Fibrin-modulating nanogels for treatment of disseminated intravascular coagulation.
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2021-02
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Disseminated intravascular coagulation (DIC) is a pathological coagulopathy associated with infection that increases mortality. In DIC, excessive thrombin generation causes symptoms from formation of microthrombi to multiorgan failure; bleeding risks can also be a concern because of clotting factor consumption. Different clinical events lead to DIC, including sepsis, trauma, and shock. Treatments for thrombotic episodes or bleeding presentation in DIC oppose each other, thus creating therapeutic dilemmas in management. The objective of this study was to develop fibrin-specific core-shell nanogels (FSNs) loaded with tissue-type plasminogen activator (tPA) to treat the microcirculatory complications of DIC, which would facilitate targeted clot dissolution to manage microthrombi and the potential consumptive coagulopathy that causes bleeding. FSNs enhance formation of actively polymerizing clots by crosslinking fibrin fibers, but they can also target preexisting microthrombi and, when loaded with tPA, facilitate targeted delivery to lyse the microthrombi. We hypothesized that this dual action would simultaneously address bleeding and microthrombi with DIC to improve outcomes. In vivo, tPA-FSNs decreased the presentation of multiorgan microthrombi, recovered platelet counts, and improved bleeding outcomes in a DIC rodent model. When incorporated with human DIC patient plasma, tPA-FSNs restored clot structure and clot growth under flow. Together, these data demonstrate that a fibrinolytic agent loaded into fibrin-targeting nanogels could improve DIC outcomes.
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Mihalko, Emily P, Megan Sandry, Nicholas Mininni, Kimberly Nellenbach, Halston Deal, Michael Daniele, Kamrouz Ghadimi, Jerrold H Levy, et al. (2021). Fibrin-modulating nanogels for treatment of disseminated intravascular coagulation. Blood advances, 5(3). pp. 613–627. 10.1182/bloodadvances.2020003046 Retrieved from https://hdl.handle.net/10161/22404.
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Kamrouz Ghadimi
Dr. Kamrouz (Kam) Ghadimi is an experienced cardiovascular acute care specialist (cardiovascular anesthesiology and intensive care), established investigator, physician leader, and associate professor of Anesthesiology and Critical Care at Duke Health.
His clinical practice is rooted in the cardiothoracic surgical ICU and operating rooms. He has broad expertise in all topics involving perioperative cardiovascular medicine and intensive care, including the management of acutely ill patients after surgery or those receiving extracorporeal life support (ECLS/ECMO). His specific area of expertise focuses on the enhancement of blood circulation through the lungs and the reversal of bleeding with prevention of thrombosis after surgery and circulatory life support. He has published original research, invited reviews, and guidance documents in several high-impact multidisciplinary journals and networks, including JAMA, Circulation, BMJ, Journal of the American College of Cardiology, Journal of Heart and Lung Transplantation, and Journal of Thrombosis & Haemostasis. He has also published in anesthesiology specialty journals, including Anesthesia & Analgesia, Anesthesiology, Current Opinion in Anesthesiology, and the British Journal of Anaesthesia. Dr. Ghadimi has served on the Editorial Board for the Journal of Cardiothoracic and Vascular Anesthesia since 2018 and has served as a peer reviewer for more than 30 top-medical journals worldwide.
Over his career, he has developed a global multidisciplinary network of collaborators and colleagues in academic medicine, private practice, larger healthcare systems, and offices of the federal government. He has experience with grant funding from a variety of sponsors, including federal, industry, foundation, philanthropy, and institutional sources. He also holds positions on several other national and international committees aimed at improving cardiovascular health in patients undergoing surgery and post-surgical intensive care. He is a selected task force and writing committee member of the 2024 American College of Cardiology and American Heart Association Perioperative Cardiovascular Guidelines. He has devoted the majority of his career to the service of patients requiring cardiovascular perioperative and surgical intensive care.
In addition to a doctorate in Medicine, Dr. Ghadimi holds a Bachelor’s in Economics from Boston University and a Master’s in Clinical Research from Duke University School of Medicine and the National Institutes of Health. He is also an inventor with patents/patents pending, a medical consultant, a mentor, and an investor. He is a founding member and the original academic director of True Learn, an eLearning company focused on board exam preparation for multiple medical subspecialties. This resource is used by many physicians around the country. Beyond developing an educational platform that has reached several thousand physicians and physicians-in-training, Dr. Ghadimi has formally mentored 22 pre-doctorate and post-doctorate trainees, with several mentees continuing their faculty careers in academic practice. In addition, he serves as a resource for a multitude of other physicians, physicians-in-training, and allied healthcare professionals.
Currently, Dr. Ghadimi serves as Director of the Clinical Research Unit for the Department of Anesthesiology at Duke Health, leading a cohesive, high-performing management team that oversees 45 staff working with Anesthesiology faculty and faculty in other departments to operationalize more than 80 innovative research protocols annually (single- and multi-site studies) to advance the fields of perioperative medicine, intensive care, pain management, and brain and heart health. He is leading digital health and artificial intelligence implementation in research workflow to rapidly leverage capabilities for automation and efficiency with the evolving guidance of cybersecurity compliance. He has also led the expansion of the Human Biospecimen Repository within the Department of Anesthesiology, where participants from prospective studies have generously donated biofluids and tissue for the advancement of disease-specific biology and translational research. Dr. Ghadimi is currently involved in the One Duke Gen precision medicine initiative for Duke Health to catalyze high-impact translational discoveries through expansive data-driven partnerships.
Jerrold Henry Levy
Jerrold Levy is Professor of Anesthesiology, Critical Care, and Surgery (Cardiothoracic) at Duke University Medical Center in Durham, NC. He obtained his medical degree from the University of Miami, where he was an intern in internal medicine, and undertook his residency in the Department of Anesthesiology of the Massachusetts General Hospital and Harvard Medical School in Boston, where he was also Chief Resident, and completed fellowships in both Respiratory ICU and Cardiac Anesthesiology. He previously was Professor, Deputy Chair for Research, and Chief of Cardiothoracic Anesthesiology at Emory University School of Medicine. His clinical and research interests include anticoagulation and its reversal, therapeutic strategies to prevent and treat coagulopathy and acute inflammatory responses in critically ill patients, clinical applications of recombinant and purified protein concentrates to treat bleeding, and pharmacologic approaches to treat shock. He is currently Chair of the Subcommittee on Perioperative and Critical Care Thrombosis and Hemostasis for the International Society of Thrombosis and Hemostasis, Executive Editor of Anesthesiology, and consultant to the FDA‘s Biologic Products Advisory Committee. He is the author of over 450 publications on PubMED, with over 100,000 citations on Google Scholar and a h-index of 95. He is also fluent in French and conversational in Spanish and Japanese.
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