(A) Binding of protein C (PC) to its membrane receptor, EPCR, enhances its activation by thrombin (IIa) bound to thrombomodulin (TM). Activated protein C (APC) can dissociate from its receptor and—in the presence of cofactors—act as anticoagulant. Membrane-receptor–bound APC exerts cytoprotective activities mediated via PAR-1. (B) sEPCR supports neither PC activation nor APC activity. sEPCR can be generated by ectodomain shedding (left) or, as shown by Saposnik and colleagues in this issue of Blood, by alternative mRNA splicing in haplotype-A3–carrying cells, resulting in a protein that is not retained in the membrane but rather secreted (right).