The Translational Research Center in Thrombotic and Hemostatic Disorders at Washington University is dedicated to understanding the role of proteases in the pathophysiology of thrombosis, which is a serious complication of many common diseases. This Center will pursue an interactive, multi-disciplinary approach involving 5 Projects and 4 Core Units that focus on microvascular and macrovascular thrombosis. Project 1 will characterize the molecular basis of ADAMTS13 substrate specificity, develop optimized assays to investigate the role of ADAMTS13 deficiency in thrombotic microangiopathy, and evaluate treatments to prevent relapses in thrombotic thrombocytopenic purpura. Project 2 will employ genomic sequencing to identify defects in complement regulation and hemostasis that cause thrombotic microangiopathy, including atypical hemolytic uremic syndrome, preeclampsia, and autoimmune disorders, and determine the biochemical mechanism by which these mutations cause disease. Project 3 will engineer an improved thrombin variant with exclusive activity toward protein C to optimize its anticoagulant and anti-inflammatory activity for treating thrombosis and sepsis. Project 4 will characterize new inhibitors of tissue factor and evaluate their efficacy in animal models of thrombosis, sepsis, HUS, and cancer progression. Project 5 will develop a first-in-class nanoparticle-based direct thrombin inhibitor with dual antiplatelet activity, and evaluate it for therapeutic dissolution and magnetic resonance imaging of thrombi. These projects rely on Core Units for logistics and oversight (Core A), patient enrollment and sample banking (Core C), and genomic analysis (Core D). New investigators will receive mentoring and training in translational and clinical research (Core B). The experimental approaches of the Center encompass basic molecular and state-of-the-art genetic methods, animal models, and biochemical and physiological studies of informative patients, as well as clinical studies to assess mechanism-based therapeutic approaches. These projects will facilitate the rapid translation of basic research discoveries into innovations in clinical care.

Public Health Relevance

The central goal of the TRC-THD at Washington University is to improve the health and survival of patients with thrombosis. This Center brings together basic scientists and clinical researchers to accelerate the translation of laboratory discoveries into new treatments for thrombosis, which is often a disabling or fatal event. (End of abstract)

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Specialized Center--Cooperative Agreements (U54)
Project #
Application #
Study Section
Special Emphasis Panel (ZHL1-CSR-C (F1))
Program Officer
Link, Rebecca P
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington University
Internal Medicine/Medicine
Schools of Medicine
Saint Louis
United States
Zip Code
Vemuri, Chandu; Upadhya, Gundumi A; Arif, Batool et al. (2018) Antithrombin Perfluorocarbon Nanoparticles Improve Renal Allograft Function in a Murine Deceased Criteria Donor Model. Transplant Direct 4:e384
Chinnaraj, Mathivanan; Chen, Zhiwei; Pelc, Leslie A et al. (2018) Structure of prothrombin in the closed form reveals new details on the mechanism of activation. Sci Rep 8:2945
Chakraborty, Pradipta; Acquasaliente, Laura; Pelc, Leslie A et al. (2018) Interplay between conformational selection and zymogen activation. Sci Rep 8:4080
Girard, T J; Grunz, K; Lasky, N M et al. (2018) Re-evaluation of mouse tissue factor pathway inhibitor and comparison of mouse and human tissue factor pathway inhibitor physiology. J Thromb Haemost 16:2246-2257
Wu, Xiaobo; Hutson, Irina; Akk, Antonina M et al. (2018) Contribution of Adipose-Derived Factor D/Adipsin to Complement Alternative Pathway Activation: Lessons from Lipodystrophy. J Immunol 200:2786-2797
Sivaraja, Mohanram; Pozzi, Nicola; Rienzo, Matthew et al. (2018) Reversible covalent direct thrombin inhibitors. PLoS One 13:e0201377
Barranco-Medina, Sergio; Murphy, Mary; Pelc, Leslie et al. (2017) Rational Design of Protein C Activators. Sci Rep 7:44596
Liszewski, M Kathryn; Java, Anuja; Schramm, Elizabeth C et al. (2017) Complement Dysregulation and Disease: Insights from Contemporary Genetics. Annu Rev Pathol 12:25-52
Shen, Guomin; Cui, Weidong; Zhang, Hao et al. (2017) Warfarin traps human vitamin K epoxide reductase in an intermediate state during electron transfer. Nat Struct Mol Biol 24:69-76
Chakraborty, Pradipta; Di Cera, Enrico (2017) Induced Fit Is a Special Case of Conformational Selection. Biochemistry 56:2853-2859

Showing the most recent 10 out of 87 publications