Encryption of EPCR by sPLA₂-V induces cellular APC resistance. Functional EPCR loaded with a phosphatidylcholine (PCh) in its hydrophobic groove (green) promotes the generation of APC by the thrombin-thrombomodulin complex and supports APC's direct cytoprotective effects on cells. Secreted phospholipase A₂ group V (sPLA₂-V) changes the PCh in EPCR for a lysoPCh. This lysoPCh-loaded EPCR (red), or encrypted EPCR, is dysfunctional with regard to protein C and APC binding. Thus, sPLA₂-V modified EPCR fails to promote APC generation by the thrombin-thrombomodulin complex and abrogates APC's direct cytoprotective effects on cells thereby inducing cellular APC resistance with potential implications for the susceptibility to thrombosis and inflammation.