IL1B and VWF Variants Are Associated With Fibrinolytic Early Recanalization in Patients With Ischemic Stroke

Abstract

Background and Purpose-There is a great interindividual variability among patients with acute ischemic stroke regarding the response to intravenous tissue-type plasminogen activator treatment. The aim of this study was to identify genetic variants associated with recanalization, and thus treatment efficacy, after tissue-type plasminogen activator administration. Methods-A total of 140 single nucleotide polymorphisms from 97 candidate genes were successfully genotyped by SNPlex in 2 cohorts, accounting for 497 prospectively recruited tissue-type plasminogen activator-treated patients, of whom 33% recanalized during tissue-type plasminogen activator infusion. Functional studies were then performed, including assessment of interleukin 1B mRNA levels and von Willebrand factor, FIII, FVII, FVIII, and FX protein activity. Results-After replication, the following single nucleotide polymorphisms were associated with early recanalization: rs1143627 in IL1B Key Words: genetics Ⅲ pharmacogenetics Ⅲ recanalization Ⅲ stroke Ⅲ tPA I ntravenous tissue-type plasminogen activator (tPA) is the only drug currently approved for acute stroke treatment. The clinical response to intravenous tPA may be poor, because of a lack of efficacy in terms of early recanalization of the occluded vessel in 48% to 65% of patients 1 or because of safety concerns such as symptomatic hemorrhagic transformation occurring in 1.7% to 6.4% of cases and leading to death in 6.5% to 12.7% of cases. 2 A longer time to recanalization highly correlates with a larger infarcted area and worse neurological outcome, overall leading to poor clinical recovery from stroke. 3 The identification of factors predicting tPA efficacy could be useful to improve the management of patients with stroke, especially those not responding well to tPA treatment, because in these patients, the intra-arterial administration of tPA with or without coadjuvant drugs could be more effective than intravenous tPA treatment alone. In previous studies, we already identified some predictors of recanalization efficacy, namely thrombin-antithrombin complex levels and variants in the thrombin activable fibrinolysis inhibitor gene. 4,5 The aim of this study was to identify single nucleotide polymorphisms (SNPs) that could be used by physicians as new predictors of early recanalization to individualize and improve acute ischemic stroke treatment. Methods Study PopulationWhite patients with an acute ischemic stroke with a documented arterial occlusion by transcranial Doppler (TCD) and who received tPA in a standard dose of 0.9 mg/kg (10% bolus, 90% 1-hour continuous infusion) within the first 4.5 hours after onset of symptoms were consecutively recruited in the emergency department.The original The clinical data of both cohorts is available in online-only Data Supplement Table I. Clinical and TCD ProtocolOn admission to the emergency department, a detailed history of vascular risk factors and current medication was obtained from each patient. Stroke severity was assessed with the National In...

Effects of Danhong injection on hemodynamics and the inflammation-related NF-κB signaling pathway in patients with acute cerebral infarction

“…IL-6, another inflammatory cytokine secreted by vascular endothelial cells and macrophages, is also highly expressed in the serum of patients with acute cerebral infarction and is positively correlated to cerebral infarction size and degree of neurologic impairment (Xu et al, 2005;Choi et al, 2014). IL-1β is a major inflammatory-promoting cytokine, and it has been demonstrated that serum levels of IL-1β in patients with cerebral infarction are significantly increased, which is possibly associated with the development of cerebral infarction (Fernández-Cadenas et al, 2012). In the current study, the analysis of serum levels of inflammatory cytokines including IL-6, TNF-α and IL-1β in patients with cerebral infarction revealed higher than normal expression levels of these cytokines, which is consistent with previous reports.…”

“…Tanshinone and salvianolic acid can reduce blood viscosity, increase blood flow and erythrocyte deformation, inhibit thrombosis, scavenge free radicals, and improve microcirculation. Carthamin can dilate blood vessels, reduce platelet aggregation, and inhibit thrombosis (Fernández-Cadenas et al, 2012). Additionally, it has been reported that Danhong injection inhibits the expression of inflammatory cytokines and the resultant inflammatory cascade and reduces damage to organs and cells (Wang et al, 2013).…”

Acute Ischemic Stroke Therapy Overview

“…The IST (International Stroke Trial)-3 randomized the largest cohort of patients (3035) to IV tPA versus placebo and showed that despite early hazards from an increased risk of ICH, thrombolysis within 6 hours improved functional outcomes even in patients aged >80 years. 78 Although some studies have suggested that genetic polymorphisms, 79,80 race, and sex may influence the efficacy of tPA, 81,82 only certain comorbidities such as hypertension and hyperglycemia have been found to significantly and negatively impact thrombolytic response in AIS patients.…”

Stroke Recovery Genetics

“…33,34 Large efforts on studying genetic impact on early treatment effects of thrombolysis are underway. 40 Longer term prognosis on neurological/physical deficit can be grouped into neurological outcomes, stroke recurrence, and mortality. Alterations in the BDNF gene are often studied in stroke recovery.…”

“…A study of 140 single nucleotide polymorphisms in ischemic stroke patients treated with tissue-type plasminogen activator reported that variants in the IL1B and vWF genes were associated with early recanalization and suggested a relation to activity of coagulation factors. 40 In a microarray study, patients with hemorrhagic transformation after tissue-type plasminogen activator treatment had altered expression of genes related to apoptosis and neutrophil regulation pathways. 68 The genetic impact on metabolism and response to anticoagulation therapy would have important clinical consequences for stroke recovery.…”