In this issue of Blood, May and colleagues1 demonstrate that the recently described platelet receptor CLEC-2 is important for stabilizing platelet cohesion and thrombus development under flow conditions. The absence of CLEC-2 in vivo is manifested by a continuous release of individual platelets from the growing thrombus and the embolization of small platelet aggregates, resulting in impaired occlusion of damaged vessels in CLEC-2–deficient mice.
The mechanisms that support platelet activation and adhesion to the extracellular matrix have been studied intensively, leading to the identification of a handful of now well-known receptors that participate in each phase of platelet function (reviewed in Kunicki and Nugent2 ). In early stages of platelet recruitment to areas of blood vessel damage, the glycoprotein (GP) Ib complex binds to von Willebrand factor (VWF) and mediates transient platelet attachment to collagens in the extracellular matrix. Platelet GPVI and the integrin α2β1 then become involved to mediate a more stable attachment to collagens and contribute to platelet activation, which is enhanced by the binding of key platelet-activating agonists. Some of the most important agonists, like adenosine diphosphate (ADP) and thromboxane A2, are released from platelets and bind to their cognate receptors. Other platelet agonists, such as thrombin, are produced by the concurrent process of prothrombin conversion, which is accelerated on the activated platelet surface. In the subsequent stages of thrombus formation, activated integrin αIIbβ3 binds to fibrinogen and/or VWF and mediates platelet cohesion or aggregate formation. We have grown comfortable with these well-described agonists and receptors, but new evidence indicates that our picture of platelet thrombus formation is not quite complete and that additional receptors contribute to this important process.
One of the newest and most exciting developments is the discovery of the contributions of platelet CLEC-2. This membrane receptor was originally identified in immune cells, where its precise function remains unclear.3 Suzuki-Inoue and colleagues4 were the first to show that it is also expressed on platelets and represents the receptor bound by the platelet-activating protein rhodocytin, isolated from the venom of the Malayan pit viper Calloselasma rhodostoma. Additional studies have demonstrated that podoplanin, expressed by certain tumors, is also a ligand for CLEC-2. Ligand engagement by CLEC-2 causes phosphorylation of a tyrosine residue in the CLEC-2 cytoplasmic domain and subsequent signaling via Syk.4,5 The identification of the natural ligands that engage and activate CLEC-2 during thrombus formation remains to be determined.
CLEC-2 is a potential novel target for antithrombotic therapy, and evidence in May et al1 shows that it can be specifically targeted and functionally inactivated in vivo by antibodies, such as INU1. Treatment of mice in vivo with an antibody against CLEC-2 induced a specific and prolonged CLEC-2 deficiency, which was associated with significant protection from occlusive thrombus formation. At the same time, a moderate but significant increase in bleeding times was found in roughly one-half of the treated mice. In the near future, rational drug design approaches can exploit this knowledge to develop specific inhibitors of CLEC-2 function.
Clearly, there is a new platelet receptor in the picture, reinforcing again the concept that redundancy in platelet-related hemostatic pathways serves to ensure adequate hemostasis while regulating undesirable thrombosis.
Conflict-of-interest disclosure: The author declares no competing financial interests. ■
