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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:296.)
© 2008 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Prothrombotic Effects of Fibronectin Isoforms Containing the EDA Domain

Anil K. Chauhan; Janka Kisucka; Maria R. Cozzi; Meghan T. Walsh; Federico A. Moretti; Monica Battiston; Mario Mazzucato; Luigi De Marco; Francisco E. Baralle; Denisa D. Wagner; Andrés F. Muro

From the CBR Institute for Biomedical Research (A.K.C., J.K., M.T.W., D.D.W.) and the Department of Pathology (A.K.C., J.K., D.D.W.), Harvard Medical School, Boston, Mass; the Centro di Riferimento Oncologico-Istituto di Ricerca e Cura a Carattere Scientifico (M.R.C., M.B., M.M., L.D.M.), National Cancer Institute, Aviano, Italy; and the International Centre for Genetic Engineering and Biotechnology (F.A.M., F.E.B., A.F.M.), Trieste, Italy.

Correspondence to Andrés F. Muro, International Centre for Genetic Engineering and Biotechnology, Padriciano 99, I-34012, Trieste, Italy. E-mail muro{at}icgeb.org Denisa D. Wagner, CBR Institute for Biomedical Research and Department of Pathology, Harvard Medical School, 800 Huntingdon Avenue, Boston, MA 02115. E-mail wagner@cbr.med.harvard.edu.

Abstract

Objective— Fibronectin (FN) plays an important role in the formation of stable arterial thrombi at the site of vascular injury. FN containing Extra Domain A (EDA⁺FN) is absent from normal plasma, but elevated plasma levels of EDA⁺FN are found in several pathological conditions. We hypothesized that EDA⁺FN plays a special role in thrombosis.

Methods and Results— We used mouse strains constitutively including (EDA^+/+) or excluding (EDA^–/–) the EDA domain in all tissues and plasma. Using a flow chamber and the ferric-chloride injury model we found that EDA⁺FN accelerates thrombosis both in vitro and in vivo at arterial shear rates. In EDA^+/+ mice thrombi (>30 µm) grew faster when compared with EDA^WT/WT (6.6±0.2 minutes versus 8.3±0.6 minutes, P<0.05) and the mean vessel occlusion time was shorter (9.9±0.4 minutes versus 14.6±1.7 minutes, P<0.05). However, the presence of EDA⁺FN affected neither single platelet adhesion to subendothelium nor thrombosis in veins. In addition, the mortality rate of EDA^+/+ mice after collagen/epinephrine infusion was twice that of EDA^WT/WT or EDA^–/– mice.

Conclusions— Our findings reveal that EDA⁺FN has prothrombotic activity, and its presence in plasma may worsen pathological conditions in which this form is elevated.

EDA⁺FN is absent in normal plasma but elevated levels are observed in several pathological conditions. We found that EDA⁺FN has prothrombotic potential that is revealed at arterial shear rates. Thus the presence of EDA⁺FN in plasma may aggravate peripheral arterial disease, coronary artery disease, stroke, and other conditions.

Key Words: plasma fibronectin • fibronectin splice variants isoforms • arterial thrombosis • intravital microscopy • thromboembolism • arterial and venous injury

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