Grant: Operating Grant: Fall 2008 Priority Announcement (IMHA)

Anti-phospholipid antibodies (aPL), in association with clinical manifestations (thrombosis [blood clots] and recurrent fetal loss), define an autoimmune disease called anti-phospholipid syndrome (APS). It is unclear why some patients with aPL develop thrombosis, while others do not. It is also unknown why an event occurs in one place in the body and not in another, or on one day and not on another. We hypothesize that a minimum of two factors are needed to produce APS: (1) persistent and high levels of aPL; and (2) exposure to a factor (e.g., infection, inflammation, or injury) that initiates a process called "innate immune activation". This process can cause localized "priming" of the blood vessels to make them more prone to thrombosis, by activating them or physically altering them. Together, these two factors can cause thrombosis of blood vessels, especially if other risk factors (e.g., smoking) that predispose to thrombosis are present. We propose to directly test this hypothesis in a murine model of thrombosis by creating an environment in which both factors (aPL and innate immune activation) are present. The finding that these two factors play a significant role in APS will not only provide insight into the mechanisms responsible for this disease, but will also provide new approaches to monitoring patients at risk for developing APS and preventing the development of thrombosis in these individuals.