Circulating Tissue Factor Levels and Risk of Stroke: Findings From the EPICOR Study.
OBJECTIVE
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 ratioIVvsI quartile, 2.01; 95% confidence interval, 1.25-3.23). The association was independent from several potential confounders (odds ratioIVvsI 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 ratioIVvsI 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 ratioIVvsI 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.
From the Laboratory of Molecular and Nutritional Epidemiology, Department of Epidemiology and Prevention, IRCCS Istituto Neurologico Mediterraneo Neuromed, Pozzilli (IS), Italy (L.I., A.D.C., A.d.C., G.d.G., M.B.D.); Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy (C.A., S.G.); Cancer Registry ASP, Ragusa, Italy (G.F., R.T.); Dipartimento di Medicina Clinica e Chirurgia, University of Naples "Federico II", Napoli, Italy (A.M., S.P.); Department of Medical Sciences, University of Torino, Torino, Italy (G.M.); Human Genetics Foundation (HuGeF), Turin, Italy (G.M., C.S.); Unit of Cancer Epidemiology, AO Città della Salute e della Scienza-University of Turin, Center for Cancer Prevention (CPO-Piemonte), Turin, Italy (F.R., C.S.); and Research Laboratories, Fondazione di Ricerca e Cura Giovanni Paolo II, Campobasso, Italy (E.N., R.L.). licia.iacoviello@moli-sani.org.
Licia
L
Iacoviello
From the Laboratory of Molecular and Nutritional Epidemiology, Department of Epidemiology and Prevention, IRCCS Istituto Neurologico Mediterraneo Neuromed, Pozzilli (IS), Italy (L.I., A.D.C., A.d.C., G.d.G., M.B.D.); Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy (C.A., S.G.); Cancer Registry ASP, Ragusa, Italy (G.F., R.T.); Dipartimento di Medicina Clinica e Chirurgia, University of Naples "Federico II", Napoli, Italy (A.M., S.P.); Department of Medical Sciences, University of Torino, Torino, Italy (G.M.); Human Genetics Foundation (HuGeF), Turin, Italy (G.M., C.S.); Unit of Cancer Epidemiology, AO Città della Salute e della Scienza-University of Turin, Center for Cancer Prevention (CPO-Piemonte), Turin, Italy (F.R., C.S.); and Research Laboratories, Fondazione di Ricerca e Cura Giovanni Paolo II, Campobasso, Italy (E.N., R.L.).
Augusto
A
Di Castelnuovo
From the Laboratory of Molecular and Nutritional Epidemiology, Department of Epidemiology and Prevention, IRCCS Istituto Neurologico Mediterraneo Neuromed, Pozzilli (IS), Italy (L.I., A.D.C., A.d.C., G.d.G., M.B.D.); Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy (C.A., S.G.); Cancer Registry ASP, Ragusa, Italy (G.F., R.T.); Dipartimento di Medicina Clinica e Chirurgia, University of Naples "Federico II", Napoli, Italy (A.M., S.P.); Department of Medical Sciences, University of Torino, Torino, Italy (G.M.); Human Genetics Foundation (HuGeF), Turin, Italy (G.M., C.S.); Unit of Cancer Epidemiology, AO Città della Salute e della Scienza-University of Turin, Center for Cancer Prevention (CPO-Piemonte), Turin, Italy (F.R., C.S.); and Research Laboratories, Fondazione di Ricerca e Cura Giovanni Paolo II, Campobasso, Italy (E.N., R.L.).
Amalia
A
de Curtis
From the Laboratory of Molecular and Nutritional Epidemiology, Department of Epidemiology and Prevention, IRCCS Istituto Neurologico Mediterraneo Neuromed, Pozzilli (IS), Italy (L.I., A.D.C., A.d.C., G.d.G., M.B.D.); Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy (C.A., S.G.); Cancer Registry ASP, Ragusa, Italy (G.F., R.T.); Dipartimento di Medicina Clinica e Chirurgia, University of Naples "Federico II", Napoli, Italy (A.M., S.P.); Department of Medical Sciences, University of Torino, Torino, Italy (G.M.); Human Genetics Foundation (HuGeF), Turin, Italy (G.M., C.S.); Unit of Cancer Epidemiology, AO Città della Salute e della Scienza-University of Turin, Center for Cancer Prevention (CPO-Piemonte), Turin, Italy (F.R., C.S.); and Research Laboratories, Fondazione di Ricerca e Cura Giovanni Paolo II, Campobasso, Italy (E.N., R.L.).
Claudia
C
Agnoli
From the Laboratory of Molecular and Nutritional Epidemiology, Department of Epidemiology and Prevention, IRCCS Istituto Neurologico Mediterraneo Neuromed, Pozzilli (IS), Italy (L.I., A.D.C., A.d.C., G.d.G., M.B.D.); Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy (C.A., S.G.); Cancer Registry ASP, Ragusa, Italy (G.F., R.T.); Dipartimento di Medicina Clinica e Chirurgia, University of Naples "Federico II", Napoli, Italy (A.M., S.P.); Department of Medical Sciences, University of Torino, Torino, Italy (G.M.); Human Genetics Foundation (HuGeF), Turin, Italy (G.M., C.S.); Unit of Cancer Epidemiology, AO Città della Salute e della Scienza-University of Turin, Center for Cancer Prevention (CPO-Piemonte), Turin, Italy (F.R., C.S.); and Research Laboratories, Fondazione di Ricerca e Cura Giovanni Paolo II, Campobasso, Italy (E.N., R.L.).
Graziella
G
Frasca
From the Laboratory of Molecular and Nutritional Epidemiology, Department of Epidemiology and Prevention, IRCCS Istituto Neurologico Mediterraneo Neuromed, Pozzilli (IS), Italy (L.I., A.D.C., A.d.C., G.d.G., M.B.D.); Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy (C.A., S.G.); Cancer Registry ASP, Ragusa, Italy (G.F., R.T.); Dipartimento di Medicina Clinica e Chirurgia, University of Naples "Federico II", Napoli, Italy (A.M., S.P.); Department of Medical Sciences, University of Torino, Torino, Italy (G.M.); Human Genetics Foundation (HuGeF), Turin, Italy (G.M., C.S.); Unit of Cancer Epidemiology, AO Città della Salute e della Scienza-University of Turin, Center for Cancer Prevention (CPO-Piemonte), Turin, Italy (F.R., C.S.); and Research Laboratories, Fondazione di Ricerca e Cura Giovanni Paolo II, Campobasso, Italy (E.N., R.L.).
Amalia
A
Mattiello
From the Laboratory of Molecular and Nutritional Epidemiology, Department of Epidemiology and Prevention, IRCCS Istituto Neurologico Mediterraneo Neuromed, Pozzilli (IS), Italy (L.I., A.D.C., A.d.C., G.d.G., M.B.D.); Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy (C.A., S.G.); Cancer Registry ASP, Ragusa, Italy (G.F., R.T.); Dipartimento di Medicina Clinica e Chirurgia, University of Naples "Federico II", Napoli, Italy (A.M., S.P.); Department of Medical Sciences, University of Torino, Torino, Italy (G.M.); Human Genetics Foundation (HuGeF), Turin, Italy (G.M., C.S.); Unit of Cancer Epidemiology, AO Città della Salute e della Scienza-University of Turin, Center for Cancer Prevention (CPO-Piemonte), Turin, Italy (F.R., C.S.); and Research Laboratories, Fondazione di Ricerca e Cura Giovanni Paolo II, Campobasso, Italy (E.N., R.L.).
Giuseppe
G
Matullo
From the Laboratory of Molecular and Nutritional Epidemiology, Department of Epidemiology and Prevention, IRCCS Istituto Neurologico Mediterraneo Neuromed, Pozzilli (IS), Italy (L.I., A.D.C., A.d.C., G.d.G., M.B.D.); Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy (C.A., S.G.); Cancer Registry ASP, Ragusa, Italy (G.F., R.T.); Dipartimento di Medicina Clinica e Chirurgia, University of Naples "Federico II", Napoli, Italy (A.M., S.P.); Department of Medical Sciences, University of Torino, Torino, Italy (G.M.); Human Genetics Foundation (HuGeF), Turin, Italy (G.M., C.S.); Unit of Cancer Epidemiology, AO Città della Salute e della Scienza-University of Turin, Center for Cancer Prevention (CPO-Piemonte), Turin, Italy (F.R., C.S.); and Research Laboratories, Fondazione di Ricerca e Cura Giovanni Paolo II, Campobasso, Italy (E.N., R.L.).
Fulvio
F
Ricceri
From the Laboratory of Molecular and Nutritional Epidemiology, Department of Epidemiology and Prevention, IRCCS Istituto Neurologico Mediterraneo Neuromed, Pozzilli (IS), Italy (L.I., A.D.C., A.d.C., G.d.G., M.B.D.); Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy (C.A., S.G.); Cancer Registry ASP, Ragusa, Italy (G.F., R.T.); Dipartimento di Medicina Clinica e Chirurgia, University of Naples "Federico II", Napoli, Italy (A.M., S.P.); Department of Medical Sciences, University of Torino, Torino, Italy (G.M.); Human Genetics Foundation (HuGeF), Turin, Italy (G.M., C.S.); Unit of Cancer Epidemiology, AO Città della Salute e della Scienza-University of Turin, Center for Cancer Prevention (CPO-Piemonte), Turin, Italy (F.R., C.S.); and Research Laboratories, Fondazione di Ricerca e Cura Giovanni Paolo II, Campobasso, Italy (E.N., R.L.).
Carlotta
C
Sacerdote
From the Laboratory of Molecular and Nutritional Epidemiology, Department of Epidemiology and Prevention, IRCCS Istituto Neurologico Mediterraneo Neuromed, Pozzilli (IS), Italy (L.I., A.D.C., A.d.C., G.d.G., M.B.D.); Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy (C.A., S.G.); Cancer Registry ASP, Ragusa, Italy (G.F., R.T.); Dipartimento di Medicina Clinica e Chirurgia, University of Naples "Federico II", Napoli, Italy (A.M., S.P.); Department of Medical Sciences, University of Torino, Torino, Italy (G.M.); Human Genetics Foundation (HuGeF), Turin, Italy (G.M., C.S.); Unit of Cancer Epidemiology, AO Città della Salute e della Scienza-University of Turin, Center for Cancer Prevention (CPO-Piemonte), Turin, Italy (F.R., C.S.); and Research Laboratories, Fondazione di Ricerca e Cura Giovanni Paolo II, Campobasso, Italy (E.N., R.L.).
Sara
S
Grioni
From the Laboratory of Molecular and Nutritional Epidemiology, Department of Epidemiology and Prevention, IRCCS Istituto Neurologico Mediterraneo Neuromed, Pozzilli (IS), Italy (L.I., A.D.C., A.d.C., G.d.G., M.B.D.); Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy (C.A., S.G.); Cancer Registry ASP, Ragusa, Italy (G.F., R.T.); Dipartimento di Medicina Clinica e Chirurgia, University of Naples "Federico II", Napoli, Italy (A.M., S.P.); Department of Medical Sciences, University of Torino, Torino, Italy (G.M.); Human Genetics Foundation (HuGeF), Turin, Italy (G.M., C.S.); Unit of Cancer Epidemiology, AO Città della Salute e della Scienza-University of Turin, Center for Cancer Prevention (CPO-Piemonte), Turin, Italy (F.R., C.S.); and Research Laboratories, Fondazione di Ricerca e Cura Giovanni Paolo II, Campobasso, Italy (E.N., R.L.).
Rosario
R
Tumino
From the Laboratory of Molecular and Nutritional Epidemiology, Department of Epidemiology and Prevention, IRCCS Istituto Neurologico Mediterraneo Neuromed, Pozzilli (IS), Italy (L.I., A.D.C., A.d.C., G.d.G., M.B.D.); Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy (C.A., S.G.); Cancer Registry ASP, Ragusa, Italy (G.F., R.T.); Dipartimento di Medicina Clinica e Chirurgia, University of Naples "Federico II", Napoli, Italy (A.M., S.P.); Department of Medical Sciences, University of Torino, Torino, Italy (G.M.); Human Genetics Foundation (HuGeF), Turin, Italy (G.M., C.S.); Unit of Cancer Epidemiology, AO Città della Salute e della Scienza-University of Turin, Center for Cancer Prevention (CPO-Piemonte), Turin, Italy (F.R., C.S.); and Research Laboratories, Fondazione di Ricerca e Cura Giovanni Paolo II, Campobasso, Italy (E.N., R.L.).
Emanuela
E
Napoleone
From the Laboratory of Molecular and Nutritional Epidemiology, Department of Epidemiology and Prevention, IRCCS Istituto Neurologico Mediterraneo Neuromed, Pozzilli (IS), Italy (L.I., A.D.C., A.d.C., G.d.G., M.B.D.); Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy (C.A., S.G.); Cancer Registry ASP, Ragusa, Italy (G.F., R.T.); Dipartimento di Medicina Clinica e Chirurgia, University of Naples "Federico II", Napoli, Italy (A.M., S.P.); Department of Medical Sciences, University of Torino, Torino, Italy (G.M.); Human Genetics Foundation (HuGeF), Turin, Italy (G.M., C.S.); Unit of Cancer Epidemiology, AO Città della Salute e della Scienza-University of Turin, Center for Cancer Prevention (CPO-Piemonte), Turin, Italy (F.R., C.S.); and Research Laboratories, Fondazione di Ricerca e Cura Giovanni Paolo II, Campobasso, Italy (E.N., R.L.).
Roberto
R
Lorenzet
From the Laboratory of Molecular and Nutritional Epidemiology, Department of Epidemiology and Prevention, IRCCS Istituto Neurologico Mediterraneo Neuromed, Pozzilli (IS), Italy (L.I., A.D.C., A.d.C., G.d.G., M.B.D.); Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy (C.A., S.G.); Cancer Registry ASP, Ragusa, Italy (G.F., R.T.); Dipartimento di Medicina Clinica e Chirurgia, University of Naples "Federico II", Napoli, Italy (A.M., S.P.); Department of Medical Sciences, University of Torino, Torino, Italy (G.M.); Human Genetics Foundation (HuGeF), Turin, Italy (G.M., C.S.); Unit of Cancer Epidemiology, AO Città della Salute e della Scienza-University of Turin, Center for Cancer Prevention (CPO-Piemonte), Turin, Italy (F.R., C.S.); and Research Laboratories, Fondazione di Ricerca e Cura Giovanni Paolo II, Campobasso, Italy (E.N., R.L.).
Giovanni
G
de Gaetano
From the Laboratory of Molecular and Nutritional Epidemiology, Department of Epidemiology and Prevention, IRCCS Istituto Neurologico Mediterraneo Neuromed, Pozzilli (IS), Italy (L.I., A.D.C., A.d.C., G.d.G., M.B.D.); Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy (C.A., S.G.); Cancer Registry ASP, Ragusa, Italy (G.F., R.T.); Dipartimento di Medicina Clinica e Chirurgia, University of Naples "Federico II", Napoli, Italy (A.M., S.P.); Department of Medical Sciences, University of Torino, Torino, Italy (G.M.); Human Genetics Foundation (HuGeF), Turin, Italy (G.M., C.S.); Unit of Cancer Epidemiology, AO Città della Salute e della Scienza-University of Turin, Center for Cancer Prevention (CPO-Piemonte), Turin, Italy (F.R., C.S.); and Research Laboratories, Fondazione di Ricerca e Cura Giovanni Paolo II, Campobasso, Italy (E.N., R.L.).
Salvatore
S
Panico
From the Laboratory of Molecular and Nutritional Epidemiology, Department of Epidemiology and Prevention, IRCCS Istituto Neurologico Mediterraneo Neuromed, Pozzilli (IS), Italy (L.I., A.D.C., A.d.C., G.d.G., M.B.D.); Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy (C.A., S.G.); Cancer Registry ASP, Ragusa, Italy (G.F., R.T.); Dipartimento di Medicina Clinica e Chirurgia, University of Naples "Federico II", Napoli, Italy (A.M., S.P.); Department of Medical Sciences, University of Torino, Torino, Italy (G.M.); Human Genetics Foundation (HuGeF), Turin, Italy (G.M., C.S.); Unit of Cancer Epidemiology, AO Città della Salute e della Scienza-University of Turin, Center for Cancer Prevention (CPO-Piemonte), Turin, Italy (F.R., C.S.); and Research Laboratories, Fondazione di Ricerca e Cura Giovanni Paolo II, Campobasso, Italy (E.N., R.L.).
Maria Benedetta
MB
Donati
D000328:Adult; D000368:Aged; D002545:Brain Ischemia / Q000097:blood; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D020300:Intracranial Hemorrhages / Q000097:blood; D007558:Italy; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012307:Risk Factors; D020521:Stroke / Q000097:blood*; D013925:Thromboplastin / Q000378:metabolism*
D013925:Thromboplastin
biological markers; blood coagulation; stroke; thromboplastin