A schematic view of the mechanisms of blood vessel–lymphatic vessel separation. (A) In embryos, the lymphatic vessels develop from embryonic veins. The junction between the anterior cardinal vein and the first lymphatic vessel structure, called the lymph sac, is closed by a platelet plug. However, various defects of platelets allow blood entry into the lymphatic vessels. (B) Podoplanin is O-glycosylated during its biosynthesis in lymphatic endothelial cells. Cell surface–exposed podoplanin provides binding sites for the platelet receptor CLEC-2. Podoplanin-bound CLEC-2 activates the Syk tyrosine kinase and SLP-76 adaptor protein, which leads to downstream activation of phospholipase C-gamma2 (PLC-g2), with resulting platelet activation including release of platelet alpha granules. The numbers next to the various molecules correspond to the references reporting the deletion phenotypes, for example, PLC-g2.¹⁰