Control of thrombus embolization and fibronectin internalization by integrin αIIbβ3 engagement of the fibrinogen γ chain

Fibrin(ogen) deficiency (Fg(-/-)) was shown previously to be compatible with rapid thrombus growth within injured arterioles, but platelet fibronectin content was increased and newly formed thrombi were unstable. To further define the role of fibrin(ogen) in thrombus formation and stabilization, platelet biology was examined in mice expressing a form of fibrinogen that clots normally but lacks the gamma chain C-terminal binding site for alphallbbeta3 (FggammaDelta5). Thrombus growth within the arterioles of FggammaDelta5 mice appeared faster than in wild-type mice despite a far greater emboli formation. Unlike Fg(-/-) mice, the emboli were relatively small and released from the top of thrombi, rather than by fracture at the vessel wall. The fibronectin content in FggammaDelta5 platelets was also dramatically increased through a beta3 integrin-dependent mechanism. The following has been concluded: (1) Fibrin formation contributes to, but is not sufficient for, the stabilization of arterial thrombi. Platelet receptor engagement of the C-terminal of the Fggamma chain contributes to the stable incorporation of platelets into thrombi. (2) Alternative ligands to fibrinogen can support efficient thrombus growth. (3) Fibrinogen is internalized through alphallbbeta3 engagement of the fibrinogen gamma chain element, and this interaction secondarily controls the fibronectin content of platelets. (C) 2003 by The American Society of Hematology.