The idiopathic inflammatory vasculitides are a group of multiorgan system diseases that have in common the findings of inflammation of vessels of varying sizes that results in serious, organ and lifethreatening disease. Current treatments are highly toxic and not fully effective. The importance of thrombosis in vasculitis is increasingly being recognized. Recently, Dr. Merkel and his colleagues have demonstrated that patients with Wegener's granulomatosis have a 20-fold increased incidence of venous thrombotic events and that these events are associated with active vasculitis. There is increasing evidence strongly linking multiple aspects of thrombosis with vascular inflammation and these areas are the focus of this application. In this construct, """"""""thrombosis"""""""" is not limited to the large vessel thrombi seen clinically but may include """"""""microthrombosis"""""""" associated with a cycle of damage and repair, some of which may be pathological. Similarly, aspects of what has traditionally been referred to as """"""""inflammation"""""""" can stimulate """"""""thrombosis"""""""". We propose that while inflammation may be the initial cause of damage in vasculitis, each hemostatic component of thrombosis, i) platelet-dependent factors;ii) the coagulation cascade;and iii) fibrinolysis, is also triggered, leading to a """"""""second hit"""""""" of thrombosis and subsequently a vicious cycle of inflammation and thrombosis. Understanding the roles various aspects of thrombosis play in vasculitis will not only provide important insight into the pathophysiology of these diseases, but will also potentially address three critical but unmet medical needs in vasculitis: i) the development of biomarkers of disease activity;ii) the discovery of predictors of disease activity and outcome;and iii) a rationale for testing novel classes of therapeutic interventions. In this application we propose evaluating the association of markers of thrombosis with thrombotic events, overall disease activity, and long-term outcome in vasculitis by achieving three related specific aims: 1. Studying the association of selective markers of thrombosis with disease activity in Wegener's granulomatosis;2. Studying the associations between selective thrombosis factors and the presence or absence of clinically evident thrombosis in patients with Wegener's granulomatosis;3. Studying the predictive value of markers of thrombosis for response to therapy in patients with Wegener's granulomatosis. We will utilize clinical data and biological specimens from several large cohorts of patients with vasculitis and partner with experts in the basic science of vascular biology and thrombosis. This research is directly relevant to public health because it explores the relationship between two critical biological processes: inflammation and thrombosis (clotting). This work will potentially lead to a better understanding and better treatment of inflammatory diseases.
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