Thrombosis to Hemostasis (TtoH) ARC
Thrombosis to Hemostasis (TtoH) ARC brings together basic and translational research towards
understanding thrombosis secondary to organ pathology. While studies of primary thrombosis (owing to
platelet/vessel malfunction) have been extensively investigated, our proposed ARC is unique in that it opens
new focus on mechanisms of organ-induced changes in thrombosis and vascular hemostasis, and consequent
complications. Thrombosis resulting in cardiovascular and cerebrovascular events is the number one cause of
death in the world and also contributes to severe morbidity in toxin-mediated diseases. Thrombosis is a
complex process, which lies at the intersection of several of disciplines and epitomizes the essence of a
multidisciplinary approach not only to gain deeper understanding of its pathogenesis but also for developing
novel personalized predictive tools and therapeutic targets. Leveraging the experience of PIs in the
fundamental components of thrombosis, the TtoH ARC proposes to examine the novel mediators (metabolites
and proteins secreted by a diseased organ) of thrombosis identified by the BU investigators. Once considered
as innocent bystanders retained in renal failure, emerging data indicate prothrombotic properties of some of the
metabolites in patients of renal failure. Indole metabolites (indoxyl sulfate and indoxyl acetate) have been
recently identified as inducers of tissue factor and enhancer of thrombosis. Lysyl oxidase (LOX) is an
extracellular copper enzyme that is released from cells and initiates the cross-linking of collagen and elastin in
fibrotic organs (kidney included), and now found to have an unexpected role as a potent regulator of
thrombosis.
The central hypothesis of this proposal is that the newly identified mediators (proteins/metabolites)
evoke thrombosis during organ pathology, as well as following systemic influence of infectious pathogens. The
following translational and mechanistic aims will provide initial guides for examining this central hypothesis.