Genetics of platelet traits in ischaemic stroke: focus on mean platelet volume and platelet count

Purpose/Aim of the study: The aim of this review is to summarize the role of genetic variants affecting mean platelet volume (MPV) and platelet count (PLT) leading to higher platelet reactivity and in turn to thrombotic events like stroke and cardiovascular diseases.

Materials and Methods: A search was conducted in PUBMED, MEDLINE, EMBASE, PROQUEST, Science Direct, Cochrane Library, and Google Scholar related to the studies focussing on genome-wide association studies (GWAS), whole exome sequencing (WES), whole genome sequencing (WGS), phenome-wide association studies (PheWAS) and multi-omic analysis that have been employed to identify the genetic variants influencing MPV and PLT.

Results: Antiplatelet agents underscore the crucial role of platelets in the pathogenesis of stroke. Higher platelet reactivity in terms of mean platelet volume (MPV) and platelet count (PLT) contributes significantly to the interindividual variation in platelet reaction at the site of vessel wall injury. Some individuals encounter thrombotic events as platelets get occluded at the site of vessel wall injury whereas others heal the injury without occluding the circulation. Evidence suggests that MPV and PLT have a strong genetic component. High throughput techniques including genome-wide association studies (GWAS), whole exome sequencing (WES), whole genome sequencing (WGS), phenome-wide association studies (PheWAS) and multi-omic analysis have identified different genetic variants influencing MPV and PLT.

Conclusions: Identification of complex genetic cross talks affecting PLT and MPV might help to develop novel treatment strategies in treating neurovascular diseases like stroke.     

Comparison of classification methods for tissue outcome after ischaemic stroke

In acute ischaemic stroke, identifying brain tissue at high risk of infarction is important for clinical decision‐making. This tissue may be identified with suitable classification methods from magnetic resonance imaging data. The aim of the present study was to assess and compare the performance of five popular classification methods (adaptive boosting, logistic regression, artificial neural networks, random forest and support vector machine) in identifying tissue at high risk of infarction on human voxel‐based brain imaging data. The classification methods were used with eight MRI parameters, including diffusion‐weighted imaging and perfusion‐weighted imaging obtained in 55 patients. The five criteria used to assess the performance of the methods were the area under the receiver operating curve (AUC_roc), the area under the precision–recall curve (AUC_pr), sensitivity, specificity and the Dice coefficient. The methods performed equally in terms of sensitivity and specificity, while the results of AUC_roc and the Dice coefficient were significantly better for adaptive boosting, logistic regression, artificial neural networks and random forest. However, there was no statistically significant difference between the performances of these five classification methods regarding AUC_pr, which was the main comparison metric. Machine learning methods can provide valuable prognostic information using multimodal imaging data in acute ischaemic stroke, which in turn can assist in developing personalized treatment decision for clinicians after a thorough validation of methods with an independent data set.     

Plasma brain natriuretic peptide predicts death during hospitalization in acute ischaemic stroke and transient ischaemic attack patients with atrial fibrillation

Background and purpose: Atrial fibrillation (AF) is the most powerful predictor of early death in patients with acute ischaemic stroke. We investigated whether the plasma brain natriuretic peptide (BNP) level on admission can serve as a biological marker of in‐hospital death in acute ischaemic stroke and transient ischaemic attack (TIA) patients with AF. Methods: We prospectively enrolled ischaemic stroke and TIA patients with AF within 24 h of onset and measured plasma BNP on admission. Patients were divided into two groups: the deceased group, who died during hospitalization, and the survival group. The factors associated with in‐hospital death were investigated by multivariate logistic regression analysis. Results: A total of 221 patients with AF were enrolled. Death occurred in 24 (10.9%) patients. The mean ± SD of the plasma BNP level of the deceased group was significantly higher than that of the survival group (714.1 ± 716.3 vs. 320.0 ± 380.7 pg/ml, P < 0.0001). The optimal cutoff level, sensitivity, and specificity of BNP levels to distinguish the deceased group from the survival group were 320 pg/ml, 79.2, and 69.0%, respectively. Multivariate logistic regression analysis demonstrated that age per 10 years increase (OR, 3.56; 95% CI, 1.728–7.346, P = 0.0006), internal carotid artery occlusion (OR, 10.20; 95% CI, 2.525–41.177, P = 0.0011), NIHSS score of >17 (OR, 4.68; 95% CI, 1.137–19.286, P = 0.0325), and plasma BNP level of >320 pg/ml (OR, 4.74; 95% CI, 1.260–17.800, P = 0.0213) were independent factors associated with in‐hospital death. Conclusion: The plasma BNP level on admission can predict in‐hospital death in acute ischaemic stroke and TIA patients with AF.     

Significance of microbleeds in patients with transient ischaemic attack

Background and purpose: The aim of this study was to determine the prognostic significance of microbleeds in TIA‐patients. In patients with a transient ischaemic attack (TIA), the prognostic value of microbleeds is unknown. Methods: In 176 consecutive TIA patients, the number, size, and location of microbleeds with or without acute ischaemic lesions were assessed. We compared microbleed‐positive and microbleed‐negative patients with regard to the end‐point stroke within 3 months. Results: Four of the seven patients with subsequent stroke had microbleeds. Microbleed‐positive patients had a higher risk for stroke [odds ratios (OR) 8.91, 95% CI 1.87–42.51, P < 0.01] than those without microbleeds. Microbleed‐positive patients with accompanying acute ischaemic lesions had a higher stroke risk than those with neither an acute ischaemia nor a microbleed (OR 6.20, 95% CI 1.10–35.12; P = 0.04). Conclusion: Microbleeds alone or in combination with acute ischaemic lesions may increase the risk for subsequent ischaemic stroke after TIA within 3 months.     

An intravenous insulin protocol for strict glycemic control in acute ischaemic stroke

Background and purpose: There is a J‐shaped association between admission glycemia and outcome. We designed an intravenous insulin protocol aiming at rapid and strict glucose control in hyperglycemic ischaemic stroke patients. Here, we describe the initial experience, safety, and efficacy of this protocol to achieve and maintain euglycemia in the first 48 h. Methods: The protocol is based on parallel scales for adjustment of insulin infusion rate according to current glycemia and the rate of change of glycemia, which was recommended in our stroke unit in 4/2007 in acute ischaemic stroke patients with glycemia > 6 mM. Data were registered in the Acute Stroke Registry and Analysis of Lausanne (ASTRAL). Capillary blood glycemia was measured hourly with fingerprick test at onset of treatment and after each scale change. Target glycemia was 4.0–6.0 mM pre‐prandially (5.5–8.0 mM post‐prandially). Hypokalemia was defined as serum potassium < 3.5 mM and measured every 12 h. Specific algorithms were employed during meals and for patients leaving temporarily the stroke unit for diagnostic or therapeutic workup. Results: In the 90 protocol patients, the first normoglycemia was achieved within 8 h of treatment in 91.1% of patients (median interval 4 h (interquartile range (IQR): 3–6). During the median treatment duration of 25.5 h (IQR: 19.7–37.7), median glucose reduction was 2.5 mM (IQR: 1.3–4.3 mM). The overall rate of hypoglycemias was 4.5% and hypokalemias 18.5%. There was a significant increase in the proportion of hypokalemias on the first on‐treatment measurement compared to admission (24.4% vs. 8.9%, P = 0.002). Conclusions: The proposed intravenous insulin protocol controls acute post‐stroke hyperglycemia but frequently leads to hypokalemia. This issue needs to be addressed for the protocol to be suitable for use in larger, randomized controlled trial to explore its clinical effect.     

Long-term outcome after ischaemic stroke/transient ischaemic attack

During the first 30 days after a stroke, the case fatality is about 25% and the major cause of death is the index stroke and its sequelae. The most consistent predictor of 30-day mortality after stroke is stroke severity. Other predictors include increasing age, a history of previous stroke, cardiac failure, and a high blood glucose concentration and white blood cell count. Other less common, but important, causes of early mortality are recurrent ischaemic stroke and a coronary event. The risk of a recurrent cerebrovascular event is highest in the first month (4%) and year (12%) after a stroke and transient ischaemic attack (TIA), probably reflecting the presence of active, unstable atherosclerotic plaque. Thereafter, the risk of a recurrent cerebrovascular event falls to about 5% per year, similar to the risk of a coronary event. During years 1-5 after a TIA and ischaemic stroke, cardiovascular disease increasingly becomes the major cause of death, reflecting the generalized nature of atherothrombosis, the most common cause of the index stroke. The most robust predictor of death within 1-5 years after stroke is increasing age, closely followed by cardiac failure. Additional baseline predictors of longer-term mortality include a history of previous symptomatic atherothrombosis (TIA, ischaemic stroke, peripheral arterial disease, and early-onset ischaemic heart disease), risk factors for atherothrombosis (smoking), other heart diseases (cardiac failure, atrial fibrillation) and increasing stroke severity. Lacunar syndromes can be predictive of relative longevity. At 5 years after stroke, survival is about 40%, and about half of survivors are disabled and dependent. The most robust predictors of disability at 5 years after stroke are increasing age, stroke severity, and recurrent stroke. The most powerful predictor of early recurrent stroke (within 30 days after stroke) is an atherosclerotic ischaemic stroke caused by large-artery atherosclerosis with >50% stenosis, whereas the strongest predictor of stroke recurrence over 5 years is diabetes. Other predictors of recurrent stroke include increasing age, previous TIA, atrial fibrillation, high alcohol consumption, haemorrhagic index stroke, and hypertension at discharge. The clinical implication of these findings is that strategies for optimizing long-term outcome after TIA and stroke should be directed toward reducing the high risk of recurrent stroke and coronary events by removing/recanalizing the symptomatic atherosclerotic plaque, controlling the underlying causal vascular risk factors, and administering long-term, effective antiplatelet therapy.     

Predictive value of ankle brachial index in patients with acute ischaemic stroke

Background: The ankle brachial index (ABI) is a known measure of lower‐limb peripheral artery disease (PAD), as well as a marker for other cardiovascular disease events. Objective: Our goal was to compare the prevalence of abnormal ABI scores (ABI ≤ 0.9) between: consecutive patients with acute ischaemic stroke (IS), primary care patients with refractory hypertension (rHT), and patients at intermediate cardiovascular risk (ICVR). Also, to determine the prognostic value of abnormal ABI for stroke recurrence in patients with IS. Methods: We compared 116 consecutive patients with IS with 190 rHT and 150 ICVR patients. Clinical data and ultrasonographic findings were recorded. Stroke recurrence and risk of new vascular events were assessed after 18 months of follow‐up. Results: Low ABI was more frequent in rHT (35.8%) than in the IS (24.1%) and ICVR (24.7%) groups (P = 0.031). Amongst patients with IS, ABI ≤ 0.9 was associated with vascular risk factors (VRF) ≥3 (33.8% vs. 7.1%, P = 0.001) and large‐artery atherosclerosis (LAA) (43.5% vs. 19.4%, P = 0.015). Multivariate analyses (logistic regression) only identified VRF > 3 as independently associated with low ABI (OR: 6.46; 1.81‐23.02; P = 0.004). Abnormal ABI was associated with stroke recurrence (32.1% vs. 13.6%, P = 0.027) and the appearance of any major vascular event (50.0% vs. 17.0%, P < 0.001). In the logistic regression analysis, adjusted for VRF, age, and LAA, ABI remained as an independent predictor of vascular events (HR 3.99; 1.90–8.41 P < 0.001). Conclusion: Abnormal ABI was associated with classical risk factors, especially hypertension. The measurement of ABI amongst patients with IS appeared to be useful to identify high‐risk patients and plan adequate prevention therapies.     

The ischaemic penumbra

The concept of an ischaemic penumbra, surrounding a focal cerebral lesion, is now widely accepted, although no universal definition of the 'penumbra' exists. In the present review, we consider the penumbra as that volume of brain tissue at the periphery of a focal, irreversibly damaged area that is threatened by recruitment into necrosis. Implicit to such a definition are several secondary concepts. First, the penumbra is both spatial, in that it surrounds the densely ischaemic core, but it is also temporal, in that its evolution toward infarction is a relatively progressive phenomenon. The pertinent literature is summarized. Second, penumbral tissue is potentially salvageable; the most recent animal studies are reviewed. Third, because electrically silent and pathologically damaged tissues have identical functional characteristics, it is evident that most clinical rating scales, be they neurological, behavioural, or psychological, are poorly adapted to address the problem of the penumbra. Finally, the penumbral tissue is remarkably and intensively 'active': multiple processes of cell death and repair occur and involve molecular mechanisms, electrophysiology and the vasculature.     

Post-surgical ischaemic myelopathy

Ischaemic myelopathy is an infrequent but well-known cause of spinal cord injury. While the overall incidence of neurological injury following thoraco-abdominal aortic surgery is low (1-14%), procedures requiring surgical cross-clamping of the aorta have been reported as the major cause of ischaemic cord injury (31%). Little has been reported regarding the clinical and functional outcomes of these injuries. Three patients with a non-penetrating aortic injury who showed evidence of ischaemic cord injury within 72 hours of surgical cross-clamping of the aorta are presented. Data includes functional assessments, muscle strength testing and electromyographic findings. All three patients showed lower thoracic incomplete motor and sensory spinal cord injuries. These findings suggest that, after a period of neurological improvement, a plateau phase is reached at approximately 3 months post injury after which no significant gain in muscle strength is made. All patients were functionally independent and able to ambulate using a straight cane.     

Platelet activation and secretion in patients with major depression,thoracic aortic atherosclerosis,or renal dialysis treatment

Relatively little is known concerning the magnitude of alterations of platelet activation and secretion markers of patients with major depression when compared to patients at increased risk for, or with current, clinically significant atherosclerosis. Markers of in vivo platelet stimulation and secretion were measured under basal conditions in normal comparison subjects (n = 12) and three patient groups: patients diagnosed with DSM-IV major depression (n = 15), dialysis-dependent patients (n = 12), and patients with severe thoracic aortic atherosclerosis (n = 10). In comparison to normal comparison subjects, depressed patients and patients with thoracic aortic atherosclerosis exhibited the greatest platelet stimulation as detected by increased anti-LIBS platelet binding. Dialysis-dependent patients exhibited the highest plasma concentrations of the renally-excreted platelet-specific secretion protein, beta-thromboglobulin. This study extends previous observations of increased platelet activation in patients with major depression and documents similar alterations in patients with transesophageal echocardiography (TEE)-documented thoracic aortic atherosclerosis. Future studies will determine whether the magnitude of platelet stimulation and secretion in patients with comorbid depression and atherosclerotic aortic disease is greater than that observed in nondepressed patients with atherosclerotic aortic disease or major depression alone. These findings provide further evidence for either increased platelet activation and/or intrinsic heightened platelet reactivity as one of the biological substrates underlying the increased risk of depressed patients for cardiovascular disease.     

Spinal ischaemic stroke: clinical and radiological findings and short‐term outcome

Background and purpose: The mechanism and pathogenesis of ischemic spinal stroke remain largely undetermined because most clinical studies have included mostly patients without a systematic study of associated vascular and concomitant disease of the vertebral body. Therefore, we assessed the pathogenetic mechanisms and short‐term outcomes of the patients with spinal stroke based on clinical data and magnetic resonance imaging findings. Methods: We studied clinical, imaging, and outcome data for 36 patients with acute spinal stroke admitted between 1998 and 2008. There were 16 men and 20 women (mean age 73, range 56–85 years). Results: Twelve patients (33%) had anterior spinal artery patterns, 8 (22%) had anterior and 6 (17%) had posterior unilateral infarct, 5 (14%) had posterior spinal artery infarct pattern, 3 (8%) had central involvement, and 2 (5%) had transverse syndrome. Twelve patients (33%) had no cause of stroke. Patients with central infarct and transverse infarct had a high frequency of peripheral vascular disease and prolonged hypotension, and one patient each had a chronic spinal disease. The onset of all other infarcts was associated with mechanical triggering movements in 12 patients (41%, P < 0.05), and with diseases of the spine in 19 (66%; P < 0.001), with the clinical picture suggesting root involvement at the level of the spinal cord ischemia. The short‐term outcomes were favorable in two‐thirds of patients, while 25% of them did not show any recovery on leaving the hospital. Conclusion: The most common type of spinal cord ischemia is bilateral or unilateral anterior spinal artery infarcts due to radicular artery disease with acute or chronic spinal disease and followed by central and transverse infarcts due to extensive spinal cord hypoperfusion and arteriopathy.