Interpaly of Thrombosis and Inflammation in Vasculitis

Boston University Medical Campus, Boston MA

Investigators

Linked publications & trials

Abstract

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