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Platelets (PLTs) stored at 4°C exhibit equivalent or superior hemostatic function compared with 22°C PLTs, but have shorter circulation times and a decreased ability to modulate vascular permeability. These differences may be due to morphological changes and storage-induced activation. Using a proteomics-based approach, we found that 4°C-stored PLTs express decreased α-tubulin, a key PLT structural protein. PLT activation is characterized by α-tubulin deacetylation, which is regulated by histone deacetylase-6 (HDAC-6). We hypothesized that inhibition of HDAC-6 in stored PLTs will improve their ability to regulate vascular permeability through reduced activation and α-tubulin deacetylation. In an in vivo model of vascular permeability, treatment of 4°C PLTs with the HDAC-6 inhibitor tubacin enhanced the vasculoprotective properties of untreated 4°C PLTs. 4°C PLT circulation, however, was unchanged by tubacin treatment, suggesting that circulation time may not be a critical factor in determining the vasculoprotective effects of PLTs. Assessing the factor content of stored PLTs revealed that angiopoietin-1 (Ang-1) increased in 4°C PLTs over time, which was further enhanced by tubacin treatment. In addition, angiopoietin-2, an inducer of vascular leak and antagonist of Ang-1, inhibited PLT barrier protection, suggesting involvement of the Tie-2 pathway. This study demonstrates that HDAC-6 inhibition with tubacin attenuates the diminished vasculo-protective properties of 4°C PLTs, and these properties may be independent of PLT circulation time.

The MARCH (Massive hemorrhage, Airway, Respirations, Circulation, and Hypothermia/Head injuries) algorithm taught to military medics includes interventions to prevent hypothermia. As possible sequelae from major trauma, hypothermia is associated with coagulopathy and lower survival. This paper sought to define hypothermia within our combat trauma population using an outcomes-based method, and determine clinical variables associated with hypothermia.This is a secondary analysis of a previously described dataset from the Department of Defense Trauma Registry focused on casualties who received prehospital care. A receiver operating curve was constructed and Youden's index was used to define hypothermia within the predetermined population based on mortality risk. A multivariable regression model was used to identify associations.There were 23,243 encounters that met the inclusion criteria for this study with patients having received prehospital care and documentation of at least one emergency department temperature. An optimal threshold of 36.2° C was found to predict mortality; 3,159 casualties had temperatures below this threshold (14%). Survival to discharge was lower among casualties with hypothermia (91% versus 98%). Hypothermic casualties were less likely to undergo blanket application (38% versus 40%). However, they had higher proportions with Hypothermia Prevention and Management Kit application (11% versus 7%) and radiant warming (2% versus 1%). On multivariable regression modeling, none of the hypothermia interventions were associated with a decreased likelihood of hypothermia. Non-hypothermia interventions associated with hypothermia included prehospital intubation (OR 1.57, 95% CI 1.45-1.69) and blood product administration.Hypothermia, including a single recorded low temperature in the patient care record, was associated with worse outcomes in this combat trauma population. Prehospital intubation was most strongly associated with developing hypothermia. Prehospital warming interventions were not associated with a reduction in hypothermia risk. Our dataset suggests that current methods for prehospital warming are inadequate.

Background The use of low-titer group O whole blood is increasing. To reduce wastage, unused units can be converted to packed red blood cells. Supernatant is currently discarded post-conversion; however, it could be a valuable transfusable product. The aim of this study was to evaluate supernatant prepared from late-storage low-titer group O whole blood being converted to red blood cells, hypothesizing it will have higher hemostatic activity compared to fresh never-frozen liquid plasma. Methods Low-titer group O whole blood supernatant (n=12) prepared on storage day 15 was tested on day 15, 21, and 26 and liquid plasma (n=12) on 3, 15, 21, and 26. Same day assays included cell counts, rotational thromboelastometry, and thrombin generation. Centrifuged plasma from units was banked for microparticle characterization, conventional coagulation, clot structure, hemoglobin, and additional thrombin generation assays. Results Low-titer group O whole blood supernatant contained more residual platelets and microparticles compared to liquid plasma. At day 15, low-titer group O whole blood supernatant elicited a faster intrinsic clotting time compared to liquid plasma (257 +/- 41 vs. 299 +/- 36 seconds, p=0.044), and increased clot firmness (49 +/- 9 vs. 28 +/- 5 mm, p Conclusions Plasma supernatant produced from late-storage low-titer group O whole blood shows comparable, if not enhanced, in vitro hemostatic efficacy to liquid plasma.

The causes of endotheliopathy are multifactorial and trauma dependent, and the temporal mechanistic link that it has with acute traumatic coagulopathy (ATC) has yet to be fully determined. Therefore, we sought to define early characteristics and markers of endotheliopathy in two rat models, a time-course of acute lethal hemorrhage shock and polytrauma with hemorrhagic shock, to answer the following questions: (1) how soon can elevated biomarkers of endotheliopathy be detected in non-survivable (decompensated) hemorrhagic shock; (2) does extended hemorrhage time and accumulated hemorrhage impact biomarker levels; and (3) does the addition of polytrauma contribute to the further elevation of said biomarkers? In this study, we delineated a significant, acute elevation in end plasma levels of syndecan-1, thrombomodulin, and heparan sulfate, whose shedding patterns are a function of time as well as total hemorrhage volume vs. the addition of polytrauma. Additionally, we found that correlation of syndecan-1 and thrombomodulin to lactate levels and prothrombin times at trauma end revealed a potential for these markers to acutely predict downstream consequences of these trauma indications. Our results are of great relevance to the continued effort towards the identification and characterization of vascular dysfunction for early interventions in combat casualty care.

Introduction In recent conflicts, the Joint Theater Trauma System (JTTS) led the systematic approach to improve battlefield trauma care, substantially contributing to the unprecedented survival of combat casualties. The Joint Trauma System (JTS) was codified in 2016 to preserve the lessons learned and functions of the JTTS, including the Department of Defense Trauma Registry. Concurrently, Combatant Commands (CCMD) were directed to establish CCMD Trauma Systems (CTS) “modeled after the JTTS” and to maintain a baseline of core functions intended to rapidly scale as needed. The complex nature of both CCMDs and the military trauma system has challenged the full implementation of the CTS. Analyzing the historical experiences of the JTTS, JTS, and CTS within a military doctrinal framework might enable the further success of the military trauma system. Methods The strategic, operational, and tactical levels of warfare, in accordance with Joint Publication 1-0, Doctrine of the Armed Forces of the United States, and Joint Publication 3-0, Joint Operations, established the analytic framework for this study. The literature regarding the JTTS, CTS, and JTS was reviewed for relevant information concerning organizational structure and functions of trauma system performance improvement (PI) capabilities. A comprehensive analysis was performed using a thematic approach to evaluating descriptive data contained within the collected data set. Deployed trauma system PI tasks, functions, and responsibilities were identified, defined, and correlated according to the respective levels of warfare. Results The comprehensive analysis revealed both discrete and overlapping tasks, functions, and responsibilities of the trauma system PI capabilities at each of the three levels of warfare. Strategic-level actions were categorized according to 12 distinct themes: reduce mortality; strategic reporting; centralized trauma registry; strategic communications; centralized organization; direct support to CCMDs; Department of Defense policy and doctrine; strategic-level PI; clinical practice guidelines; training and readiness standards; force structure, standardization, and interoperability; and research and development. Operational-level actions were categorized according to seven distinct themes: theater trauma system policies and requirements; theater trauma system leadership; stakeholder coordination; theater communication; theater standards for readiness and skill sustainment; trauma system planning; and medical logistics support. Tactical-level actions were categorized according to seven distinct themes: trauma system personnel; PI; documentation enforcement and patient care data collection; tactical planning recommendations for employing medical assets; research support; communication and reporting; and training and skills sustainment. Conclusion The deployed U.S. military trauma system requires a robust PI capability to optimize combat casualty care. Policy updates, a joint military trauma system doctrine, and force design updates are necessary for deployed military trauma system PI capabilities to function optimally across all levels of warfare.

Major trauma frequently occurs in the deployed, combat setting and is especially applicable in the recent conflicts with explosives dominating the combat wounded. In future near-peer conflicts, we will likely face even more profound weapons including mortars and artillery. As such, the number of severely wounded will likely increase. Hypocalcemia frequently occurs after blood transfusions, secondary to the preservatives in the blood products; however, recent data suggests major trauma in and of itself is a risk factor for hypocalcemia. Calcium is a major ion involved in heart contractility; thus, hypocalcemia can lead to poor contractility. Smaller studies have linked hypocalcemia to worse outcomes, but it remains unclear what causes hypocalcemia and if intervening could potentially save lives. The objective of this study is to determine the incidence of hypocalcemia on hospital arrival and the association with survival. We are seeking to address the following scientific questions, (1) Is hypocalcemia present following traumatic injury prior to transfusion during resuscitation? (2) Does hypocalcemia influence the amount of blood products transfused? (3) To what extent is hypocalcemia further exacerbated by transfusion? (4) What is the relationship between hypocalcemia following traumatic injury and mortality? We will conduct a multicenter, prospective, observational study. We will gather ionized calcium levels at 0, 3, 6, 12, 18, and 24 hours as part of scheduled calcium measurements. This will ensure we have accurate data to assess the early and late effects of hypocalcemia throughout the course of resuscitation and hemorrhage control. These data will be captured by a trained study team at every site. Our findings will inform clinical practice guidelines and optimize the care delivered in the combat and civilian trauma setting. We are seeking 391 patients with complete data to meet our a priori inclusion criteria. Our study will have major immediate short-term findings including risk prediction modeling to assess who is at risk for hypocalcemia, data assessing interventions associated with the incidence of hypocalcemia, and outcome data including mortality and its link to early hypocalcemia.

Mesenchymal stromal cells (MSCs) express surface tissue factor (TF), which may affect hemostasis and detract from therapeutic outcomes of MSCs if administered intravenously. In this study, we determine a safe dose of MSCs for intravenous (IV) administration and further demonstrate the impact of IV-MSC on acute traumatic coagulopathy (ATC) in rats.Tissue factor expression of rat bone marrow-derived mesenchymal stromal cell (BMSC) or adipose-derived mesenchymal stromal cell (AMSC) was detected by immunohistochemistry and enzyme-linked immunosorbent assay. The coagulation properties were measured in MSC-treated rat whole blood, and blood samples were collected from rats after IV administration of MSCs. Acute traumatic coagulopathy rats underwent polytrauma and 40% hemorrhage, followed by IV administration of 5 or 10 million/kg BMSCs (BMSC-5, BMSC-10), or vehicle at 1 hour after trauma.Rat MSCs expressed TF, and incubation of rat BMSCs or AMSCs with whole blood in vitro led to a significantly shortened clotting time. However, a dose-dependent prolongation of prothrombin time with reduction in platelet counts and fibrinogen was found in healthy rat treated with IV-MSCs. Bone marrow-derived mesenchymal stromal cells at 5 million/kg or less led to minimal effect on hemostasis. Mesenchymal stromal cells were not found in circulation but in the lungs after IV administration regardless of the dosage. Acute traumatic coagulopathy with prolonged prothrombin time was not significantly affected by 5 or 10 million/kg BMSCs. Intravenous administration of 10 million/kg BMSCs led to significantly lower fibrinogen and platelet counts, while significantly higher levels of lactate, wet/dry weight ratio, and leukocyte infiltration in the lung were present compared with BMSC-5 or vehicle. No differences were seen in immune or inflammatory profiles with BMSC treatment in ATC rats, at least in the acute timeframe.Intravenous administration of MSCs leads to a risk of coagulopathy associated with a dose-dependent reduction in platelet counts and fibrinogen and is incapable of restoring hemostasis of rats with ATC after polytrauma and hemorrhagic shock.

Before death, patients commonly experience impaired consciousness for a significant period, frequently preventing family and others from final interactions with the patient. Some of these episodes of cognitive impairment may be treatable, with treatment not offered owing to the perception of ultimate futility or expense, or both. One of the causes of terminal loss of consciousness or decreased lucidity can be inadequate cerebral oxygen delivery. We report five cases from four institutions where an infusion of a hemoglobin-based oxygen carrier to patients who were unconscious or not lucid owing to acute severe anemia (hemoglobin range, 2.1-5.2 g/dL) resulted in awakening or lucidity. We review briefly human cognitive function and anemia and remark about the use of a hemoglobin-based oxygen carrier for acute severe anemia when red cell transfusion is not an option.

While mesenchymal stromal cells are an appealing therapeutic option for a range of clinical applications, their potential to induce clotting when used systemically remains a safety concern, particularly in hypercoagulable conditions, such as in patients with severe COVID‐19, trauma, or cancers. Here, we tested a novel preclinical approach aimed at improving the safety of mesenchymal stromal cell (MSC) systemic administration by use of a bioreactor. In this system, MSCs are seeded on the exterior of a hollow‐fiber filter, sequestering them behind a hemocompatible semipermeable membrane with defined pore‐size and permeability to allow for a molecularly defined cross talk between the therapeutic cells and the whole blood environment, including blood cells and signaling molecules. The potential for these bioreactor MSCs to induce clots in coagulable plasma was compared against directly injected “free” MSCs, a model of systemic administration. Our results showed that restricting MSCs exposure to plasma via a bioreactor extends the time necessary for clot formation to occur when compared with “free” MSCs. Measurement of cell surface data indicates the presence of known clot inducing factors, namely tissue factor and phosphatidylserine. Results also showed that recovering cells and flushing the bioreactor prior to use further prolonged clot formation time. Furthermore, application of this technology in two in vivo models did not require additional heparin in fully anticoagulated experimental animals to maintain target activated clotting time levels relative to heparin anticoagulated controls. Taken together the clinical use of bioreactor housed MSCs could offer a novel method to control systemic MSC exposure and prolong clot formation time., Here we developed a plasma‐based coagulation assay that allowed for clot formation potential of mesenchymal stromal cells (MSCs) across a range of exposures. We conclude that immobilization of MSCs in a hollow fiber filter contributes to a reduced clot initiation potential relative to directly injected MSCs. Further removal of cellular byproducts through saline flushing of the bioreactor further reduces clot formation potential.

High-quality evidence guiding optimal transfusion and other supportive therapies to reduce bleeding is needed to improve outcomes for patients with either severe bleeding or hemostatic disorders that are associated with poor outcomes. Alongside challenges in performing high-quality clinical trials in patient populations who are at risk of bleeding or who are actively bleeding, the interpretation of research evaluating hemostatic agents has been limited by inconsistency in the choice of primary trial outcomes. This lack of standardization of primary endpoints or outcomes decreases the ability of clinicians to assess the validity of endpoints and compare research results across studies, impairs meta-analytic efforts, and, ultimately, delays the translation of research results into clinical practice. To address this challenge, an international panel of experts was convened by the National Heart Lung and Blood Institute and the US Department of Defense on September 23 and 24, 2019, to develop expert opinion, consensus-based recommendations for primary clinical trial outcomes for pivotal trials in pediatric and adult patients with six categories in various clinical settings. This publication documents the conference proceedings from the workshop funded by the National Heart Lung and Blood Institute and the US Department of Defense that consolidated expert opinion regarding clinically meaningful outcomes across a wide range of disciplines to provide guidance for outcomes of future trials of hemostatic products and agents for patients with active bleeding.

Background We sought to determine the extent of loss of endothelial basement membrane (BM), leukocyte recruitment, and changes in coagulation after hemorrhagic shock, followed by limited-volume resuscitation (LVR) with 5% albumin (ALB). Methods Anesthetized rats were bled 40% of blood volume and assigned to treatment groups: untreated (n = 6), LVR with normal saline (NS; n = 8), or LVR with ALB (n = 8). Sham rats (n = 6) underwent all procedures except hemorrhage or resuscitation. Blood samples were assayed for active proteases, such as metalloproteinase 9 (MMP-9) and a disintegrin and metalloproteinase 10 (ADAM-10), BM-type heparan sulfate proteoglycan (perlecan), cell count, and coagulation function. Leukocyte transmigration was used to estimate the net efficiency of leukocyte recruitment in cremaster venules. Results Hemorrhage significantly lowered red cell count, but white cell and platelet counts did not change (vs. sham). Ionized calcium in plasma was significantly reduced in untreated and remained so after NS. In contrast, ionized calcium was normalized after ALB. Plasma expansion after NS and ALB further reduced leukocyte and platelet counts. Metalloproteinase 9, ADAM-10, and perlecan were significantly higher in untreated rats (vs. sham). Albumin normalized MMP-9, ADAM-10, and perlecan levels, while NS further increased MMP-9, ADAM-10, and perlecan (vs. sham). Transmigrated leukocytes doubled in the untreated group and remained elevated after NS (vs. sham) but normalized after ALB. Albumin reduced every stage of the leukocyte recruitment process to sham levels. Conclusion Despite similar plasma expansion, NS weakened platelet function contrary to ALB. Plasma expansion with ALB resulted in restoration of BM integrity and attenuation of leukocyte recruitment to tissues, in contrast to NS. Albumin plays a critical role in restoring BM integrity, attenuating leukocyte recruitment to tissues, and optimizing hemostasis by increasing ionized calcium in plasma.

Synthetic biology adopts an engineering design approach to create innovative treatments that are reliable, scalable, and customizable to individual patients. Interest in substitutes for allogenic blood components, primarily red blood cells and platelets, increased in the 1980s because of concerns over infectious disease transmission. However, only now, with emerging synthetic approaches, are such substitutes showing genuine promise. Affordable alternatives to donated blood would be of enormous benefit worldwide. Several approaches to replacing the oxygen-carrying function of red cells are under advanced investigation. Hemoglobin-based oxygen carriers incorporate modifications to reduce the renal toxicity and nitric oxide scavenging of free hemoglobin. While use of earlier-generation hemoglobin-based oxygen carriers may be limited to circumstances in which blood transfusion is not an option, recent advances in chemical modification of hemoglobin may eventually overcome such problems. Another approach encases hemoglobin molecules in biocompatible synthetic nanoparticles. An alternative is the ex vivo production of red cells in bioreactors, with or without genetic manipulation, that offers the potential of a universal donor product. Various strategies to manufacture synthetic platelets are also underway, ranging from simple phospholipid liposomes encapsulating adenosine diphosphate and decorated with fibrinogen fragments, to more complex capsules with multiple receptor peptide sequences. Ex vivo production of platelets in bioreactors is also possible including, for example, platelets derived from induced pluripotent stem cells that are differentiated into a megakaryocytic lineage. Prior to clinical use, trials assessing synthetic blood components must evaluate meaningful safety and effectiveness outcomes in relatively large numbers of critically ill patients. Overcoming these challenges may be as much a hurdle as product design. This article reviews the state of the science of the synthetic biology approach to developing blood component substitutes.

Complementopathy, endotheliopathy, and coagulopathy following a traumatic injury are key pathophysiological mechanisms potentially associated with multiple-organ failure (MOF) and mortality. However, the heterogeneity in the responses of complementopathy, endotheliopathy, and coagulopathy to trauma, the nature and extent of their interplay, and their relationship to clinical outcomes remain unclear. Fifty-four poly-trauma patients were enrolled and divided into three subgroups based on their ISS. Biomarkers in blood plasma reflecting complement activation, endothelial damage, and coagulopathy were measured starting from admission to the emergency department and at 3, 6, 12, 24, and 120 hours after admission. Comparative analyses showed that severely injured patients (ISS>24) were associated with longer days on mechanical ventilation, in the intensive care unit and hospital stays, and a higher incidence of hyperglycemia, bacteremia, respiratory failure and pneumonia compared to mildly (ISS1.57 μg/ml, syndecan-1 >66.6 ng/ml or D-dimer >6 mg/L at admission were associated with a higher risk of MOF/mortality. After adjusting for ISS, each increase of the triadic score defined above (Bb>1.57 µg/ml/Syndecan-1>66.6 ng/ml/D-dimer>6.0mg/L) was associated with a 6-fold higher in the odds ratio of MOF/death [OR: 6.83 (1.04-44.96, P=0.046], and a 4-fold greater in the odds of infectious complications [OR: 4.12 (1.04-16.36), P=0.044]. These findings provide preliminary evidence of two human injury response endotypes (traumatized triad and non-traumatized triad) that align with clinical trajectory, suggesting a potential endotype defined by a high triadic score. Patients with this endotype may be considered for timely intervention to create a pro-survival/organ-protective phenotype and improve clinical outcomes.

Screening for the risk of thromboembolism (TE) due to tranexamic acid (TXA) in patients with severe traumatic injury has not been performed in randomized clinical trials. Our objective was to determine if TXA dose was independently-associated with thromboembolism.This is a secondary analysis of a single-center, double-blinded, randomized controlled trial comparing placebo to a 2-g or 4-g intravenous TXA bolus dose in trauma patients with severe injury. We used multivariable discrete-time Cox regression models to identify associations with risk for thromboembolic events within 30 days post-enrollment. Event curves were created using discrete-time Cox regression.There were 50 patients in the placebo group, 49 in the 2-g, and 50 in the 4-g TXA group. In adjusted analyses for thromboembolism, a 2-g dose of TXA had an hazard ratio (HR, 95% confidence interval [CI]) of 3.20 (1.12-9.11) (p = .029), and a 4-g dose of TXA had an HR (95% CI) of 5.33 (1.94-14.63) (p = .001). Event curves demonstrated a higher probability of thromboembolism for both doses of TXA compared to placebo. Other parameters independently associated with thromboembolism include time from injury to TXA administration, body mass index, and total blood products transfused.In patients with severe traumatic injury, there was a dose-dependent increase in the risk of at least one thromboembolic event with TXA. TXA should not be withheld, but thromboembolism screening should be considered for patients receiving a dose of at least 2-g TXA intravenously for traumatic hemorrhage.

Battlefield pain occurs in combat casualties who experience multiple severe injuries. The nature of battlefield scenarios requires a distinct approach to battlefield pain research. A battlefield pain summit was thus convened to identify shortcomings in the current understanding of battlefield pain management, review the current state of battlefield pain research, and shape the direction of future research.On January 10 to 11, 2022, a hybrid in-person and virtual meeting hosted by the US Army Institute of Surgical Research defined research priorities for the Combat Casualty Care Research Program's Battlefield Pain research portfolio. Summit participants identified the following key focus areas under the umbrella of battlefield pain research: battlefield injury patterns; use of ketamine and nonopioid analgesics; analgesic delivery systems; the impact of analgesia on performance, cognition, and survival; training methods; battlefield regional anesthesia; and research models. Preliminary statements presented during the summit were refined and rank ordered through a Delphi process.Consensus was achieved on 7 statements addressing ideal analgesic properties, delivery systems, operational performance concerns, and pain training. Ketamine was identified as safe and effective for battlefield use, and further research into nonopioid analgesics represented a high priority.The 7 consensus statements that emerged from this battlefield pain summit serve as a template to define the near-term research priorities for military-specific battlefield pain research.

IntroductionWithin the Military Health System, the process of transporting patients from an initial point of injury and throughout the entire continuum of care is called “en route care.” A Committee on En Route Combat Casualty Care was established in 2016 as part of the DoD Joint Trauma System to create practice guidelines, recommend training standards, and identify research priorities within the military en route care system.Materials and MethodsFollowing an analysis of currently funded research, future capabilities, and findings from a comprehensive scoping study, members of a sub-working group for research identified the top research priorities that were needed to better guide evidence-based decisions for practice and policy, as well as the future state of en route care.ResultsBased on the input from the entire committee, 10 en route care research topics were rank-ordered in the following manner: (1) medical documentation, (2) clinical decision support, (3) patient monitoring, (4) transport physiology, (5) transfer of care, (6) maintaining normothermia, (7) transport timing following damage control resuscitation or surgery, (8) intelligent tasking, (9) commander’s risk assessment, and (10) unmanned transport. Specific research questions and technological development needs were further developed by committee members in an effort to guide future research and development initiatives that can directly support operational en route care needs. The research priorities reflect three common themes, which include efforts to enhance or increase care provider capability and capacity; understand the impact of transportation on patient physiology; and increase the ability to coordinate, communicate, and facilitate patient movement. Technology needs for en route care must support interoperability of medical information, equipment, and supplies across the global military health system in addition to adjusting to a dynamic transport environment with the smallest possible weight, space, and power requirements.ConclusionsTo ensure an evidence-based approach to future military conflicts and other medical challenges, focused research and technological development to address these 10 en route care research gaps are urgently needed.

There has been renewed interest in the use of low titer group O whole blood (LTOWB) for the resuscitation of civilian casualties. LTOWB offers several advantages over conventional components such as providing balanced resuscitation in one bag that contains less additive/preservative solution than an equivalent volume of conventional components, is easier and faster to transfuse than multiple components, avoids blood product ratio confusion, contains cold stored platelets, and reduces donor exposures. The resurgence in its use in the resuscitation of civilian trauma patients has led to the publication of an increasing number of studies on its use, primarily amongst adult recipients but also in pediatric patients. These studies have indicated that hemolysis does not occur amongst adult and pediatric non-group O recipients of a modest quantity of LTOWB. The published studies to date on mortality have shown conflicting results with some demonstrating a reduction following LTOWB transfusion while most others have not shown a reduction; there have not been any studies to date that have found significantly increased overall mortality amongst LTOWB recipients. Similarly, when other clinical outcomes, such as venous thromboembolism, sepsis, hospital or intensive care unit lengths of stay are evaluated, LTOWB recipients have not demonstrated worse outcomes compared to conventional component recipients. While definitive proof of the trends in these morbidity and mortality outcomes awaits confirmation in randomized controlled trials, the evidence to date indicates the safety of transfusing LTOWB to injured civilians.

Graphical abstract Traumatic injuries are a leading cause of death and disability in both military and civilian populations. Given the complexity and diversity of traumatic injuries, novel and individualized treatment strategies are required to optimize outcomes. Cellular therapies have potential benefit for the treatment of acute or chronic injuries, and various cell-based pharmaceuticals are currently being tested in preclinical studies or in clinical trials. Cellular therapeutics may have the ability to complement existing therapies, especially in restoring organ function lost due to tissue disruption, prolonged hypoxia or inflammatory damage. In this article we highlight the current status and discuss future directions of cellular therapies for the treatment of traumatic injury. Both published research and ongoing clinical trials are discussed here.