Early Trauma-induced Coagulopathy Research Articles

Physiopathology and treatment of critical bleeding: a literature review

Objectivesto develop the different factors involved in the physiopathology of trauma-induced coagulopathy, through a review of publications on the matter; as well as to assess the evidence available on the treatment of critical bleeding and the recommendations by clinical practice guidelines. Methodsa search has been conducted on the bibliography published about the physiopathology and treatment of critical bleeding in the PUBMED, BestPractice, UpToDate databases and the Cochrane Plus Library. The main key words used for this search were “early trauma induced coagulopathy”, “mechanisms of early trauma-induced coagulopathy”, “blood transfusion guidelines”, “massive transfusion guidelines” and “fibrinogen replacement therapy”. The most clinically relevant articles were selected for this review. Conclusionsthe physiopathology of the trauma-induced coagulopathy is a more complex matter and involves more factors than was initially assumed. The early treatment of the coa-gulopathy is critical for the initial management of the critical bleeding. However, the use of blood derivatives should be rational and based on homogeneous and high-quality scientific evidence.The main cornerstones for the treatment of critical bleeding are: fluid therapy, fibrinogen concentrate, prothrombin complex concentrate, plasma, erythrocyte or platelet concentrates, tranexamic acid, and calcium. Their administration should be assessed depending on the clinical condition of each patient.

ITACTIC \u2013 implementing Treatment Algorithms for the Correction of Trauma-Induced Coagulopathy: study protocol for a multicentre, randomised controlled trial

BackgroundTraumatic injury is the fourth leading cause of death globally. Half of all trauma deaths are due to bleeding and most of these will occur within 6 h of injury. Haemorrhagic shock following injury has been shown to induce a clotting dysfunction within minutes, and this early trauma-induced coagulopathy (TIC) may exacerbate bleeding and is associated with higher mortality and morbidity. In spite of improved resuscitation strategies over the last decade, current transfusion therapy still fails to correct TIC during ongoing haemorrhage and evidence for the optimal management of bleeding trauma patients is lacking. Recent publications describe increasing the use of Viscoelastic Haemostatic Assays (VHAs) in trauma haemorrhage; however, there is insufficient evidence to support their superiority to conventional coagulation tests (CCTs).Methods/designThis multicentre, randomised controlled study will compare the haemostatic effect of an evidence-based VHA-guided versus an optimised CCT-guided transfusion algorithm in haemorrhaging trauma patients. A total of 392 adult trauma patients will be enrolled at major trauma centres. Participants will be eligible if they present with clinical signs of haemorrhagic shock, activate the local massive haemorrhage protocol and initiate first blood transfusion. Enrolled patients will be block randomised per centre to either VHA-guided or CCT-guided transfusion therapy in addition to that therapy delivered as part of standard care, until haemostasis is achieved. Patients will be followed until discharge or 28 days. The primary endpoint is the proportion of subjects alive and free of massive transfusion (less than 10 units of red blood cells) at 24 h. Secondary outcomes include the effect of CCT- versus VHA-guided therapy on organ failure, total hospital and intensive care lengths of stay, health care resources needed and mortality. Surviving patients will be asked to complete a quality of life questionnaire (EuroQol EQ-5DTM) at day 90.DiscussionCCTs have traditionally been used to detect TIC and monitor response to treatment in traumatic major haemorrhage. The use of VHAs is increasing, but limited evidence exists to support the superiority of these technologies (or comparatively) for patient-centred outcomes. This knowledge gap will be addressed by this trial.Trial registrationClinicalTrials.gov, ID: NCT02593877. Registered on 15 October 2015.Trial sponsorQueen Mary University of LondonThe contact person of the above sponsor organisation is: Dr. Sally Burtles, Director of Research Services and Business Development, Joint Research Management Office, QM Innovation Building, 5 Walden Street, London E1 2EF; phone: 020 7882 7260; Email: sponsorsrep@bartshealth.nhs.ukTrial sitesAcademic Medical Centre, Amsterdam, The NetherlandsKliniken der Stadt Köln gGmbH, Cologne, GermanyRigshospitalet (Copenhagen University Hospital), Copenhagen, DenmarkJohn Radcliff Hospital, Oxford, United KingdomOslo University Hospital, Oslo, NorwayThe Royal London Hospital, London, United KingdomCentre for Trauma Sciences, Blizard Institute, Queen Mary University of London, London, United KingdomHealth Economics Research Centre, Nuffield Department of Population Health, University of Oxford, Oxford, United KingdomSites that are planning to start recruitment in mid/late 2017Nottingham University Hospitals, Queen’s Medical Centre, Nottingham, United KingdomUniversity of Kansas Hospital (UKH), Kansas City, MO, USAProtocol version: 3.0/14.03.2017 (Additional file 1)

The current understanding of trauma-induced coagulopathy (TIC): a focused review on pathophysiology.

The emergency management of acute severe bleeding in trauma patients has changed significantly in recent years. In particular, greater attention is now being devoted to a prompt assessment of coagulation alterations, which allows for immediate haemostatic resuscitation procedures when necessary. The importance of an early trauma-induced coagulopathy (TIC) diagnosis has led physicians to increase the efforts to better understand the pathophysiological alterations observed in the haemostatic system after traumatic injuries. As yet, the knowledge of TIC is not exhaustive, and further studies are needed. The aim of this review is to gather all the currently available data and information in an attempt to gain a better understanding of TIC. A comprehensive literature search was performed using MEDLINE database. The bibliographies of relevant articles were screened for additional publications. In major traumas, coagulopathic bleeding stems from a complex interplay among haemostatic and inflammatory systems, and is characterized by a multifactorial dysfunction. In the abundance of biochemical and pathophysiological changes occurring after trauma, it is possible to discern endogenously induced primary predisposing conditions and exogenously induced secondary predisposing conditions. TIC remains one of the most diagnostically and therapeutically challenging condition.

Early Trauma-Induced Coagulopathy is Associated with Increased Ventilator-Associated Pneumonia in Spinal Cord Injury Patients.

Early trauma-induced coagulopathy may increase susceptibility to nosocomial infections such as ventilator-associated pneumonia. However, the relationship between trauma- induced coagulopathy and the development of ventilator-associated pneumonia in spinal cord injury patients has not been evaluated. We conducted a 5-year retrospective study of 300 spinal cord injury patients admitted to Level 1 trauma center. Standard coagulation studies were evaluated upon arrival, prior to fluid resuscitative efforts, and at 24 h after admission. Based on these studies, three groups of patients were identified: no coagulopathy, latent coagulopathy, and admission coagulopathy. Ventilator- associated pneumonia was identified utilizing Centers for Disease Control and Prevention criteria. Since we used the data in the trauma registry and did not have the information on FiO2 and PEEP, we elected to use the VAP terminology and not the VAE sequence. Demographic, injury, and clinical characteristics were compared among no coagulopathy, latent coagulopathy, and admission coagulopathy groups using chi-square test and ANOVA for categorical and continuous variables, respectively. A logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between coagulopathy and both ventilator-associated pneumonia and mortality. The incidence of ventilator-associated pneumonia was 54.5% (OR 4.01, 95% CI 1.76-9.15) in spinal cord injury patients with admission coagulopathy, compared with the 17.5% in spinal cord injury patients with no coagulopathy. Mortality was significantly higher in spinal cord injury patients with admission coagulopathy than in spinal cord injury patients with no coagulopathy (OR 6.14, 95% CI 1.73-21.73).After adjusting for age, race, injury mechanism, Injury Severity Score, base deficit at admission, the number of pRBC units transfused in the first 24 h, and hospital stay, only the association of ventilator-associated pneumonia among those with admission coagulopathy remained significant (OR 3.51, 95% CI 1.48-8.32). Compared with those with no coagulopathy, patients with admission coagulopathy had a higher odds of death (4.10, 95% CI 1.53-11.02), though this association lost significance after adjustment (OR 3.56, 95% CI 0.90-14.12). There was no statistical difference in mortality for latent coagulopathy compared with no coagulopathy patients. Coagulopathy on admission in patients with spinal cord injury is associated with a statistically significant increase in ventilator-associated pneumonia incidence. Additional research is warranted to further characterize this association.

Mechanisms of early trauma-induced coagulopathy: The clot thickens or not?

Traumatic-induced coagulopathy (TIC) is a hemostatic disorder that is associated with significant bleeding, transfusion requirements, morbidity and mortality. A disorder similar or analogous to TIC was reported around 70 years ago in patients with shock, hemorrhage, burns, cardiac arrest or undergoing major surgery, and the condition was referred to as a "severe bleeding tendency," "defibrination syndrome," "consumptive disorder," and later by surgeons treating US Vietnam combat casualties as a "diffuse oozing coagulopathy." In 1982, Moore's group termed it the "bloody vicious cycle," others "the lethal triad," and in 2003 Brohi and colleagues introduced "acute traumatic coagulopathy" (ATC). Since that time, early TIC has been cloaked in many names and acronyms, including a "fibrinolytic form of disseminated intravascular coagulopathy (DIC)." A global consensus on naming is urgently required to avoid confusion. In our view, TIC is a dynamic entity that evolves over time and no single hypothesis adequately explains the different manifestations of the coagulopathy. However, early TIC is not DIC because an increased thrombin-generating potential in vitro does not imply a clinically relevant thrombotic state in vivo as early TIC is characterized by excessive bleeding, not thrombosis. DIC with its diffuse anatomopathologic fibrin deposition appears to be a latter phase progression of TIC associated with unchecked inflammation and multiple organ dysfunction.

Defining Early Trauma-induced Coagulopathy Using Thromboelastography

Early trauma-induced coagulopathy (ETIC) is abnormal coagulation detected on presentation, but a clear description is lacking. We used thromboelastography (TEG) to characterize ETIC. Data were prospectively collected on high-acuity trauma activations at an urban Level I trauma center between July 2012 and May 2013. Patients with admission TEG before any blood transfusion were stratified by Injury Severity Score (ISS): mild (less than 16), moderate (16 to 24), severe (25 or greater). TEG parameters were compared between groups. ETIC was defined as any abnormality detected on TEG. Fifty-two patients were included; mean age was 49 years and mean time to the emergency department was 26 minutes. Mean ISS for the cohort was 17 with 28 patients in mild, eight in moderate, and 16 in severe. Glasgow Coma Score was lower and head Abbreviated Injury Scale was higher in severe (P < 0.001). Forty-three (83%) patients had an abnormal TEG. Shortened reaction (R) time was noted in 42 patients. There were no differences in any TEG parameters between the injury severity groups. Hyperfibrinolysis was detected in four (8%) patients. ETIC was present in over 80 per cent of high-acuity trauma activations irrespective of injury severity and characterized primarily by shortened R time, indicating ETIC is initially described by a hypercoagulable state as a result of thrombin generation.

Update on massive transfusion

Massive haemorrhage requires massive transfusion (MT) to maintain adequate circulation and haemostasis. For optimal management of massively bleeding patients, regardless of aetiology (trauma, obstetrical, surgical), effective preparation and communication between transfusion and other laboratory services and clinical teams are essential. A well-defined MT protocol is a valuable tool to delineate how blood products are ordered, prepared, and delivered; determine laboratory algorithms to use as transfusion guidelines; and outline duties and facilitate communication between involved personnel. In MT patients, it is crucial to practice damage control resuscitation and to administer blood products early in the resuscitation. Trauma patients are often admitted with early trauma-induced coagulopathy (ETIC), which is associated with mortality; the aetiology of ETIC is likely multifactorial. Current data support that trauma patients treated with higher ratios of plasma and platelet to red blood cell transfusions have improved outcomes, but further clinical investigation is needed. Additionally, tranexamic acid has been shown to decrease the mortality in trauma patients requiring MT. Greater use of cryoprecipitate or fibrinogen concentrate might be beneficial in MT patients from obstetrical causes. The risks and benefits for other therapies (prothrombin complex concentrate, recombinant activated factor VII, or whole blood) are not clearly defined in MT patients. Throughout the resuscitation, the patient should be closely monitored and both metabolic and coagulation abnormalities corrected. Further studies are needed to clarify the optimal ratios of blood products, treatment based on underlying clinical disorder, use of alternative therapies, and integration of laboratory testing results in the management of massively bleeding patients.

Early trauma induced coagulopathy (ETIC): Prevalence across the injury spectrum

IntroductionNewer studies have hypothesised about a coagulopathy that occurs early after trauma, early trauma induced coagulopathy, ETIC, and is defined by an elevated admission prothrombin time (PT). Also, referred to by some authors as acute traumatic coagulopathy, it has been most often studied in cohorts of severely injured or hypotensive patients. However, we wanted to prospectively investigate ETIC in a large all-comers cohort to confirm its prevalence across the entire spectrum of injury, to evaluate its risk pattern and to determine a possible relationship to reduced survival. MethodsWe conducted a prospective cohort study at a Level I trauma centre from July 15, 2008 to November 15, 2009. Demographics, injury mechanism, time from injury and to hospital arrival, fluid and blood administration and vital signs were collected at hospital arrival and to the time of first blood sample collection for all patients admitted for 24h or longer. Our primary outcome was the incidence of mortality by the 28th hospital day, referred to as 28 day in-hospital mortality. Results701 patients were included in the final study cohort. There was 75.3% male, 25.7% penetrating, with a mean age of 39 years. The overall mortality was 7.3%. ETIC occurred in 114 patients (16.3%) and was found to be independently associated with death (odds of death (per 0.10s increase in PT): 1.10, p=0.001). ETIC patients, as a group, were more severely injured, had more hypotension and head injury and used more crystalloid and blood products than non-ETIC patients. However, even mildly injured patients, who had an ISS<16, normal RTS score, and no fluid resuscitation, had an ETIC prevalence of 11.7% (11/94). ConclusionsETIC is an early, primary post-injury coagulopathy that occurs in 16.3% of admitted trauma patients. It is associated with an increase in mortality, even when controlling for crystalloids, vital signs, injury severity and head injury. It can also be found in approximately 11% of mildly injured patients (patients without physiological derangement or blood product administration). Therefore, further elucidation of ETIC is strategic to impacting trauma patient outcome.

Endothelial glycocalyx degradation induces endogenous heparinization in patients with severe injury and early traumatic coagulopathy

There is emerging evidence that early trauma-induced coagulopathy (TIC) is mechanistically linked to disruption of the vascular endothelium and its glycocalyx, assessed by thrombomodulin and syndecan 1, respectively. This study evaluated if degradation of the endothelial glycocalyx and ensuing release of its heparin-like substances induce autoheparinization and thereby contributes to TIC. Prospective observational study of 77 trauma patients admitted to a Level I trauma center having blood sampled at admission. Data on demography, hematology, Injury Severity Score, transfusion requirements, 30-day mortality, and thrombelastography (TEG, concurrent kaolin-activated/kaolin-heparinase-activated) were recorded. Retrospective analysis of plasma/serum for biomarkers reflecting endothelial glycocalyx and cell damage (syndecan 1, thrombomodulin), tissue injury (histone-complexed DNA fragments), sympathoadrenal activation (adrenaline, noradrenaline), coagulation activation/anticoagulation (prothrombin fragment 1+2, fibrinogen, von Willebrand factor, factor XIII, antithrombin, protein C, activated protein C, tissue factor pathway inhibitor), fibrinolysis (tissue-type plasminogen activator, plasminogen activator inhibitor 1) and inflammation (interleukin 6, terminal complement complex). Stratification of patients was according to the degree of TEG-measured heparinization. Four patients (5.2%) displayed evidence of high-degree autoheparinization, and these patients had higher Injury Severity Score (median [interquartile range], 31 [26-37] vs. 17 [10-26]), increased glucose (median, 13.6 vs. 8.0 mmol/L), and lower hemoglobin level (median, 5.8 vs. 8.4 mmol/L) and received more transfusions during the first 1 hour (median, 5 vs. 0) and 24 hours (median, 10 vs. 0) (all p < 0.05). Importantly, patients with autoheparinization had fourfold higher syndecan 1 levels (median [interquartile range], 116 ng/mL [78-140 ng/mL] vs. 31 ng/mL [18-49 ng/mL]), and they had higher international normalized ratio (median, 1.4 vs. 1.1), thrombomodulin (median, 4.1 vs. 1.7 ng/mL) and interleukin 6 (median, 129 vs. 71 pg/mL) but lower protein C (85% vs. 109%) (all p < 0.05), indicating profound endothelial damage, coagulopathy and inflammation. Five percent of the patients with trauma in the present study had evidence of acute endogenous coagulopathy with autoheparinization by TEG, which appeared mechanistically linked to endothelial glycocalyx degradation. Acute endogenous autoheparinization may contribute to TIC. Prognostic study, level III.

Base deficit as a marker of survival after traumatic injury

Damage control resuscitation (DCR) has improved outcomes in severely injured patients. In civilian centers, massive transfusion protocols (MTPs) represent the most formal application of DCR principles, ensuring early, accurate delivery of high fixed ratios of blood components. Recent data suggest that DCR may also help address early trauma-induced coagulopathy. Finally, base deficit (BD) is a long-recognized and simple early prognostic marker of survival after injury. Outcomes of patients with admission BD data resuscitated during the DCR era (2007-2010) were compared with previously published data (1995-2003) of patients cared for before the DCR era (pre-DCR). Patients were considered to have no hypoperfusion (BD, >-6), mild (BD, -6 to -14.9), moderate (BD, -15 to -23.9), or severe hypoperfusion (BD, <-24). Of 6,767 patients, 4,561 were treated in the pre-DCR era and 2,206 in the DCR era. Of the latter, 218 (9.8%) represented activations of the MTP. DCR patients tended to be slightly older, more likely victims of penetrating trauma, and slightly more severely injured as measured by trauma scores and BD. Despite these differences, overall survival was unchanged in the two eras (86.4% vs. 85.7%, p = 0.67), and survival curves stratified by mechanism of injury were nearly identical. Patients with severe BD who were resuscitated using the MTP, however, experienced a substantial increase in survival compared with pre-DCR counterparts. Despite limited adoption of formal DCR, overall survival after injury, stratified by BD, is identical in the modern era. Patients with severely deranged physiology, however, experience better outcomes. BD remains a consistent predictor of mortality after traumatic injury. Predicted survival depends more on the energy level of the injury (stab wound vs. nonstab wound) than the mechanism of injury (blunt vs. penetrating).

Anesthesia Literature Review

Anesthesia Literature Review

Pathophysiology of early trauma-induced coagulopathy: emerging evidence for hemodilution and coagulation factor depletion.

Trauma patients present with a coagulopathy, termed early trauma-induced coagulopathy (ETIC), that is associated with increased mortality. This study investigated hemostatic changes responsible for ETIC. Case-control study of trauma patients with and without ETIC, defined as prolonged prothrombin time (PT), was performed from prospective cohort of consecutive trauma patients who presented to Level I trauma center. Univariate and multivariate analyses were performed. The case-control study group (n = 91) was 80% male, with mean age of 37 years, 17% penetrating trauma and 7% mortality rate. Patients with ETIC demonstrated decreased common and extrinsic pathway factor activities (factors V and VII) and decreased inhibition of the coagulation cascade (antithrombin and protein C activities) when compared with the matched control patients without ETIC. Both cohorts had evidence of increased thrombin and fibrin generation (prothrombin fragment 1.2 levels, thrombin-antithrombin complexes, and soluble fibrin monomer), increased fibrinolysis (d-dimer levels), and increased inhibition of fibrinolysis (plasminogen activator inhibitor-1 activity) above normal reference values. Patients with versus without ETIC had increased mortality and received increased amount of blood products. ETIC following injury is associated with decreased factor activities without significant differences in thrombin and fibrin generation, suggesting that despite these perturbations in the coagulation cascade, patients displayed a balanced hemostatic response to injury. The lower factor activities are likely secondary to increased hemodilution and coagulation factor depletion. Thus, decreasing the amount of crystalloid infused in the early phases following trauma and administration of coagulation factors may prevent the development.

Disseminated intravascular coagulation or acute coagulopathy of trauma shock early after trauma? An observational study

IntroductionIt is debated whether early trauma-induced coagulopathy (TIC) in severely injured patients reflects disseminated intravascular coagulation (DIC) with a fibrinolytic phenotype, acute coagulopathy of trauma shock (ACoTS) or yet other entities. This study investigated the prevalence of overt DIC and ACoTS in trauma patients and characterized these conditions based on their biomarker profiles.MethodsAn observational study was carried out at a single Level I Trauma Center. Eighty adult trauma patients (≥18 years) who met criteria for full trauma team activation and had an arterial cannula inserted were included. Blood was sampled a median of 68 minutes (IQR 48 to 88) post-injury. Data on demography, biochemistry, injury severity score (ISS) and mortality were recorded. Plasma/serum was analyzed for biomarkers reflecting tissue/endothelial cell/glycocalyx damage (histone-complexed DNA fragments, Annexin V, thrombomodulin, syndecan-1), coagulation activation/inhibition (prothrombinfragment 1+2, thrombin/antithrombin-complexes, antithrombin, protein C, activated protein C, endothelial protein C receptor, protein S, tissue factor pathway inhibitor, vWF), factor consumption (fibrinogen, FXIII), fibrinolysis (D-dimer, tissue-type plasminogen activator, plasminogen activator inhibitor-1) and inflammation (interleukin (IL)-6, terminal complement complex (sC5b-9)). Comparison of patients stratified according to the presence or absence of overt DIC (International Society of Thrombosis and Hemostasis (ISTH) criteria) or ACoTS (activated partial thromboplastin time (APTT) and/or international normalized ratio (INR) above normal reference).ResultsNo patients had overt DIC whereas 15% had ACoTS. ACoTS patients had higher ISS, transfusion requirements and mortality (all P < 0.01) and a biomarker profile suggestive of enhanced tissue, endothelial cell and glycocalyx damage and consumption coagulopathy with low protein C, antithrombin, fibrinogen and FXIII levels, hyperfibrinolysis and inflammation (all P < 0.05). Importantly, in non-ACoTS patients, apart from APTT/INR, higher ISS correlated with biomarkers of enhanced tissue, endothelial cell and glycocalyx damage, protein C activation, coagulation factor consumption, hyperfibrinolysis and inflammation, that is, resembling that observed in patients with ACoTS.ConclusionsACoTS and non-ACoTS may represent a continuum of coagulopathy reflecting a progressive early evolutionarily adapted hemostatic response to the trauma hit and both are parts of TIC whereas DIC does not appear to be part of this early response.