Prothrombotic effects of fibronectin Isoforms containing the EDA domain

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 mu m) 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.