Minding the gaps to promote thrombus growth and stability

Abstract

Efforts to understand the role of platelets in hemostasis and thrombosis have largely focused on the earliest events of platelet activation, those that lead to aggregation. Although much remains to be learned about those early events, this Review examines a later series of events: the interactions between platelets that can only occur once aggregation has begun, bringing platelets into close contact with each other, creating a protected environment in the gaps between aggregated platelets, and fostering the continued growth and stability of the hemostatic plug.

Figure 1

Events in the gap. The gap between activated platelets in a growing thrombus is small enough for integrins and other cell adhesion molecules (CAMs) to interact and for interactions to occur between receptors such as Eph kinases and their cell surface ligands, known as ephrins. The space between platelets also provides a protected environment in which soluble agonists (ADP and TxA₂) and the proteolytically shed exodomains of platelet surface proteins can accumulate. Signaling by ephrins and Eph kinases promotes integrin engagement and outside-in signaling. The mechanical forces generated by the contraction of actin/myosin filaments may compress the space between platelets, improving contacts and increasing the concentration of soluble agonists. The binding of cell adhesion molecules to their partners may limit diffusion into and out of the space between platelets in addition to stabilizing platelet/platelet interactions.

Figure 2

Eph/ephrin interactions between platelets. Agonists such as thrombin, ADP, and TxA₂ are ligands for G protein–coupled receptors, causing a rapid increase in the cytosolic Ca²⁺ concentration and producing the inside-out signaling events that lead to integrin α_IIbβ₃ activation (i). The increasingly stable contacts between platelets permit ephrinB1 to bind to EphA4 and EphB1. As discussed in the text, Eph/ephrin interactions support inside-out signaling by activating Rap1b (ii) and also promote outside-in signaling by promoting the tyrosine phosphorylation of the β subunit of α_IIbβ₃ (iii).