Sarina Falcione1, Danielle Munsterman2, Twinkle Joy2, Joseph Kamtchum-Tatuene2, Gina Sykes2, Glen Jickling2. 1. From the Division of Neurology (S.F., D.M., T.J., G.S., G.J.), Department of Medicine, and Neuroscience and Mental Health Institute (J.K.-T.), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada. sfalcion@ualberta.ca. 2. From the Division of Neurology (S.F., D.M., T.J., G.S., G.J.), Department of Medicine, and Neuroscience and Mental Health Institute (J.K.-T.), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada.
Abstract
BACKGROUND AND OBJECTIVES: Thrombosis is central to the pathogenesis of acute ischemic stroke, with higher thrombin generation being associated with increased stroke risk. The immune system may contribute to thrombin generation in stroke and thus may offer novel strategies for stroke prevention. This study addresses the research question regarding the relationship of thrombin generation to leukocyte gene expression in patients with acute ischemic stroke. METHODS: We isolated RNA from whole blood and examined the relationship to thrombin generation capacity in patients with acute ischemic stroke. Due to its effects on thrombin generation, patients on anticoagulants were excluded from the study. The relationship of gene expression with peak thrombin was evaluated by analysis of covariance across peak thrombin quartiles adjusted for sex and age. RESULTS: In 97 patients with acute ischemic stroke, peak thrombin was variable, ranging from 252.0 to 752.4 nM. Increased peak thrombin was associated with differences in thromboinflammatory leukocyte gene expression, including a decrease in ADAM metallopeptidase with thrombospondin type 1 motif 13 and an increase in nuclear factor κB (NF-κB)-activating protein, protein disulfide isomerase family A member 5, and tissue factor pathway inhibitor 2. Pathways associated with peak thrombin included interleukin 6 signaling, thrombin signaling, and NF-κB signaling. A linear discriminant analysis model summarizing the immune activation associated with peak thrombin in a first cohort of stroke could distinguish patients with low peak thrombin from high peak thrombin in a second cohort of 112 patients with acute ischemic stroke. DISCUSSION: The identified genes and pathways support a role of the immune system contributing to thrombus formation in patients with stroke. These may have relevance to antithrombotic strategies for stroke prevention.
BACKGROUND AND OBJECTIVES: Thrombosis is central to the pathogenesis of acute ischemic stroke, with higher thrombin generation being associated with increased stroke risk. The immune system may contribute to thrombin generation in stroke and thus may offer novel strategies for stroke prevention. This study addresses the research question regarding the relationship of thrombin generation to leukocyte gene expression in patients with acute ischemic stroke. METHODS: We isolated RNA from whole blood and examined the relationship to thrombin generation capacity in patients with acute ischemic stroke. Due to its effects on thrombin generation, patients on anticoagulants were excluded from the study. The relationship of gene expression with peak thrombin was evaluated by analysis of covariance across peak thrombin quartiles adjusted for sex and age. RESULTS: In 97 patients with acute ischemic stroke, peak thrombin was variable, ranging from 252.0 to 752.4 nM. Increased peak thrombin was associated with differences in thromboinflammatory leukocyte gene expression, including a decrease in ADAM metallopeptidase with thrombospondin type 1 motif 13 and an increase in nuclear factor κB (NF-κB)-activating protein, protein disulfide isomerase family A member 5, and tissue factor pathway inhibitor 2. Pathways associated with peak thrombin included interleukin 6 signaling, thrombin signaling, and NF-κB signaling. A linear discriminant analysis model summarizing the immune activation associated with peak thrombin in a first cohort of stroke could distinguish patients with low peak thrombin from high peak thrombin in a second cohort of 112 patients with acute ischemic stroke. DISCUSSION: The identified genes and pathways support a role of the immune system contributing to thrombus formation in patients with stroke. These may have relevance to antithrombotic strategies for stroke prevention.
Authors: Donald Lloyd-Jones; Robert Adams; Mercedes Carnethon; Giovanni De Simone; T Bruce Ferguson; Katherine Flegal; Earl Ford; Karen Furie; Alan Go; Kurt Greenlund; Nancy Haase; Susan Hailpern; Michael Ho; Virginia Howard; Brett Kissela; Steven Kittner; Daniel Lackland; Lynda Lisabeth; Ariane Marelli; Mary McDermott; James Meigs; Dariush Mozaffarian; Graham Nichol; Christopher O'Donnell; Veronique Roger; Wayne Rosamond; Ralph Sacco; Paul Sorlie; Randall Stafford; Julia Steinberger; Thomas Thom; Sylvia Wasserthiel-Smoller; Nathan Wong; Judith Wylie-Rosett; Yuling Hong Journal: Circulation Date: 2009-01-27 Impact factor: 29.690
Authors: Ahamad Hassan; Beverley J Hunt; Michael O'Sullivan; Kiran Parmar; John M Bamford; Dennis Briley; Martin M Brown; Dafydd J Thomas; Hugh S Markus Journal: Brain Date: 2003-02 Impact factor: 13.501
Authors: Gina P Sykes; Joseph Kamtchum-Tatuene; Sarina Falcione; Sarah Zehnder; Danielle Munsterman; Boryana Stamova; Bradley P Ander; Frank R Sharp; Glen Jickling Journal: Stroke Date: 2021-03-01 Impact factor: 7.914