Schistosomes are intravascular parasitic platyhelminthes infecting > 200 million people globally and causing a debilitating disease, schistosomiasis. Despite the relatively large size of the adult worms and their disruption of blood flow, surprisingly, they do not appear to provoke thrombus formation around them in vivo. We hypothesize that proteins expressed at the host-parasite interface are key to this ability. Here, we functionally express an ectonucleotide pyrophosphatase/phosphodiesterase homologue, SmNPP5, that is expressed at the tegumental surface of intravascular Schistosoma mansoni. We report that SmNPP5, a known virulence factor for the worms, is a type one glycoprotein that cleaves the artificial substrate p-Nph-5'-TMP in a reaction that requires cations and at an optimal pH of 9. Using immunolocalization and enzyme activity measurements, we confirm that SmNPP5 is exclusively expressed at the host interactive surface of all intravascular life stages. SmNPP5 inhibits platelet aggregation in a dose-dependent manner, as measured by multiple electrode aggregometry (MEA) using whole blood. Inhibition is apparent when either collagen or adenosine diphosphate (ADP) is used as agonist but is lost following heat treatment of SmNPP5. Unlike its mammalian homologue, NPP5, the schistosome protein cleaves ADP and with a Km of 246 ± 34 µM. In sum, SmNPP5 is expressed in the intravascular environment where it can degrade ADP and act as an anticoagulant. In this manner, the protein likely helps limit blood clot formation around the worms in vivo to permit the parasites free movement within the vasculature.,Schattauer GmbH Stuttgart.