Summary of differences in platelets signaling and spreading during αIIbβ3-mediated interaction with low- versus high-density fibrinogen. Attachment of platelets to low-density fibrinogen requires activity of Src, PKC, and PI3 kinases and actin polymerization. Full platelet spreading depends on Rac-1 and Rho kinase. Platelet adhesion to low-density fibrinogen further leads to inside-out signaling, resulting in αIIbβ3 activation and recruitment of additional platelets on top of the adherent platelets. In contrast, platelet attachment to high-density fibrinogen is possible even in the presence of inhibitors of Src, PKC, PI3-kinase, and actin polymerization. Platelet spreading depends on Src, PI3K, PKC, Rac-1, and Rho kinase activation. Few platelets are recruited to the adherent platelets indicating inadequate inside-out signaling or inhibition of luminal αIIbβ3 activation.