Traumatic Coagulopathy Research Articles

Evaluation of the Potential for Improvement of Clinical Outcomes in Trauma Patients with Massive Hemorrhage by Maintaining a High Plasma-to-Red Blood Cell Ratio during the First Hour of Hospitalization.

Several reports indicate that early plasma transfusion may promote survival and reduce the incidence of traumatic coagulopathy in situations of massive bleeding. Consequently, it is recommended to maintain a plasma and RBC transfusion ratio between 1 : 1 and 1 : 2 at the start of admission. This retrospective study examined the effect of an early high plasma : RBC ratio on mortality rates by adopting a massive transfusion protocol (MTP) that forced an early and rapid issue of plasma products. Patients who received massive transfusions at a single trauma center between January 2014 and May 2020 were included in the study. A new protocol was established in January 2020, wherein a fixed amount of plasma was issued following MTP activation. Patients who underwent massive transfusions before and after the adoption of the new protocol were compared. In total, 1059 patients met the inclusion criteria. Fifty-one patients who underwent MTP were propensity score-matched with the patients who received a nonprotocolized massive transfusion. The MTP group had a higher plasma : RBC ratio at 1 h (0.8 vs. 0.2) and 4 h of hospitalization (1.1 vs. 0.6), with no significant between-group difference in the plasma : RBC ratio at 24 h of hospitalization. The MTP group had a lower 24 h mortality rate than the control group. There was no significant difference in the 30-day mortality. Using MTP to achieve a high plasma : RBC ratio in the early period of hospitalization appeared to affect 24-hour mortality; however, 30-day mortality did not change.

How to recognize a dying patient? Acute traumatic coagulopathy: experience in a level I trauma center

Background: It is possible to detect abnormal clotting parameters in 25-35% of injured patients at their arrival to the hospital, which are proportional to the severity of the injuries and associate with higher morbimortality rates. Objectives: Therefore, it arises the question whether the results of conventional laboratory tests carried out while monitoring the injured patient may be used as early available predictors. Methods: We conducted a prospective, descriptive and observational multivariable study at the Central Hospital of the Mexican Red Cross to determine the correlation between the alterations in the results of clotting tests obtained at the time of hospital admission of the patient and the likelihood of emergency surgery necessity or death within the first 48 hours of hospital stay. Results: We included 327 patients, between 1-92 years old, 20.79% patients were admitted with ATC criteria, 40.36% required emergency surgery (54.41% in the context of ATC) and 18.65% died (10.39% of them during or after the surgical management, and 47.05% with ATC criteria). Conclusions: According with our results conventional clotting tests are quite sensitive tools for identifying patients at high risk of early death and good predictors of poor outcomes in the treatment.

Omics Signatures of Tissue Injury and Hemorrhagic Shock in Swine.

Advanced mass spectrometry methods were leveraged to analyze both proteomics and metabolomics signatures in plasma upon controlled tissue injury (TI) and hemorrhagic shock (HS)-isolated or combined-in a swine model, followed by correlation to viscoelastic measurements of coagulopathy via thrombelastography. TI and HS cause distinct molecular changes in plasma in both animal models and trauma patients. However, the contribution to coagulopathy of trauma, the leading cause of preventable mortality in this patient population remains unclear. The recent development of a swine model for isolated or combined TI+HS facilitated the current study. Male swine (n=17) were randomized to either isolated or combined TI and HS. Coagulation status was analyzed by thrombelastography during the monitored time course. The plasma fractions of the blood draws (at baseline; end of shock; and at 30 minutes, 1, 2, and 4 hours after shock) were analyzed by mass spectrometry-based proteomics and metabolomics workflows. HS-isolated or combined with TI-caused the most severe omic alterations during the monitored time course. While isolated TI delayed the activation of coagulation cascades. Correlation to thrombelastography parameters of clot strength (maximum amplitude) and breakdown (LY30) revealed signatures of coagulopathy which were supported by analysis of gene ontology-enriched biological pathways. The current study provides a comprehensive characterization of proteomic and metabolomic alterations to combined or isolated TI and HS in a swine model and identifies early and late omics correlates to viscoelastic measurements in this system.

Letter to the editor for "Detecting traumatic brain injury-induced coagulopathy: What we are testing and what we are not".

Letter to the editor for "Detecting traumatic brain injury-induced coagulopathy: What we are testing and what we are not".

Effects of serum fibrinogen correction on outcome of traumatic cranial surgery: A randomized, single-blind, placebo-controlled clinical trial

BackgroundTraumatic brain injury (TBI) is strongly associated with coagulopathy that occurs in 25–35% of patients. This complication is linked to higher mortality and morbidity. Recent lines of evidance have supported administration of fibrinogen concentrate (FC) in patients with severe TBI, while its efficacy remains controversial. In this study we aim to evaluate the effectiveness of serum fibrinogen level correction from 1.5 and 2.0 g/l to more than 2.0 g/l in patients with severe TBI undergoing traumatic cranial surgery. MethodThis randomized, single-blind, placebo-controlled clinical trial included trauma patients who had abbreviated injury scale (AIS) more than 3 in head and below 3 in other organs. FC was administered intravenously to patients with severe TBI undergoing TBI to correct the fibrinogen level above 2 g/l. Patients were randomly assigned to FC and control groups. The amount of intra-operative blood loss, packed cell (PC) transfusion, formation of new intracranial hemorrhage, and hemovac drainage were compared between the two study groups. ResultsForty-seven of 65 participants received the study intervention within 40–112 min of admission. Intra-operative PC transfusion was higher in FC group (80%) compared to control group (55.5%) while the differance was not statistically significant (p > 0.05). Intra-operative blood loss was significantly higher in control group than FC group (P = 0.036). Chance of re-operation and new intracranial hematoma were not significantly different between two study groups. ConclusionEarly delivery of FC, decreases intraoperative bleeding. Although based on our findings it has no other effect on other parameters, further multicenter studies are recommended to investigate the role of early FC administration in management of post traumatic coagulopathy.

Diseases and Treatment with NOA: Mini Review of Trauma Coagulopathy

Background: A key element of a geriatric patient is the problem of frailty. We generally identify a frail subject through sarcopenia, that is, the progressive reduction and thinning of the muscle mass. The sarcopenic subject falls because he cannot stand on his legs, including a whole series of endocrine, glucidic and neurological dysregulations that should have an extremely significant probability of falling. Objective: The purpose of this article is, starting from pharmacological aspects of noa, to evaluate how to deal with a traumatized patient in the treatment with noa. Methods: Both personal knowledge of pharmacology and the use of both paper books and international website databases such as pubmed, scopus, google scholar, researchgate were used to develop the article, typing in keywords such as "trauma coagulopathy" or "elderly patient treatment with noa" associated with specific compound names. Conclusions: In an elderly subject who reports a head injury, even a mild one, we may find a chronic subdural hematoma that is so easily achieved due to cerebral atrophy, the greater excursion of the brain into the skull that tears the subdural vessels. In addition, why frequently the elderly subject takes the antithrombotic drug: cardioaspirin, warfarin, but above all the new oral anticoagulants.

Admission Thromboelastography at the Intersection of Traumatic Coagulopathy and Inflammation: A Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) Study Subanalysis.

Acute traumatic coagulopathy (ATC) has many phenotypes and varying morbidity and mortality. The MA-R ratio, calculated from the admission thromboelastogram, serves as a biomarker to identify 1 phenotype of ATC and has previously been associated with significant derangements in the inflammatory response. This study evaluates outcomes related to abnormal MA-R ratios, including inflammatory responses, in a heterogeneous patient population. Patients from the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) dataset were included. The MA-R ratio was calculated from admission thromboelastography, with a CRITICAL ratio defined as 11 or less. Key inflammatory mediators were identified as a priori. Cytokine expression was assessed during 24 hours using multivariable logistic regression. Significant elevations in the proinflammatory cytokines IL-1b, IL-6, and IL-8, as well as in the chemokines eotaxin, IFN-γ-induced protein 10, monocyte chemoattractant protein-1, and macrophage inflammatory protein-1β, persisted during the first 24 hours. CRITICAL patients had significantly lower survival at 1, 3, 6, 12, and 18 hours and demonstrated significantly increased ARDS (odds ratio [OR] 1.817, 95% CI 1.082 to 3.051, p = 0.0239). CRITICAL patients had fewer ICU-free days (CRITICAL, 10 days, interquartile range [IQR] 0 to 25; vs NORMAL, 22 days, IQR 4 to 26, p < 0.0001) and fewer ventilator-free days (CRITICAL, 15 days, IQR 0 to 28; vs NORMAL, 26 days, IQR 9 to 28, p < 0.0001). CRITICAL patients were protected against systemic inflammatory response (OR 0.521, 95% CI 0.322 to 0.816, p = 0.0044). The subtype of ATC identified by the low MA-R ratio is associated with significant elevations in multiple proinflammatory cytokines at admission. Early mortality remains elevated in the CRITICAL group, in part due to coagulopathy. The MA-R ratio at admission is associated with a particularly morbid type of coagulopathy, associated with significant alterations in the inflammatory response after severe injury in heterogeneous patient populations.

Evaluation of coagulopathy frequency and risk factors in trauma patients in intensive care unit

Background: Post traumatic coagulopathy is a frequently encountered problem. However, risk factors related to coagulopathy are not exactly known. Objectives: In this study it is targeted to determine the frequency of coagulopathy related to trauma, risk factors and its affect to prognosis on patients admitted to Intensive Care Unit(ICU) after trauma retrospectively. Methods: 184 patients admitted to mixed type adult ICU, which is having 20 beds, in the years between 2011 and 2017 due to trauma have been studied. Patients have been separated into two groups as patients having coagulopathy and not having coagulopathy by examining their laboratory results. Patients having; thrombocyte count &lt;100 000/μL on the first and third days, Prothrombin Time(PT)&gt;16s, activated Partial Thromboplastine Time(aPTT)&gt;40s, International Normalized Ratio(INR)&gt;1.6 are being accepted as having coagulopathy. Medical records of patients have been recorded retrospectively. Results: The average age of 184 patients that are included in the study is 41.77; 19% of them are Female and 81% of them are Male. Coagulopathy detected on 78 patients (42.4%) (on the first day 32.6%, on the third day 9.8%). It has been detected that, patients developed coagulopathy were having more accompanying diseases(p&lt;0.05), lower Glasgow Coma Score (GCS)(p&lt;0.05), lower albumin values(p&lt;0.05) and higher 28-day mortality rates(p&lt;0.001) compared to patients that have not developed coagulopathy. Revised Trauma Score(RTS) of two groups are not significant(p&gt;0.05). Having accompanying diseases, having low GCS and albumin values are being determined as independent risk factors in coagulopathy development. Conclusion: As a conclusion; since it is not possible to change GCS and risk factors belong to critical trauma patients, we think that it is possible to decrease the frequency of coagulopathy development as well as mortality rate by preventing risk factors such as hypoalbuminemia by means of suitable approaches.

Correction of haemorrhagic shock-associated coagulopathy and impaired haemostasis by plasma, prothrombin complex concentrates or an activated protein C-targeted DNA aptamer in mice

Even with extensive transfusion support, trauma-induced bleeding often leads to death. Early intervention may improve outcomes, yet which blood products, factor concentrates, or other drugs constitute optimal treatment is unclear. Patients with acute traumatic coagulopathy (ATC), arising from trauma and haemorrhagic shock, have the worst prognosis. Here, multiple interventions were compared in a mouse model of ATC. After the trauma of tissue excision, anaesthetized mice were bled to 35 mm Hg mean arterial pressure, maintained under shock for 60 min, and resuscitated with fluids equal in volume to the shed blood. Resuscitated mice were subjected to liver laceration to test haemostasis and blood loss was quantified. Saline-treated mice lost two- to three-fold more blood than sham-treated animals and were coagulopathic by prothrombin time elevation post- versus pre-procedure. Murine fresh-frozen plasma (mFFP), anti-activated protein C aptamer HS02-52G, or prothrombin complex concentrates eliminated the bleeding diathesis and coagulopathy; fibrinogen, plasminogen activator inhibitor-1, or tranexamic acid ameliorated bleeding or coagulopathy, but not both. HS02-52G and mFFP also eliminated the changes in plasma aPC and tissue plasminogen activator levels observed in saline-treated mice, as judged via microtiter plate biomarker assays. Procoagulant interventions, especially inhibiting aPC, could be beneficial in human ATC.

Patterns of Platelet Mapping Thromboelastography Abnormalities in Trauma.

Platelet mapping thromboelastography (TEG-PM) to evaluate trauma induced coagulopathy has become more prevalent. The objective of this study was to evaluate associations between TEG-PM and outcomes in trauma patients, including patients with TBI. A retrospective review was conducted utilizing the American College of Surgeons National Trauma Database. Chart review was conducted to obtain specific TEG-PM parameters. Patients were excluded if they were on anti-platelets, anticoagulation, or received blood products prior to arrival. TEG-PM values and their associations with outcomes were evaluated using generalized linear model and Cox cause-specific hazards model. Outcomes included in-hospital death, hospital and ICU length of stay (LOS). Relative risk (RR) and hazard ratio (HR) and their 95% confidence intervals (CIs) are provided. A total of 1066 patients were included, with 151 (14%) diagnosed with isolated TBI. ADP inhibition was associated with significant increase rate of hospital LOS and ICU LOS (RR per % increase = 1.002 and RR = 1.006 per % increase, respectively) while increased MA(AA) and MA(ADP) were significantly associated with decrease rate of hospital LOS and ICU LOS (RR = .993 per mm increase and RR = .989 per mm increase, respectively, and RR = .986 per mm increase and RR = .989 per mm increase). R (per minute increase) and LY30 (per % increase) were associated with increased risk of in-hospital mortality (HR = 1.567 and HR = 1.057, respectively). No TEG-PM values significantly correlated with ISS. Specific TEG-PM abnormalities are associated with worse outcomes in trauma patients, including TBI patients. These results require further investigation to understand associations between traumatic injury and coagulopathy.

The European guideline on management of major bleeding and coagulopathy following trauma: sixth edition

BackgroundSevere trauma represents a major global public health burden and the management of post-traumatic bleeding continues to challenge healthcare systems around the world. Post-traumatic bleeding and associated traumatic coagulopathy remain leading causes of potentially preventable multiorgan failure and death if not diagnosed and managed in an appropriate and timely manner. This sixth edition of the European guideline on the management of major bleeding and coagulopathy following traumatic injury aims to advise clinicians who care for the bleeding trauma patient during the initial diagnostic and therapeutic phases of patient management.MethodsThe pan-European, multidisciplinary Task Force for Advanced Bleeding Care in Trauma included representatives from six European professional societies and convened to assess and update the previous version of this guideline using a structured, evidence-based consensus approach. Structured literature searches covered the period since the last edition of the guideline, but considered evidence cited previously. The format of this edition has been adjusted to reflect the trend towards concise guideline documents that cite only the highest-quality studies and most relevant literature rather than attempting to provide a comprehensive literature review to accompany each recommendation.ResultsThis guideline comprises 39 clinical practice recommendations that follow an approximate temporal path for management of the bleeding trauma patient, with recommendations grouped behind key decision points. While approximately one-third of patients who have experienced severe trauma arrive in hospital in a coagulopathic state, a systematic diagnostic and therapeutic approach has been shown to reduce the number of preventable deaths attributable to traumatic injury.ConclusionA multidisciplinary approach and adherence to evidence-based guidelines are pillars of best practice in the management of severely injured trauma patients. Further improvement in outcomes will be achieved by optimising and standardising trauma care in line with the available evidence across Europe and beyond.

Control of positive systems with an unknown state-dependent power law input delay and input saturation

This paper is motivated by a class of positive systems with an input that is subject to an unknown state-dependent power law delay as well as saturation. For example, biological networks have non-negative protein concentration states. Mass action kinetics in these systems result in power law behavior, while complex interactions cause signal propagation delays. Incomplete network characterization makes delay state-dependence unknown. Manipulating network activity via modulated protein concentrations to attain desired performance is restricted by upper-bounds on concentration actuator authority. Here, an innovative control law exploits system dynamics to compensate for control domain restrictions. A Lyapunov stability analysis establishes that the reference tracking error of the closed-loop system is uniformly ultimately bounded. Numerical simulations on a human coagulation model show controller efficacy and better performance compared to the relevant literature. This example application steps toward personalized, closed-loop treatments for trauma coagulopathy, which currently has 30% mortality with open-loop clinical approaches.

Circ_0001274 Competitively Binds miR-143-3p to Upregulate VWF Expression to Improve Acute Traumatic Coagulopathy.

Accumulating evidence has noted the circRNA-microRNA- (circRNA-miRNA-) mRNA competing endogenous RNA (ceRNA) regulatory network in disease development and progression. The current study explored the ceRNA network in acute traumatic coagulopathy (ATC). Potential ATC-related genes were screened, and upstream miRNAs and circRNAs of VWF (the candidate target) were assayed through database searching and high-throughput sequencing technology. circ_0001274/miR-143-3p/VWF ceRNA regulatory network was constructed and validated. The expression of circ_0001274/miR-143-3p/VWF was determined in the peripheral blood samples from ATC patients and ATC mouse models. Online database and circRNA sequencing analysis results identified VWF as a key gene in ATC as supported by assays and that VWF was lowly expressed in ATC patients and mice. Further experiments demonstrated that miR-143-3p could target and inhibit VWF, and circ_0001274 could competitively sponge miR-143-3p. Functionally, circ_0001274 could competitively sequester miR-143-3p to upregulate VWF expression, potentially improving ATC. Our study highlights the critical role of circ_0001274/miR-143-3p/VWF axis in improving ATC.

“TEG” talks: technology worth spreading?

“TEG” talks: technology worth spreading?

Traumatic coagulopathy in the older patient: analysis of coagulation profiles from the Activation of Coagulation and Inflammation in Trauma-2 (ACIT-2) observational, multicenter study

BackgroundMost studies describing traumatic coagulopathy have used data from patient cohorts with an average age of between 35 and 45 years. The last 10 years has seen a steep increase in the number of patients admitted with significant injury and bleeding who are older than the age of 65 years. Many coagulation protein levels alter significantly with normal aging, and it is possible that traumatic coagulopathy has a different signature with age. ObjectivesThe aim of this study was to report the coagulation profiles, including standard and extended laboratory, as well as viscoelastic hemostatic assays, stratified according to age to explore age-related differences in hemostatic capability. MethodsIn total, 1576 patients were analyzed from 6 European level 1 trauma centers. ResultsAs age increased, there was evidence of higher fibrinogen, greater thrombin generation, greater clotting factor consumption, and greater activation of fibrinolysis. Despite this, shock and severe injury led to the same pattern of changes within age groups: lower procoagulant factors (including fibrinogen), increased fibrinolysis, and higher levels of activated protein C. Thromboelastography and rotational thromboelastometry tests detected traumatic coagulopathy with prolongation of R/clotting time and reductions in clot amplitudes in each age cohort. Advancing age strongly correlated with higher fibrinogen levels and greater fibrinolysis. ConclusionAge-related coagulation changes are evident in injured patients. Broadly, similar patterns of coagulation abnormalities are seen across age groups following severe injury/shock, but thresholds for single clotting factors differ. Age-related differences may need to be considered when clinical treatments (eg, transfusion therapy) are indicated.

Traumatic Bleeding and Mortality in Mice Are Intensified By Iron Deficiency Anemia and Can be Rescued with Tranexamic Acid Prophylaxis

Introduction Pre-traumatic anemia, particularly iron-deficiency anemia (IDA), is independently associated with poor outcomes and increased mortality. There is also mounting clinical evidence that anemia aggravates hemorrhage which may be particularly detrimental during trauma, where accelerated hemorrhage may worsen coagulopathy. In order to better understand what extent IDA could influence traumatic hemorrhaging, coagulopathy and mortality, we employed a model of traumatic liver injury in iron deficient mice, and evaluated the effects of prophylactic tranexamic acid (TXA) on bleeding and mortality in the setting of anemia. Materials and Methods Severe IDA was generated in C57BL/6J mice. Three week old mice were fed an iron-deficient diet for 6 weeks. Control mice (non-anemic) were fed a normal laboratory diet. Development of IDA was confirmed by complete blood count (CBC), red cell indices, and liver iron content. Mice were pre-treated with saline or TXA (10mg/kg) and subjected to liver laceration. Blood loss (determined by weighing blood-soaked sponges in the abdominal cavity), development of coagulopathy [APTT, Factor (F)II, FV, FVIII, FX and fibrinogen), thrombin-antithrombin (TAT) complexes and plasmin-antiplasmin (PAP) complexes] were analyzed at 15 and 60 minutes after trauma. All data were expressed as the median and were compared by Mann-Whitney test. The number of mice in each group was 8-20. Seven day survival was analyzed using Kaplan-Meier survival curves, which were compared using the Mantel-Cox log-rank test. Results IDA was ascertained by the development of hypochromic/microcytic anemia with significantly lower hematocrit (32% vs 48%, p=<0.0001) and hepatic iron content (20.04 µg/g vs. 72.41 µg/g, p=<0.0001) in anemic compared to non-anemic mice, respectively. Anemic mice demonstrated more rapid and increased blood loss when compared to non-anemic mice. At 15 and 60 minutes after liver laceration, median blood loss was 14.5 and 20.6 µL/g (p=<0.0001) in non-anemic mice and 20.3 and 24.5 µL/g (p=0.004), in anemic mice, respectively. Prophylaxis with TXA reduced blood loss significantly in both anemic and anemic mice to a threshold of ~15 µL/g. Bleeding led to a similar degree of acute traumatic coagulopathy (ATC) in both non-anemic and anemic mice, and was characterized by progressive APTT prolongation, TAT-complex formation, and depletion of FV, FVIII, and fibrinogen. FII and FX were not affected, consistent with the presence of ATC, rather than disseminated intravascular coagulation. In contrast, the extent of fibrinolysis differed between anemic and non-anemic mice in that PAP complex formation (not elevated at 15 minutes) rose significantly in anemic compared to non-anemic mice at 60 minutes (median 44 vs 28 ng/mL, p=0.0004). TXA prophylaxis promoted the correction of ATC by near-normalization of TAT-complexes, FV, FVIII, and fibrinogen in anemic and non-anemic mice alike. However, TXA only corrected PAP-complex formation and APTT in the non-anemic mice, without affecting these parameters in anemic mice. This suggests that anemia accelerated fibrinolysis which was not controlled by TXA. The 7-day survival of anemic mice was lower compared to non-anemic mice (50% vs 75%), but increased significantly with TXA (80%, p=0.04). Conclusion In a murine trauma model, IDA resulted in enhanced bleeding and mortality, which were both rescued by TXA prophylaxis. However, while ATC occurred to a similar extent in anemic and non-anemic mice and was corrected by TXA, only anemic mice developed exaggerated fibrinolysis that could not be suppressed by TXA. These findings suggest that hyper-fibrinolysis contributes to enhanced anemic bleeding, but that bleed and mortality rescue were not dependent on the anti-fibrinolytic effects of TXA alone. Therefore, less well defined properties of TXA (beyond fibrinolysis control) relating to vascular barrier stabilization and/or immune/cytokine modulation, may be involved in mitigation of early ATC (and, thereby, bleed control) and survival. These findings open new investigations into under-recognized pharmaco-dynamic effects of TXA beyond fibrinolysis mitigation, and could be critical for rescuing catastrophic bleeding situations (e.g. trauma, postpartum hemorrhage), especially in the presence of pre-existing anemia.

Selective Modulation of Activated Protein C Activities By an Exosite-Specific Nanobody Library

Background Activated protein C (APC) is a pleiotropic coagulation protease with anticoagulant, anti-inflammatory, and cytoprotective activities. Antibodies that can selectively modulate these APC activities could contribute to the understanding of the regulation of these physiological mechanisms and the development of therapeutics for the pathologies associated with these pathways Aim We sought to construct an antibody library consisting of small-sized nanobodies that could target neo-epitopes on the exosites of the activated form of protein C that are potentially inaccessible or whose three-dimensional structure is not recognized by conventional antibody formats. These APC-specific nanobodies will be used to determine the effect of the blockade of different exosites on APC pleiotropic activities. Methods A nanobody phage library specific for APC exosites was derived from peripheral blood mononuclear cells of llamas immunized with active site-blocked APC (APC-PPACK). The nanobody library was panned for APC-specificity. Biolayer interferometry (BLI) was used to determine the KDs and to epitope bin nanobodies into different clusters. APC functional assays, including Protac-APTT clotting assays, histone H3 cleavage assay, and SEAP-PAR1 cleavage assay with HEK293 cells, were employed to characterize the effects of the nanobodies on APC's pleiotropic activities. Results Of the total 1128 monoclonal phage clones screened in the library, 725 clones were identified as APC-PPACK binders. These clones were sequenced and 158 were found to be unique clones. Among them, 21 nanobodies belonging to 18 families were further characterized by their binding diversity. Overall, 3 clusters of nanobodies were identified based on their competition for APC exosites in BLI studies. APC functional assays for anticoagulant activity, histone H3 cleavage, and SEAP-PAR1 cleavage, were employed to understand the diversity of the nanobodies. These functional assays revealed 13 novel nanobody-induced APC activity profiles via the selective modulation of APC pleiotropic activities, with the potential of regulating specific mechanisms for therapeutic purposes. Within these, 3 nanobodies (LP2, LP8, LP17) inhibited all 3 APC functions. Five nanobodies (LP1, LP5, LP10, LP16, LP20) inhibited only 2 of the 3 functions. Mono-function inhibition specific to APC anticoagulation activity was observed only by 2 nanobodies (LP 9, LP11). LP 9 and LP11 are 2 of the nanobodies within the library that inhibited APC by >90% in a clotting assay (Table 1). The monospecific inhibition of APC anticoagulant activity could induce a pro-hemostatic effect in hemophilia and traumatic coagulopathy conditions. The molecular basis of APC's cytoprotective functions is based on its biased agonism of PAR1 by cleaving at R46. Interestingly, in R46/R41 cleavage ratio studies on SEAP-PAR1 cell lines, LP11 increased the APC pro-cytoprotective cleavage of R46 by up to 87%. The novel property of LP11 in enhancing R46 cleavage may potentially provide additional cytoprotection signaling and may potentially further benefit the outcome of these bleeding conditions. Conclusions A library of APC exosite-specific llama nanobodies yielded 21 nanobodies that can selectively modulate APC anticoagulation and cytoprotection pathways. The non-competing nature of nanobodies from each cluster allows the possibility of combining nanobodies from different clusters to better understand and study the biology of APC. These nanobodies represent a tool kit of 13 categories of antibodies based on their cluster and activity profile and offer the opportunity to develop novel therapeutics for the treatment of an array of APC-associated indications including acute bleeding, hemophilia, ischemia, and sepsis. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Dynamic structures and emerging trends in the management of major trauma: A bibliometric analysis of publications between 2012 and 2021.

Major trauma is currently a global public health issue with a massive impact on health at both the individual and population levels. However, there are limited bibliometric analyses on the management of major trauma. Thus, in this study we aimed to identify global research trends, dynamic structures, and scientific frontiers in the management of major trauma between 2012 and 2021. We searched the Web of Science Core Collection to access articles and reviews concerning the management of major traumas and conducted a bibliometric analysis using CiteSpace. Overall, 2,585 studies were screened and published by 403 institutions from 110 countries/regions. The most productive country and institution in this field of research were the USA and Monash University, respectively. Rolf Lefering was the most prolific researcher and Holcomb JB had the most co-citations. Injury published the highest number of articles, and the Journal of Trauma was the most co-cited journal. A dual-map overlay of the literature showed that the articles of most publications were confined to the areas of medicine/medical/clinical and neurology/sports/ophthalmology. Document clustering indicated severe traumatic brain injury, traumatic coagulopathy, and resuscitative endovascular balloon occlusion as the recent hot topics. The most recent burst keywords were "trauma management," "neurocritical care," "injury severity," and "emergency medical services." The dynamic structures and emerging trends in the management of major trauma were extensively analyzed using CiteSpace, a visualization software. Based on the analysis, the following research hotspots emerged: management of severe traumatic brain injury and massive hemorrhage, neurocritical care, injury severity, and emergency medical service. Our findings provide pertinent information for future research and contribute toward policy making in this field.

Coagulopathy management of multiple injured patients - a comprehensive literature review of the European guideline 2019.

The European guideline on the management of trauma-induced major bleeding and coagulopathy summarises the most relevant recommendations for trauma coagulopathy management. The management of trauma-induced major bleeding should interdisciplinary follow algorithms which distinguish between life-threatening and non-life-threatening bleeding. Point-of-care viscoelastic methods (VEM) assist target-controlled haemostatic treatment. Neither conventional coagulation assays nor VEM should delay treatment in life-threatening trauma-induced bleeding. Adjustments may be rational due to local circumstances, including the availability of blood products, pharmaceuticals, and employees.

281 Out-of-Hospital TXA Administration Opportunities in Trauma Patients Transported by ALS Ground EMS - A Descriptive Study

As many as 30% of severely injured trauma patients demonstrate evidence of acute coagulopathy of trauma (ACOT) at the time of ED admission. Early administration of tranexamic acid (TXA) may improve patient outcomes with ACOT. Within our system, TXA is currently available only to helicopter EMS (HEMS) units. The purpose of the current study was to determine whether there was a cohort of trauma patients transported by ground EMS (GEMS) who might benefit from out-of-hospital TXA administration.