The amyloid beta-protein and its parent protein, amyloid beta-protein precursor (APP), are major constituents of neuritic plaques and cerebrovascular deposits in Alzheimer's disease and Down's syndrome. We reported that the protease inhibitor protease nexin-2 (PN-2) is the secreted form of APP that contains the Kunitz protease inhibitor domain. Previous studies suggested that circulating forms of PN-2/APP exist. Recently, we reported that PN-2/APP is a platelet alpha granule protein and is secreted upon platelet activation. Subsequent studies revealed that platelets are the major circulating repository for PN-2/APP and may contribute to its deposition in Alzheimer's disease. Protease inhibition measurements demonstrated that PN-2/APP is a potent inhibitor of certain serine proteases, particularly intrinsic blood coagulation factor XIa. Together, these findings indicate that PN-2/APP regulates blood coagulation, and possibly other proteolytic events, at sites of vascular injury.