Fibrin-modulating nanogels for treatment of disseminated intravascular coagulation.

Abstract

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.

Department

Description

Provenance

Subjects

Citation

Published Version (Please cite this version)

10.1182/bloodadvances.2020003046

Publication Info

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.

This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.

Scholars@Duke

Ghadimi

Kamrouz Ghadimi

Associate Professor of Anesthesiology

Overview
Dr. Ghadimi is a cardiothoracic anesthesiologist, intensivist (ICU doctor), researcher, educator, and director of the clinical research unit in the Department of Anesthesiology at Duke Health. He has published over 100 peer-reviewed manuscripts, book chapters, online reviews, and editorials. His expertise involves the perioperative and intensive care management of patients undergoing cardiac and noncardiac surgery, with a special focus on the treatment of bleeding and inflammation related to shock and mechanical circulatory support and on the modification of pulmonary circulation to optimize end-organ blood flow.

Clinical Education
Dr. Ghadimi is a medical school graduate of Boston University School of Medicine, completed his internship in general surgery at the University of California Irvine Medical Center and Long Beach Veterans Affairs Medical Center and completed clinical anesthesiology residency at the Allegheny Health Network in Pittsburgh, Pennsylvania. He completed advanced clinical fellowship specialization in adult Critical Care Medicine (surgical focus) and Cardiothoracic Anesthesiology at the University of Pennsylvania Health System in Philadelphia, Pennsylvania. 

Expertise
Dr. Ghadimi's expertise and instruction spans across the cardiothoracic operating rooms and cardiothoracic surgical ICU environments. His expertise includes perioperative hemostasis & thrombosis, critical care of the heart or lung transplant recipient, and critical care for the patient on mechanical circulatory support, which may include extracorporeal life support (ECMO) or ventricular assist devices/systems.

Research Education
Dr. Ghadimi is a clinical and translational researcher and holds a Master in Health Sciences (M.H.Sc.) from the Duke-NIH Clinical Research Training Program. 

Levy

Jerrold Henry Levy

Professor of Anesthesiology

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.




Unless otherwise indicated, scholarly articles published by Duke faculty members are made available here with a CC-BY-NC (Creative Commons Attribution Non-Commercial) license, as enabled by the Duke Open Access Policy. If you wish to use the materials in ways not already permitted under CC-BY-NC, please consult the copyright owner. Other materials are made available here through the author’s grant of a non-exclusive license to make their work openly accessible.