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Friday January 25, 2019 -- The Coagulation Cascade in Sepsis and Inflammation

SMBB Auditorium 2650, 11:45 am

Speaker: Owen McCarty, Professor & Interim Chair, Department of Biomedical Engineering, Oregon Health and Science University

A native of Rochester, Dr. McCarty received his B.S. in Chemical Engineering from SUNY Buffalo, and a Ph.D. degree in Chemical Engineering from Johns Hopkins University, where his research focused on the identification and characterization of tumor cell receptors for blood platelets and leukocytes. He performed his postdoctoral research on platelet cell biology in the Pharmacology Department at the University of Oxford and University of Birmingham, UK in the group of Dr. Steve Watson. Dr. McCarty joined Oregon Health & Science University in 2005, where he holds an appointment as a Professor in the Departments of Biomedical Engineering and Cell, Developmental & Cancer Biology and the Division of Hematology & Medical Oncology in the OHSU School of Medicine. Dr. McCarty serves as the Interim Chair of the Biomedical Engineering Department and a fellow of the American Heart Association.

Presentation Abstract:

Hemostatic plug formation upon blood vessel breach is initiated by platelet recruitment, activation and aggregation in concert with thrombin generation and fibrin formation. However, a similar process can also lead to pathological thrombus formation and consequential deep vein thrombosis, ischemic stroke, or myocardial infarction, among others. We have developed narrow mechanism-specific neutralizing antibodies targeting the intrinsic pathway of coagulation and demonstrated that experimental thrombosis in primates is interrupted by selective inhibition of activation of coagulation factor (F)XI by FXIIa or contact activation of FXII. Our studies suggest that FXI is a multifunctional enzyme, and the function of FXIa in hemostasis and thrombosis may include activities that bypass the classical intrinsic pathway of thrombin generation. We hypothesize that in addition to its known procoagulant activities, FXI may also promote thrombin generation through the inactivation of endogenous anticoagulants as well as feedback to activate FXII and the complement pathway. In this seminar, I will present new data on the role of the endothelium in inactivating FXI, as well as studies on whether inhibiting FXI is beneficial in a primate model of sepsis. I will present our first data from our clinical trial on the safety of inhibition of FXI, and plans to test the efficacy of FXI inhibition in dialysis. The understanding of the mechanisms by which the intrinsic pathway of coagulation promotes thrombus formation may support the rationale for the development of selective, safe and effective antithrombotic strategies targeting FXI.