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      Procoagulant in vitro effects of clinical cellular therapeutics in a severely injured trauma population

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          Abstract

          Clinical trials in trauma populations are exploring the use of clinical cellular therapeutics (CCTs) like human mesenchymal stromal cells (MSC) and mononuclear cells (MNC). Recent studies demonstrate a procoagulant effect of these CCTs related to their expression of tissue factor (TF). We sought to examine this relationship in blood from severely injured trauma patients and identify methods to reverse this procoagulant effect. Human MSCs from bone marrow, adipose, and amniotic tissues and freshly isolated bone marrow MNC samples were tested. TF expression and phenotype were quantified using flow cytometry. CCTs were mixed individually with trauma patients' whole blood, assayed with thromboelastography (TEG), and compared with healthy subjects mixed with the same cell sources. Heparin was added to samples at increasing concentrations until TEG parameters normalized. Clotting time or R time in TEG decreased relative to the TF expression of the CCT treatment in a logarithmic fashion for trauma patients and healthy subjects. Nonlinear regression curves were significantly different with healthy subjects demonstrating greater relative decreases in TEG clotting time. In vitro coadministration of heparin normalized the procoagulant effect and required dose escalation based on TF expression. TF expression in human MSC and MNC has a procoagulant effect in blood from trauma patients and healthy subjects. The procoagulant effect is lower in trauma patients possibly because their clotting time is already accelerated. The procoagulant effect due to MSC/MNC TF expression could be useful in the bleeding trauma patient; however, it may emerge as a safety release criterion due to thrombotic risk. The TF procoagulant effect is reversible with heparin.

          Abstract

          Clinical cellular therapeutic (CCT) procoagulant effects in trauma and healthy subjects. Error bars represent a 95% confidence interval. CCTs have a greater procoagulant effect in healthy subjects from a tissue factor load of 250 to 1700. Trauma patients are hypercoaguable at baseline and have less physiological capacity for an additional procoagulant response.

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          Most cited references 25

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          Clinical trials in head injury.

          Traumatic brain injury (TBI) remains a major public health problem globally. In the United States the incidence of closed head injuries admitted to hospitals is conservatively estimated to be 200 per 100,000 population, and the incidence of penetrating head injury is estimated to be 12 per 100,000, the highest of any developed country in the world. This yields an approximate number of 500,000 new cases each year, a sizeable proportion of which demonstrate significant long-term disabilities. Unfortunately, there is a paucity of proven therapies for this disease. For a variety of reasons, clinical trials for this condition have been difficult to design and perform. Despite promising pre-clinical data, most of the trials that have been performed in recent years have failed to demonstrate any significant improvement in outcomes. The reasons for these failures have not always been apparent and any insights gained were not always shared. It was therefore feared that we were running the risk of repeating our mistakes. Recognizing the importance of TBI, the National Institute of Neurological Disorders and Stroke (NINDS) sponsored a workshop that brought together experts from clinical, research, and pharmaceutical backgrounds. This workshop proved to be very informative and yielded many insights into previous and future TBI trials. This paper is an attempt to summarize the key points made at the workshop. It is hoped that these lessons will enhance the planning and design of future efforts in this important field of research.
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            Acute lung injury: epidemiology, pathogenesis, and treatment.

            Acute lung injury (ALI) remains a significant source of morbidity and mortality in the critically ill patient population. Defined by a constellation of clinical criteria (acute onset of bilateral pulmonary infiltrates with hypoxemia without evidence of hydrostatic pulmonary edema), ALI has a high incidence (200,000 per year in the US) and overall mortality remains high. Pathogenesis of ALI is explained by injury to both the vascular endothelium and alveolar epithelium. Recent advances in the understanding of pathophysiology have identified several biologic markers that are associated with worse clinical outcomes. Phase III clinical trials by the NHLBI ARDS Network have resulted in improvement in survival and a reduction in the duration of mechanical ventilation with a lung-protective ventilation strategy and fluid conservative protocol. Potential areas of future treatments include nutritional strategies, statin therapy, and mesenchymal stem cells.
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              Are therapeutic human mesenchymal stromal cells compatible with human blood?

              Multipotent mesenchymal stromal cells (MSCs) are tested in numerous clinical trials. Questions have been raised concerning fate and function of these therapeutic cells after systemic infusion. We therefore asked whether culture-expanded human MSCs elicit an innate immune attack, termed instant blood-mediated inflammatory reaction (IBMIR), which has previously been shown to compromise the survival and function of systemically infused islet cells and hepatocytes. We found that MSCs expressed hemostatic regulators similar to those produced by endothelial cells but displayed higher amounts of prothrombotic tissue/stromal factors on their surface, which triggered the IBMIR after blood exposure, as characterized by formation of blood activation markers. This process was dependent on the cell dose, the choice of MSC donor, and particularly the cell-passage number. Short-term expanded MSCs triggered only weak blood responses in vitro, whereas extended culture and coculture with activated lymphocytes increased their prothrombotic properties. After systemic infusion to patients, we found increased formation of blood activation markers, but no formation of hyperfibrinolysis marker D-dimer or acute-phase reactants with the currently applied dose of 1.0-3.0 × 10(6) cells per kilogram. Culture-expanded MSCs trigger the IBMIR in vitro and in vivo. Induction of IBMIR is dose-dependent and increases after prolonged ex vivo expansion. Currently applied doses of low-passage clinical-grade MSCs elicit only minor systemic effects, but higher cell doses and particularly higher passage cells should be handled with care. This deleterious reaction can compromise the survival, engraftment, and function of these therapeutic cells. Copyright © 2012 AlphaMed Press.
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                Author and article information

                Contributors
                mitchell.j.george@uth.tmc.edu
                Journal
                Stem Cells Transl Med
                Stem Cells Transl Med
                10.1002/(ISSN)2157-6580
                SCT3
                Stem Cells Translational Medicine
                John Wiley & Sons, Inc. (Hoboken, USA )
                2157-6564
                2157-6580
                06 January 2020
                April 2020
                : 9
                : 4 ( doiID: 10.1002/sct3.v9.4 )
                : 491-498
                Affiliations
                [ 1 ] Department of Surgery McGovern Medical School at The University of Texas Health Science Center Houston Texas
                [ 2 ] Department of Pediatric Surgery McGovern Medical School at The University of Texas Health Science Center Houston Texas
                [ 3 ] U.S. Army Institute of Surgical Research JBSA‐FT Sam Houston San Antonio Texas
                Author notes
                [* ] Correspondence

                Mitchell J. George, MD, Department of Surgery, McGovern Medical School at The University of Texas Health Science Center, 6431 Fannin Street, MSB 5.004, Houston, Texas 77030.

                Email: mitchell.j.george@ 123456uth.tmc.edu

                Article
                SCT312656
                10.1002/sctm.19-0206
                7103617
                31903737
                © 2020 The Authors. stem cells translational medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                Counts
                Figures: 3, Tables: 3, Pages: 8, Words: 5946
                Product
                Funding
                Funded by: NIH , open-funder-registry 10.13039/100000002;
                Award ID: T32 GM008792‐17
                Funded by: Glassell Family Stem Cell Research Program
                Categories
                Standards, Protocols, Policies, and Regulations for Cell‐based Therapies
                Standards, Protocols, Policies, and Regulations for Cell‐based Therapies
                Custom metadata
                2.0
                April 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.7.8 mode:remove_FC converted:30.03.2020

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