This 5-year career development grant encompasses an educational and experiential plan for this pediatric critical care physician to gain research expertise and training in the area of coagulation disorder and thrombotic microangiopathy associated with critical illness. The educational activities include focused, advanced didactic courses offered at Baylor College of Medicine and weekly clinical and research conferences in thrombosis. There is a well-defined plan for mentoring by experienced researchers and academicians. An oversight committee has been formed to follow progress, identify barriers to success, and provide guidance to the candidate and feedback to his departmental leaders. The candidate's previous works have identified two groups of children in the intensive care unit with increased risk of death, one with severe sepsis, a form of systemic inflammation, and the other with thrombocytopenia-associated multiple organ failure. More than 50% of these children have a deficiency in von Willebrand factor (VWF)-cleaving protease (a.k.a. ADAMTS-13), and a presence of ultra-large VWF multimers, which place these patients at risk for having disseminated platelets/VWF micro-thrombi. In addition, autopsies reveal VWF-rich disseminated microthrombi. The mechanism of ADAMTS-13 deficiency is unknown in an inflamed state, as it could arise from problems of ADAMTS-13 synthesis, clearance and/or inhibition. It is also unknown whether recombinant (r) ADAMTS-13 could improve survival in ADAMTS-13 deficient states. The hypotheses of this grant are: 1) inflammatory cytokines and bacterial toxins suppress ADAMTS-13 synthesis and function. 2) rADAMTS-13 could improve survival in ADAMTS-13 deficient illnesses. The proposal's specific aims are to determine whether: 1) inflammatory cytokines and bacterial toxins suppress the synthesis and function of ADAMTS-13 from endothelial and hepatic cells;2) ADAMTS-13 inhibitors, especially autoantibodies and VWF, are present in plasma of septic patients that contribute to acquired ADAMTS-13 deficiency;and 3) rADAMTS-13 and its truncated variant could improve survival in mouse models of endotoxemia and experimental sepsis.
|Nguyen, Trung C; Han, Yong Y (2011) Plasma exchange therapy for thrombotic microangiopathies. Organogenesis 7:28-31|
|Nguyen, Trung C; Han, Yong Y; Kiss, Joseph E et al. (2008) Intensive plasma exchange increases a disintegrin and metalloprotease with thrombospondin motifs-13 activity and reverses organ dysfunction in children with thrombocytopenia-associated multiple organ failure. Crit Care Med 36:2878-87|