Inhibitors of Inorganic Polyphosphate and Nucleic Acids Attenuate in vitro Thrombin Generation in Plasma from Trauma Patients.

BACKGROUND: Inorganic polyphosphate (polyP) is a procoagulant polyanion. We assessed the impact of polyP inhibition on thrombin generation after trauma using the novel polyP antagonists, macromolecular polyanion inhibitor 8 (MPI 8) and universal heparin reversal agent 8 (UHRA-8). METHODS: Plasma thrombin generation (calibrated automated thrombogram, CAT), in 56 trauma patients and 39 controls +/- MPI 8 and UHRA-8 (50 µg/mL), was expressed as lag time (LT, minutes), peak height (PH, nM), and time to peak (ttPeak, minutes), with change in LT (ΔLT) and change in ttPeak (ΔttPeak) quantified. Results expressed in median and quartiles [Q1, Q3], Wilcoxon matched-pairs testing, p < 0.05 significant. RESULTS: Trauma patients had greater baseline PH than controls (182.9 [121.0, 255.2]; 120.5 [62.1, 174.8], p < 0.001). MPI 8 treatment prolonged LT and ttPeak in trauma (7.20 [5.88, 8.75]; 6.46 [5.45, 8.93], p = 0.020; 11.28 [8.96, 13.14]; 11.00 [8.95, 12.94], p = 0.029) and controls (7.67 [6.67, 10.50]; 6.33 [5.33, 8.00], p < 0.001; 13.33 [11.67, 15.33]; 11.67 [10.33, 13.33], p < 0.001). UHRA-8 treatment prolonged LT and ttPeak and decreased PH in trauma (9.09 [7.45, 11.33]; 6.46 [5.45, 8.93]; 14.02 [11.78, 17.08]; 11.00 [8.95, 12.94]; 117.4 [74.5, 178.6]; 182.9 [121.0, 255.2]) and controls (9.83 [8.00, 12.33]; 6.33 [5.33, 8.00]; 16.67 [14.33, 20.00]; 11.67 [10.33, 13.33]; 55.3 [30.2, 95.9]; 120.5 [62.1, 174.8]), all p < 0.001. Inhibitor effects were greater for controls (greater ΔLT and ΔttPeak for both inhibitors, p < 0.001). CONCLUSION: PolyP inhibition attenuates thrombin generation, though to a lesser degree in trauma than in controls, suggesting that polyP contributes to accelerated thrombin generation after trauma.

Size of Splenic Subcapsular Hematoma Is Associated With Varying Outcomes of Nonoperative Management.

The presence of a splenic subcapsular hematoma (SCH) has been associated with higher rates of failure of nonoperative management (FNOM) in patients with blunt splenic injury (BSI), with rates up to 80%. We hypothesized that contemporary rates are lower. A retrospective review was conducted of patients admitted with BSI to a level I trauma center (2016-2021). Patients with SCH who had FNOM were compared to those who did not. There were 661 BSI patients, of which 102 (15.4%) had SCH. Among the SCH patients, 8 (7.8%) had FNOM. Failure of nonoperative management was higher in patients who had a SCH measuring 15 mm or greater. To the best of our knowledge, this is the largest study to date examining the relationship between SCH and FNOM. The presence of a SCH alone is not associated with a high risk for FNOM contrary to previous literature. However, SCH thickness was larger in those who failed.

Community of trauma care partnering with stakeholders to improve injury outcomes: focus group analysis.

Introduction: Engaging trauma survivors/caregivers results in research findings that are more relevant to patients' needs and priorities. Although their perspectives increase research significance, there is a lack of understanding about how best to incorporate their insights. We aimed to capture stakeholder perspectives to ensure research is meaningful, respectful, and relevant to the injured patient and their caregivers. Methods: A multiphase, inductive exploratory qualitative study was performed, the first phase of which is described here. Virtual focus groups to elicit stakeholder perspectives and preferences were conducted across 19 trauma centers in the USA during 2022. Discussion topics were chosen to identify patients' motivation to join research studies, preferences regarding consent, suggestions for increasing diversity and access, and feelings regarding outcomes, efficacy, and exception from informed consent. The focus groups were audio recorded, transcribed, coded, and analyzed to identify the range of perspectives expressed and any common themes that emerged. Results: Ten 90-minute focus groups included patients/caregiver (n=21/1) and researchers (n=14). Data analysis identified common themes emerging across groups. The importance of trust and preexisting relationships with the clinical care team were the most common themes across all groups. Conclusion: Our findings reveal common themes in preferences, motivations, and best practices to increase patient/caregiver participation in trauma research. The project's next phases are distribution of a vignette-based survey to establish broad stakeholder consensus; education and dissemination activities to share strategies that increase research engagement and relevance for patients; and the formation of a panel of patients to support future research endeavors. Level of evidence: Level IV.

Circular RNA Cdr1as inhibits proliferation and delays injury-induced regeneration of the intestinal epithelium.

Circular RNAs (circRNAs) are highly expressed in the mammalian intestinal epithelium, but their functions remain largely unknown. Here, we identified the circRNA Cdr1as as a repressor of intestinal epithelial regeneration and defense. Cdr1as levels increased in mouse intestinal mucosa after colitis and septic stress, as well as in human intestinal mucosa from patients with inflammatory bowel disease and sepsis. Ablation of the Cdr1as locus from the mouse genome enhanced renewal of the intestinal mucosa, promoted injury-induced epithelial regeneration, and protected the mucosa against colitis. We found approximately 40 microRNAs, including miR-195, differentially expressed between intestinal mucosa of Cdr1as-knockout (Cdr1as-/-) versus littermate mice. Increasing the levels of Cdr1as inhibited intestinal epithelial repair after wounding in cultured cells and repressed growth of intestinal organoids cultured ex vivo, but this inhibition was abolished by miR-195 silencing. The reduction in miR-195 levels in the Cdr1as-/- intestinal epithelium was the result of reduced stability and processing of the precursor miR-195. These findings indicate that Cdr1as reduces proliferation and repair of the intestinal epithelium at least in part via interaction with miR-195 and highlight a role for induced Cdr1as in the pathogenesis of unhealed wounds and disrupted renewal of the intestinal mucosa.

A pseudo-dilemma: Are we over-diagnosing and over-treating traumatic splenic intraparenchymal pseudoaneurysms?

BACKGROUND: Splenic embolization for traumatic vascular abnormalities in stable patients is a common practice. We hypothesize that modern contrast-enhanced computed tomography (CT) over diagnoses posttraumatic splenic vascular lesions, such as intraparenchymal pseudoaneurysms (PSA) that may not require embolization. METHODS: We reviewed the experience at our high-volume center with endovascular management of blunt splenic injuries from January 2016 to December 2021. Multidisciplinary review was used to compared initial CT findings with subsequent angiography, analyzing management and outcomes of identified vascular lesions. RESULTS: Of 853 splenic injuries managed overall during the study period, 255 (29.9%) underwent angiography of the spleen at any point during hospitalization. Vascular lesions were identified on 58% of initial CTs; extravasation (12.2%) and PSA (51.0%). Angiography was performed a mean of 22 hours after admission, with 38% done within 6 hours. Embolization was performed for 90.5% (231) of patients. Among the 130 patients with PSA on initial CT, 36 (27.7%) had no visible lesion on subsequent angiogram. From the 125 individuals who did not have a PSA identified on their initial CT, 67 (54%) had a PSA seen on subsequent angiography. On postembolization CT at 48 hours to 72 hours, persistently perfused splenic PSAs were seen in 41.0% (48/117) of those with and 22.2% (2/9) without embolization. Only one of 24 (4.1%) patients with PSA on angiography observed without embolization required delayed splenectomy, whereas 6.9% (16/231) in the embolized group had splenectomy at a mean of 5.5 ± 4 days after admission. CONCLUSION: There is a high rate of discordance between CT and angiographic identification of splenic PSAs. Even when identified at angiogram and embolized, close to half will remain perfused on follow-up imaging. These findings question the use of routine angioembolization for all splenic PSAs. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level IV.

A murine multiple-injury model for the study of thromboinflammation.

INTRODUCTION: Neutrophil extracellular traps (NETs) contribute to trauma-induced coagulopathy. We aimed to develop a murine multiple-injury model that induces thrombo-inflammatory response, that is, NETosis and accelerated thrombin generation. METHODS: Wild-type male mice (n = 10, aged 8-12 weeks) underwent multiple injuries (gastrocnemius crush, femur fracture, and laparotomy) and were compared with an uninjured control group (n = 10). Mice were euthanized by cardiac puncture performed 3 hours after injury. Whole blood samples were immediately processed to platelet poor plasma for thrombin generation kinetics (calibrated automated thrombogram), myeloperoxidase (MPO), and von Willebrand factor quantification. Immunohistochemistry of lung tissue was performed to assess for citrullinated histone 3 (CitH3) and MPO. A NETosis cluster was defined as 3+ neutrophils staining for CitH3 at 400× magnification (CitH3 cluster). Data were presented either as mean (SD) or median (interquartile range) with p < 0.05 significant. Sham and trauma treated animals were compared by the two-sample Wilcoxon rank-sum test. RESULTS: Animals subjected to multiple injuries had accelerated thrombin generation compared with controls with greater peak height (61.3 [41.2-73.2] vs. 28.4 [19.5-37.5] nM, p = 0.035) and shorter time to peak (3.37 [2.81-3.81] vs. 4.5 [4.08-4.75] minutes, p = 0.046). Markers of neutrophil activation were greater following multiple injuries than in controls (MPO, 961.1 [858.1-1116.8] vs. 481.3 [438.0-648.9] ng/mL; p = 0.004). NETosis, as evidenced by the aforementioned defined number of CitH3 clusters in the lung, was greater in multiple-injury animals than in controls (mean [SD], 3 [2.9] vs. 0.2 [0.7]; p = 0.009). CONCLUSION: This is the first study to demonstrate that NETosis and accelerated thrombin generation can be induced using a murine multiple-injury model, as early as 3 hours following injury.

Injury-induced endotheliopathy: What you need to know.

ABSTRACT: The endotheliopathy of trauma involves a complex interplay between the glycocalyx, von Willebrand factor, and platelets that leads to abnormalities in coagulation, inflammation, and endothelial cell (EC) function. The current review presents a synopsis of EC function under homeostatic conditions, the structure and function of the endothelial glycocalyx; mechanisms of EC injury and activation after trauma; pathological consequences of the EoT at the cellular level; and clinical implications of the EoT. Recent evidence is presented that links the EoT to extracellular vesicles and hyperadhesive ultralarge von Willebrand factor multimers through their roles in coagulopathy. Lastly, potential therapeutics to mitigate the EoT are discussed. Most research to date has focused on blood products, primarily plasma, and its contribution to restoring postinjury EC dysfunction. Additional therapeutic adjuvants that target the glycocalyx, ultralarge von Willebrand factor, low ADAMTS-13, and pathologic extracellular vesicles are reviewed. Much of the pathobiology of EoT is known, but a better mechanistic understanding can help guide therapeutics to further repair the EoT and improve patient outcomes.

Immediate use cryoprecipitate products provide lasting organ protection in a rodent model of trauma/hemorrhagic shock and prolonged hypotensive resuscitation.

BACKGROUND: Cryoprecipitate (CP) can augment hemostasis after hemorrhagic shock (HS). Similar to fresh frozen plasma (FFP), CP may provide short-term endothelial protection. We tested a new 5-day postthaw CP (5-day pathogen-reduced cryoprecipitate [5PRC]) and lyophilized pathogen-reduced cryoprecipitate (LPRC) to overcome challenges of early administration and hypothesized that 5PRC and LPRC would provide lasting organ protection in a rodent model of HS. METHODS: Mice underwent trauma/HS (laparotomy then HS), mean arterial pressure (MAP) 35 × 90 minutes, and then 6 hours of hypotensive resuscitation (MAP, 55-60 mm Hg) with lactated Ringer's solution (LR), FFP, CP, 5PRC, or LPRC and compared with shams. Animals were followed for 72 hours. Organs and blood were collected. Data are presented as mean ± SD and analysis of variance with Bonferroni post hoc. RESULTS: Mean arterial pressure was comparable between experimental groups at baseline, preresuscitation, and 6 hours per protocol. However, volume needed to resuscitate to target MAP over 6 hours was less than half for CP, 5PRC, LPRC, and FFP compared with LR, suggesting that CP products can serve as effective resuscitative agents. Mean arterial pressure at 72 hours was also significantly higher in the CP, 5PRC, and FFP groups compared with LR. Resuscitation with CP, 5PRC, and LPRC provided lasting protection from gut injury and enhanced syndecan immunostaining comparable with FFP, while LR mice demonstrated persistent organ dysfunction. Sustained endothelial protection was demonstrated by lessened lung permeability, while cystatin C was an indicator of kidney function, and liver aspartate aminotransferase and alanine transaminase returned to sham levels in all groups. CONCLUSION: Cryoprecipitate products can provide lasting organ protection comparable with FFP in a sustained rodent model of trauma/HS and hypotensive resuscitation. The availability of 5PRC and LPRC will allow for investigation into the immediate use of cryoprecipitate for severely injured patients. As lyophilized products such as cryoprecipitate become available clinically, their use has important implications for prehospital, rural, and battlefield usage.

Extracellular RNA Sensing Mediates Inflammation and Organ Injury in a Murine Model of Polytrauma.

Severe traumatic injury leads to marked systemic inflammation and multiorgan injury. Endogenous drivers such as extracellular nucleic acid may play a role in mediating innate immune response and the downstream pathogenesis. Here, we explored the role of plasma extracellular RNA (exRNA) and its sensing mechanism in inflammation and organ injury in a murine model of polytrauma. We found that severe polytrauma-bone fracture, muscle crush injury, and bowel ischemia-induced a marked increase in plasma exRNA, systemic inflammation, and multiorgan injury in mice. Plasma RNA profiling with RNA sequencing in mice and humans revealed a dominant presence of miRNAs and marked differential expression of numerous miRNAs after severe trauma. Plasma exRNA isolated from trauma mice induced a dose-dependent cytokine production in macrophages, which was almost abolished in TLR7-deficient cells but unchanged in TLR3-deficient cells. Moreover, RNase or specific miRNA inhibitors against the selected proinflammatory miRNAs (i.e., miR-7a-5p, miR-142, let-7j, miR-802, and miR-146a-5p) abolished or attenuated trauma plasma exRNA-induced cytokine production, respectively. Bioinformatic analyses of a group of miRNAs based on cytokine readouts revealed that high uridine abundance (>40%) is a reliable predictor in miRNA mimic-induced cytokine and complement production. Finally, compared with the wild-type, TLR7-knockout mice had attenuated plasma cytokine storm and reduced lung and hepatic injury after polytrauma. These data suggest that endogenous plasma exRNA of severely injured mice and ex-miRNAs with high uridine abundance prove to be highly proinflammatory. TLR7 sensing of plasma exRNA and ex-miRNAs activates innate immune responses and plays a role in inflammation and organ injury after trauma.

Early lyophilized cryoprecipitate enhances the ADAMTS13/VWF ratio to reduce systemic endotheliopathy and lessen lung injury in a mouse multiple-trauma hemorrhage model.

BACKGROUND: Recent studies in severely injured patients suggest an important role of von Willebrand Factor (VWF) and ADAMTS13 in the endotheliopathy of trauma (EoT). We hypothesized that the early use of cryoprecipitate would be effective as an endothelial protector by supplementing physiologic VWF and ADAMTS13 to reverse the EoT. We tested a pathogen-reduced lyophilized cryoprecipitate (LPRC) that could expedite the early administration of cryoprecipitate in the battlefield. METHODS: A mouse multiple-trauma model with uncontrolled hemorrhage (UCH) from liver injury was utilized followed by hypotensive resuscitation (mean arterial pressure, 55-60) × 3 hours with lactated Ringer's (LR), fresh frozen plasma (FFP), conventional pathogen-reduced cryoprecipitate (CC), and LPRC. Blood was collected for measurement of syndecan-1, VWF, and ADAMTS13 by ELISA. Lungs were stained for histopathologic injury and syndecan-1 and bronchial alveolar lavage (BAL) fluid harvested for protein as an indicator of permeability. Statistical analysis was by ANOVA followed by Bonferroni correction. RESULTS: Following multiple trauma and UCH, blood loss was similar across groups. Mean volume of resuscitation was higher in the LR group compared with the other resuscitation groups. Lung histopathologic injury, syndecan-1 immunostaining and BAL protein were higher with LR compared with resuscitation with FFP and CC, while LPRC further reduced BAL compared with FFP and CC. The ADAMTS13/VWF ratio was significantly lower in LR but improved with FFP and CC, comparable to shams while LPRC further increased this ratio. CONCLUSION: The protective effects of CC and LPRC were comparable to FFP in ameliorating the EoT in our murine multiple trauma and UCH model. Lyophilized cryoprecipitate may also provide additional benefit by enhancing the ADAMTS13/VWF ratio. These data provide evidence of the safety and efficacy of LPRC and warrants further investigation for its potential application in military settings once approved for human administration.

Fibrinogen Inhibits Metalloproteinase-9 Activation and Syndecan-1 Cleavage to Protect Lung Function in ApoE Null Mice After Hemorrhagic Shock.

INTRODUCTION: Obesity is associated with higher mortality following trauma, although the pathogenesis is unclear. Both obesity and trauma are associated with syndecan-1 shedding and metalloproteinase-9 (MMP-9) activation, which can adversely affect endothelial cell function. We recently demonstrated that fibrinogen stabilizes endothelial cell surface syndecan-1 to reduce shedding and maintain endothelial barrier integrity. We thus hypothesized that MMP-9 activation and syndecan-1 shedding would be exacerbated by obesity after trauma but attenuated by fibrinogen-based resuscitation. MATERIALS AND METHODS: ApoE null (-/-) mice were fed a Western diet to induce obesity. Mice were subjected to hemorrhage shock and laparotomy then resuscitated with Lactated Ranger's (LR) or LR containing fibrinogen and compared to null and lean sham wild type mice. Mean arterial pressure (MAP) was monitored. Bronchial alveolar lavage protein as an indicator of permeability and lung histopathologic injury were assessed. Syndecan-1 protein and active MMP-9 protein were measured. RESULTS: MAP was similar between lean sham and ApoE-/- sham mice. However, following hemorrhage, ApoE-/- mice resuscitated with fibrinogen had significantly higher MAP than LR mice. Lung histopathologic injury and permeability were increased in LR compared to fibrinogen resuscitated animals. Compared with lean sham mice, both active MMP-9 and cleaved syndecan-1 level were significantly higher in ApoE-/- sham mice. Resuscitation with fibrinogen but not lactated Ringers largely reduced these changes. CONCLUSIONS: Fibrinogen as a resuscitative adjunct in ApoE-/- mice after hemorrhage shock augmented MAP and reduced histopathologic injury and lung permeability, suggesting fibrinogen protects the endothelium by inhibiting MMP-9-mediated syndecan-1 cleavage in obese mice.

Contemporary management and outcomes of penetrating colon injuries: Validation of the 2020 AAST Colon Organ Injury Scale.

INTRODUCTION: The American Association for the Surgery of Trauma Colon Organ Injury Scale (OIS) was updated in 2020 to include a separate OIS for penetrating colon injuries and included imaging criteria. In this multicenter study, we describe the contemporary management and outcomes of penetrating colon injuries and hypothesize that the 2020 OIS system correlates with operative management, complications, and outcomes. METHODS: This was a retrospective study of patients presenting to 12 Level 1 trauma centers between 2016 and 2020 with penetrating colon injuries and Abbreviated Injury Scale score of <3 in other body regions. We assessed the association of the new OIS with surgical management and clinical outcomes and the association of OIS imaging criteria with operative criteria. Bivariate analysis was done with χ 2 , analysis of variance, and Kruskal-Wallis, where appropriate. Multivariable models were constructed in a stepwise selection fashion. RESULTS: We identified 573 patients with penetrating colon injuries. Patients were young and predominantly male; 79% suffered a gunshot injury, 11% had a grade V destructive injury, 19% required ≥6 U of transfusion, 24% had an Injury Severity Score of >15, and 42% had moderate-to-large contamination. Higher OIS was independently associated with a lower likelihood of primary repair, higher likelihood of resection with anastomosis and/or diversion, need for damage-control laparotomy, and higher incidence of abscess, wound infection, extra-abdominal infections, acute kidney injury, and lung injury. Damage control was independently associated with diversion and intra-abdominal and extra-abdominal infections. Preoperative imaging in 152 (27%) cases had a low correlation with operative findings ( κ coefficient, 0.13). CONCLUSION: This is the largest study to date of penetrating colon injuries and the first multicenter validation of the new OIS specific to these injuries. While imaging criteria alone lacked strong predictive value, operative American Association for the Surgery of Trauma OIS colon grade strongly predicted type of interventions and outcomes, supporting use of this grading scale for research and clinical practice. LEVEL OF EVIDENCE: Prognostic and Epidemiological; Level III.

Time to Splenic Angioembolization Does Not Impact Splenic Salvage Rates.

We aimed to determine whether early (<6 hours) vs delayed (≥6 hours) splenic angioembolization (SAE) after blunt splenic trauma (grades II-V) impacted splenic salvage rates at a level I trauma center (2016-2021). The primary outcome was delayed splenectomy by timing of SAE. Mean time of SAE was determined for those who failed vs those who had successful splenic salvage. We retrospectively identified 226 individuals, from which 76 (33.6%) were in the early group and 150 (66.4%) were in the delayed group. The early group had higher AAST grade, greater amount of hemoperitoneum on CT, and 3.9x greater odds of undergoing delayed splenectomy (P = .046). Time to embolization was shorter in the group that failed splenic salvage (5 vs 10 hours, P = .051). On multivariate analysis, timing of SAE had no effect on splenic salvage. This study supports performing SAE on an urgent rather than emergent basis in stable patients after blunt splenic injury.

A Cautionary Tale: The Use of Propensity Matching to Evaluate Hemorrhage-Related Trauma Mortality in the American College of Surgeons TQIP Database.

BACKGROUND: Propensity-matched methods are increasingly being applied to the American College of Surgeons TQIP database to evaluate hemorrhage control interventions. We used variation in systolic blood pressure (SBP) to demonstrate flaws in this approach. STUDY DESIGN: Patients were divided into groups based on initial SBP (iSBP) and SBP at 1 hour (2017 to 2019). Groups were defined as follows: iSBP 90 mmHg or less who decompensated to 60 mmHg or less (immediate decompensation [ID]), iSBP 90 mmHg or less who remained greater than 60 mmHg (stable hypotension [SH]), and iSBP greater than 90 mmHg who decompensated to 60 mmHg or less (delayed decompensation [DD]). Individuals with Head or Spine Abbreviated Injury Scale score 3 or greater were excluded. Propensity score was assigned using demographic and clinical variables. Outcomes of interest were in-hospital mortality, emergency department death, and overall length of stay. RESULTS: Propensity matching yielded 4,640 patients per group in analysis #1 (SH vs DD) and 5,250 patients per group in analysis #2 (SH vs ID). The DD and ID groups had 2-fold higher in-hospital mortality than the SH group (DD 30% vs 15%, p < 0.001; ID 41% vs 18%, p < 0.001). Emergency department death rate was 3 times higher in the DD group and 5 times higher in the ID group (p < 0.001), and length of stay was 4 days shorter in the DD group and 1 day shorter in the ID group (p < 0.001). Odds of death were 2.6 times higher for the DD vs SH group and 3.2 times higher for the ID vs SH group (p < 0.001). CONCLUSIONS: Differences in mortality rate by SBP variation underscore the difficulty of identifying individuals with a similar degree of hemorrhagic shock using the American College of Surgeons TQIP database despite propensity matching. Large databases lack the detailed data needed to rigorously evaluate hemorrhage control interventions.

Surveillance Imaging Associated With Delayed Splenectomy in High-Grade Blunt Splenic Trauma.

This retrospective, single-site study at a level I trauma center (2016-2021) sought to determine whether repeat CT had an impact on clinical decision making after splenic angioembolization following blunt splenic trauma (grades II-V). The primary outcome was need for intervention after subsequent imaging (defined as angioembolization and/or splenectomy) by high- or low-grade injury. Of the 400 individuals examined, 78 (19.5%) underwent intervention after repeat CT, from which 17% were in the low-grade group (grades II and III) and 22% were in the high-grade group (grades IV and V). Individuals in the high-grade group were 3.6 times more likely to undergo delayed splenectomy than those in the low-grade group (P = .006). Delayed intervention after surveillance imaging in blunt splenic injury is driven mostly by the identification of new vascular lesions and leads to greater rates of splenectomy in high-grade injuries. Surveillance imaging should be considered for all AAST injury grades II or higher.

Raising the bar on fibrinogen: a retrospective assessment of critical hypofibrinogenemia in severely injured trauma patients.

Objectives: Fibrinogen depletion may occur at higher levels than historically referenced. We evaluated hypofibrinogenemia and associated mortality and multiple organ failure (MOF) after severe injury. Methods: Retrospective investigation including 417 adult patients with Injury Severity Score (ISS) >15. Demographics and injury characteristics were collected. Fibrinogen within 30 minutes of admission was described: <150 mg/dL, 150 mg/dL to 200 mg/dL and >200 mg/dL. Primary outcome: 28-day mortality. Secondary outcomes: 28-day MOF and blood product transfusion. Multivariable logistic regression model evaluated association of fibrinogen categories on risk of death, after controlling for confounding variables. Results presented as OR and 95% CIs. Results: Fibrinogen <150 mg/dL: 4.8%, 150 mg/dL to 200 mg/dL: 18.2%, >200 mg/dL: 77.0%. 28-day mortality: 15.6%. Patients with <150 mg/dL fibrinogen had over fourfold increased 28-day mortality risk (OR: 4.9, 95% CI 1.53 to 15.7) after adjusting for age, ISS and admission Glasgow Coma Scale. Patients with lower fibrinogen were more likely to develop MOF (p=0.04) and receive larger red blood cell transfusion volumes at 3 hours and 24 hours (p<0.01). Conclusions: Fibrinogen <150 mg/dL is significantly associated with increased 28-day mortality. Patients with fibrinogen <150 mg/dL were more likely to develop MOF and required increased administration of blood products. The optimal threshold for critically low fibrinogen, the association with MOF and subsequent fibrinogen replacement requires further investigation. Level of evidence: Level III.