A novel method to quantify fibrin-fibrin and fibrin-α2-antiplasmin cross-links in thrombi formed from human trauma patient plasma.

BACKGROUND: The widespread use of the antifibrinolytic agent, tranexamic acid (TXA), interferes with the quantification of fibrinolysis by dynamic laboratory assays such as clot lysis, making it difficult to measure fibrinolysis in many trauma patients. At the final stage of coagulation, factor (F)XIIIa catalyzes the formation of fibrin-fibrin and fibrin-α2-antiplasmin (α2AP) cross-links, which increases clot mechanical strength and resistance to fibrinolysis. OBJECTIVES: Here, we developed a method to quantify fibrin-fibrin and fibrin-α2AP cross-links that avoids the challenges posed by TXA in determining fibrinolytic resistance in conventional assays. METHODS: Fibrinogen alpha (FGA) chain (FGA-FGA), fibrinogen gamma (FGG) chain (FGG-FGG), and FGA-α2AP cross-links were quantified using liquid chromatography-mass spectrometry (LC-MS) and parallel reaction monitoring in paired plasma samples from trauma patients prefibrinogen and postfibrinogen replacement. Differences in the abundance of cross-links in trauma patients receiving cryoprecipitate (cryo) or fibrinogen concentrate (Fg-C) were analyzed. RESULTS: The abundance of cross-links was significantly increased in trauma patients postcryo, but not Fg-C transfusion (P < .0001). The abundance of cross-links was positively correlated with the toughness of individual fibrin fibers, the peak thrombin concentration, and FXIII antigen (P < .05). CONCLUSION: We have developed a novel method that allows us to quantify fibrin cross-links in trauma patients who have received TXA, providing an indirect measure of fibrinolytic resistance. Using this novel approach, we have avoided the effect of TXA and shown that cryo increases fibrin-fibrin and fibrin-α2AP cross-linking when compared with Fg-C, highlighting the importance of FXIII in clot formation and stability in trauma patients.

Fibrinogen levels in severe trauma: A preliminary comparison of Clauss Fibrinogen, ROTEM Sigma, ROTEM Delta and TEG 6s assays from the FEISTY pilot randomised clinical trial.

OBJECTIVE: To describe the relationships between different methods of measuring functional fibrinogen levels in severely injured, bleeding trauma patients across multiple timepoints during hospitalisation. METHODS: In 100 adult trauma patients enrolled in the FEISTY pilot randomised clinical trial at four tertiary trauma centres in Australia, blood samples were collected prospectively. Consistency of agreement was calculated, comparing functional fibrinogen levels measured by four methods - ROTEM® Delta and Sigma FIBTEM A5, TEG® 6s CFF MA, and gold-standard Clauss Fibrinogen. RESULTS: Comparing the ROTEM® Delta and new-generation ROTEM® Sigma machine, consistency of agreement for FIBTEM A5, measured by calculating intraclass correlation coefficients (ICCs), was ≥0.73 across all analysed timepoints, with mean differences (Sigma minus Delta) of 0.10-3.57 mm. Corresponding values comparing the ROTEM® Sigma FIBTEM A5 and TEG® 6s CFF MA were ICC = 0.55-0.82 and ICC = 4.69-7.97 (CFF MA minus A5). Comparing ROTEM® Sigma FIBTEM A5 and Clauss Fibrinogen Analysis (CFA), among statistically significant simple linear regression models, R2 was 0.25-0.67, and comparing TEG® 6s CFF MA and CFA (CFA) 0.65-0.82, although not all differences were significant with the latter comparison. Relationships across all timepoints combined were Clauss Fibrinogen (CF) (g/L) = 0.21𝑥 + 0.004 (where 𝑥 = ROTEM® Sigma FIBTEM A5 in mm) and (g/L) = 0.16𝑥 - 0.06 (where 𝑥 = TEG® 6s CFF MA in mm). CONCLUSIONS: The present study revealed acceptable agreement between four different assays measuring functional fibrinogen, with current- and previous-generation ROTEM® machines (Sigma, Delta) performing similarly measuring functional fibrinogen via FIBTEM assay. This suggests that haemostatic resuscitation algorithms designed for the ROTEM® Delta can be applied to the ROTEM® Sigma to guide fibrinogen replacement.

Patient blood management guideline for adults with critical bleeding.

INTRODUCTION: The management of patients with critical bleeding requires a multidisciplinary approach to achieve haemostasis, optimise physiology, and guide blood component use. The 2011 Patient blood management guidelines: module 1 - critical bleeding/massive transfusion were updated and published. Systematic reviews were conducted for pre-specified research questions, and recommendations were based on meta-analyses of included studies. MAIN RECOMMENDATIONS: The critical bleeding/massive transfusion guideline includes seven recommendations and 11 good practice statements addressing: major haemorrhage protocols (MHPs) facilitating a multidisciplinary approach to haemorrhage control, correction of coagulopathy and normalisation of physiological derangement; measurement of physiological, biochemical and metabolic parameters in critical bleeding/massive transfusion; the optimal ratio of red blood cells to other blood components; the use of tranexamic acid; viscoelastic haemostatic assays; and cell salvage. CHANGES IN MANAGEMENT AS A RESULT OF THE GUIDELINE: The new guideline recommends MHPs be established as standard of care in all institutions managing patients with critical bleeding. In addition to routine physiological markers, the new guideline recommends temperature, biochemistry and coagulation profiles be measured early and frequently, providing parameters that define critical derangements. Ratio-based MHPs should include no fewer than four units of fresh frozen plasma and one adult unit of platelets for every eight units of red blood cells. In the setting of trauma and obstetric haemorrhage, administration of tranexamic acid within three hours of bleeding onset is recommended. The use of recombinant activated factor VII (rFVIIa) is not recommended. There was insufficient evidence to make recommendations on the use of viscoelastic haemostatic assays or cell salvage as part of MHPs.

Hemostatic Profiles of Patients Who Underwent Transcatheter Versus Surgical Aortic Valve Replacement Versus Percutaneous Coronary Intervention.

Guidelines for transcatheter aortic valve replacement (TAVR) antithrombotic prophylaxis are extrapolated predominantly from percutaneous coronary intervention (PCI) data. Here, we examined temporal coagulation changes occurring in the early perioperative period to determine the pathobiologic validity of this supposition. This was a prospective observational study of consecutive patients who underwent transfemoral TAVR (n = 27), PCI (n = 12), or surgical aortic valve replacement (SAVR) requiring cardiopulmonary bypass and cross-clamping (n = 12). Blood samples were taken at 4 time points: T1 (baseline), after general anesthesia or sedation; T2, after heparin administration; T3, at the end of the procedure; and T4, 6 hours after the procedure. The samples were assessed concurrently using standard laboratory coagulation tests and viscoelastic tests of whole blood clotting, including the latest generation thromboelastometry (ROTEM sigma) and thromboelastometry (TEG 6s). Patients in the TAVR cohort were older and a had lower baseline hemoglobin level than patients in the PCI and SAVR cohorts. The baseline platelet function was similar between the TAVR and PCI cohorts and impaired in the SAVR cohort Figure S1. The baseline hemostatic measures were comparable among cohorts. Regarding the per-patient change from baseline, the TAVR cohort showed an overall more prothrombotic state than the other cohorts, with the most marked differences from the SAVR cohort after intraoperative heparin administration and from the PCI cohorts 6 hours after the procedure. In addition, the ROTEM and TEG parameters were well correlated but not interchangeable. In conclusion, patients who underwent TAVR have a more prothrombotic hemostatic profile than PCI and SAVR patients. These findings question the current guidelines that extrapolate antithrombotic regimens from PCI to TAVR settings.

Rotational thromboelastometry values across age groups in all trauma patients presenting to a level 1 trauma centre: An observational study.

OBJECTIVES: To describe rotational thromboelastometry (ROTEM) values (FIBTEM A5, EXTEM A5 and EXTEM CT) across age groups and assess for a statistical trend; and to determine whether any trend in ROTEM values is affected by severity of injury and packed red blood cells (PRBC) requirement. METHODS: Retrospective observational study at a level 1 trauma centre in Queensland, Australia. A total of 1601 consecutive trauma patients presenting to the ED. ROTEM data described included FIBTEM A5, EXTEM A5 and EXTEM CT. These values are described by age group (≤30 years, 31-45 years, 46-60 years, 61-75 years and >75 years), Injury Severity Score (ISS) category (<12, ≥12, <25 and ≥25) and number of PRBCs transfused in the first 24 h of admission (0 units, 1-4 units, 5-9 units and ≥10 units). RESULTS: The median age of participants was 37 years (interquartile range [IQR] 25-54 years), with 48.2% of patients had severe trauma (ISS >12) and 13.2% receiving at least one unit of PRBC in the first 24 h of admission. Median (IQR) values for FIBTEM A5, EXTEM A5 and EXTEM CT were 13 mm (10-16 mm), 45 mm (40-49 mm) and 62 s (56-71 s), respectively. A test for trend over progressive age groups showed an increase in FIBTEM A5 (P < 0.001) and EXTEM A5 values (P < 0.001) and a decrease in EXTEM CT values (P < 0.001). CONCLUSION: The present study demonstrated a pattern of increasing coagulability, as defined by ROTEM, with increasing age group in trauma patients, even among the severely injured. Further investigation is required to determine the clinical impact of these findings on both the ROTEM-guided management and longitudinal outcomes of these patients and whether an age-specific approach is beneficial.

Venoarterial extracorporeal membrane oxygenation for cardiac support in human immunodeficiency virus-positive patients: a case report and review of a multicentre registry.

BACKGROUND: Human immunodeficiency virus (HIV) is associated with increased risk of heart failure via multiple mechanisms both in patients with and without access to highly active antiretroviral therapy (HAART). Limited information is available on outcomes among this population supported on Venoarterial Extracorporeal Membrane Oxygenation (VA ECMO), a form of temporary mechanical circulatory support. METHODS: We aimed to assess outcomes and complications among patients with HIV supported on VA ECMO reported to a multicentre registry and present a case report of a 32 year old male requiring VA ECMO for cardiogenic shock as a consequence of his untreated HIV and acquired immune deficiency syndrome (AIDS). A retrospective analysis of the Extracorporeal Life Support Organization (ELSO) registry data from 1989 to 2019 was performed in HIV patients supported on VA ECMO. RESULTS: 36 HIV positive patients were reported to the ELSO Database who received VA ECMO during the study period with known outcomes. 15 patients (41%) survived to discharge. No significant differences existed between survivors and non-survivors in demographic variables, duration of VA ECMO support or cardiac parameters. Inotrope and/or vasopressor requirement prior to or during VA ECMO support was associated with increased mortality. Survivors were more likely to develop circuit thrombosis. The patient presented was supported on VA ECMO for 14 days and was discharged from hospital day 85. CONCLUSIONS: A limited number of patients with HIV have been supported with VA ECMO and more data is required to ascertain the indications for ECMO in this population. HIV should not be considered an absolute contraindication to VA ECMO as they may have comparable outcomes to other patient groups requiring VA ECMO support.

Implementing and sustaining Point of Care ROTEM® into a trauma activation protocol for the management of patients with traumatic injury: A mixed-methods study.

BACKGROUND: Up to 40% of patients with traumatic injury experience critical bleeding, many requiring transfusion of blood products. International transfusion guidelines recommend the use of viscoelastic testing to guide blood product replacement. We implemented a Point of Care ROTEM® blood test for trauma patients who present and initiate a trauma activation. OBJECTIVES: The aim of this study was to undertake an evaluation of the implementation data to identify factors which helped and hindered this new practice. METHODS: A sequential mixed-methods design was conducted to evaluate intervention implementation. The intervention was designed with interprofessional collaboration and incorporated education and skills training supplemented with a decision aide. Patients aged ≥ 18 years who met the trauma activation criteria were included. Data collection occurred throughout the 21-month implementation period inclusive of initial roll out, maintenance and sustainability and include the number of ROTEM® blood tests taken and clinical characteristics of patients. Individual interviews were conducted with health professionals with experience of the intervention after the implementation period was complete. RESULTS: A total of 1570 eligible patients were included. The number of patients who had a ROTEM® blood test taken increased over time to 63%. The proportion of patients having a ROTEM® blood test obtained was higher for major trauma patients (n=162, 66.9%) who were admitted to the Intensive Care Unit. Regression analysis found trauma service presence on arrival and the sustainability phase of implementation increased the likelihood of having a ROTEM® taken. Qualitative data suggest that a more tailored approach to intervention implementation would assist with adoption. CONCLUSION: Implementation of new practice requires careful planning and should be undertaken with input from end-users. Continuous evaluation is necessary to support ongoing implementation and sustainability. To ensure effective implementation occurs, complex interventions need to be made workable and integrated in everyday health care practice.

Cryoprecipitate transfusion in trauma patients attenuates hyperfibrinolysis and restores normal clot structure and stability: Results from a laboratory sub-study of the FEISTY trial.

BACKGROUND: Fibrinogen is the first coagulation protein to reach critical levels during traumatic haemorrhage. This laboratory study compares paired plasma samples pre- and post-fibrinogen replacement from the Fibrinogen Early In Severe Trauma studY (FEISTY; NCT02745041). FEISTY is the first randomised controlled trial to compare the time to administration of cryoprecipitate (cryo) and fibrinogen concentrate (Fg-C; Riastap) in trauma patients. This study will determine differences in clot strength and fibrinolytic stability within individuals and between treatment arms. METHODS: Clot lysis, plasmin generation, atomic force microscopy and confocal microscopy were utilised to investigate clot strength and structure in FEISTY patient plasma. RESULTS: Fibrinogen concentration was significantly increased post-transfusion in both groups. The rate of plasmin generation was reduced 1.5-fold post-transfusion of cryo but remained unchanged with Fg-C transfusion. Plasminogen activator inhibitor 1 activity and antigen levels and Factor XIII antigen were increased post-treatment with cryo, but not Fg-C. Confocal microscopy analysis of fibrin clots revealed that cryo transfusion restored fibrin structure similar to those observed in control clots. In contrast, clots remained porous with stunted fibres after infusion with Fg-C. Cryo but not Fg-C treatment increased individual fibre toughness and stiffness. CONCLUSIONS: In summary, our data indicate that cryo transfusion restores key fibrinolytic regulators and limits plasmin generation to form stronger clots in an ex vivo laboratory study. This is the first study to investigate differences in clot stability and structure between cryo and Fg-C and demonstrates that the additional factors in cryo allow formation of a stronger and more stable clot.

Fibrinogen Early In Severe paediatric Trauma studY (FEISTY junior): protocol for a randomised controlled trial.

INTRODUCTION: Trauma causes 40% of child deaths in high-income countries, with haemorrhage being a leading contributor to death in this population. There is a growing recognition that fibrinogen and platelets play a major role in trauma-induced coagulopathy (TIC) but the exact physiological mechanisms are poorly understood. METHODS AND ANALYSIS: This is a prospective multicentre, open-label, randomised, two-arm parallel feasibility study conducted in the emergency departments, intensive care units and operating theatres of participating hospitals. Severely injured children, aged between 3 months and 18 years, presenting with traumatic haemorrhage requiring transfusion of blood products will be screened for inclusion.Sixty-eight patients will be recruited and will be allocated to fibrinogen replacement using fibrinogen concentrate (FC) or cryoprecipitate in a 1:1 ratio. Fibrinogen replacement will be administered to patients with a FIBTEM A5 of ≤10. All other aspects of the currently used rotational thromboelastometry-guided treatment algorithm and damage-control approach to trauma remain the same in both groups.The primary outcome is time to administration of fibrinogen replacement from time of identification of hypofibrinogenaemia. Clinical secondary outcomes and feasibility outcomes will also be analysed. ETHICS AND DISSEMINATION: This study has received ethical clearance from the Children's Health Queensland Human Research Ethics Committee (HREC/17/QRCH/78). Equipment and consumables for sample testing have been provided to the study by Haemoview Diagnostics, Werfen Australia and Haemonetics Australia. FC has been provided by CSL Behring, Australia. The funding bodies and industry partners have had no input into the design of the study, and will not be involved in the preparation or submission of the manuscript for publication.The use of viscoelastic haemostatic assays and early fibrinogen replacement has the potential to improve outcomes in paediatric trauma through earlier recognition of TIC. This in turn may reduce transfusion volumes and downstream complications and reduce the reliance on donor blood products such as cryoprecipitate.The use of FC has implications for regional and remote centres who would not routinely have access to cryoprecipitate but could store FC easily. Access to early fibrinogen replacement in these centres could make a significant impact and assist in closing the gap in trauma care available to residents of these communities.Outcomes of this study will be submitted for publication in peer-reviewed journals and submitted for presentation at national and international scientific fora. TRIAL REGISTRATION NUMBER: NCT03508141.

Rotational thromboelastometry in children presenting to an Australian major trauma centre: A retrospective cohort study.

OBJECTIVE: This retrospective cohort study aims to describe patterns of rotational thromboelastometry (ROTEM™) results in paediatric trauma following the implementation of a ROTEM-guided critical bleeding algorithm and major haemorrhage protocol (MHP). METHODS: This retrospective observational study was conducted in a tertiary trauma hospital in Queensland, Australia, where point-of-care ROTEM was introduced for paediatric patients in 2014. All children aged less than 18 years who had a ROTEM test during their presentation between January 2014 and December 2017 for a traumatic injury were included in the dataset. Other children with a record in the hospital's trauma registry in the same period were also screened for blood product usage. Data were collected for frequency of ROTEM testing, pathology and ROTEM results, blood product and antifibrinolytic use along with injury related data. Compliance with recommended treatment thresholds for detected coagulopathy was also reviewed. RESULTS: A total of 1039 children were listed in the trauma registry, including 167 children having a ROTEM test for trauma. Factors significantly associated with having a ROTEM test were older age, higher injury severity score (ISS >12) and penetrating injury. A result exceeding a treatment threshold was returned for 122 (73.1%) of 167 children, with hyperfibrinolysis identified in 88 (52.6%) of 167 and hypofibrinogenaemia identified in 54 (32.3%) of 167. Adherence with the recommended treatments for those children where a treatment threshold was exceeded was low in this cohort. CONCLUSION: The use of ROTEM-guided blood component replacement is an emerging practice in children for both traumatic and non-traumatic bleeding. Targeted replacement of identified coagulation defects guided by rapid point-of-care testing is an emerging alternative to fixed-ratio-based protocols. Further research is required to validate treatment thresholds in the paediatric population and further investigate the clinical outcomes for patients as a result of early correction of trauma-induced coagulopathy.

Trauma-induced coagulopathy: Mechanisms and clinical management.

INTRODUCTION: Trauma-induced coagulopathy (TIC) is a form of coagulopathy unique to trauma patients and is associated with increased mortality. The complexity and incomplete understanding of TIC have resulted in controversies regarding optimum management. This review aims to summarise the pathophysiology of TIC and appraise established and emerging advances in the management of TIC. METHODS: This narrative review is based on a literature search (MEDLINE database) completed in October 2020. Search terms used were "trauma induced coagulopathy", "coagulopathy of trauma", "trauma induced coagulopathy pathophysiology", "massive transfusion trauma induced coagulopathy", "viscoelastic assay trauma induced coagulopathy", "goal directed trauma induced coagulopathy and "fibrinogen trauma induced coagulopathy'. RESULTS: TIC is not a uniform phenotype but a spectrum ranging from thrombotic to bleeding phenotypes. Evidence for the management of TIC with tranexamic acid, massive transfusion protocols, viscoelastic haemostatic assays (VHAs), and coagulation factor and fibrinogen concentrates were evaluated. Although most trauma centres utilise fixed-ratio massive transfusion protocols, the "ideal" transfusion ratio of blood to blood products is still debated. While more centres are using VHAs to guide blood product replacement, there is no agreed VHA-based transfusion strategy. The use of VHA to quantify the functional contributions of individual components of coagulation may permit targeted treatment of TIC but remains controversial. CONCLUSION: A greater understanding of TIC, advances in point-of-care coagulation testing, and availability of coagulation factors and fibrinogen concentrates allows clinicians to employ a more goal-directed approach. Still, hospitals need to tailor their approaches according to available resources, provide training and establish local guidelines.

Substitution of ROTEM FIBTEM A5 for A10 in trauma: an observational study building a case for more rapid analysis of coagulopathy.

PURPOSE: Rotational thromboelastometry (ROTEM®) allows guided blood product resuscitation to correct trauma-induced coagulopathy in bleeding trauma patients. FIBTEM amplitude at 10 min (A10) has been widely used to identify hypofibrinogenaemia; locally a threshold of < 11 mm has guided fibrinogen replacement. Amplitude at 5 min (A5) carries an inherent time advantage. The primary aim was to explore the relationship between FIBTEM A5 and A10 in a trauma. Secondary aim was to investigate the use of A5 as a surrogate for A10 within a fibrinogen-replacement algorithm. METHODS: Retrospective observational cohort study of arrival ROTEM results from 1539 consecutive trauma patients at a Level 1 trauma centre in Australia. Consistency of agreement between FIBTEM A5 and A10 was assessed. A new fibrinogen replacement threshold was developed for A5 using the A5-A10 bias; this was clinically compared to the existing A10 threshold. RESULTS: FIBTEM A5 displayed excellent consistency of agreement with A10. Intraclass correlation coefficient = 0.972 (95% confidence interval [CI] 0.969-0.974). Bias of A5 to A10 was - 1.49 (95% CI 1.43-1.56) mm. 19.34% patients met the original local threshold of A10 < 11 mm; 19.28% patients met the new, bias-adjusted threshold of A5 < 10 mm. CONCLUSION: ROTEM FIBTEM A5 reliably predicts A10 in trauma. This further validates use of the A5 result over A10 allowing faster decision-making in time-critical resuscitation of trauma patients. A modification of -1 to the A10 threshold might be appropriate for use with the A5 value in trauma patients.

Diagnostic Sensitivity of Plasma Endothelin-1 for Cerebral Vasospasm After Subarachnoid Hemorrhage, a Multicentre Double-Blind Study.

The purpose of this study is to establish the diagnostic sensitivity of Endothelin-1 for risk stratification and screening of clinical vasospasm after subarachnoid hemorrhage.This is a multicentre, observational study, correlating daily blood Endothelin-1 with clinical variables. Binary logistic regression used to examine if Endothelin-1 levels could be used to predict clinical vasospasm. Bivariate modelling used to explore associations between patient characteristics and vasospasm. A Receiver Operating Curve used to explore cut-off values for Endothelin-1. Sensitivity and specificity was used to validate the cut-point found in the pilot study. A total of 96 patients were enrolled over two years. Median Endothelin-1 was higher for patients who experienced clinical vasospasm except for day-5, where median endothelin for patients without vasospasm was higher (3.6 IQR = 5.3), compared to patients with vasospasm (3.3 IQR = 8.5) although differences were not significant. The Receiver Operating Curve analysis confirmed that day-5 Endothelin-1 was not a good indicator of vasospasm, with an area under the curve of 0.506 (95% CI: 0.350-0.663, p = 0.938). The levels of Endothelin-1 in blood do not discriminate patients who may develop symptomatic vasospasm. The high variability in Endothelin-1 levels, aligns with the pathophysiological variability of most biomarkers, decreasing their ability to predict a clinical event.

Epidemiology of Massive Transfusion - A Common Intervention in Need of a Definition.

While massive transfusion (MT) recipients account for a small proportion of all transfused patients, they account for approximately 10% of blood products issued. Furthermore, MT events pose organizational and logistical challenges for health care providers, laboratory and transfusion services. Overall, the majority of MT events are to support major bleeding in surgical patients, trauma and gastrointestinal hemorrhage. The clinical context in which the bleeding event occurred, the number of blood products required, patient age and comorbidities are the most important predictors of outcomes for short- and long-term survival. These data are important to inform blood services, clinicians and health care providers in order to improve care and outcomes for patients with major bleeding. There is no standard accepted definition of MT, with most definitions based on number of blood components administered within a certain time-period or activation of MT protocol. The type of definition used has implications for the clinical characteristics of MT recipients included in epidemiological and interventional studies. In order to understand trends in incidence of MT, variation in blood utilization and patient outcomes, and to harmonize research outcomes, a standard and universally accepted definition of MT is urgently required.

Fibrinogen in traumatic haemorrhage.

PURPOSE OF REVIEW: Recent advances in the understanding of the pathophysiological processes associated with traumatic haemorrhage and trauma-induced coagulopathy (TIC) have resulted in improved outcomes for seriously injured trauma patients. However, a significant number of trauma patients still die from haemorrhage. This article reviews the role of fibrinogen in normal haemostasis, the effect of trauma and TIC on fibrinogen levels and current evidence for fibrinogen replacement in the management of traumatic haemorrhage. RECENT FINDINGS: Fibrinogen is usually the first factor to reach critically low levels in traumatic haemorrhage and hypofibrinogenaemia after severe trauma is associated with increased risk of massive transfusion and death. It is postulated that the early replacement of fibrinogen in severely injured trauma patients can improve outcomes. There is, however, a paucity of evidence to support this, and in addition, there is little evidence to support or refute the effects of cryoprecipitate or fibrinogen concentrate for fibrinogen replacement. SUMMARY: The important role fibrinogen plays in haemostasis and effective clot formation is clear. A number of pilot trials have investigated different strategies for fibrinogen replacement in severe trauma. These trials have formed the basis of several large-scale phase III trials, which, cumulatively will provide a firm evidence base to harmonise worldwide clinical management of severely injured trauma patients with major haemorrhage.

Fibrinogen Early In Severe Trauma studY (FEISTY): results from an Australian multicentre randomised controlled pilot trial.

Background: Haemorrhage is a major cause of death in severe trauma. Fibrinogen plays a critical role in maintaining haemostasis in traumatic haemorrhage, and early replacement using fibrinogen concentrate (FC) or cryoprecipitate (Cryo) is recommended by several international trauma guidelines. Limited evidence supports one product over the other, with widespread geographic and institutional variation in practice. Two previous trials have investigated the feasibility of rapid FC administration in severely injured trauma patients, with conflicting results. Objective: To compare the time to fibrinogen replacement using FC or Cryo in severely injured trauma patients with major haemorrhage and hypofibrinogenaemia. Design, setting, patients and interventions: A multicentre controlled pilot trial in which adult trauma patients with haemorrhage were randomly assigned (1:1) to receive FC or Cryo for fibrinogen replacement, guided by FIBTEM A5 (functional fibrinogen assessment at 5 minutes after clot formation, using rotational thromboelastometry). Main outcome measures: The primary outcome was time to commencement of fibrinogen replacement. Secondary outcomes included effects of the intervention on plasma fibrinogen levels and clinical outcomes including transfusion requirements and mortality. Results: Of the 100 randomly assigned patients, 62 were hypofibrinogenaemic and received the intervention (n = 37) or Cryo (n = 25). Median (interquartile range [IQR]) time to delivery of FC was 29 min (23-40 min) compared with 60 min (40-80 min) for Cryo (P = 0.0001). All 62 patients were hypofibrinogenaemic before receiving FC or Cryo (FC: median FIBTEM A5, 8 mm [IQR, 7-9 mm]; Cryo: median FIBTEM A5, 9 mm [IQR, 5-10 mm]). In the FC arm patients received a median of 3 g FC (IQR, 2-4 g), and in the Cryo arm patients received a median of 8 units of Cryo (IQR, 8-14 units). Restoration of fibrinogen levels was achieved in both arms after the intervention. Blood product transfusion, fluid resuscitation and thromboembolic complications were similar in both arms. Overall mortality was 15.3%, with more deaths in the FC arm. Conclusion: Fibrinogen replacement in severely injured trauma patients with major haemorrhage and hypofibrinogenaemia was achieved substantially faster using FC compared with Cryo. Fibrinogen levels increased appropriately using either product. The optimal method for replacing fibrinogen in traumatic haemorrhage is controversial. Our results will inform the design of a larger trial powered to assess patient-centred outcomes.

Implementation of point-of-care ROTEM® into a trauma major haemorrhage protocol: A before and after study.

OBJECTIVE: The aim of the present study was to assess transfusion practices with the implementation of a targeted viscoelastic haemostatic assay (VHA) (ROTEM®) guided coagulation management programme into a major haemorrhage protocol for trauma patients requiring ICU admission, starting from time of arrival in the ED. METHODS: This retrospective observational study was conducted in a major trauma centre in Australia. One hundred and sixty-two trauma patients admitted to the ICU between January 2013 and December 2015 with an Injury Severity Score ≥12 and who received blood products were included: 37 in the pre-group, 48 during implementation and 77 in post-group. The primary outcome was blood and blood product administration amounts. RESULTS: Packed red blood cell transfusion amounts did not significantly change post introduction of the ROTEM®. There was a significant increase in fibrinogen replacement between the pre- and post-groups (P < 0.001), accompanied by a reduction in the use of fresh frozen plasma (P < 0.001) and prothrombinex (P < 0.001). Platelet usage in the post-group was higher but not reaching statistical significance (P = 0.051). Post-implementation point-of-care ROTEM® testing was able to be performed in the ED in 94.8% of cases. CONCLUSION: Although there was no overall reduction of packed red blood cell usage, a change in the pattern of administration of other blood products was observed with the implementation of a targeted VHA (ROTEM®) guided coagulation management programme. Larger studies are needed to further define the role of early VHA testing to guide correction of trauma-induced coagulopathy and the effect on clinical outcomes.

Targeted cryoprecipitate transfusion in severe traumatic haemorrhage.

BACKGROUND: Severe traumatic haemorrhage is the leading cause of death in young adults. Trauma Induced Coagulopathy is a complex and multifactorial phenomenon associated with severe traumatic haemorrhage. Fibrinogen is one of the first coagulation factors to become depleted in TIC and evidence suggests that severely injured trauma patients with hypofibrinogenaemia have poor outcomes. It is postulated that early fibrinogen replacement can improve clinical outcomes. This study investigated cryoprecipitate transfusion in hyopfibrinogeneamic trauma patients. METHODS: This retrospective, single center, observational study investigated the use of cryoprecipitate in severely injured trauma patients admitted to an Australian Level I Trauma Centre. The primary outcome was time to administration of cryoprecipitate after identification of hypofibrinogenaemia using ROTEM (FIBTEM A5). Data collected included demographics, ISS, laboratory values of coagulation and blood product usage. RESULTS: 71 patients received cryoprecipitate with a median time of 61 minutes [IQR 37-93] from FIBTEM A5 result to initial cryoprecipitate administration. At 24 hours following admission to ED, Clauss Fibrinogen levels increased by 1.30g/L [IQR 0.45-1.85] and FIBTEM A5 assay increased by 8mm [IQR 3.0-11.3]. Changes in both variables were highly significant (p<0.001) and Clauss Fibrinogen versus FIBTEM A5 values showed moderate to strong correlation (R=0.75-0.80). CONCLUSION: This study demonstrated that early administration of cryoprecipitate was both feasible and efficacious in fibrinogen replacement in severe traumatic haemorrhage. High-level evidence supporting cryoprecipitate or fibrinogen concentrate replacement with regards to efficacy and feasibility is required to guide future clinical practice. This study provided baseline data to inform the design of further clinical trials investigating fibrinogen replacement in traumatic haemorrhage.

Viscoelastic haemostatic assays in aeromedical transport.

OBJECTIVE: To assess the feasibility of using rotational thromboelastometry (ROTEM®)-sigma and thromboelastography (TEG®)-6s viscoelastic point-of-care assays during rotary wing aeromedical transport, and to determine the reliability of the results obtained. METHODS: A single centre, prospective, observational, non-interventional feasibility study performed at Gold Coast University Hospital intensive care unit, and in a LifeFlight Retrieval Medicine operated Leonardo AW139 helicopter. Blood was collected from eight healthy volunteers on 18 April 2019 and all testing was performed on that day. Functions measured were ROTEM-sigma extrinsically activated thromboelastometry (EXTEM) clotting time (CT), EXTEM amplitude at 5 min after CT (A5) and fibrin-based extrinsically activated thromboelastometry (FIBTEM) A5, and TEG-6s Kaolin (CK) reaction time (R), functional fibrinogen (CFF) maximal amplitude (MA) and CFF amplitude at 10 min after R (A10). Differences between the results obtained in the helicopter and control results at Gold Coast University Hospital during flight and after flight, and also differences in control results over time up to 3 h were analysed. RESULTS: During flight both the ROTEM-sigma and TEG-6s devices failed to give reliable results. Post flight, the helicopter and control samples correlated well. Repeat testing of control samples at 1 and 3 h also revealed good correlation over time. CONCLUSION: It is feasible to reliably run tests on both the ROTEM-sigma and TEG-6s after the devices have been flown in a rotary wing aircraft. However, testing cannot be performed while in flight conditions. It is also possible to run blood samples collected up to 3 h prior and acquire results which correlate well with initial testing.

Viscoelastic haemostatic assays and fibrinogen in paediatric acute traumatic coagulopathy: A comprehensive review.

OBJECTIVE: Haemorrhage in paediatric trauma remains a significant cause of morbidity and mortality. Over recent years there has been increasing attention to the role of fibrinogen in traumatic haemorrhage and the association of low fibrinogen levels with poor patient outcomes. In addition, there has been a move towards using viscoelastic haemostatic assays (VHAs) to rapidly assess coagulation status and guide clinicians in the replacement of coagulation factors, including fibrinogen. In the paediatric population, there has been limited uptake of these principles and a paucity of data to support a change in practice. This paper summarises the available evidence in the published literature through a systematic review, presented in narrative format. RESULTS: There is limited high-quality prospective data on the use of VHA in the management of acute traumatic coagulopathy in the paediatric population. While the use of fibrinogen early in major haemorrhage is becoming standard practice, there are currently no randomised prospective studies comparing fibrinogen concentrate to cryoprecipitate. CONCLUSIONS: The early identification of hypo-fibrinogenemia and acute traumatic coagulopathy in paediatric trauma using VHA testing and subsequent early fibrinogen replacement with a concentrated off the shelf product is an attractive treatment option. However, there is currently insufficient high-level evidence to support the use of fibrinogen concentrate over cryoprecipitate in the paediatric trauma population. Pilot studies currently under way will go some way to addressing this important knowledge gap, and facilitate the design of larger definitive multi-centre randomised trials.