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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:1391.)
© 2006 American Heart Association, Inc.

Thrombosis

Decreased Plasma Fibronectin Leads to Delayed Thrombus Growth in Injured Arterioles

Jana Matuskova; Anil K. Chauhan; Beatrice Cambien; Sophie Astrof; Vandana S. Dole; Crystal L. Piffath; Richard O. Hynes; Denisa D. Wagner

From the CBR Institute for Biomedical Research (J.M., A.K.C., B.C., V.S.D., C.L.P., D.D.W.)and Department of Pathology (J.M., A.K.C., B.C., V.S.D., D.D.W.), Harvard Medical School, Boston; and Howard Hughes Medical Institute (S.A., R.O.H.), Center for Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge.

Correspondence to Denisa D. Wagner, PhD, CBR Institute for Biomedical Research, 800 Huntington Ave, Boston, MA, 02115. E-mail wagner{at}cbr.med.harvard.edu

Objective— Plasma fibronectin (FN) is decreased in several clinical conditions. We were interested to study the thrombotic and hemostatic consequences of the decrease in plasma FN (pFN), the role of FN splice variants in thrombosis, and to examine whether pFN incorporates into thrombi in vivo.

Methods and Results— We compared the thrombotic response to a vessel injury in FN heterozygous (FN+/–) mice and corresponding FN+/+ mice. Although normal thrombosis in venules was observed, a decrease to half in the pFN concentration in FN+/– mice caused a delay in the appearance of thrombi in arterioles and consequently a delay in their occlusion. We were able to rescue the thrombotic defect in the FN+/– mice by infusion of rat pFN. Additionally, we could show intense incorporation of fluorescent pFN-coated microspheres into the developing thrombi. Moreover, we found that mice expressing FN without the EIIIA or EIIIB domains specific to cellular FN including platelet FN had no thrombotic defect.

Conclusions— Mice heterozygous for FN have a striking defect in thrombus initiation and growth in arterioles attributable to the decrease of pFN. Our study is an example of haploid insufficiency for FN, and it emphasizes the fundamental role of this plasma protein in thrombosis in the arterial system.

We show that mice with half the normal plasma fibronectin levels have a striking defect in thrombus growth specifically at arterial shear rate attributed to a decrease of plasma fibronectin. Our study emphasizes the fundamental role of this protein in thrombosis.

Key Words: plasma fibronectin • arterial and venous injury • thrombus • fibronectin splice variants • intravital microscopy

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