1502 Stroke June 2015 contribute to a procoagulant state in patients with acute cardiac and brain

Tissue factor (TF) is an integral membrane glycoprotein that is expressed by activated endothelial cells, macrophages, and vascular smooth muscle cells in response to various inflammatory stimuli. When exposed to blood flow TF binds coagulation factor VII and its activated form (VIIa), starting the coagulation process and leading ultimately to thrombin generation, fibrin deposition, and thrombus formation. Coagulation activation and consequent thrombus formation are key mechanisms in the pathogenesis of ischemic arterial disease. TF expression is increased in inflammatory atherosclerotic plaques and has been related to their thrombogenicity. TF present in the arterial wall has been considered in the past responsible for the initiation of the coagulation cascade and thrombus formation. According to this paradigm, coagulation is initiated after a vessel is damaged and blood with its cellular components, particularly platelets, is exposed to vessel wall TF. More recently, also blood-borne TF, mainly generated by leukocytes and blood platelets, was proven to be inherently thrombogenic and could be involved in thrombus propagation at the site of vascular injury. Several studies have investigated TF levels in blood of patients with ischemic vascular disease. Blood-borne TF may Background and Purpose—Tissue factor (TF) expression is increased in inflammatory atherosclerotic plaques and has been related to their thrombogenicity. Blood-borne TF has been also demonstrated to contribute to thrombogenesis. However, few studies have evaluated the association of circulating levels of TF with stroke. We investigated the association of baseline circulating levels of TF with stroke events occurred in the European Prospective Investigation into Cancer and Nutrition-Italy cohort. Methods—Using a nested case–cohort design, a center-stratified random sample of 839 subjects (66% women; age range, 35–71 years) was selected as subcohort and compared with 292 strokes in a mean follow-up of 9 years. Blood samples were collected at baseline in citrate, plasma was stored in liquid nitrogen and TF was measured by ELISA (IMUBIND, TF ELISA, Instrumentation Laboratory, Milan, Italy). The odd ratios and 95% confidence intervals, adjusted by relevant confounders (covariates of TF) and stratified by center, were estimated by a Cox regression model using Prentice method. Results—Individuals in the highest compared with the lowest quartile of TF plasma levels had significantly increased risk of stroke (odds ratio IVvsI quartile , 2.01; 95% confidence interval, 1.25–3.23). The association was independent from several potential confounders (odds ratio IVvsI quartile , 1.91; 95% confidence interval, 1.15–3.19). No differences were observed between men and women. The increase in risk was restricted to ischemic strokes (odds ratio IVvsI quartile , 2.13; 95% confidence interval, 1.10–4.12; fully adjusted model), whereas high levels of TF were not associated with the risk of hemorrhagic stroke (odds ratio IVvsI quartile , 1.12; 95% confidence interval, 0.49–2.55; fully adjusted model). Conclusions—Our data provide evidence that elevated levels of circulating TF are potential risk factors for ischemic strokes. (Stroke. 2015;46:1501-1507. DOI: 10.1161/STROKEAHA.115.008678.)