Publications

BACKGROUND: Evidence suggests that variation in light exposure strongly influences the dynamic of inflammation, coagulation, and the immune system. Multiple injuries induce systemic inflammation that can lead to end-organ injury. Here, we hypothesize that alterations in light exposure influence posttrauma inflammation, coagulopathy, and end-organ injury.

METHODS: C57BL/6 mice underwent a validated multiple-injury and hemorrhage model performed following 72 hours of exposure to red (617 nm, 1,700 lux), blue (321 nm, 1,700 lux), and fluorescent white light (300 lux) (n = 6-8/group). The animals were sacrificed at 6 hours posttrauma. Plasma samples were evaluated and compared for proinflammatory cytokine expression levels, coagulation parameters, markers of liver and renal injury, and histological changes (Carstairs staining). One-way analysis of variance statistical tests were applied to compare study groups.

RESULTS: Preexposure to long-wavelength red light significantly reduced the inflammatory response at 6 hours after multiple injuries compared with blue and ambient light, as evidenced by decreased levels of interleukin 6, monocyte chemoattractant protein-1 (both p < 0.001), liver injury markers (alanine transaminase, p < 0.05), and kidney injury markers (cystatin C, p < 0.01). In addition, Carstairs staining of organ tissues revealed milder histological changes in the red light-exposed group, indicating reduced end-organ damage. Furthermore, prothrombin time was significantly lower ( p < 0.001), and fibrinogen levels were better maintained ( p < 0.01) in the red light-exposed mice compared with those exposed to blue and ambient light.

CONCLUSION: Prophylactic light exposure can be optimized to reduce systemic inflammation and coagulopathy and minimize acute organ injury following multiple injuries. Understanding the mechanisms by which light exposure attenuates inflammation may provide a novel strategy to reducing trauma-related morbidity.

Trauma is the leading cause of death in individuals up to 45 years of age. Alterations in platelet function are a critical component of trauma-induced coagulopathy (TIC), yet these changes and the potential resulting dysfunction is incompletely understood. The lack of clinical assays available to explore platelet function in this patient population has hindered detailed understanding of the role of platelets in TIC. The objective of this study was to assess trauma patient ex vivo flow-dependent platelet hemostatic capacity in a microfluidic model. We hypothesized that trauma patients would have flow-regime dependent alterations in platelet function. Blood was collected from trauma patients with level I activations (N = 34) within 60 min of hospital arrival, as well as healthy volunteer controls (N = 10). Samples were perfused through a microfluidic model of injury at venous and arterial shear rates, and a subset of experiments were performed after incubation with fluorescent anti-CD41 to quantify platelets. Complete blood counts were performed as well as plasma-based assays to quantify coagulation times, fibrinogen, and von Willebrand factor (VWF). Exploratory correlation analyses were employed to identify relationships with microfluidic hemostatic parameters. Trauma patients had increased microfluidic bleeding times compared to healthy controls. While trauma patient samples were able to deposit a substantial amount of clot in the model injury site, the platelet contribution to microfluidic hemostasis was attenuated. Trauma patients had largely normal hematology and plasma-based coagulation times, yet had elevated D-Dimer and VWF. Venous microfluidic bleeding time negatively correlated with VWF, D-Dimer, and mean platelet volume (MPV), while arterial microfluidic bleeding time positively correlated with oxygenation. Arterial clot growth rate negatively correlated with red cell count, and positively with mean corpuscular volume (MCV). We observed changes in clot composition in trauma patient samples reflected by significantly diminished platelet contribution, which resulted in reduced hemostatic function in a microfluidic model of vessel injury. We observed a reduction in platelet clot contribution under both venous and arterial flow ex vivo in trauma patient samples. While our population was heterogenous and had relatively mild injury severity, microfluidic hemostatic parameters correlated with different patient-specific data depending on the flow setting, indicating potentially differential mechanistic pathways contributing to platelet hemostatic capacity in the context of TIC. These data were generated with the goal of identifying key features of platelet dysfunction in bleeding trauma patients under conditions of flow and to determine if these features correlate with clinically available metrics, thus providing preliminary surrogate markers of physiological platelet dysfunction to be further studied across larger cohorts. Future studies will continue to explore those relationships and further define mechanisms of TIC and their relationship with patient outcomes.

BACKGROUND: Platelet (PLT) product transfusion is a life-saving therapy for actively bleeding patients. There is an urgent need to maintain PLT function and extend shelf life to improve outcomes in these patients. Cold-stored PLT (CS-PLT) maintain hemostatic potential better than room temperature-stored PLT (RT-PLT). However, whether function in long-term CS-PLT is maintained under physiological flow regimes and/or determined by cold-induced metabolic changes is unknown.

OBJECTIVES: This study aimed to (i) compare the function of RT-PLT and CS-PLT under physiological flow conditions, (ii) determine whether CS-PLT maintain function after 3 weeks of storage, and (iii) identify metabolic pathways associated with the CS-PLT lesion.

METHODS: We performed phenotypic and functional assessments of RT- and CS-PLT (22 °C and 4 °C storage, respectively; N = 10 unique donors) at storage days 0, 5, and/or 21 via metabolomics, flow cytometry, aggregation, thrombin generation, viscoelastic testing, and a microfluidic assay to measure primary hemostatic function.

RESULTS: Day 21 4 °C PLT formed an occlusive thrombus under arterial shear at a similar rate to day 5 22 °C PLT. Day 21 4 °C PLTs had enhanced thrombin generation capacity compared with day 0 PLT and maintained functionality comparable to day RT-PLT across all assays performed. Key metrics from microfluidic assessment, flow cytometry, thrombin generation, and aggregation were associated with 4 °C storage, and metabolites involved in taurine and purine metabolism significantly correlated with these metrics. Taurine supplementation of PLT during storage improved hemostatic function under flow.

CONCLUSION: CS-PLT stored for 3 weeks maintain hemostatic activity, and storage-induced phenotype and function are associated with taurine and purine metabolism.

BACKGROUND: Thrombosis within extracorporeal membrane oxygenation (ECMO) circuits is a common complication that dominates clinical management of patients receiving mechanical circulatory support. Prior studies have identified that over 80% of circuit thrombosis can be attributed to tubing-connector junctions.

METHODS: A novel connector was designed that reduces local regions of flow stagnation at the tubing-connector junction to eliminate a primary source of ECMO circuit thrombi. To compare clotting between the novel connectors and the traditional connectors, both in vitro loops and an in vivo caprine model of long-term (48 h) ECMO were used to generate tubing-connector junction clots.

RESULTS: In vitro, the traditional connectors uniformly (9/9) formed large thrombi, while novel connectors formed a small thrombus in only one of nine (p < 0.0001). In the long-term goat ECMO circuits, the traditional connectors exhibited more thrombi (p < 0.04), and these thrombi were more likely to protrude into the lumen of the tubing (p < 0.001).

CONCLUSION: Both in vitro and in vivo validation experiments successfully recreated circuit thrombosis and demonstrate that the adoption of novel connectors can reduce the burden of circuit thrombosis.

Here, we present a series of illustrated capsules from the State of the Art (SOA) speakers at the 2024 International Society on Thrombosis and Haemostasis Congress in Bangkok, Thailand. This year's Congress marks the first time that the International Society on Thrombosis and Haemostasis has held its flagship scientific meeting in Southeast Asia and is the first to be organized by an international Planning Committee. The Bangkok program will feature innovative science and clinical updates from around the world, reflecting the diversity and multidisciplinary growth of our field. In these illustrated SOA capsules, you will find an exploration of novel models of thrombosis and bleeding and biomaterial discoveries that can trigger or block coagulation. Thromboinflammation is now understood to drive many disease states, and the SOA speakers cover cellular and coagulation responses to COVID-19 and other infections. The theme of crosstalk between coagulation and inflammation expands with capsules on protein S signaling, complement, and fibrinolytic inhibitors. Novel agents for hemophilia and thrombosis prevention are introduced. Challenging clinical conditions are also covered, such as inherited platelet disorders and antiphospholipid antibody syndrome. The scientific program in Bangkok will also showcase the work of clinicians and scientists from all parts of the world and chronicle real-world challenges. For example, 2 SOA capsules address the diagnosis and management of von Willebrand disease in low-income settings. Take some time to browse through these short illustrated reviews; we're sure that you'll be entertained, educated, and inspired to further explore the world of thrombosis and hemostasis.

OBJECTIVE: To determine the feasibility, efficacy, and safety of early cold stored platelet transfusion compared with standard care resuscitation in patients with hemorrhagic shock.

BACKGROUND: Data demonstrating the safety and efficacy of early cold stored platelet transfusion are lacking following severe injury.

METHODS: A phase 2, multicenter, randomized, open label, clinical trial was performed at 5 US trauma centers. Injured patients at risk of large volume blood transfusion and the need for hemorrhage control procedures were enrolled and randomized. The intervention was the early transfusion of a single apheresis cold stored platelet unit, stored for up to 14 days versus standard care resuscitation. The primary outcome was feasibility and the principal clinical outcome for efficacy and safety was 24-hour mortality.

RESULTS: Mortality at 24 hours was 5.9% in patients who were randomized to early cold stored platelet transfusion compared with 10.2% in the standard care arm (difference, -4.3%; 95% CI, -12.8% to 3.5%; P =0.26). No significant differences were found for any of the prespecified ancillary outcomes. Rates of arterial and/or venous thromboembolism and adverse events did not differ across treatment groups.

CONCLUSIONS AND RELEVANCE: In severely injured patients, early cold stored platelet transfusion is feasible, safe and did not result in a significant lower rate of 24-hour mortality. Early cold stored platelet transfusion did not result in a higher incidence of arterial and/or venous thrombotic complications or adverse events. The storage age of the cold stored platelet product was not associated with significant outcome differences.

TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04667468.

INTRODUCTION: Recent randomized clinical trials have demonstrated that prehospital tranexamic acid (TXA) administration following injury is safe and improves survival. However, the effect of prehospital TXA on adverse events, transfusion requirements, and any dose-response relationships require further elucidation.

METHODS: A secondary analysis was performed using harmonized data from two large, double-blinded, randomized prehospital TXA trials. Outcomes, including 28-day mortality, pertinent adverse events, and 24-hour red cell transfusion requirements, were compared between TXA and placebo groups. Regression analyses were used to determine the independent associations of TXA after adjusting for study enrollment, injury characteristics, and shock severity across a broad spectrum of injured patients. Dose-response relationships were similarly characterized based upon grams of prehospital TXA administered.

RESULTS: A total of 1,744 patients had data available for secondary analysis and were included in the current harmonized secondary analysis. The study cohort had an overall mortality of 11.2% and a median Injury Severity Score of 16 (interquartile range, 5-26). Tranexamic acid was independently associated with a lower risk of 28-day mortality (hazard ratio, 0.72; 95% confidence interval [CI], 0.54-0.96; p = 0.03). Prehospital TXA also demonstrated an independent 22% lower risk of mortality for every gram of prehospital TXA administered (hazard ratio, 0.78; 95% CI, 0.63-0.96; p = 0.02). Multivariable linear regression verified that patients who received TXA were independently associated with lower 24-hour red cell transfusion requirements ( β= - 0.31; 95% CI, -0.61 to -0.01; p = 0.04) with a dose-response relationship ( β= - 0.24; 95% CI, -0.45 to -0.02; p = 0.03). There was no independent association of prehospital TXA administration on thromboembolism, seizure, or stroke.

CONCLUSION: In this secondary analysis of harmonized data from two large randomized interventional trials, prehospital TXA administration across a broad spectrum of injured patients is safe. Prehospital TXA is associated with a significant 28-day survival benefit and lower red cell transfusion requirements at 24 hours and demonstrates a dose-response relationship.

LEVEL OF EVIDENCE: Therapeutic/Care Management; Level III.

BACKGROUND: Some studies in both children and adults have shown a mortality benefit for the use of low titer group O whole blood (LTOWB) compared with component therapy for traumatic resuscitation. Although LTOWB is not widely available at pediatric trauma centers, its use is increasing. We hypothesized that in children who received whole blood after injury, the proportion of whole blood in relation to the total blood product resuscitation volume would impact survival.

METHODS: The trauma database from a single academic pediatric Level I trauma center was queried for pediatric (age <18 years) recipients of LTOWB after injury (years 2015-2022). Weight-based blood product (LTOWB, red blood cells, plasma, and platelet) transfusion volumes during the first 24 hours of admission were recorded. The ratio of LTOWB to total transfusion volume was calculated. The primary outcome was in-hospital mortality. Multivariable logistic regression model adjusted for the following variables: age, sex, mechanism of injury, Injury Severity Score, shock index, and Glasgow Coma Scale score. Adjusted odds ratio representing the change in the odds of mortality by a 10% increase in the LTOWB/total transfusion volume ratio was reported.

RESULTS: There were 95 pediatric LTOWB recipients included in the analysis, with median (interquartile range [IQR]) age of 10 years (5-14 years), 58% male, median (IQR) Injury Severity Score of 26 (17-35), 25% penetrating mechanism. The median (IQR) volume of LTOWB transfused was 17 mL/kg (15-35 mL/kg). Low titer group O whole blood comprised a median (IQR) of 59% (33-100%) of the total blood product resuscitation. Among patients who received LTOWB, there was a 38% decrease in in-hospital mortality for each 10% increase in the proportion of WB within total transfusion volume ( p < 0.001) after adjusting for age, sex, mechanism of injury, Injury Severity Score, shock index, and Glasgow Coma Scale score.

CONCLUSION: Increased proportions of LTOWB within the total blood product resuscitation was independently associated with survival in injured children. Based on existing data that suggests safety and improved outcomes with whole blood, consideration may be given to increasing the use of LTOWB over CT resuscitation in pediatric trauma resuscitation.

LEVEL OF EVIDENCE: Therapeutic/Care Management; Level III.

OBJECTIVE: To determine the feasibility, efficacy, and safety of early cold stored platelet transfusion compared with standard care resuscitation in patients with hemorrhagic shock.

BACKGROUND: Data demonstrating the safety and efficacy of early cold stored platelet transfusion are lacking following severe injury.

METHODS: A phase 2, multicenter, randomized, open label, clinical trial was performed at 5 US trauma centers. Injured patients at risk of large volume blood transfusion and the need for hemorrhage control procedures were enrolled and randomized. The intervention was the early transfusion of a single apheresis cold stored platelet unit, stored for up to 14 days versus standard care resuscitation. The primary outcome was feasibility and the principal clinical outcome for efficacy and safety was 24-hour mortality.

RESULTS: Mortality at 24 hours was 5.9% in patients who were randomized to early cold stored platelet transfusion compared with 10.2% in the standard care arm (difference, -4.3%; 95% CI, -12.8% to 3.5%; P =0.26). No significant differences were found for any of the prespecified ancillary outcomes. Rates of arterial and/or venous thromboembolism and adverse events did not differ across treatment groups.

CONCLUSIONS AND RELEVANCE: In severely injured patients, early cold stored platelet transfusion is feasible, safe and did not result in a significant lower rate of 24-hour mortality. Early cold stored platelet transfusion did not result in a higher incidence of arterial and/or venous thrombotic complications or adverse events. The storage age of the cold stored platelet product was not associated with significant outcome differences.

TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04667468.

Haemorrhagic shock is frequent in critical care settings and responsible for a high mortality rate due to multiple organ dysfunction and coagulopathy. The management of critically ill patients with bleeding and shock is complex, and treatment of these patients must be rapid and definitive. The administration of large volumes of blood components leads to major physiological alterations which must be mitigated during and after bleeding. Early recognition of bleeding and coagulopathy, understanding the underlying pathophysiology related to specific disease states, and the development of individualised management protocols are important for optimal outcomes. This review describes the contemporary understanding of the pathophysiology of various types of coagulopathic bleeding; the diagnosis and management of critically ill bleeding patients, including major haemorrhage protocols and post-transfusion management; and finally highlights recent areas of opportunity to better understand optimal management strategies for managing bleeding in the intensive care unit (ICU).