Novel Platelet Functions in Sepsis and Venous Thromboembolism

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DESCRIPTION (provided by applicant): Sepsis is a pro-coagulant illness characterized by injurious and widespread inflammation. Although the role of leukocytes and monocytes is well studied, there is a paucity of data on platelet biology in sepsis. Changes in platelet function may contribute directly to inflammation and thrombosis in sepsis. My preliminary data demonstrate that platelets isolated from sepsis patients produce new tissue factor (TF) mRNA and accelerate clot times. My data also shows that TF mRNA production correlates with illness severity and mortality. Thus, platelets appear to have biological functions important in sepsis. In the proposed application, I will study platelet activites in sepsis patients and healthy controls. My proposed studies will prospectively charaterize (1) novel synthesis of TF mRNA, (2) platelet activation measured with P-selectin flow cytometry, and (3) platelet turnover measured with thiazole orange flow cytometry. I will determine if these platelet activities and functions predict 28-day mortality, overt DIG, and venous thromboembolism (VTE) in sepsis patients. I will also compare these platelet activities in sepsis patients to health controls. These investigations may provide additional understanding of platelet functions and activities in human diseases. These novel observations will allow us to further characterize molecular pathways and to develop new therapies in the treatment of sepsis and VTE. These studies build on our robust preliminary data and will be accomplished in an extremely supportive environment. I have two mentors with strong research and mentoring experience, an advisory panel with national recognition for their expertise in inflammation and thrombosis, an personal track record of productive research, and a fully committed department. I also have constructed a career-development-plan that incorporates structured, didactic training in research methods, participation in ongoing research conferences, and training in the responsible conduct of research. These investigations will not only provide significant contributions to our understanding of platelet functions in sepsis and VTE, but will also lay the foundation for me to advance from junior investigator to an independently-funded clinician-scientist. RELEVANCE (See instructions): The research proposed in this application will expand our understanding of how platelets influence morbidity and mortality in sepsis. These studies may ultimately provide new therapeutic targets to improve our care of patients with sepsis.