Mechanisms of Deep Vein Thrombosis (DVT) and Vein Wall Fibrosis

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This CSR&D VA Career Development Award (CDA-2) will develop Dr. Khanh Nguyen as a vascular surgeon-scientist trained in both basic and translational research approaches to study vascular disease and apply discoveries to improve the care of patients. With the support of an excellent mentorship team at the VA Portland Health Care System (VAPORHCS) and Oregon Health & Science University (OHSU) headed by her primary mentor, Dr. Edward Neuwelt, she will study deep vein thrombosis (DVT), where clots form in the deep veins of the body. Despite modern medical treatment, chronic or recurrent DVT and post thrombotic syndrome (PTS), where signs and symptoms of DVT persist or worsen causing lifelong disability. Recent clinical trials have shown that even with the addition of catheter directed thrombolysis to standard anticoagulation therapy, PTS still occurs. Anticoagulation treatment, primarily with warfarin or direct oral anticoagulants (DOAC) such as rivaroxaban or apixaban, are inadequate to prevent PTS, although some early studies suggest that the DOAC rivaroxaban may decrease the incidence of PTS but does not eliminate it. The goal of this proposal is to understand the process of inflammation and fibrosis in DVT resolution. During DVT healing, these processes may be beneficial by directing tissue remodeling and dissolving thrombus but may be detrimental by damaging vein walls, valves and surrounding tissues; thereby leading PTS. Aim 1 of this proposal will examine the role of relaxin (RLX), that has anti- inflammatory and anti-fibrotic effects in other vascular diseases, on the molecular, structural and biomechanical changes of the thrombus and vein wall during DVT resolution using advanced molecular, immunohistochemical, biomechanical and in-vivo imaging techniques including a novel contrast, ferumoxytol enhanced-Magnetic Resonance Imaging (Fe-MRI). We will use in-vivo mouse models of DVT, transgenic mice with deficiency in RLX (RLX -/-) under anticoagulant conditions (warfarin versus rivaroxaban). Aim 2 will study the incidence of PTS defined by the clinical Villalta score in patients after acute proximal lower extremity DVT that have been randomized to either standard warfarin or rivaroxaban and explore RLX as a plasma biomarker and Fe-MRI as a radiographic biomarker in a small, double blinded, randomized, controlled trial. RLX's potential as an effective anti-inflammatory or anti-fibrotic makes it a promising therapeutic agent for preventing PTS. This award will provide the support for Dr. Nguyen to develop expertise in: (1) advanced molecular and imaging techniques including ultrasound (US), Fe-MRI and in-vivo molecular imaging, (2) pre- clinical approaches and models, (3) training in advanced patient-oriented research including research design, implementation and biostatistics, and (4) professional academic training including management and leadership. To achieve these goals, Dr. Nguyen has assembled a diverse and multidisciplinary team of physicians and scientists and designed a training plan to develop essential skills required to achieve her career goals and complete this scientific proposal. With a combination of hands on scientific training and formal didactic education through OHSU's graduate school programs, she will improve her proficiency in the following specific areas: 1) vascular and molecular biology, 2) immunology, 3) advanced microscopy, 4) Fe-MRI and micro-CT, 4) US including elastography, 5) biomechanical analysis, 6) prospective clinical research design and implementation, 7) clinical data collection and management and 8) data analysis and biostatistics. The creative and collaborative environment at OHSU will allow her to complete the aims in this proposal and achieve her long-term goal of becoming a surgeon-scientist with a focus on vascular biology and venous diseases.