Comment on Nanda et al, page 3028
Nanda and colleagues identify members of the SLAM family of homotypic receptors as important in platelet-platelet cohesion and downstream signaling events during platelet aggregation.
Platelet aggregation involves a complex series of steps that begins with the binding of agonists to receptors on the plasma membrane and proceeds through signals from these receptors that set off a variety of intracellular responses, including the production of autocrine agonists such as thromboxane A2 and secretion of granule contents that themselves contain agonists such as adenosine diphosphate and adhesive proteins such as fibrinogen and von Willebrand factor (VWF). The common target of the stimulatory pathways initiated by these agonists is the major platelet integrin, αIIbβ3, which is converted from a quiescent form to a form capable of binding soluble fibrinogen or VWF, proteins that serve as the glue holding the platelets together. Binding of αIIbβ3 to adhesive ligands also generates intracellular signals and brings into proximity other receptor-counterreceptor pairs on adjacent platelets, some of which require signals from the integrin to facilitate their interaction, while others engage each other simply by being brought into proximity. These receptors then also transmit signals that generally function to stabilize the platelet aggregate and may facilitate such downstream events as clot retraction. Secondary signals that require platelet aggregation have been termed “contact-dependent” signals.1 Examples of receptors involved in such signaling include CD40 ligand, which enhances platelet aggregation by binding to both CD40 and αIIbβ32,3 and the receptor-counterreceptor pairs ephrins and Eph kinases.1
In this issue of Blood, Nanda and colleagues identify yet another set of platelet receptors that are engaged when platelets aggregate and participate in stabilizing the platelet aggregate. These investigators identified CD84 and signaling lymphocytic activation molecule (SLAM) as proteins phosphorylated during platelet aggregation. CD84 and SLAM are members of the SLAM/CD2 subfamily of the immunoglobulin (Ig) superfamily that are also expressed on lymphocytes, monocytes, and macrophages.4,5 In T cells, CD84 and other members of the SLAM family act as homotypic costimulatory receptors that find each other in the immunologic synapse formed when the T-cell antigen receptor encounters major histocompatibility complex (MHC)/antigen complexes on antigen-presenting cells.4 Platelets form analogous “adhesion synapses” at sites where αIIbβ3 complexes are brought together by fibrinogen; it is possible that it is in these sites that members of the SLAM family associate. Indeed, Nanda and colleagues showed that phosphorylation of both CD84 and SLAM in platelets requires platelet aggregation, as it was blocked by αIIbβ3 antagonists. However, at least in the case of CD84, phosphorylation does not depend on signals from the integrin, as the receptor also becomes phosphorylated when cross-linked by antibodies and through homotypic association when platelets are allowed to spread over a surface coated with the extracellular domain of CD84. Spreading on the CD84-coated surface was not prevented in platelets from mice carrying a mutant αIIbβ3 that is defective in ligand-induced signaling. Unlike the situation in T cells, phosphorylation of SLAM receptors in platelets did not require association with the intracellular adaptor SLAM-associated protein (SAP), which in thymocytes brings the Src family kinase Fyn to the receptor.
Defects in agonist-induced aggregation were apparent in SLAM-deficient mice, but not in mice deficient in SAP. However, when tested in a ferric chloride model of arterial thrombosis, both SAP- and SLAM-deficient mice—but only the females—demonstrated defects in thrombus formation.
These studies, while informative, highlight the paucity of existing knowledge about events occurring subsequent to platelet aggregation during the formation of a thrombus. Signaling events occurring after platelets aggregate undoubtedly influence not only the stability of the thrombus, but also its ability to retract, and eventually, its dissolution. ▪
