Impaired platelet aggregation and sustained bleeding in mice lacking the fibrinogen motif bound by integrin α(IIb)β3

Abstract

Blood loss at sites of vascular rupture is controlled by the adhesion and aggregation of platelets and the formation of an insoluble fibrin matrix. Fibrinogen is considered to be critical in these processes by both providing an abundant dimeric ligand for α(IIb)β3-mediated platelet aggregation, and serving as the fundamental building block of the fibrin polymer. To establish an in vivo model system to examine in detail the importance of α(IIb)β3-fibrinogen interactions in platelet function, hemostasis, response to injury and vaso-occlusive disease, and to test the prevailing hypothesis that the C-terminal segment of the fibrinogen γ chain is essential for α(IIb)β3 binding, we have used gene-targeting technology in mice to eliminate the last five residues (QAGDV) from the γ chain. Mice homozygous for the modified γ chain gene (γΔ5/γΔ5) displayed a generally normal hematological profile, including normal platelet count, plasma fibrinogen level, clotting time and fibrin crosslinking. However, both γΔ5-fibrinogen binding to α(IIb)β3 and platelet aggregation were highly defective. Remarkably, another α(IIb)β3-dependent process, clot retraction, was unaffected by the γΔ5 mutation. Despite the preservation of clotting function, γΔ5/γΔ5 mice were unable to control blood loss following a surgical challenge and occasionally developed fatal neonatal bleeding events.