Trauma remains a leading cause of death and disability in adults, and about 20% of deaths occur due to intractable bleeding. Trauma-induced coagulopathy (TIC) is a complex hemostatic disorder characterized by an abnormal coagulation response, which can manifest as either a hypo-coagulable state, leading to excessive bleeding, or a hypercoagulable state, resulting in thromboembolic events and multiple organ failure. Early diagnosis and correction of hypocoagulability may be lifesaving. Replacement of coagulation factors using blood components as well as counteracting enhanced fibrinolysis with tranexamic acid in association with a strategy of damage control are the current practices in the management of TIC. Nevertheless, the improved comprehension of the several mechanisms involved in the development of TIC might offer space for a tailored treatment with improvement of clinical outcome. This review aims to outline the pathophysiology of TIC and evaluate both established and emerging management strategies. A thorough literature review was made with a specific emphasis on articles discussing the molecular mechanisms of trauma-induced coagulopathy. We utilized PubMed, Scopus, and Web of Science with the main search terms "trauma-induced coagulopathy", "molecular mechanisms", and "coagulation pathways".

The transfusion of platelets and fresh frozen plasma (FFP) to critically ill neonates in neonatal intensive care units (NICUs) is a common intervention, yet it is still widely performed without adhering to international guidelines. The guidance itself on the therapeutic management of neonatal coagulation disorders is generally limited due to the absence of strong indications for treatment and is mainly aimed at the prevention of major hemorrhagic events such as intraventricular hemorrhage (IVH) in premature neonates. Historically, the underrepresentation of neonates in clinical studies related to transfusion medicine had led to significant gaps in our knowledge regarding the best transfusion practices in this vulnerable group and to a wide variability in policies among different neonatal units, often based on local experience or guidance designed for older children or adults, and possibly increasing the risk of inappropriate or ineffective interventions. Platelet transfusion and, particularly, FFP administration have been linked to potentially fatal complications in neonates and thus any decision needs to be carefully balanced and requires a thorough consideration of multiple factors in the neonatal population. Despite recent advances toward more restrictive practices, platelet and FFP transfusions are still subject to wide variability in practices.This review examines the existing literature on platelet and FFP transfusions and on the management of massive hemorrhage in neonates, provides a summary of evidence-based guidelines on these topics, and highlights current developments and areas for ongoing and future research with the aim of improving clinical practices.

Hemorrhagic shock from traumatic injury results in a massive systemic response with activation of the hypothalamic-pituitary-adrenal (HPA) axis, pro-thrombotic and clot-lysis pathways as well as development of an endotheliopathy. With ongoing hemorrhage, these responses become dysregulated and are associated with worsening coagulopathy, microvascular dysfunction, and increased transfusion requirements. Our transfusion practices as well as our understanding of the molecular response to hemorrhage have undergone significant advancement during war. Currently, resuscitation practices address the benefit of the early recognition and management of acute coagulopathy and advocates for balanced resuscitation with either whole blood or a 1:1 ratio of packed red blood cells to fresh frozen plasma (respectively). However, a significant volume of evidence in the last two decades has recognized the importance of the early modulation of traumatic endotheliopathy and the HPA axis via the early administration of plasma, whole blood, and adjunctive treatments such as tranexamic acid (TXA) and calcium. This evidence compels us to rethink our understanding of 'balanced resuscitation' and begin creating a more structured practice to address additional competing priorities beyond coagulopathy. The following manuscript reviews the benefits of addressing the additional interrelated physiologic responses to hemorrhage and seeks to expand beyond our understanding of 'balanced resuscitation'.

Until the beginning of the century, bleeding management was similar in elective surgeries or exsanguination scenarios: clotting tests were used to guide blood product orders and, while awaiting these results, an aggressive resuscitation with crystalloids was recommended. The high mortality rate in severe hemorrhages managed with this strategy endorsed the need for a special resuscitation plan. As a result, modifications were recommended to develop a new clinical approach to these patients, called "Damage Control Resuscitation". This strategy includes four principles: damage control surgery, minimization of crystalloids, permissive hypotension and hemostatic resuscitation. The latter involves the use of antifibrinolytics, correction of preconditions of hemostasis (calcium, pH and temperature) and the early and rapid restoration of intravascular volume with blood products. To enable timely availability and transfusion of blood products, specific actions in different hospital areas need to be synchronized, which are usually organized through Massive Transfusion Protocols or, as they have recently been rebranded, Major Hemorrhage Protocols (MHPs). Although these bundles of actions represent a paradigm change, essential aspects such as their historical evolution, theoretical foundations, terminology and operational elements have yet to be well explored. Considering the wide application range of these tools (emergency departments, interventional radiology, operating rooms and military fields), it is essential to integrate all professionals involved with severe hemorrhage scenarios in the implementation of the aforementioned protocols, from conception to execution and management. This review paper addresses MHP aspects relevant to anesthesiologists, transfusion services and other areas involved with the care of patients with severe bleeding.

Severe injuries and some pathologies associated with massive bleeding, such as maternal hemorrhage, gastrointestinal and perioperative bleeding, and rupture of an aneurysm, often lead to major blood loss and the development of hemorrhagic shock. A sharp decrease in circulating blood volume triggers a vicious cycle of vasoconstriction and coagulopathy leading to ischemia of all internal organs and, in severe decompensated states, ischemia of the brain and heart. The basis of tissue damage and dysfunction in hemorrhagic shock is an interruption in the supply of oxygen and substrates for energy production to the cells, making the mitochondria a source and target of oxidative stress and proapoptotic signaling. Based on these mechanisms, different strategies are proposed to treat the multiple organ failure that occurs in shock. The main direction of such treatment is to provide the cells with a sufficient amount of substrates that utilize oxidative phosphorylation at different stages and increase the efficiency of energy production by the mitochondria. These strategies include restoring the efficiency of mitochondrial complexes, for example, by restoring the nicotinamide adenine dinucleotide (NAD) pool. Another direction is approaches to minimize oxidative stress as well as apoptosis, which are primarily dependent on the mitochondria. There are also a number of other methods to reduce mitochondrial dysfunction and improve the quality of the mitochondrial population. In this review, we consider such strategies for the treatment of hemorrhagic shock and show the promise of therapeutic approaches aimed at restoring the bioenergetic functions of the cell and protecting mitochondria.

Traumatic brain injury (TBI) represents a significant public health concern. Besides the initial primary injury, a defining point of TBI is causing secondary, delayed damage through inflammatory biochemical processes. Among the complications arising from this inflammatory response, coagulopathy emerges as a critical concern. With an overall prevalence of 32.7 %, TBI-induced coagulopathy significantly contributes to increased mortality rates and unfavorable patient outcomes, through its clinical manifestations, such as progressive hemorrhagic injury (PHI). This chapter investigates biomarkers capable of accurately detecting coagulopathy and PHI in TBI, evaluating their potential utility based on statistical evidence from various studies and exploring their possible association in the biochemical processes guiding or following TBI-induced coagulopathy. Notably, glucose emerges as a standout candidate, exhibiting a sensitivity of 91.5 % and specificity of 87.5 % for predicting coagulopathy. Furthermore, interleukin-33, with a sensitivity of 93.3 % and specificity of 66.7 %, and galectin-3, with a sensitivity of 67.7 % and specificity of 85.5 %, are promising for PHI. Despite these encouraging findings, significant efforts remain necessary to translate biomarker diagnostic utility into clinical practice effectively. Further research and validation studies are imperative to elucidate the intricate biochemical processes underlying TBI-induced coagulopathy and to refine the clinical application of biomarkers for improved patient management and outcomes in real-world settings.

Trauma-induced coagulopathy describes a complex set of coagulation changes affecting severely injured patients. The thrombomodulin-protein C axis is believed to be central to the evolution of trauma-induced coagulopathy. Soluble thrombomodulin (sTM) levels are elevated after injury. Our objectives were to explore whether sTM (at concentrations found in patients after injury) plays an important role in trauma-induced coagulopathy, and specifically to evaluate the effects of sTM and activated protein C (APC) on thrombin generation (TG) and clot lysis time (CLT). Plasma from healthy volunteers was spiked with rising concentrations of sTM and APC and the effects on TG and CLT were analyzed. Plasma samples from a cohort of trauma patients were evaluated using TG and CLT, and results correlated to clinical parameters and factor VIII, factor V, APC, sTM and fibrinolytic measures. Increasing sTM concentrations in volunteer plasma led to reductions in endogenous thrombin potential and prolongation of 50% CLT, in a dose-dependent manner. No effect on TG or CLT was seen with rising APC concentrations. In 91 trauma patients, higher sTM values were associated with greater, rather than reduced, endogenous thrombin potential (median 1,483 vs. 1,681 nM/min) and longer 50% CLT (41.9 vs. 54.0 mins). In conclusion, sTM concentrations, across ranges found after trauma, affect both TG and 50% CLT, unlike APC. Despite increased circulating sTM levels, the overriding dynamic coagulation effects seen after injury are: (i) accelerated TG and (ii) increased rates of fibrinolysis. We found no evidence for sTM as the major determinant of the coagulation changes seen in early trauma-induced coagulopathy.

 Trauma-induced coagulopathy (TIC) is common in severely injured patients and is associated with significant morbidity and mortality.

 The association of two parameters of blood gas analysis (hemoglobin [Hb], base excess [BE]) with standard coagulation tests (SCTs) and rotational thrombelastometry (ROTEM) using the database of the TraumaRegister DGU between 2015 and 2022 was studied. In a stepwise approach, the occurrence of a TIC, the correlations between Hb/BE levels and SCT, as well as ROTEM were calculated respectively. Then we aimed to detect relations between different Hb/BE levels and the occurrence of TIC, using standard clotting studies and/or ROTEM respectively.

 TIC occurred in 17.2% of the 68,996 primarily admitted adult patients with Injury Severity Score ≥9. A high correlation was found between Hb/BE and SCT. With a decrease in Hb and BE, the frequency of TIC increased and at an admission Hb <8 g/dL and BE < -6 mmol/L, >60% of patients presented with TIC. Clinical conditions associated with TIC were Glasgow Coma Scale ≤8, blood pressure ≤90 mmHg on the scene or at hospital admission, prehospital volume >1,000 mL, serious injuries to the head and/or the thorax and/or the abdomen and/or the extremities.

 Almost one-sixth of patients present with a TIC at hospital admission. Blood gas analysis samples showed relevant correlations between Hb/BE levels and SCT. The combined closer inspection of Hb/BE and the clinical presentation of the patient is able to predict TIC in the majority of patients.

Ghrelin exerts widespread effects in several diseases, but its role and mechanism in Acute Traumatic Coagulopathy (ATC) are largely unknown. The effect of ghrelin on cell proliferation was examined using three assays: 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT), Lactate Dehydrogenase (LDH), and flow cytometry. The barrier function of the endothelial cells was evaluated using the Trans-Endothelial Electrical Resistance (TEER) and the endothelial permeability assay. An ATC mouse model was established to evaluate the in vivo effects of ghrelin. The Ras homolog family member A (RhoA) overexpression plasmid or adenovirus was used to examine the molecular mechanism of ghrelin. Ghrelin enhanced Human Umbilical Vein Endothelial Cells (HUVEC) proliferation and endothelial cell barrier function and inhibited HUVEC permeability damage in vitro. Additionally, ghrelin decreased the activated Partial Thromboplastin Time (aPTT) and Prothrombin Time (PT) in mice blood samples in the ATC mouse model. Ghrelin also improved the pathological alterations in postcava. Mechanistically, ghrelin acts through the RhoA/ Rho-associated Coiled-coil Containing Kinases (ROCK)/ Myosin Light Chain 2 (MLC2) pathway. Furthermore, the protective effects of ghrelin, both in vitro and in vivo, were reversed by RhoA overexpression. Our findings demonstrate that ghrelin may reduce vascular endothelial cell damage and endothelial barrier dysfunction by blocking the RhoA pathway, suggesting that ghrelin may serve as a potential therapeutic target for ATC treatment.

Trauma-associated coagulopathy has been considered to develop as a result of increased fibrinolysis due to massive bleeding, tissue damage and hypoperfusion. However, it has not been investigated whether hematoma may cause trauma-associated coagulopathy. Using experimental animal model, we analyzed the effects of hematoma formation on coagulation and fibrinolysis parameters.

Male Wistar rats were used for the studies.

We made an animal model of subcutaneous hematoma without tissue injuries. This model can be categorised as a kind of trauma models. We created experimentally subcutaneous hematomas in test animals using blood collected from other animals. We performed blood sampling to measure blood cell counts and coagulation parameters from test animals at 1, 6, 24, 48 and 96 hours after hematoma generation. Blood samples were collected and immediately sent for measurement of CBC, Prothrombin, FDP, D-dimer, Fibrinogen, Antithrombin, AST and ALT. Furthermore, after 1, 24 and 48 hours, we performed dynamic evaluation of coagulation/fibrinolysis function using thromboelastometry method.

After the hematoma were created, FDP and D-dimer increased over time, and reached a plateau after 48 hours. During the period, there was no decrease in Fibrinogen and Antithrombin, and no thrombocytopenia occurred. Moreover, no obvious changes in coagulation/fibrinolysis function were observed employing thromboelastometry.

Elevated FDP and D-dimer after hematoma creation are assumed to be synthesized in the hematoma, not in the streaming blood. Thromboelastometry also shows that elevated levels of FDP and D-dimer are not caused by intravascular coagulation and subsequent fibrinolysis.

The study showed that subcutaneous hematomas caused increases in FDP and D-dimer levels, without activating the blood coagulation/fibrinolysis system.

The relationship between thromboelastogram (TEG) hypercoagulation status and perioperative deep vein thrombosis (DVT) in patients with femoral and pelvic fractures is not well understood. We aimed to investigate the relationship between hypercoagulation status identified by thromboelastography and postoperative DVT formation in patients with femoral and pelvic fractures, as well as to evaluate the role of thromboelastography in assessing hypercoagulation status and predicting postoperative DVT formation.

Data from 2,065 patients with femoral and pelvic fractures who underwent surgical treatment at a hospital in China between May 2018 and December 2023 were retrospectively analysed. Hypercoagulable TEG was defined as reaction time (R) < 5 min, coagulation time (K) < 1 min, alpha angle (α) > 72 degrees, maximum amplitude (MA) > 70 mm, and/or coagulation index (CI) > 3. The correlation between preoperative hypercoagulability identified by TEG and postoperative DVT formation was assessed using multivariate logistic regression. Propensity score matching (PSM) was performed to control for confounding factors.

Compared to the non-DVT group, the DVT group had decreased R and K values, while the α, MA, and CI values significantly increased (P < 0.05). Multivariate logistic regression analysis demonstrated that hypercoagulable TEG findings were predictive of postoperative DVT formation. PSM, using a 0.1 calliper value, matched 296 patients from the hypercoagulation and non-hypercoagulation groups in a 1:1 ratio. Before PSM, hypercoagulable TEG was associated with DVT in femoral and pelvic fractures (P < 0.001, odds ratio [OR]:1.860, 95% confidence interval: 1.389-2.492). After PSM, these two variables remained correlated (P = 0.001, OR = 1.878, 95% confidence interval:1.301 - 2.709).

The hypercoagulable state identified by TEG can predict thromboembolic events in patients with femoral and pelvic fractures.

The study was registered in the Chinese Clinical Trial Register ( https://www.chictr.org.cn/bin/home ) on April 16, 2024, with registration number ChiCTR2400083135.

In multiple trauma patients, the occurrence of trauma-induced coagulopathy (TIC) is closely associated with tissue damage and coagulation function abnormalities in the pathophysiological process.

This study established a multiple trauma and shock model in Sprague-Dawley (SD) rats and comprehensively utilized histological staining and radiographic imaging techniques to observe injuries in the intestine, liver, skeletal muscles, and bones. Monitoring activated partial thromboplastin time (APTT), platelet (PLT) count, respiratory rate, blood pressure, and other physiological indicators revealed time-dependent alterations in coagulation function and physiological indicators. Enzyme-linked immunosorbent assay (ELISA) measurements of inflammatory factors Tumor Necrosis Factor-alpha (TNF-α), Interleukin-6 (IL-6) and vascular endothelial injury marker (Syndecan-1) were also conducted.

Experimental results demonstrated significant changes in tissue structure after multiple traumas, although widespread necrosis or hemorrhagic lesions were not observed. There were time-dependent alterations in coagulation function and physiological indicators. ELISA measurements showed a strong positive correlation between the significant decrease in PLT count and the increase in TNF-α and IL-6 concentrations.

The study provides crucial information for the early diagnosis and treatment of TIC. The findings suggest that structured monitoring of coagulation and inflammatory indicators can help in understanding the pathophysiological changes and aid in the management of TIC in multiple trauma patients.

Trauma-induced coagulopathy (TIC) refers to an abnormal coagulation process, an imbalance between coagulation and fibrinolysis due to several pathological factors, such as haemorrhage and tissue injury. Platelet activation and subsequent clot formation are associated with mitochondrial activity, suggesting a possible role for mitochondria in TIC. Comprehensive studies of mitochondrial dysfunction in platelets from severe trauma patients have not yet been performed.

In this prospective case-control study, patients with severe trauma (ISS≥16) had venous blood samples taken at arrival to the Emergency Unit of a Level 1 Trauma Centre. Mitochondrial functional measurements (Oxygraph-2k, Oroboros) were performed to determine oxygen consumption in different respiratory states, the H2O2 production and extramitochondrial Ca2+ movements. In addition, standard laboratory and coagulation tests, viscoelastometry (ClotPro) and aggregometry (Multiplate) were performed. Measurements data were compared with age and sex matched healthy control patients.

Severe trauma patients (n = 113) with a median age of 38 years (IQR, 20-51), a median ISS of 28 (IQR, 20-48) met our inclusion criteria. Oxidative phosphorylation in platelet mitochondria from severe trauma patients significantly decreased compared to controls (34.7 ± 8.8 pmol/s/mL vs. 48.0 ± 19.7 pmol/s/mL). The mitochondrial H2O2 production significantly increased and greater endogenous Ca2+ release was found in the polytrauma group. Consistent with these results, clotting time (CT) increased while maximum clot firmness (MCF) decreased with the EX-test and FIB-test in severe trauma samples. Multiplate aggregometry showed significantly decreased ADP-test (38 ± 12 AUC vs. 112 ± 14 AUC) and ASPI test (78 ± 22 AUC vs. 84 ± 28 AUC) also tended to decrease in mitochondria of polytrauma patients as compared with controls. Significant strong correlation has been demonstrated between mitochondrial OxPhos and MCF while it was negatively correlated with ISS (R2=0.448, P˂0.05), INR, CT and lactate level of patients.

The present study revealed that severe trauma is associated with platelet mitochondrial dysfunction resulting in reduced ATP synthesis and impaired extramitochondrial Ca2+ movement. These factors are required for platelet activation, recruitment and clot stability likely thus, platelet mitochondrial dysfunction contributes to the development of TIC.

Clinical evidence suggests that anemia exacerbates traumatic bleeding and worsens outcomes.

To study the influence of iron deficiency anemia on traumatic bleeding, coagulopathy, and mortality.

C57BL/6J mice received an iron-deficient diet (8 weeks; ±1 mg intraperitoneal iron dextran 2 weeks before trauma). Control mice received a normal diet. Iron deficiency anemia was confirmed by hematocrit, red cell indices, and liver iron. Mice received saline or tranexamic acid (TXA; 10 mg/kg) just before liver laceration. Blood loss, coagulopathy (activated partial thromboplastin time, factor [F]II, FV, FVIII, FX, and fibrinogen), D-dimer, thrombin-antithrombin complexes, and plasmin-alpha-2-antiplasmin complexes were analyzed at 15 and 60 minutes, and a cytokine panel was performed at 60 minutes and 6 hours after trauma. Survival was monitored for 7 days.

Compared with nonanemic mice, anemic mice had lower hematocrit and hepatic iron content. Anemic mice experienced higher blood loss compared with nonanemic mice, which was reduced by TXA. Both groups developed traumatic coagulopathy characterized by activated partial thromboplastin time prolongation, thrombin-antithrombin complex formation, and depletion of FV, FVIII, and fibrinogen. TXA corrected the coagulopathy. However, plasmin-alpha-2-antiplasmin complex formation and D-dimers, markers of fibrinolysis, were higher in anemic mice and were not corrected by TXA. Seven-day survival was low in anemic mice, and rescued by TXA, but high in nonanemic mice without additional improvement by TXA. Among cytokines, only interleukin-6 increased, which was prevented by TXA most notably in anemic mice.

These observations provide first and critical proof-of-principle evidence that anemia accelerates traumatic bleeding and increases mortality, which could be rescued by anemia correction (parenteral iron) or periprocedural TXA.

Patients with trauma exhibit a complex balance of coagulopathy manifested by both bleeding and thrombosis. Antithrombin III is a plasma protein that functions as an important regulator of coagulation. Previous studies have found a high incidence of antithrombin III deficiency among patients with trauma.

To assess whether changes in antithrombin III activity are associated with thrombohemorrhagic complications among patients with trauma.

This cohort study was conducted from December 2, 2015, to March 24, 2017, at a level I trauma center. A total of 292 patients with trauma were followed up from their arrival through 6 days from admission. Data, including quantification of antithrombin III activity, were collected for these patients. Thromboprophylaxis strategy; hemorrhage, deep vein thrombosis (DVT), and pulmonary embolism screenings; and follow-up evaluations were conducted per institutional protocols. Data analyses were performed from September 28, 2023, to June 4, 2024.

The primary study outcome measurements were associations between antithrombin III levels and outcomes among patients with trauma, including ventilator-free days, hospital-free days, intensive care unit (ICU)-free days, hemorrhage, venous thromboembolic events, and mortality.

The 292 patients had a mean (SD) age of 54.4 (19.0) years and included 211 men (72.2%). Patients with an antithrombin III deficiency had fewer mean (SD) ventilator-free days (27.8 [5.1] vs 29.6 [1.4]; P = .0003), hospital-free days (20.3 [8.2] vs 24.0 [5.7]; P = 1.37 × 10-6), and ICU-free days (25.7 [4.9] vs 27.7 [2.3]; P = 9.38 × 10-6) compared with patients without a deficiency. Antithrombin III deficiency was also associated with greater rates of progressive intracranial hemorrhage (21.1% [28 of 133] vs 6.3% [10 of 159]; P = .0003) and thrombocytopenia (24.8% [33 of 133] vs 5.0% [8 of 159]; P = 1.94 × 10-6). Although antithrombin III deficiency was not significantly associated with DVT, patients who developed a DVT had a more precipitous decrease in antithrombin III levels that were significantly lower than patients who did not develop a DVT.

In this cohort study of patients with trauma, antithrombin III deficiency was associated with greater injury severity, increased hemorrhage, and increased mortality, as well as fewer ventilator-free, hospital-free, and ICU-free days. Although this was an associative study, these data suggest that antithrombin III levels may be useful in the risk assessment of patients with trauma.

This paper aims to outline current practices and examine promising new advancements in the modern management of haemorrhage in orthopaedic trauma. Many prehospital and perioperative haemorrhage control strategies and techniques have been available to clinicians for multiple decades, yet our understanding and utilisation of these practices continues to be refined and optimised. There is a particular focus in this article on issues related to resuscitation and coagulation in trauma. We examine the complex mechanisms that lead to coagulopathy in trauma patients as well as the transformative effect tranexamic acid has had in limiting blood loss. We also explore some emerging technologies such as endovascular interventions and clot-stabilising dressings and devices that are likely to have a significant impact going forward.

Tranexamic acid (TXA) demonstrates therapeutic efficacy in the management of traumatic brain injury (TBI). The objective of this systematic review and meta-analysis was to evaluate the safety and effectiveness of TXA in patients with TBI.

The databases, namely PubMed, Embase, Web of Science, and Cochrane Library databases, were systematically searched to retrieve randomized controlled trials (RCTs) investigating the efficacy of TXA for TBI from January 2000 to November 2023.

The present meta-analysis incorporates ten RCTs. Compared to the placebo group, administration of TXA in patients with TBI resulted in a significant reduction in mortality (P = 0.05), hemorrhage growth (P = 0.03), and volume of hemorrhage growth (P = 0.003). However, no significant impact was observed on neurosurgery outcomes (P = 0.25), seizure occurrence (P = 0.78), or pulmonary embolism incidence (P = 0.52).

The administration of TXA is significantly associated with reduced mortality and hemorrhage growth in patients suffering from TBI, while the need of neurosurgery, seizures, and incidence of pulmonary embolism remains comparable to that observed with placebo.

Improvements have been made in optimizing initial care of trauma patients, both in prehospital systems as well as in the emergency department, and these have also favorably affected longer term outcomes. However, as specific treatments for bleeding are largely lacking, many patients continue to die from hemorrhage. Also, major knowledge gaps remain on the impact of tissue injury on the host immune and coagulation response, which hampers the development of interventions to treat or prevent organ failure, thrombosis, infections or other complications of trauma. Thereby, trauma remains a challenge for intensivists. This review describes the most pressing research questions in trauma, as well as new approaches to trauma research, with the aim to bring improved therapies to the bedside within the twenty-first century.

Activated protein C (APC) is one of the mechanisms contributing to coagulopathy, which is associated with high mortality. The counteraction of the APC pathway could help ameliorate bleeding. However, patients also transform frequently from a hemorrhagic state to a prothrombotic state at a later time. Therefore, a prohemostatic therapeutic intervention should take this thrombotic risk into consideration.

CT-001 is a novel factor VIIa (FVIIa) with enhanced activity and desialylated N-glycans for rapid clearance. We assessed CT-001 clearance in multiple species and its ability to reverse APC-mediated coagulopathic blood loss.

The N-glycans on CT-001 were characterized by liquid chromatography-mass spectrometry. Three species were used to evaluate the pharmacokinetics of the molecule. The potency and efficacy of CT-001 under APC pathway-induced coagulopathic conditions were assessed by coagulation assays and bleeding models.

The N-glycosylation sites of CT-001 had high occupancy of desialylated N-glycans. CT-001 exhibited 5 to 16 times higher plasma clearance in human tissue factor knockin mice, rats, and cynomolgus monkeys than wildtype FVIIa. CT-001 corrected the activated partial thromboplastin time and thrombin generation of coagulopathic plasma to normal in in vitro studies. In an APC-mediated saphenous vein bleeding model, 3 mg/kg of CT-001 reduced bleeding time in comparison with wildtype FVIIa. The correction of bleeding by CT-001 was also observed in a coagulopathic tail amputation severe hemorrhage mouse model. The efficacy of CT-001 is independent of the presence of tranexamic acid, and the combination of CT-001 and tranexamic acid does not lead to increased thrombogenicity.

CT-001 corrected APC pathway-mediated coagulopathic conditions in preclinical studies and could be a potentially safe and effective procoagulant agent for addressing APC-mediated bleeding.

Recently, we have shown alterations in the anticoagulant response to recombinant activated factor VII (rFVIIa)-induced coagulation activation in patients with thrombophilia.

This study aimed to extend this in vivo model to fibrinolysis biomarkers.

This interventional in vivo study included 56 patients with thrombophilia and previous venous thromboembolism (VTE+), 38 without VTE (VTE-), and 35 healthy controls. Plasma levels of D-dimer, plasmin-α2-antiplasmin (PAP) complex, and plasminogen activator inhibitor-1 (PAI-1) were monitored for over 8 hours after rFVIIa infusion (15 μg/kg) along with thrombin markers and activated protein C (APC).

Throughout cohorts, median PAP increased by 40% to 52% (P < 3.9 × 10-10) and PAI-1 decreased by 59% to 79% (P < 3.5 × 10-8). In contrast to thrombin-antithrombin (TAT) complex, which also increased temporarily (44% to 115%, P < 3.6 × 10-6), changes in PAP and PAI-1 did not reverse during the observation period. The area under the measurement-time curves (AUCs) of PAP and TAT, which are measures of plasmin and thrombin formation, respectively, were each greater in the VTE+ cohort than in healthy controls (median PAP-AUC = 0.48 vs 0.27 ng·h/L [P = .003], TAT-AUC = 0.12 vs 0.03 nmol·h/L [P = 2.5 × 10-4]) and were correlated with one another (r = 0.554). As evidenced by the respective AUCs, asymptomatic factor (F)V Leiden carriers showed less PAP formation (0.22 vs 0.41 ng·h/L, P = 9 × 10-4), more pronounced PAI-1 decline (0.10 vs 0.18 ng·h/L, P = .01), and increased APC formation (28.7 vs 15.4 pmol·h/L, P = .02) than those within the VTE+ group (n = 19 each).

rFVIIa-induced thrombin formation is associated with fibrinolysis parameter changes outlasting the concomitant anticoagulant response. Both correlate with thrombosis history in FV Leiden and might help explain its variable clinical expressivity.

Trauma-induced coagulopathy (TIC) is a global inflammatory state accompanied by coagulation derangements, acidemia, and hypothermia, which occurs after traumatic injury. It occurs in approximately 25% of severely injured patients, and its incidence is directly related to injury severity. The mechanism of TIC is multifaceted; proposed contributing factors include dysregulation of activated protein C, increased tPA, systemic endothelial activation, decreased fibrinogen, clotting factor consumption, and platelet dysfunction. Effects of TIC include systemic inflammation, coagulation derangements, acidemia, and hypothermia. Trauma-induced coagulopathy may be diagnosed by conventional coagulation tests including platelet count, Clauss assay, international normalized ratio, thrombin time, prothrombin time, and activated partial thromboplastin time; viscoelastic hemostatic assays such as thrombelastography and rotational thrombelastography; or a clinical scoring system known as the Trauma Induced Coagulopathy Clinical Score. Preventing TIC begins in the prehospital phase with early hemorrhage control, blood product resuscitation, and tranexamic acid therapy. Early administration of prothrombin complex concentrate is also being studied in the prehospital environment. The mainstays of TIC treatment include hemorrhage control, blood and component transfusions, and correction of abnormalities such as hypocalcemia, acidosis, and hypothermia.

Therapeutic/Care Management; Level III.

Activated Protein C (aPC) plays dual roles after injury, driving both trauma-induced coagulopathy (TIC) by cleaving, and thus inactivating, factors Va and VIIIa and depressing fibrinolysis while also mediating an inflammomodulatory milieu via protease activated receptor-1 (PAR-1) cytoprotective signaling. Because of this dual role, it represents and ideal target for study and therapeutics after trauma. A known aPC variant, 3K3A-aPC, has been engineered to preserve cytoprotective activity while retaining minimal anticoagulant activity rendering it potentially ideal as a cytoprotective therapeutic after trauma. We hypothesized that 3K3A-aPC would mitigate the endotheliopathy of trauma by protecting against endothelial permeability.

We used electric cell-substrate impedance sensing to measure permeability changes in real time in primary endothelial cells. These were cultured, grown to confluence, and treated with a 2 μg/mL solution of 3K3A-aPC at 180 minutes, 120 minutes, 60 minutes, 30 minutes prior to stimulation with ex vivo plasma taken from severely injured trauma patients (Injury Severity Score > 15 and BD < -6) (trauma plasma [TP]). Cells treated with thrombin and untreated cells were included in this study as control groups. Permeability changes were recorded in real time via electric cell-substrate impedance sensing for 30 minutes after treatment with TP. We quantified permeability changes in the control and treatment groups as area under the curve (AUC). Rac1/RhoA activity was also compared between these groups. Statistical significance was determined by one-way ANOVA followed by a post hoc analysis using Tukey's multiple comparison's test.

Treatment with aPC mitigated endothelial permeability induced by ex vivo trauma plasma at all pre-treatment time points. The AUC of the 30-minute 3K3A-aPC pretreatment group was higher than TP alone (mean diff. 22.12 95% CI [13.75, 30.49], p < 0.0001) (Figure). Moreover, the AUC of the 60-minute, 120-minute, and 180-minute pretreatment groups was also higher than TP alone (mean diff., 16.30; 95% confidence interval [CI], 7.93-24.67; 19.43; 95% CI, 11.06-27.80, and 18.65; 95% CI, 10.28-27.02;, all p < 0.0001, respectively). Rac1/RhoA activity was higher in the aPC pretreatment group when compared with all other groups ( p < 0.01).

Pretreatment with 3K3A-aPC, which retains its cytoprotective function but has only ~5% of its anticoagulant function, abrogates the effects of trauma-induced endotheliopathy. This represents a potential therapeutic treatment for dysregulated thromboinflammation for injured patients by minimizing aPC's role in trauma-induced coagulopathy while concurrently amplifying its essential cytoprotective function.

Prognostic and Epidemiological; Level III.

Very often the performance of a Bayesian Network (BN) is affected when applied to a new target population. This is mainly because of differences in population characteristics. External validation of the model performance on different populations is a standard approach to test model's generalisability. However, a good predictive performance is not enough to show that the model represents the unique population characteristics and can be adopted in the new environment.

In this paper, we present a methodology for updating and recalibrating developed BN models - both their structure and parameters - to better account for the characteristics of the target population. Attention has been given on incorporating expert knowledge and recalibrating latent variables, which are usually omitted from data-driven models.

The method is successfully applied to a clinical case study about the prediction of trauma-induced coagulopathy, where a BN has already been developed for civilian trauma patients and now it is recalibrated on combat casualties.

The methodology proposed in this study is important for developing credible models that can demonstrate a good predictive performance when applied to a target population. Another advantage of the proposed methodology is that it is not limited to data-driven techniques and shows how expert knowledge can also be used when updating and recalibrating the model.

Tissue plasminogen activator (tPA) added to thrombelastography (TEG) detects hyperfibrinolysis by measuring clot lysis at 30 min (tPA-challenge-TEG). We hypothesize that tPA-challenge-TEG is a better predictor of massive transfusion (MT) than existing strategies in trauma patients with hypotension.

Trauma activation patients (TAP, 2014-2020) with 1) systolic blood pressure <90 mmHg (early) or 2) those who arrived normotensive but developed hypotension within 1H postinjury (delayed) were analyzed. MT was defined as >10 RBC U/6H postinjury or death within 6H after ≥1 RBC unit. Area under the receiver operating characteristics curves were used to compare predictive performance. Youden index determined optimal cutoffs.

tPA-challenge-TEG was the best predictor of MT in the early hypotension subgroup (N = 212) with positive (PPV) and negative predictive values (NPV) of 75.0%, and 77.6%, respectively. tPA-challenge-TEG was a better predictor of MT than all but TASH (PPV = 65.0%, NPV = 93.3%) in the delayed hypotension group (N = 125).

The tPA-challenge-TEG is the most accurate predictor of MT in trauma patients arriving hypotensive and offers early recognition of MT in patients with delayed hypotension.

The base deficit, international normalized ratio, and Glasgow Coma Scale (BIG) score was previously developed to predict the outcomes of pediatric trauma patients. We designed this study to explore and improve the prognostic value of the BIG score in adult patients with traumatic brain injury (TBI).

Adult patients diagnosed with TBI in a public critical care database were included in this observational study. The BIG score was calculated based on the Glasgow Coma Scale (GCS), the international normalized ratio (INR), and the base deficit. Logistic regression analysis was performed to confirm the association between the BIG score and the outcome of included patients. Receiver operating characteristic (ROC) curves were drawn to evaluate the prognostic value of the BIG score and novel constructed models.

In total, 1,034 TBI patients were included in this study with a mortality of 22.8%. Non-survivors had higher BIG scores than survivors (p < 0.001). The results of multivariable logistic regression analysis showed that age (p < 0.001), pulse oxygen saturation (SpO2) (p = 0.032), glucose (p = 0.015), hemoglobin (p = 0.047), BIG score (p < 0.001), subarachnoid hemorrhage (p = 0.013), and intracerebral hematoma (p = 0.001) were associated with in-hospital mortality of included patients. The AUC (area under the ROC curves) of the BIG score was 0.669, which was not as high as in previous pediatric trauma cohorts. However, combining the BIG score with age increased the AUC to 0.764. The prognostic model composed of significant factors including BIG had the highest AUC of 0.786.

The age-adjusted BIG score is superior to the original BIG score in predicting mortality of adult TBI patients. The prognostic model incorporating the BIG score is beneficial for clinicians, aiding them in making early triage and treatment decisions in adult TBI patients.

Severe traumatic bleeding depletes coagulation factor XIII (FXIII) and fibrinogen. However, the role of FXIII level in bleeding-related outcomes is unknown.

To evaluate the association between FXIII levels at hospital arrival and critical administration threshold (≥3 red blood cell units in 1 hour within the first 24 hours), bleeding-related outcomes, death, and baseline characteristics.

A retrospective cohort study was conducted in severely injured adult patients (Injury Severity Score of ≥22 or ≥2 red blood cell units transfused in 24 hours) admitted to a level 1 trauma center. Clinical and laboratory data were collected. Baseline FXIII antigen levels were measured in banked patient plasma. Multivariable logistic and linear regression models were used to estimate the association between FXIII levels, outcomes, and baseline characteristics.

Three hundred sixty-four of 1730 subjects admitted during a 2-year period were analyzed. Median age was 44 years (IQR, 27-62 years), and median Injury Severity Score was 29 (IQR, 22-34). FXIII levels were not associated with critical administration threshold (odds ratio [OR], 1.06; 95% CI, 0.97-1.17) or death (OR, 0.98; 95% CI, 0.90-1.07). FXIII was associated with major bleeding (OR, 1.10; 95% CI, 1.02-1.2) and massive transfusion (OR, 1.25; 95% CI, 1.08-1.44). Lower baseline FXIII levels were associated with arrival from a referring hospital (FXIII level, -0.07 U/mL; 95% CI, -0.11 to -0.03), hemoglobin (FXIII level, -0.05 U/mL; 95% CI, -0.07 to -0.03), fibrinogen level (FXIII level, -0.05 U/mL; 95% CI, -0.08 to -0.02), and platelet count (FXIII level, -0.02 U/mL; 95% CI, -0.04 to -0.008).

Baseline FXIII levels in severely injured patients were inconsistently associated with bleeding-related outcomes and mortality. However, their association with major bleeding warrants further investigation of the role of FXIII in massively transfused patients with trauma.

In the Study of Tranexamic Acid During Air and Ground Prehospital Transport (STAAMP) Trial, prehospital tranexamic acid (TXA) was associated with lower mortality in specific patient subgroups. The underlying mechanisms responsible for a TXA benefit remain incompletely characterized. We hypothesized that TXA may mitigate endothelial injury and sought to assess whether TXA was associated with decreased endothelial or tissue damage markers among all patients enrolled in the STAAMP Trial.

We collected blood samples from STAAMP Trial patients and measured markers of endothelial function and tissue damage including syndecan-1, soluble thrombomodulin (sTM), and platelet endothelial cell adhesion molecule-1 at hospital admission (0 hours) and 12 hours, 24 hours, and 72 hours after admission. We compared these marker values for patients in each treatment group during the first 72 hours, and modeled the relationship between TXA and marker concentration using regression analysis to control for potential confounding factors.

We analyzed samples from 766 patients: 383 placebo, 130 abbreviated dosing, 119 standard dosing, and 130 repeat dosing. Lower levels of syndecan-1, TM, and platelet endothelial cell adhesion molecule measured within the first 72 hours of hospital admission were associated with survival at 30 days ( p < 0.001). At hospital admission, syndecan-1 was lower in the TXA group (28.30 [20.05, 42.75] vs. 33.50 [23.00, 54.00] p = 0.001) even after controlling for patient, injury, and prehospital factors ( p = 0.001). For every 1 g increase in TXA administered over the first 8 hours of prehospital transport and hospital admission, there was a 4-ng/mL decrease in syndecan-1 at 12 hours controlling for patient, injury, and treatment factors ( p = 0.03).

Prehospital TXA was associated with decreased syndecan-1 at hospital admission. Syndecan-1 measured 12 hours after admission was inversely related to the dose of TXA received. Early prehospital and in-hospital TXA may decrease endothelial glycocalyx damage or upregulate vascular repair mechanisms in a dose-dependent fashion.

Therapeutic/Care Management; Level III.

The base deficit (B), international normalized ratio (I), and Glasgow coma scale (GCS) (BIG) score is useful in predicting mortality in pediatric trauma patients; however, studies on the use of BIG score in adult patients with trauma are sparse. In addition, studies on the correlation between the BIG score and massive transfusion (MT) have not yet been conducted. This study aimed to evaluate the predictive value of BIG score for mortality and the need for MT in adult trauma patients. This retrospective study used data collected between 2016 and 2020 at our hospital's trauma center and registry. The predictive value of BIG score was compared with that of the Injury Severity Score (ISS) and Revised Trauma Score (RTS). Logistic regression analysis was carried out to assess whether BIG score was an independent risk factor. Receiver operating characteristic (ROC) curve analysis was performed, and predictive values were evaluated by measuring the area under the ROC curve (AUROC). In total, 5,605 patients were included in this study. In logistic regression analysis, BIG score was independently associated with in-hospital mortality (odds ratio (OR): 1.1859; 95% confidence interval (CI): 1.1636-1.2086) and MT (OR: 1.0802; 95% CI: 1.0609-1.0999). The AUROCs of BIG score for in-hospital mortality and MT were 0.852 (0.842-0.861) and 0.848 (0.838-0.857), respectively. Contrastingly, the AUROCs of ISS and RTS for in-hospital mortality were 0.795 (0.784-0.805) and 0.859 (0.850-0.868), respectively. Moreover, AUROCs of ISS and RTS for MT were 0.812 (0.802-0.822) and 0.838 (0.828-0.848), respectively. The predictive value of BIG score for mortality and MT was significantly higher than that of the ISS. The BIG score also showed a better AUROC for predicting in-hospital mortality compared with RTS. In conclusion, the BIG score is a useful indicator for predicting mortality and the need for MT in adult trauma patients.

Upon cellular injury, damage-associated molecular patterns (DAMPs) are released into the extracellular space and evoke proinflammatory and prothrombotic responses in animal models of sterile inflammation. However, in clinical settings, the dynamics of DAMP levels after trauma and links between DAMPs and trauma-associated coagulopathy remain largely undetermined.

Thirty-one patients with severe trauma, who were transferred to Kagoshima City Hospital between June 2018 and December 2019, were consecutively enrolled in this study. Blood samples were taken at the time of delivery, and 6 and 12 h after the injury, and once daily thereafter. The time-dependent changes of coagulation/fibrinolysis markers, including thrombin-antithrombin complex, α2-plasmin inhibitor (α2-PI), plasmin-α2-PI complex, and plasminogen activator inhibitor-1 (PAI-1), and DAMPs, including high mobility group box 1 and histone H3, were analyzed. The relationship between coagulation/fibrinolysis markers, DAMPs, Injury Severity Score, in-hospital death, and amount of blood transfusion were analyzed.

The activation of coagulation/fibrinolysis pathways was evident at the time of delivery. In contrast, PAI-1 levels remained low at the time of delivery, and then were elevated at 6-12 h after traumatic injury. Histone H3 and high mobility group box 1 levels were elevated at admission, and gradually subsided over time. PAI-1 levels at 6 h were associated with serum histone H3 levels at admission. Increased histone H3 levels and plasmin-α2-PI complex levels were associated with in-hospital mortality. α2-PI levels at admission showed the strongest negative correlation with the amount of blood transfusion.

The elevation of histone H3 levels and fibrinolysis perturbation are associated with fatal outcomes in patients with traumatic injury. Patients with low α2-PI levels at admission tend to require blood transfusion.

Trauma-induced coagulopathy (TIC) is a major cause of morbidity and mortality in patients with traumatic injury. It describes the spectrum of coagulation abnormalities that occur because of the trauma itself and the body's response to the trauma. These coagulation abnormalities range from hypocoagulability and hyperfibrinolysis, resulting in potentially fatal bleeding, in the early stages of trauma to hypercoagulability, leading to widespread clot formation, in the later stages. Pathological changes in the vascular endothelium and its regulation of haemostasis, a phenomenon known as the endotheliopathy of trauma (EoT), are thought to underlie TIC. Our understanding of EoT and its contribution to TIC remains in its infancy largely due to the scarcity of experimental research. This review discusses the mechanisms employed by the vascular endothelium to regulate haemostasis and their dysregulation following traumatic injury before providing an overview of the available experimental in vitro and in vivo models of trauma and their applicability for the study of the EoT and its contribution to TIC.

Abdominal compartment syndrome (ACS) after blunt abdominal trauma is a rare complication that requires early recognition and subsequent surgical intervention for optimal outcome. We aimed to investigate how differences in injured abdominal organs affect ACS development in patients with severe blunt abdominal trauma.

This nested case-control study used a nationwide registry of trauma patients, namely, the Japan Trauma Data Bank (JTDB), and only included patients aged ≥ 18 years with blunt severe abdominal trauma, defined as an AIS score of abdomen ≥ 3, sustained between 2004 and 2017. Patients without ACS were used as control subjects and identified using propensity score (PS) matching. Characteristics and outcomes between patients with and without ACS were compared and logistic regression was used to identify specific risk factors for ACS.

Among 294,274 patients in the JTDB, 11,220 were eligible for inclusion before PS matching, and 150 (1.3%) developed ACS after trauma. PS matching led to the inclusion of 131 and 655 patients with and without ACS, respectively. Compared to controls, patients with ACS had higher number of injured organs in the abdomen and displayed a greater frequency of vascular and pancreatic injuries, need for blood transfusion, and disseminated intravascular coagulopathy, a complication of ACS. In-hospital mortality was higher in patients with ACS than those without ACS (51.1% vs. 26.0%, p < 0.01). Logistic regression analysis revealed that a higher number of injured organs in the abdomen [odds ratio (OR) (95% confidence interval [CI]): 1.76 (1.23-2.53)] and pancreatic injury [OR (95% CI): 1.53 (1.03-2.27)] were independently associated with ACS.

Greater number of injured organs in abdomen and pancreatic injury are independent risk factors for the development of ACS.

Trauma remains one of the leading causes of death in adults despite the implementation of preventive measures and innovations in trauma systems. The etiology of coagulopathy in trauma patients is multifactorial and related to the kind of injury and nature of resuscitation. Trauma-induced coagulopathy (TIC) is a biochemical response involving dysregulated coagulation, altered fibrinolysis, systemic endothelial dysfunction, platelet dysfunction, and inflammatory responses due to trauma. The aim of this review is to report the pathophysiology, early diagnosis and treatment of TIC. A literature search was performed using different databases to identify relevant studies in indexed scientific journals. We reviewed the main pathophysiological mechanisms involved in the early development of TIC. Diagnostic methods have also been reported which allow early targeted therapy with pharmaceutical hemostatic agents such as TEG-based goal-directed resuscitation and fibrinolysis management. TIC is a result of a complex interaction between different pathophysiological processes. New evidence in the field of trauma immunology can, in part, help explain the intricacy of the processes that occur after trauma. However, although our knowledge of TIC has grown, improving outcomes for trauma patients, many questions still need to be answered by ongoing studies.

Tissue injury (TI) and hemorrhagic shock (HS) are the major contributors to trauma-induced coagulopathy (TIC). However, the individual contributions of these insults are difficult to discern clinically because they typically coexist. TI has been reported to release procoagulants, while HS has been associated with bleeding. We developed a large animal model to isolate TI and HS and characterize their individual mechanistic pathways. We hypothesized that while TI and HS are both drivers of TIC, they provoke different pathways; specifically, TI reduces time to clotting, whereas, HS decreases clot strength stimulates hyperfibrinolysis.

After induction of general anesthesia, 50 kg male, Yorkshire swine underwent isolated TI (bilateral muscle cutdown of quadriceps, bilateral femur fractures) or isolated HS (controlled bleeding to a base excess target of - 5 mmol/l) and observed for 240 min. Thrombelastography (TEG), calcium levels, thrombin activatable fibrinolysis inhibitor (TAFI), protein C, plasminogen activator inhibitor 1 (PAI-1), and plasminogen activator inhibitor 1/tissue-type plasminogen activator complex (PAI-1-tPA) were analyzed at pre-selected timepoints. Linear mixed models for repeated measures were used to compare results throughout the model.

TI resulted in elevated histone release which peaked at 120 min (p = 0.02), and this was associated with reduced time to clot formation (R time) by 240 min (p = 0.006). HS decreased clot strength at time 30 min (p = 0.003), with a significant decline in calcium (p = 0.001). At study completion, HS animals had elevated PAI-1 (p = 0.01) and PAI-1-tPA (p = 0.04), showing a trend toward hyperfibrinolysis, while TI animals had suppressed fibrinolysis. Protein C, TAFI and skeletal myosin were not different among the groups.

Isolated injury in animal models can help elucidate the mechanistic pathways leading to TIC. Our results suggest that isolated TI leads to early histone release and a hypercoagulable state, with suppressed fibrinolysis. In contrast, HS promotes poor clot strength and hyperfibrinolysis resulting in hypocoagulability.

Platelet activation and aggregation are critical to the initiation of hemostasis after trauma with hemorrhage. Platelet dysfunction is a well-recognized phenomenon contributing to trauma-induced coagulopathy. The goal of this study was to evaluate the timing and severity of platelet dysfunction in massively transfused, traumatically injured patients during the first 72 hours after injury and its association with 30-day survival.

A retrospective secondary cohort study of platelet count and function was performed using samples from the Pragmatic Randomized Optimal Platelet and Plasma Ratios trial. Platelet characteristics were measured at 8 timepoints during the first 72 hours of hospitalization and compared between 30-day survivors and nonsurvivors. Platelet counts were assessed via flow cytometry. Platelet function was analyzed with the use of serial thrombelastography and impedance aggregometry with agonists arachidonic acid, adenosine diphosphate, collagen, thrombin receptor activating peptide, and ristocetin.

In total, 680 patients were included for analysis. Platelet counts were significantly lower from baseline to 72 hours after hospital admission with further 1.3 to 2-fold reductions noted in nonsurvivors compared to survivor patients. Platelet aggregation via adenosine diphosphate, arachidonic acid, collagen, thrombin receptor activating peptide, and ristocetin was significantly lower in nonsurvivors at all time points. The nadir of platelet aggregation was 2 to 6 hours after admission with significant improvements in viscoelastic maximum clot formation and agonist-induced aggregation by 12 hours without concomitant improvement in platelet count.

Platelet aggregability recovers 12 hours after injury independent of worsening thrombocytopenia. Failure of platelet function to recover portends a poor prognosis.

In damage control orthopaedics (DCO), fractures are initially stabilised with external fixation followed by delayed conversion to definitive internal fixation. The aim of this study is to determine whether the timing of the conversion influences the development of deep infection and fracture healing in a cohort of patients treated by DCO after a closed fracture of the lower limb. Furthermore, we wanted to evaluate whether the one-stage conversion procedure is always safe.

A retrospective cohort study was conducted at a single level 1 trauma centre. Ninety-four cases of closed fractures of lower limb treated by DCO subsequently converted to internal fixation from 2012 to 2019 were included. Development of deep infection, superficial infection, non-union and time to union were recorded. Patients were then divided into three groups according to the timing of conversion: Group A (<7 days), Group B (7-13 days), Group C (> 14 days). Comparison between groups was performed to assess intergroup variabilty.

The mean number of days between DCO and conversion was 6.7±4.52 (range 1-22). We observed one case of deep infection (1.1%), one case of non-union (1.1%), four cases of superficial infection (4.3%) and mean time to union was 4.9±1.38 months months. Comparison between groups demonstrated no significant correlation between timing of conversion and development of superficial or deep infection and non-union, while it highlighted that complexity of the fracture and longer surgical time of conversion procedure were significantly higher in Group C.

One-stage conversion to definitive internal fixation within 22 days from DCO is a safe and feasible procedure, which does not influence the incidence of infection or non-union.

Primary blast lung injury (PBLI), caused by exposure to high-intensity pressure waves from explosions in war, terrorist attacks, industrial production, and life explosions, is associated with pulmonary parenchymal tissue injury and severe ventilation insufficiency. PBLI patients, characterized by diffused intra-alveolar destruction, including hemorrhage and inflammation, might deteriorate into acute respiratory distress syndrome (ARDS) with high mortality. However, due to the absence of guidelines about PBLI, emergency doctors and rescue teams treating PBLI patients rely on experience. The goal of this review is to summarize the mechanisms of PBLI and their cross-linkages, exploring potential diagnostic and therapeutic targets of PBLI. We summarize the pathophysiological performance and pharmacotherapy principles of PBLI. In particular, we emphasize the crosstalk between hemorrhage and inflammation, as well as coagulation, and we propose early control of hemorrhage as the main treatment of PBLI. We also summarize several available therapy methods, including some novel internal hemostatic nanoparticles to prevent the vicious circle of inflammation and coagulation disorders. We hope that this review can provide information about the mechanisms, diagnosis, and treatment of PBLI for all interested investigators.

Persistent occult hypoperfusion after initial resuscitation is strongly associated with increased morbidity and mortality after severe trauma. The objective of this study was to analyze regional tissue oxygenation, along with other global markers, as potential detectors of occult shock in otherwise hemodynamically stable trauma patients.

Trauma patients undergoing active resuscitation were evaluated 8 h after hospital admission with the measurement of several global and local hemodynamic/metabolic parameters. Apparently hemodynamically stable (AHD) patients, defined as having SBP ≥ 90 mmHg, HR < 100 bpm and no vasopressor support, were followed for 48 h, and finally classified according to the need for further treatment for persistent bleeding (defined as requiring additional red blood cell transfusion), initiation of vasopressors and/or bleeding control with surgery and/or angioembolization. Patients were labeled as "Occult shock" (OS) if they required any intervention or "Truly hemodynamically stable" (THD) if they did not. Regional tissue oxygenation (rSO₂) was measured non-invasively by near-infrared spectroscopy (NIRS) on the forearm. A vascular occlusion test was performed, allowing a 3-min deoxygenation period and a reoxygenation period following occlusion release. Minimal rSO₂ (rSO₂min), Delta-down (rSO₂-rSO₂min), maximal rSO₂ following cuff-release (rSO₂max), and Delta-up (rSO₂max-rSO₂min) were computed. The NIRS response to the occlusion test was also measured in a control group of healthy volunteers.

Sixty-six consecutive trauma patients were included. After 8 h, 17 patients were classified as AHD, of whom five were finally considered to have OS and 12 THD. No hemodynamic, metabolic or coagulopathic differences were observed between the two groups, while NIRS-derived parameters showed statistically significant differences in Delta-down, rSO₂min, and Delta-up.

After 8 h of care, NIRS evaluation with an occlusion test is helpful for identifying occult shock in apparently hemodynamically stable patients.

IV, descriptive observational study.

ClinicalTrials.gov Registration Number: NCT02772653.

Trauma activates the innate immune system to modulate hemostasis and minimize the damage caused by physiological bodily responses, including the activation of coagulation. Sufficiently severe trauma overwhelms physiological responses and elicits the systemic inflammatory response syndrome, which leads to the onset of disseminated intravascular coagulation (DIC), characterized by dysregulated inflammatory coagulofibrinolytic responses. Impaired anticoagulant mechanisms, including antithrombin, constitutes the pathology of DIC, while the dynamics of antithrombin and relevance to outcomes in trauma-induced coagulopathy have not been fully elucidated. This study investigated the associations of antithrombin activity with DIC onset and outcomes in severely injured patients.

This retrospective sub-analysis of a multicenter, prospective study included patients with an injury severity score ≥16. We characterized trauma patients with low antithrombin activity (antithrombin <80% on hospital arrival, n = 75) in comparison with those who had normal antithrombin activity (antithrombin ≥80%, n = 200). Global markers of coagulation and fibrinolysis, molecular biomarkers for thrombin generation (soluble fibrin [SF]), and markers of anticoagulation (antithrombin) were evaluated to confirm the associations of antithrombin with DIC development and outcomes, including in-hospital mortality and the multiple organ dysfunction syndrome (MODS).

Patients with low antithrombin activity had higher prevalence of shock, transfusion requirements, and in-hospital mortality. Higher DIC scores and more severe organ dysfunction were observed in the low AT group compared to that in the normal AT group. Antithrombin activity on arrival at the hospital was an independent predictor of the development of DIC in trauma patients, and levels of SF increased with lower antithrombin values (antithrombin activity > 85%). Antithrombin activity at 3 h showed good predictive performance for in-hospital mortality, and a multivariable Cox proportional-hazard regression model with a cross-product term between the antithrombin and DIC showed that the in-hospital mortality in patients with DIC increased with decreased antithrombin activity. A multivariable logistic regression model showed that the odds for the development of MODS in patients with DIC increased with lower antithrombin values.

Decreased antithrombin activity in trauma-induced coagulopathy is associated with poor outcomes through worsening of DIC.

Hyperfibrinolysis (HF) frequently occurs after severe systemic hypoperfusion during major trauma and out-of-hospital cardiac arrest (OHCA). In trauma-induced HF, hypoperfusion, the activation of protein C (APC), and the release of tissue plasminogen activator (t-PA) have been identified as the driving elements of premature clot breakdown. The APC pathway also plays a role in inflammatory responses such as neutrophil extracellular trap formation (NETosis), which might contribute to lysis through cleavage of fibrin by neutrophil elastases. We investigated whether the APC and the plasminogen pathway were general drivers of HF, even in the absence of a traumatic incident. Additionally, we were interested in inflammatory activation such as the presence of NETs as potential contributing factors to HF. A total of 41 patients with OHCA were assigned to a HF and a non-HF group based on maximum lysis (ML) in thromboelastometry. Thrombin-antithrombin (TAT)-complex, soluble thrombomodulin (sTM), APC-PC inhibitor complex, t-PA, PAI-1, t-PA-PAI-1 complex, plasmin-antiplasmin (PAP), d-dimers, neutrophil elastase, histonylated DNA (hDNA) fragments, and interleukin-6 were assessed via immunoassays in the HF group vs. non-HF. APC-PC inhibitor complex is significantly higher in HF patients. Antigen levels of t-PA and PAI-1 do not differ between groups. However, t-PA activity is significantly higher and t-PA-PAI-1 complex significantly lower in the HF group. Consistent with these results, PAP and d-dimers are significantly elevated in HF. HDNA fragments and neutrophil elastase are not elevated in HF patients, but show a high level of correlation, suggesting NETosis occurs in OHCA as part of inflammatory activation and cellular decay. Just as in trauma, hypoperfusion, the activation of protein C, and the initiation of the plasminogen pathway of fibrinolysis manifest themselves in the HF of cardiac arrest. Despite features of NETosis being detectable in OHCA patients, early pro-inflammatory responses do not appear be associated with HF in cardiac arrest.

 Detailed and decisive information about the patients' coagulation status is important in various emergency situations. Conventional global coagulation testing strategies are often used to provide a quick overview, but several limitations particularly in the trauma setting are well described. With the introduction of direct oral anticoagulations (DOACs), a milestone for several disease entities resulting in overall improved outcomes could be reached, but at the same time providing new diagnostic challenges for the emergency situation.

 As an alternative to conventional coagulation tests, there is increasing clinical and scientific interest in the use of early whole blood strategies to provide goal-directed coagulation therapies (GDCT) and hemostatic control in critically ill patients. Viscoelastic hemostatic assays (VHAs) were therefore introduced to several clinical applications and may provide as a bedside point-of-care method for faster information on the underlying hemostatic deficiency.

 The use of VHA-based algorithms to guide hemostatic control in emergency situations now found its way to several international guidelines for patients at risk of bleeding. With this qualitative review, we would like to focus on VHA-based GDCT and review the current evidence for its use, advantages, and challenges in the two different clinical scenarios of trauma and intracerebral bleeding/stroke management.

When a traumatic injury exceeds the body's internal tolerances, the innate immune and inflammatory systems are rapidly activated, and if not contained early, increase morbidity and mortality. Early deaths after hospital admission are mostly from central nervous system (CNS) trauma, hemorrhage and circulatory collapse (30%), and later deaths from hyperinflammation, immunosuppression, infection, sepsis, acute respiratory distress, and multiple organ failure (20%). The molecular drivers of secondary injury include damage associated molecular patterns (DAMPs), pathogen associated molecular patterns (PAMPs) and other immune-modifying agents that activate the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic stress response. Despite a number of drugs targeting specific anti-inflammatory and immune pathways showing promise in animal models, the majority have failed to translate. Reasons for failure include difficulty to replicate the heterogeneity of humans, poorly designed trials, inappropriate use of specific pathogen-free (SPF) animals, ignoring sex-specific differences, and the flawed practice of single-nodal targeting. Systems interconnectedness is a major overlooked factor. We argue that if the CNS is protected early after major trauma and control of cardiovascular function is maintained, the endothelial-glycocalyx will be protected, sufficient oxygen will be delivered, mitochondrial energetics will be maintained, inflammation will be resolved and immune dysfunction will be minimized. The current challenge is to develop new systems-based drugs that target the CNS coupling of whole-body function.