Control of thrombus embolization and fibronectin internalization by integrin alpha IIb beta 3 engagement of the fibrinogen gamma 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 alpha IIb beta 3 (Fg gamma Delta 5). Thrombus growth within the arterioles of Fg gamma Delta 5 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 Fg gamma Delta 5 platelets was also dramatically increased through a beta 3 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 Fg gamma 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 alpha IIb beta 3 engagement of the fibrinogen gamma chain element, and this interaction secondarily controls the fibronectin content of platelets.
Ni
Heyu
H
Center for Blood Research and Department of Pathology, Harvard Medical School, Boston, MA USA. nih@smh.toronto.on.ca
Papalia
Jessie M
JM
Degen
Jay L
JL
Wagner
Denisa D
DD
D000347:Afibrinogenemia; D000818:Animals; D001160:Arterioles / Q000473:pathology; D001665:Binding Sites / Q000235:genetics; D001792:Blood Platelets / Q000737:chemistry / Q000502:physiology; D005340:Fibrinogen / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D005353:Fibronectins / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D010973:Platelet Adhesiveness; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism*; D011485:Protein Binding; D013923:Thromboembolism / Q000209:etiology* / Q000473:pathology
D005353:Fibronectins; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D005340:Fibrinogen