The present invention relates generally to the use of modulators of podoplanin (PDPN) mediated platelet activation. For example, an agonist or mimic of podoplanin (PDPN)/C-type lectin-like receptor 2 (CLEC-2) signaling may be used to inhibit vascular leakage or promote vascular integrity. Alternatively, an antagonist of podoplanin (PDPN)/C-type lectin-like receptor 2 (CLEC-2) signaling may be used to inhibit platelet activation.