Our laboratory, led by Andrea T. Obi, MD, studies a type of abnormal blood clotting, venous thrombosis, or VT. Our work has led us to look more closely at the role of the immune system and epigenetics in clot formation and breakdown. In fact, we are one of very few laboratories in the world working in this promising area of discovery. Our goal is to take our findings and translate them into new, safer and more effective approaches to treating VT.
Current Research in the Obi Lab
Venous thrombosis affects about one million people each year in the United States alone and carries high mortality rates. Clots can break away from the vessel wall and travel to the lungs, and these pulmonary emboli can prevent oxygen exchange. Among survivors, VT also often leads to lifelong complications, including leg swelling, pain and ulceration from scarring and obstruction of the affected vein. This is known as post-thrombotic syndrome, or PTS. In addition, patients with severe infections, such as influenza, pneumonia or systemic infections (sepsis), are at greater risk of VT both during the course of their illness as well as over the following year.
Dr. Obi saw the clinical impact of VT and infection firsthand during the H1N1 influenza outbreak in 2009 and 2010. A significant number of patients developed severe lung disease, with many subsequently developing VT in the weeks and months after their recovery. Why this is the case has remained an unanswered question and motivates our work in this area. Currently, the only drugs we as clinicians have in our arsenal to treat VT are blood thinners, but these can cause serious side effects such as uncontrolled bleeding, and they don't help all patients. They also don't effectively prevent PTS.
We know that immune cells play an important role in why and how a clot forms and breaks down. But, although we have many immune-modulating drugs to treat diseases such as psoriasis, multiple sclerosis and rheumatoid arthritis as examples, we still lack a reliable way to treat and prevent blood clots. For a physician seeing patients with VT and PTS every day, the status quo is not acceptable. Studying the relationships among immune cells and VT may point us toward new ways to treat — and prevent — abnormal blood clots without the risk of bleeding.
Our investigations have led us to look closely at a number of immune-related pathways involved in blood clot formation, including in the presence of infection, as well as the pathways leading to clot resolution, venous fibrosis (vessel scarring) and PTS. These include the differentiation of a particular type of immune cell, monocytes, into macrophages, a transition critical to many disease states, including VT, and to healing. Implicated pathways may offer new therapeutic targets for treating and preventing VT and PTS.
Contributions to Science
Our laboratory is making discoveries that have the potential to change how we approach the treatment and prevention of VT, improving current strategies so that they are safer for our patients. We're making important contributions to understanding how different types of immune cells interact with the environment around a blood clot and how those interactions can lead to changes in the expression of the cells' genetic code, a process known as epigenetic regulation.
We were the first research team to identify a connection among infection, VT and how developing immune cells are "programmed" in the bone marrow to predispose individuals who have experienced severe infection to form clots. Our clinical studies have identified pneumonia and sepsis as VT risk factors in critically ill patients, and we have developed an animal model that combines VT and the bacteria and viruses that cause these infections so that we can better study why and how these patients are more vulnerable to clotting.
We also have made advances in the understanding of what happens to the vessel wall following VT, clarifying the interactions among a number of proteins and their role in recruiting immune cells to the affected area. Better understanding these relationships and processes will help us identify and translate new immune-focused therapeutics from the lab into human trials.