervention and in the subgroup who were MES-ve. These data enhance our understanding of the haemostatic/thrombotic biomarker profiles in patients with moderate-severe carotid stenosis.?
Our systematic review has shown that platelets are excessively activated in carotid stenosis patients compared with controls, recently symptomatic compared with asymptomatic carotid stenosis patients, and may become activated/hyper-reactive following carotid intervention despite commonly-prescribed antiplatelet regimens. However, the use of?ex vivo?platelet function/reactivity testing to tailor antiplatelet therapy is not currently recommended outside of a research setting.
Further prospective multicentre studies are required to determine whether models combining clinical, neurovascular-imaging, and thrombin generation/platelet biomarker data can facilitate optimised antithrombotic therapy in individual patients with carotid stenosis.
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Vascular Neurology Research Foundation
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https://tcdlocalportal.tcd.ie/pls/EnterApex/f?p=800:71:0::::P71_USERNAME:SUBRAMA1Description:
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Author: Subramanian, Arun
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Trinity College Dublin. School of Medicine. Discipline of Clinical MedicineType of material:
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