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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.

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.

Objective To address the clinical and regulatory challenges of optimal primary endpoints for bleeding patients by developing consensus-based recommendations for primary clinical outcomes for pivotal trials in patients within 6 categories of significant bleeding, (1) traumatic injury, (2) intracranial hemorrhage, (3) cardiac surgery, (4) gastrointestinal hemorrhage, (5) inherited bleeding disorders, and (6) hypoproliferative thrombocytopenia. Background A standardized primary outcome in clinical trials evaluating hemostatic products and strategies for the treatment of clinically significant bleeding will facilitate the conduct, interpretation, and translation into clinical practice of hemostasis research and support alignment among funders, investigators, clinicians, and regulators. Methods An international panel of experts was convened by the National Heart Lung and Blood Institute and the United States Department of Defense on September 23 and 24, 2019. For patients suffering hemorrhagic shock, the 26 trauma working-group members met for almost a year, utilizing biweekly phone conferences and then an in-person meeting, evaluating the strengths and weaknesses of previous high quality studies. The selection of the recommended primary outcome was guided by goals of patient-centeredness, expected or demonstrated sensitivity to beneficial treatment effects, biologic plausibility, clinical and logistical feasibility, and broad applicability. Conclusions For patients suffering hemorrhagic shock, and especially from truncal hemorrhage, the recommended primary outcome was 3 to 6-hour all-cause mortality, chosen to coincide with the physiology of hemorrhagic death and to avoid bias from competing risks. Particular attention was recommended to injury and treatment time, as well as robust assessments of multiple safety related outcomes.

Background This pilot trial focused on feasibility and safety to provide preliminary data to evaluate the hemostatic potential of cold-stored platelets (2° to 6°C) compared with standard room temperature–stored platelets (20° to 24°C) in adult patients undergoing complex cardiothoracic surgery. This study aimed to assess feasibility and to provide information for future pivotal trials. Methods A single center two-stage exploratory pilot study was performed on adult patients undergoing elective or semiurgent complex cardiothoracic surgery. In stage I, a two-armed randomized trial, platelets stored up to 7 days in the cold were compared with those stored at room temperature. In the subsequent single-arm stage II, cold storage time was extended to 8 to 14 days. The primary outcome was clinical effect measured by chest drain output. Secondary outcomes were platelet function measured by multiple electrode impedance aggregometry, total blood usage, immediate and long-term (28 days) adverse events, length of stay in intensive care, and mortality. Results In stage I, the median chest drain output was 720 ml (quartiles 485 to 1,170, n = 25) in patients transfused with room temperature–stored platelets and 645 ml (quartiles 460 to 800, n = 25) in patients transfused with cold-stored platelets. No significant difference was observed. The difference in medians between the room temperature– and cold-stored up to 7 days arm was 75 ml (95% CI, −220, 425). In stage II, the median chest drain output was 690 ml (500 to 1,880, n = 15). The difference in medians between the room temperature arm and the nonconcurrent cold-stored 8 to 14 days arm was 30 ml (95% CI, −1,040, 355). Platelet aggregation in vitro increased after transfusion in both the room temperature– and cold-stored platelet study arms. Total blood usage, number of adverse events, length of stay in intensive care, and mortality were comparable among patients receiving cold-stored and room temperature–stored platelets. Conclusions This pilot trial supports the feasibility of platelets stored cold for up to 14 days and provides critical guidance for future pivotal trials in high-risk cardiothoracic bleeding patients. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Introduction In the far forward combat environment, the use of whole blood is recommended for the treatment of hemorrhagic shock after injury. In 2016, US military special operations teams began receiving low titer group O whole blood (LTOWB) for use at the point of injury (POI). This is a case series of the initial 15 patients who received LTOWB on the battlefield. Methods Patients were identified in the Department of Defense Trauma Registry, and charts were abstracted for age, sex, nationality, mechanism of injury, injuries and physiologic criteria that triggered the transfusion, treatments at the POI, blood products received at the POI and the damage-control procedures done by the first surgical team, next level of care, initial interventions by the second surgical team, Injury Severity Score, and 30-day survival. Descriptive statistics were used to characterize the clinical data when appropriate. Results Of the 15 casualties, the mean age was 28, 50% were US military, and 63% were gunshot wounds. Thirteen patients survived to discharge, one died of wounds after arrival at the initial resuscitative surgical care, and two died prehospital. The mean Injury Severity Score was 21.31 (SD, 18.93). Eleven (68%) of the causalities received additional blood products during evacuation/role 2 and/or role 3. Vital signs were available for 10 patients from the prehospital setting and 9 patients upon arrival at the first surgical capable facility. The mean systolic blood pressure was 80.5 prehospital and 117 mm Hg (p = 0.0002) at the first surgical facility. The mean heart rate was 105 beats per minute prehospital and 87.4 beats per minute (p = 0.075) at the first surgical facility. The mean hospital stay was 24 days. Conclusion The use of cold-stored LTOWB at POI is feasible during combat operations. Further data are needed to validate and inform best practice for POI transfusion. Level of evidence Therapeutic study, level V.

BACKGROUND This study compared the resuscitation effects of platelets and fibrinogen concentrate (FC) on coagulation and hemodynamics in pigs with traumatic hemorrhage and reduced platelet counts. METHODS Thirty pigs (40 ± 3 kg) were anesthetized and catheterized with an apheresis catheter to remove platelets using the Haemonetics 9000 (Haemonetics, Braintree, MA). Afterward, a femur fracture was induced, followed by hemorrhage of 35% the estimated blood volume. Pigs were then randomized to be resuscitated with 5% human albumin (12.5 mL/kg), FC (250 mg/kg, 12.5 mL/kg), or platelets collected from apheresis (11.0 ± 0.5 mL/kg). Animals were monitored for 2 hours or until death. Blood samples were collected before (baseline [BL]) and after apheresis, after hemorrhage, and after resuscitation to assess changes in hemodynamics and coagulation using Rotem. RESULTS No change in mean arterial pressure (MAP) or heart rate (HR) was observed by platelet apheresis. Hemorrhage reduced MAP to 57% ± 5% and elevated HR to 212% ± 20% of BL (both p < 0.05). Resuscitation with albumin, FC, or platelets did not revert MAP or HR to BL. Platelet counts were reduced by apheresis from BL 383 ± 20 × 10/μL to 141 ± 14 × 10/μL and were reduced further after resuscitation with albumin (88 ± 18 × 10/μL) or FC (97 ± 13 × 10/μL, all p < 0.05), but improved with platelet resuscitation (307 ± 24 × 10/μL). Fibrinogen concentration was reduced by apheresis from BL 225 ± 9 mg/dL to 194 ± 8 mg/dL, fell after albumin infusion (134 ± 11 mg/dL), increased to 269 ± 10 mg/dL after FC resuscitation (all p < 0.05), and was not affected by platelet resuscitation. Rotem α-angle decreased from 79 ± 2 degrees to 69 ± 1 degrees by apheresis and hemorrhage (p < 0.05), and recovered similarly by resuscitation with FC (87 ± 1 degrees) or platelets (78 ± 2 degrees), but not by albumin (63 ± 3 degrees). Similar responses were observed in Rotem maximum clot firmness. CONCLUSION In this traumatic hemorrhage swine model, low-volume resuscitation with FC or platelets was similarly effective in restoring coagulation.

Background The high incidence of venous thromboembolism (VTE) following trauma persists in spite of aggressive thromboprophylaxis strategies. Approximately half of VTE patients do not achieve the recommended anti-FXa response to enoxaparin anticoagulation (0.1–0.4 IU/mL), however, research to explain or correct this phenomenon is lacking. We hypothesized that antithrombin III (AT) deficiency is associated with poor enoxaparin responsiveness in trauma patients that develop VTE which can be reversed through supplementation with AT. Methods and findings A retrospective cohort study was performed on plasma collected from trauma patients who did and did not develop pulmonary embolism (PE) as well as healthy volunteers. AT levels, thrombin generation, and anti-FXa levels were measured in the collected plasma at baseline and in response to supplementation with AT concentrate at 120–200% or plasma (30% volume). A total of 54 PE patients and 46 non-PE patients were enrolled in this study for analysis. Compared to healthy volunteers, trauma patients had lower levels of AT, elevated thrombin generation, and lower anti-FXa levels in response to enoxaparin. Moreover, thrombin generation was higher and responses to enoxaparin were lower in patients who developed PE compared to those who did not develop PE. We found that supplementation with AT, but not plasma, increased AT levels and improved enoxaparin-mediated inhibition of thrombin generation. Conclusions Supplementation with AT may provide a novel adjunct therapy to increase the effectiveness of enoxaparin thromboprophylaxis and reduce the incidence of VTE in the trauma population.

Valproic acid (VPA) has been extensively used for treatment of anxiety and seizure. Recent studies have shown that VPA has cellular protective effects in preclinical models following severe hemorrhage. This study investigated the effects of VPA on coagulation and survival in pigs after traumatic hemorrhage and hypotensive resuscitation.Following baseline measurements, femur fracture was performed in 20 anesthetized and instrumented pigs (41 ± 2 kg), followed by hemorrhage of 55% of the estimated blood volume and a 10-minute shock period. Pigs were then resuscitated for 30 minutes with normal saline (NS) alone (NS group, n = 10, 4 mL/kg) or VPA solution (VPA group, n = 10, 90 mg/kg, 2 mL/kg of 45 mg VPA/mL, plus 2 mL NS/kg). All pigs were then monitored for 2 hours or until death. Hemodynamics were recorded, and blood samples were taken for blood and coagulation analysis (Rotem) at baseline, after hemorrhage, resuscitation, and 2 hours or death.Femur fracture and hemorrhage caused similar reductions in mean arterial pressure and cardiac output, and increase in heart rate in both groups. Resuscitation with NS or VPA did not return these measurements to baseline. No differences were observed in hematocrit, pH, lactate, base excess, or total protein between the groups. Compared with NS, resuscitation with VPA decreased platelet counts and prolonged activated partial thromboplastin time, with no differences in fibrinogen levels, prothrombin time, or any of the Rotem measurements between the two groups. Neither survival rates (NS, 7 of 10 pigs; VPA, 7 of 10 pigs) nor survival times after resuscitation (NS, 97 ± 40 minutes; VPA, 98 ± 43 minutes) differed between the groups.Following traumatic hemorrhage and hypotensive resuscitation in pigs, VPA provides no benefit toward improving coagulation function or survival times.

The United States Armed Services Blood Program (ASBP) faced complex blood supply challenges during two decades of military operations in the U.S. Central Command (CENTCOM) and through an adaptive, responsive, and agile system, gained valuable insights on blood product usage in combat casualty care.A retrospective review of blood product introduction and utilization trends was compiled from ASBP data collected during CENTCOM operations from 2014 through 2021.During the study period, several blood products were introduced to the CENTCOM area of operations including Low Titer O Whole Blood (LTOWB), Cold-Stored Platelets (CSP), Liquid Plasma (LP), and French Freeze Dried Plasma (FDP) manufactured from U.S. sourced donor plasma, all while expanding Walking Blood Bank capabilities. There was a gradual substitution of component therapy for whole blood; blood utilization peaked in 2017. Transfusion of Fresh Whole Blood (FWB) from Walking Blood Banks decreased as fully pre-tested LTOWB was supplied by the ASBP. LTOWB was initially supplied in citrate-phosphate-dextrose (CPD) anticoagulant (21-day shelf life) but was largely replaced with LTOWB in citrate-phosphate-dextrose-adenine (CPDA-1) anticoagulant (35-day shelf life) by 2019. Implementation of prehospital transfusion and expansion of surgical and resuscitation teams led to an increase in the number of sites receiving blood.ASBP introduced new products to its inventory in order to meet changing blood product demands driven by changes in the Joint Trauma System Clinical Practice Guidelines and operational demands. These products were adopted into clinical practice with a resultant evolution in transfusion strategies.

ObjectivesEarly complementopathy and coagulopathy are shown often after trauma. However, the prevalence of any interplay between complement cascade (ComC) and coagulation cascade (CoaC) after trauma remains unclear. This study intended to explore whether complement-coagulation crosstalk exists, which may provide a reliable guide to clinical implications in trauma patients.MethodsThis single-center cohort study of trauma patients enrolled 100 patients along with 20 healthy volunteers. Blood samples from patients were collected at admission, 45, 90, 135 minutes, and 18 hours after admission. Demographic characteristics were recorded, blood levels of ComC and CoaC factors, and inflammatory cytokines were measured by ELISA, clot-based assays, or luminex multiplex assay, and partial thromboplastin (PT) and partial thromboplastin time (PTT) were assessed using a Behring blood coagulation system.ResultsCompared with the healthy controls, plasma levels of complement factors (C5b-9 and Bb) and 11 tested inflammatory cytokines increased in moderately and severely injured patients as early as 45 minutes after admission and sustained higher levels up to 18 hours after admission. C5b-9 correlated positively to patients’ hospital stay. In parallel, the consumption of coagulation factors I, II, X, and XIII was shown throughout the first 18 hours after admission in moderately and severely injured patients, whereas PT, PTT, D-dimer, factor VII, and factor VIII values significantly increased from the admission to 135 minutes in moderately and severely injured patients. Along with an inverse correlation between plasma Bb, factors I and II, a positive correlation between C5b-9, Bb, D-dimer, PT, and PTT was evident.ConclusionsThis study demonstrates trauma-induced early activation of plasma cascades including ComC, CoaC, and fibrinolytic cascade, and their correlation between plasma cascades in severe trauma patients. Our study suggests that the simultaneous modulation of plasma cascades might benefit clinical outcomes for trauma patients.Level of evidenceProspective study, level III.

A perfluorocarbon (PFC) investigated for treatment of traumatic brain injury (TBI) delivers oxygen to support brain function, but causes transient thrombocytopenia. TBI can cause acute inflammation with resulting thrombocytopenia; an interaction between the PFC effects and TBI inflammation might exacerbate thrombocytopenia. Therefore, PFC effects on platelet (PLT) function and hemostasis in a lipopolysaccharide (LPS) model of inflammation in the baboon were studied. Animals were randomized to receive saline ±LPS, and ± one of two doses of PFC. PLT count, transmission electron microscopy, and microparticle populations were quantified at baseline (BL) and at 2, 24, 48, 72, and 96 hours; hemostatic parameters for aggregometry and for blood clotting were measured at baseline (BL) and days 3 and 4. Injection of vehicle and LPS caused thrombocytopenia within hours; PFCs caused delayed thrombocytopenia beginning 48 hours post-infusion. LPS+PFC produced a more prolonged PLT decline and decreased clot strength. LPS+PFC increased ADP-stimulated aggregation, but PFC alone did not. Microparticle abundance was greatest in the LPS+PFC groups. LPS+PFC caused diffuse microvascular hemorrhage and death in 2 of 5 baboons in the low dose LPS-PFC group and 2 of 2 in the high dose LPS-PFC group. Necropsy and histology suggested death was caused by shock associated with hemorrhage in multiple organs. Abnormal morphology of platelets and red blood cells were notable for PFC inclusions. In summary, PFC infusion caused clinically significant thrombocytopenia and exacerbated LPS-induced platelet activation. The interaction between these effects resulted in decreased hemostatic capacity, diffuse bleeding, shock and death.

Consumption of platelets and coagulation factors during extracorporeal carbon dioxide removal (ECCOAn ECCOTwelve hours of regional acid infusion significantly inhibited platelet aggregation response to adenosine diphosphate; vWF; and platelet expression of P-selectin compared to control. It also significantly reduced consumption of fibrinogen and of coagulation factors V, VII, IX, compared to control.Regional acidification reduces platelet activation and vitamin-K-dependent coagulation-factor consumption during ECCO

Hemorrhagic shock in combat trauma remains the greatest life threat to casualties with potentially survivable injuries. Advances in external hemorrhage control and the increasing use of damage control resuscitation have demonstrated significant success in decreasing mortality in combat casualties. Presently, an expanding body of literature suggests that fluid resuscitation strategies for casualties in hemorrhagic shock that include the prehospital use of cold-stored or fresh whole blood when available, or blood components when whole blood is not available, are superior to crystalloid and colloid fluids. On the basis of this recent evidence, the Committee on Tactical Combat Casualty Care (TCCC) has conducted a review of fluid resuscitation for the combat casualty who is in hemorrhagic shock and made the following new recommendations: (1) cold stored low-titer group O whole blood (CS-LTOWB) has been designated as the preferred resuscitation fluid, with fresh LTOWB identified as the first alternate if CS-LTOWB is not available; (2) crystalloids and Hextend are no longer recommended as fluid resuscitation options in hemorrhagic shock; (3) target systolic blood pressure (SBP) resuscitation goals have been redefined for casualties with and without traumatic brain injury (TBI) coexisting with their hemorrhagic shock; and (4) empiric prehospital calcium administration is now recommended whenever blood product resuscitation is required.

This Clinical Practice Guideline (CPG) provides a brief summary of the scientific literature for prehospital blood use, with an emphasis on the en route care environment. Updates include the importance of calcium administration to counteract the deleterious effects of hypocalcemia, minimal to no use of crystalloid, and stresses the importance of involved and educated en route care medical directors alongside at a competent prehospital and en route care providers (see Table 1). With the paradigm shift to use FDA-approved cold stored low titer group O whole blood (CS-LTOWB) along with the operational need for continued use of walking blood banks (WBB) and point of injury (POI) transfusion, there must be focused, deliberate training incorporating the different whole blood options. Appropriate supervision of autologous blood transfusion training is important for execution of this task in support of deployed combat operations as well as other operations in which traumatic injuries will occur. Command emphasis on the importance of this effort as well as appropriate logistical support are essential elements of a prehospital blood program as part of a prehospital/en route combat casualty care system.

Fibrinogen plays a pathologic role in multiple diseases. It contributes to thrombosis and modifies inflammatory and immune responses, supported by studies in mice expressing fibrinogen variants with altered function or with a germline fibrinogen deficiency. However, therapeutic strategies to safely and effectively tailor plasma fibrinogen concentration are lacking. Here, we developed a strategy to tune fibrinogen expression by administering lipid nanoparticle (LNP)-encapsulated small interfering RNA (siRNA) targeting the fibrinogen α chain (siFga). Three distinct LNP-siFga reagents reduced both hepatic Fga messenger RNA and fibrinogen levels in platelets and plasma, with plasma levels decreased to 42%, 16%, and 4% of normal within 1 week of administration. Using the most potent siFga, circulating fibrinogen was controllably decreased to 32%, 14%, and 5% of baseline with 0.5, 1.0, and 2.0 mg/kg doses, respectively. Whole blood from mice treated with siFga formed clots with significantly decreased clot strength ex vivo, but siFga treatment did not compromise hemostasis following saphenous vein puncture or tail transection. In an endotoxemia model, siFga suppressed the acute phase response and decreased plasma fibrinogen, D-dimer, and proinflammatory cytokine levels. In a sterile peritonitis model, siFga restored normal macrophage migration in plasminogen-deficient mice. Finally, treatment of mice with siFga decreased the metastatic potential of tumor cells in a manner comparable to that observed in fibrinogen-deficient mice. The results indicate that siFga causes robust and controllable depletion of fibrinogen and provides the proof-of-concept that this strategy can modulate the pleiotropic effects of fibrinogen in relevant disease models.

United States Africa Command (US AFRICOM) is one of six US Defense Department's geographic combatant commands and is responsible to the Secretary of Defense for military relations with African nations, the African Union, and African regional security organizations. A full-spectrum combatant command, US AFRICOM is responsible for all US Department of Defense operations, exercises, and security cooperation on the African continent, its island nations, and surrounding waters. We seek to characterize blood product administration within AFRICOM using the in-transit visibility tracking tool known as TRAC2ES (TRANSCOM Regulating and CommandControl Evacuation System).We performed a retrospective review of TRAC2ES medical evacuations from the AFRICOM theater of operations conducted between 1 January 2008 and 31 December 2018.During this time, there were 963 cases recorded in TRAC2ES originating within AFRICOM, of which 10 (1%) cases received blood products. All patients were males. One was a Department of State employee, one was a military working dog, and the remainder were military personnel. Of the ten humans, seven were the result of trauma, most by way of gunshot wound, and three were due to medical causes. Among human subjects receiving blood products for traumatic injuries, a total of 5 units of type O negative whole blood, 29 units of packed red blood cells (pRBCs), and 9 units of fresh frozen plasma (FFP) were transfused. No subjects underwent massive transfusion of blood products, and only one subject received pRBCs and FFP in 1:1 fashion. All subjects survived until evacuation.Within the TRAC2ES database, blood product administration within AFRICOM was infrequent, with some cases highlighting lack of access to adequate blood products. Furthermore, the limitations within this database highlight the need for systems designed to capture medical care performance improvement, as this database is not designed to support such analyses. A mandate for performance improvement within AFRICOM that is similar to that of the US Central Command would be beneficial if major improvements are to occur.

Background Recent data for adult trauma patients suggest improved survival when using hemostatic resuscitation, which includes limiting crystalloids and using closer to 1:1 ratios for both fresh frozen plasma (FFP) and platelets (PLTs) relative to packed red blood cells (PRBCs). Pediatric studies have shown similar but mixed results and often lack measuring crystalloids. We seek to evaluate in-hospital survival based on crystalloid administration and different blood product ratios in pediatric casualties during the recent conflicts. Methods We queried the Department of Defense Trauma Registry for all pediatric encounters in Iraq and Afghanistan from January 2007 to January 2016 and included those with at least 40 mL/kg of total blood products administered provided that they received at least 1 U of PRBC. We grouped children as younger (0-7 years) and older (8-17 years). We grouped low versus high ratios for FFP/PRBC (≤1:2 vs. >1:2) and PLT/PRBC (≤1:6 vs. >1.6). We used a threshold of 40 mL/kg to for high versus low crystalloid resuscitation. Results During this time, there were 3,439 encounters in the registry with 521 (15.1%) that met the inclusion criteria. The median age of casualties that met the inclusion was 10 years (interquartile range, 5-13), most were male (73.5%), with a moderate median injury severity score (17; interquartile range, 13-25). We performed regression modeling with adjustments for mechanism of injury, composite injury severity score, and total blood product volume (mL/kg based), grouping children based on high versus low fluid resuscitation. In the low-volume crystalloid group, we found that higher (>1:2) FFP/PRBC was associated with improved survival (odds ratio [OR], 3.42). However, in the high fluid crystalloid resuscitation group, we found that that higher ratios for PLT/PRBC (>1:6) overall (OR, 0.46) and the FFP/PRBC (>1:2) in younger children (OR, 0.28) was associated with worse survival. The remaining associations were not statistically significant. Conclusion We found an association with survival in massively transfused pediatric trauma patients who received both a high FFP/PRBC ratio and low crystalloid administration. The benefit of this high ratio is negated, in patients receiving high crystalloid volumes, particularly among smaller children. Future studies on hemostatic resuscitation evaluating blood product ratios should also account for crystalloid and colloid administration. Level of evidence Retrospective, comparative, level III.

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., 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.

Background Hyperhemolysis syndrome (HHS) is a posttransfusion complication most frequently seen in sickle cell disease (SCD), characterized by rapid destruction of transfused and autologous red blood cells (RBCs), resulting in reticulocytopenia and a decrease in hemoglobin to below pretransfusion levels. Additional RBC transfusion can be life threatening. Most patients improve with intravenous immune globulin and steroids, but in refractory cases, hyperhemolysis may result in multiorgan failure and death in the absence of salvage therapy. The exact pathophysiology of HHS remains uncertain, yet new insights suggest that RBC destruction is driven by activated macrophages. Therefore, we propose that antimacrophage therapy may represent an effective treatment. Case report A case of life-threatening HHS, refractory to intravenous immune globulin and steroids, in a patient with SCD is presented. Marked elevation in ferritin, an indirect marker of macrophage activation, a negative direct antiglobulin test, and the absence of RBC alloantibodies was noted. A hemoglobin nadir of 2.1 g/dL and resultant hypoxemia-induced organ failure prompted the use of tocilizumab, an interleukin-6 receptor monoclonal antibody. Hemoglobin-based oxygen carrier-201, a cell-free polymerized bovine hemoglobin, was used to support the patient during critical anemia. Results Hemolysis resolved and ferritin dramatically decreased after administration of tocilizumab, which was well tolerated. A full recovery was achieved. Conclusion This case highlights both a novel and successful approach to managing refractory transfusion-induced hyperhemolysis with tocilizumab and provides further evidence supporting the role for macrophage activation in the destruction of RBCs in antibody-negative HHS. We propose that tocilizumab is an effective and rapid salvage therapy for refractory HHS.

Background Astronauts on exploration missions may be at risk for traumatic injury and medical conditions that lead to life threatening hemorrhage. Resuscitation protocols are limited by the austere conditions of spaceflight. Solutions may be found in low-resource terrestrial settings. The existing literature on alternative blood product administration and walking blood banks was evaluated for applicability to spaceflight. Study design and methods A literature review was done using PubMed and Google Scholar. References were crosschecked for additional publications not identified using the initial search terms. Twenty-seven articles were identified, including three controlled trials, six retrospective cohort analyses, 15 reviews, one case report, and two experimental studies. Results Solutions to blood transfusion in austere settings include lyophilized blood products, hemoglobin-based oxygen carriers (HBOCs), and fresh whole blood. Many of these products are investigational. Protocols for walking blood banks include methods for screening and activating donors, transfusion, and monitoring for adverse reactions. Microgravity and mission limitations create additional challenges for transfusion, including baseline physiologic changes, difficulty reconstituting lyophilized products, risk of air emboli during transfusion, equipment constraints, and limited evacuation and surgical options. Conclusion Medical planning for space exploration should consider the possibility of acute blood loss. A model for "floating" blood banks based on terrestrial walking blood bank protocols from austere environments is presented, with suggestions for future development. Constraints on volume, mass, storage, and crew, present challenges to blood transfusion in space and must be weighed against the benefits of expanding medical capabilities.

On November 29, 2018, experts in the field of infectious diseases, pathogen reduction technologies (PRTs) and other participants from blood centers, academia, and industry gathered at the Food and Drug Administration (FDA) White Oak Campus in Silver Spring, Maryland, for a 2‐day public workshop entitled “Pathogen Reduction Technologies for Blood Safety.” The workshop opened with welcome remarks from Dr. Nicole Verdun, Director, Office of Blood Research and Review (OBRR), Center for Biologics Evaluation and Research (CBER), FDA, followed by introductory remarks from Dr. Peter Marks, Director, CBER, FDA. The first day of the workshop focused on blood‐borne infectious agents and their impact on blood safety, experiences of the American Red Cross, and other blood establishments in implementing FDA‐approved pathogen inactivation (PI) technology for plasma and platelets (PLTs) in the United States and novel PRTs under consideration for whole blood (WB) and red blood cells (RBCs). The second day opened with welcome remarks from Dr. Chintamani Atreya, Associate Director for Research, OBRR, CBER, FDA. The focus was on emerging innovations relevant to PRTs and potential alternatives to PRTs. The workshop concluded with remarks on insights for future research and development in this area for blood and blood product safety from infectious agents. A brief introduction of each session by the session moderator followed by a summary of the speaker presentation as submitted by the moderator and speaker are reported here.