Prothrombotic Effects of Fibronectin Isoforms Containing the EDA Domain

Abstract

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