Assessment of platelet function in patients with stroke using multiple electrode platelet aggregometry: a prospective observational study

Sabra et al. BMC Neurology (2016) 16:254 DOI 10.1186/s12883-016-0778-x RESEARCH ARTICLE Open Access Assessment of platelet function in patients with stroke using multiple electrode platelet aggregometry: a prospective observational study Ahmed Sabra1,2,3†, Sophia N. Stanford1,2†, Sharon Storton2, Matthew Lawrence1,2, Lindsay D’Silva1,2, Roger H. K. Morris4, Vanessa Evans2, Mushtaq Wani5, John F. Potter6 and Phillip A. Evans1,2,7* Abstract Background: There is a link between high on-treatment platelet reactivity (HPR) and adverse vascular events in stroke. This study aimed to compare multiple electrode platelet aggregometry (MEA), in healthy subjects and ischaemic stroke patients, and between patients naive to antiplatelet drugs (AP) and those on regular low dose AP. We also aimed to determine prevalence of HPR at baseline and at 3–5 days after loading doses of aspirin. Methods: Patients with first ever ischaemic stroke were age and sex-matched to a healthy control group. Three venous blood samples were collected: on admission before any treatment given (baseline); at 24 h and 3–5 days after standard treatment. MEA was determined using a Mutliplate® analyser and agonists tested were arachidonic acid (ASPI), adenosine diphosphate (ADP) and collagen (COL). Results: Seventy patients (mean age 73 years [SD 13]; 42 men, 28 women) were age and sex-matched to 72 healthy subjects. Thirty-three patients were on antiplatelet drugs (AP) prior to stroke onset and 37 were AP-naive. MEA results for all agonists were significantly increased in AP-naive patients compared to healthy subjects: ADP 98 ± 31 vs 81 ± 24, p < 0.005; ASPI 117 ± 31 vs 98 ± 27, p < 0.005; COL 100 ± 25 vs 82 ± 20, p < 0.005. For patients on long term AP, 33% (10/30) of patients were considered aspirin-resistant. At 3–5 days following loading doses of aspirin, only 11.1% were aspirin resistant based on an ASPI cut-off value of 40 AU*min. Conclusions: Many patients receiving low dose aspirin met the criteria of aspirin resistance but this was much lower at 3–5 days following loading doses of aspirin. Future studies are needed to establish the causes of HPR and potential benefits of individualizing AP treatment based on platelet function testing. Keywords: Ischaemic stroke, Multiple electrode platelet aggregometry, Platelet function, Antiplatelet therapy, Aspirin, Clopidogrel, Aspirin resistance Background Platelets play a major role in arterial thrombus formation and therefore in the pathophysiology of ischaemic stroke [1–4]. Excessive platelet activation leads to increased thrombin generation and potentially abnormal thrombus formation [5]. Hence the importance of oral antiplatelet * Correspondence: † Equal contributors 1 Medical School, Swansea University, Swansea, UK 2 NISCHR Haemostasis Biomedical Research Unit, Morriston Hospital, Swansea, UK Full list of author information is available at the end of the article drugs, which are the mainstream therapy in the primary and secondary prevention of cerebrovascular disease [6, 7]. Currently, the antiplatelet (AP) drugs most widely used are aspirin and clopidogrel, and multiple electrode platelet aggregometry (MEA) has been used to study their effects on platelet function [8–11]. MEA has also been used to investigate the effects of non-opioid analgesics [12], anticoagulants [13], antifibrinolytics [14] and temperature [15] on platelet aggregation. © The Author(s). 2016 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Sabra et al. BMC Neurology (2016) 16:254 Despite the effectiveness of aspirin in the primary and secondary prevention of atherothrombotic disease, patients continue to suffer recurrent thromboembolic vascular events whilst on AP treatment [16]. This recurrence has been associated with high on-treatment platelet reactivity (HPR), with up to more than 60% of subjects being reported to be resistant to antiplatelet therapy (aspirin or clopidogrel) [17, 18]. Although some studies showed a link between HPR and major adverse vascular events [19, 20], the use of platelet function analysis to detect and manage HPR continues to be debated. Most studies that investigated HPR were undertaken for patients already receiving antiplatelet therapy without assessing baseline platelet reactivity [19, 20], which may partly explain the conflicting results. We were therefore interested in whether patients have a higher platelet reactivity at baseline, which may contribute to the suboptimal response to treatment. Hence this study aimed to compare platelet function, as determined by MEA, in healthy subjects and stroke patients prior to treatment initiation and between patients naive to AP therapy and those on regular low dose aspirin or clopidogrel. Methods Study design A prospective observational study to compare platelet function between age matched healthy controls and patients with ischaemic stroke using MEA; and between patients naive to and on baseline AP therapy. Patient population First time ischaemic stroke patients were recruited upon their presentation to the Emergency Department of a large teaching hospital (ABMU Health Board, Swansea, UK). Once a provisional diagnosis of stroke was made by the care team, strict inclusion criteria were applied. The inclusion criteria including only adults (≥18 years), the clinical assessment of ischaemic stroke was based on clinical history, examination and neuroradiology, the diagnosis of stroke was further validated by a member of the research team using WHO diagnostic criteria [21]. Full informed conset was sought from the outset and for those unable to consent due to lack of mental capacity assent was sought from personal or professional legal representatives. Exclusion criteria included: previous stroke; reciveing anticoagulant therapy; use of nonsteroidal anti-inflammatory drugs (NSAIDs) aside from low-dose aspirin; suffering from a disease known to alter coagulation (e.g. liver disease, malignancy, renal failure) or imminent death. Investigators were blinded to the result of MEA testing. Stroke patients were compared to an age-matched control group recruited from a healthy local population who were subsequently tested at the Haemostasis Biomedical Research Unit (HBRU). The helathy volunteers were Page 2 of 8 recruited via various advertising means including posters, internal email or direct invitations of staff and patients’ relatives. Healthy volunteers were recruited if over 18 y (...truncated)