Acute Traumatic Coagulopathy Research Articles

Tratamiento de la coagulopatía en la hemorragia del paciente politraumatizado

Bleeding is the most common preventable cause of death in trauma patients. Acute traumatic coagulopathy is a specific condition with a different pathophysiology from other causes of the massive bleeding. An early identification of the coagulopathy is fundamental to implementing rapid treatment. There have been many changes in the management of massive hemorrhage, for example, the administration of the tranexamic acid and the use of balanced transfusion ratio. This review presents these practical points, some of them with scientific evidence, in order to achieve a beneficial effect for patient outcomes.

An International Normalized Ratio-Based Definition of Acute Traumatic Coagulopathy Is Associated With Mortality, Venous Thromboembolism, and Multiple Organ Failure After Injury.

Acute traumatic coagulopathy is associated with adverse outcomes including death. Previous studies examining acute traumatic coagulopathy's relation with mortality are limited by inconsistent criteria for syndrome diagnosis, inadequate control of confounding, and single-center designs. In this study, we validated the admission international normalized ratio as an independent risk factor for death and other adverse outcomes after trauma and compared two common international normalized ratio-based definitions for acute traumatic coagulopathy. Multicenter prospective observational study. Nine level I trauma centers in the United States. A total of 1,031 blunt trauma patients with hemorrhagic shock. None. International normalized ratio exhibited a positive adjusted association with all-cause in-hospital mortality, hemorrhagic shock-associated in-hospital mortality, venous thromboembolism, and multiple organ failure. Acute traumatic coagulopathy affected 50% of subjects if defined as an international normalized ratio greater than 1.2 and 21% of subjects if defined by international normalized ratio greater than 1.5. After adjustment for potential confounders, acute traumatic coagulopathy defined as an international normalized ratio greater than 1.5 was significantly associated with all-cause death (odds ratio [OR], 1.88; p < 0.001), hemorrhagic shock-associated death (OR, 2.44; p = 0.001), venous thromboembolism (OR, 1.73; p < 0.001), and multiple organ failure (OR, 1.38; p = 0.02). Acute traumatic coagulopathy defined as an international normalized ratio greater than 1.2 was not associated with an increased risk for the studied outcomes. Elevated international normalized ratio on hospital admission is a risk factor for mortality and morbidity after severe trauma. Our results confirm this association in a prospectively assembled multicenter cohort of severely injured patients. Defining acute traumatic coagulopathy by using an international normalized ratio greater than 1.5 but not an international normalized ratio greater than 1.2 identified a clinically meaningful subset of trauma patients who, adjusting for confounding factors, experienced more adverse outcomes. Targeting future therapies for acute traumatic coagulopathy to patients with an international normalized ratio greater than 1.5 may yield greater returns than using a lower international normalized ratio threshold.

Massive hemorrhage management-a best evidence topic report.

IntroductionMassive hemorrhage remains a major cause of potentially preventable deaths. Better control of bleeding could improve survival rates by 10%–20%. Transfusion intervention concepts have been formulated in order to minimize acute traumatic coagulopathy. These interventions still have not been standardized and vary among medical centers.Materials and MethodsBased on a literature search using free term keywords and Medical Subject Heading (MeSH) index, we analyzed published articles addressing massive hemorrhage, component therapy, fresh whole blood, and fibrinogen from the year 2000 onward, in journals with impact factor >1.000, in Medline, PubMed, and Google Scholar. The evidence was grouped into topics including laboratory testing and transfusion interventions/viscoelastic assays vs standard laboratory tests, the effect of component therapy on patient outcome, the effect of warm fresh whole blood on patient outcome, and the effects of fibrinogen in severe bleeding. The obtained information was compared, evaluated, confronted, and was focused on to present an adequate and individual-based massive hemorrhage management approach.ResultsViscoelastic whole-blood assays are superior to standard coagulation blood tests for the identification of coagulopathy and for guiding decisions on appropriate therapy in patients with severe bleeding. Replacement of plasma, red blood cells, platelets, and fibrinogen in a ratio of 1:1:1:1 has appeared to be the best substitution for lost whole blood. There is no evidence that cryoprecipitate improves the outcome of patients with severe hemorrhage. Current literature promotes the transfusion of warm fresh whole blood, which seems to be superior to the component therapy in certain clinical situations. Some authors recommend that fibrinogen and other coagulation factors be administered according to the viscoelastic attributes of the blood clot.ConclusionThis best-evidence topic report brings comprehensive information about massive hemorrhage management.

Experimental Animal Models of Traumatic Coagulopathy: A Systematic Review.

Perturbations in coagulation function are common following trauma and are associated with poor clinical outcomes. Traditionally considered an iatrogenic process, it is now recognized that an acute coagulation dysfunction develops prior to medical intervention. The mechanisms underlying the development of this acute traumatic coagulopathy remain poorly understood. Preclinical animal research is a necessary adjunct to improve mechanistic understanding and management of this condition. This review aims to identify and evaluate existing animal models of traumatic coagulopathy for clinical relevance. A structured search of MEDLINE/PubMed was performed in September 2014 in accordance with the PRISMA guidelines. A total of 62 relevant publications describing 27 distinct models of traumatic coagulopathy were identified. Porcine models predominated, and hemodilution in isolation or in combination with hypothermia and/or acidosis was the principal mechanism for inducing coagulopathy. Acute coagulation changes in response to tissue injury and hemorrhage were evident in five publications, and pathophysiological evaluation of postulated mechanisms was performed in three studies. There are few clinically relevant animal models that reflect the contemporary understanding of traumatic coagulopathy. This relative deficiency highlights the need for further development of valid and reproducible animal models of trauma. Well-designed models will facilitate improved mechanistic understanding and development of targeted treatment strategies for traumatic coagulopathy.

Comprehensive evaluation of coagulation in swine subjected to isolated primary blast injury.

Blast is one of the major causes of injury and death in recent armed conflicts. With increased use of improvised explosive devices in Iraq and Afghanistan, more than 71% of combat casualties are caused by explosions. Blast injuries can range from primary (caused by shock wave) to quaternary injuries (e.g., burns), and such injuries can result in an acute coagulopathy denoted by a hypocoagulable state. It is not clear if this coagulopathy observed in victims of explosion is caused by local or general effect of the primary blast injury itself. In this study, 13 pigs were subjected to severe isolated open-field blast injury and we measured indices of coagulation impairment during the first hour after injury: ROTEM, prothrombin time, activated partial thromboplastin time, coagulation factors, thrombin generation potential, platelet count, platelet activation, platelet function, and procoagulant microparticle formation. After 1 h, the mortality was 33%. No coagulation dysfunction was observed in the survivors in this period. This study presented a highly reproducible and consistent isolated blast injury in large mammals with comprehensive coagulation testing. The data suggest that isolated primary blast injury is not responsible for acute coagulopathy of trauma in victims of explosion but seems to lead to an early hypercoagulable state.

Acute Traumatic Coagulopathy Accompanying Traumatic Brain Injury is Associated with Worse Long Term Cognitive and Functional Outcomes: A Retrospective Analysis of the COBRIT Data. (S27.005)

Acute Traumatic Coagulopathy Accompanying Traumatic Brain Injury is Associated with Worse Long Term Cognitive and Functional Outcomes: A Retrospective Analysis of the COBRIT Data. (S27.005)

Correction of acute traumatic coagulopathy with small-volume 7.5% NaCl adenosine, lidocaine, and Mg2+ occurs within 5 minutes: a ROTEM analysis.

Acute traumatic coagulopathy is a major contributor to mortality and morbidity following hemorrhagic shock. Our aim was to examine the effect of small-volume 7.5% NaCl with adenosine, lidocaine, and Mg (ALM) resuscitation on the timing of correction of coagulopathy in the rat model of severe hemorrhagic shock using ROTEM. Male rats (300-450 g, n = 64) were randomly assigned to (1) baseline, (2) sham, (3) bleed, (4) shock, (5) 7.5% NaCl for 5 minutes, (6) 7.5% NaCl with ALM for 5 minutes, (7) 7.5% NaCl for 60 minutes, or (8) 7.5% NaCl with ALM for 60 minutes (all n = 8). For resuscitation, 0.3-mL intravenous bolus of 7.5% NaCl was administered with and without ALM (n = 8 each group). Hemodynamics and coagulopathy were assessed. After hemorrhage, prothrombin time (PT) and activated partial thromboplastin time (aPTT) increased approximately four to six times, and ROTEM indicated hypocoagulopathy. After 60-minute shock, no sustainable clots could form. 7.5% NaCl increased mean arterial pressure (MAP) to 46 ± 2 mm Hg at 5 minutes and generated a weak clot in EXTEM with hyperfibrinolysis in all tests. At 60 minutes, 7.5% NaCl failed to sustain MAP (43 ± 5 mm Hg) and generate a viable clot. In direct contrast, 7.5% NaCl with ALM at 5 minutes resuscitated MAP to 64 ± 3 mm Hg, corrected PT and aPTT, and generated fully formed EXTEM and FIBTEM clots. At 60 minutes, MAP was 69 ± 5 mm Hg, PT and aPTT were fully corrected, and α angle, clot amplitudes (A10, A30), as well as clot firmness and elasticity were not significantly different from baseline. ALM clot lysis at 60 minutes was significantly less than bleed, shock, or 7.5% NaCl, indicating protection against hyperfibrinolysis. Small-volume 7.5% NaCl failed to resuscitate and correct coagulopathy. In contrast, 7.5% NaCl with ALM resuscitated MAP and corrected coagulopathy at 5 minutes, with further improvements at 60 minutes in clot kinetics, propagation, and firmness. ALM fully reversed hyperfibrinolysis to baseline. The possible mechanisms are discussed.

Chemical sympathectomy attenuates inflammation, glycocalyx shedding and coagulation disorders in rats with acute traumatic coagulopathy.

Acute traumatic coagulopathy (ATC) may trigger sympathoadrenal activation associated with endothelial damage and coagulation disturbances. Overexcitation of sympathetic nerve in this state would disrupt sympathetic-vagal balance, leading to autonomic nervous system dysfunction. The aim of this study was to evaluate the autonomic function in ATC and its influence on inflammation, endothelial and coagulation activation. Male Sprague-Dawley rats were randomly assigned to sham, ATC control (ATCC) and ATC with sympathectomy by 6-hydroxydopamine (ATCS) group. Sham animals underwent the same procedure without trauma and bleeding. Following trauma and hemorrhage, rats underwent heart rate variability (HRV) test, which predicts autonomic dysfunction through the analysis of variation in individual R-R intervals. Then, rats were euthanized at baseline, and at 0, 1 and 2 h after shock and blood gas, conventional coagulation test and markers of inflammation, coagulation, fibrinolysis, endothelial damage and catecholamine were measured. HRV showed an attenuation of total power and high frequency, along with a rise of low frequency and low frequency : high frequency ratio in the ATC rats, which both were reversed by sympathectomy in the ATCS group. Additionally, sympathetic denervation significantly suppressed the increase of proinflammatory cytokines, tumor necrosis factor-α and the fibrinolysis markers including tissue-type plasminogen activator and plasmin-antiplasmin complex. Serum catecholamine, soluble thrombomodulin and syndecan-1 were also effectively inhibited by sympathectomy. These data indicated that autonomic dysfunction in ATC involves both sympathetic activation and parasympathetic inhibition. Moreover, sympathectomy yielded anti-inflammatory, antifibrinolysis and endothelial protective effects in rats with ATC. The role of autonomic neuropathy in ATC should be explored further.

Evolving beyond the vicious triad: Differential mediation of traumatic coagulopathy by injury, shock, and resuscitation.

A subset of trauma patients with critical injury present with coagulopathy, portending markedly worse outcomes. Clinical practice is evolving to treat the classical risk factors of hypothermia, hemodilution, and acidosis; however, coagulopathy persists even in the absence of these factors. We sought to determine the relative importance of injury- and shock-specific factors compared with resuscitation-associated factors in coagulopathy after trauma. Comprehensive demographic data, laboratory data, and outcomes data were prospectively collected from seven trauma centers over 8 years (November 2003 to August 2011) as part of the Inflammation and the Host Response to Injury Large-Scale Collaborative Program. A total of 1,537 critically injured patients with blunt trauma and hemorrhagic shock were analyzed to evaluate predictors of admission coagulopathy (international normalized ratio [INR] ≥ 1.3), multiorgan failure, and mortality. Of 1,537 patients, 578 (37.6%) had admission INR of 1.3 or greater. Coagulopathic patients had more severe injury, more severe base deficit and lactate levels, as well as lower admission temperature, lower pH, and higher prehospital crystalloid volume (all p < 0.001). Coagulopathic patients required more blood products and mechanical ventilation and had higher rates of nosocomial infection, multiorgan failure, and mortality (all p < 0.02). Injury severity, temperature, and acidosis (all p < 0.02) independently predicted coagulopathy in multivariate analysis, with a significant interaction between lactate and prehospital crystalloid. In Cox regression models, however, coagulopathy itself remained an independent predictor of both multiorgan failure and mortality (p < 0.02) even when adjusted for injury severity, shock, and elements of the vicious triad. Most patients with coagulopathy after trauma have mixed risk factors; however, coagulopathy has deleterious effects independent of injury severity, shock, and the vicious triad. Better understanding of the biochemical mechanisms of acute traumatic coagulopathy may facilitate biochemically targeted resuscitation strategies and improve outcomes. Prognostic and epidemiologic study, level II.

Potential biomarker panel for predicting organ dysfunction and acute coagulopathy in a polytrauma porcine model.

Traumatic injury remains a major cause of morbidity and mortality worldwide, and patients who survived the initial insult are susceptible to an overwhelming inflammatory dysfunction that will lead to acute coagulopathy of trauma (ACOT) and subsequently multiple organ dysfunction syndrome (MODS). Multiple organ dysfunction syndrome-related scoring systems, although they measure organ dysfunction, present clinical markers, and single-cytokine estimates are unable to predict accurately the events of MODS in the clinical setting to aid risk stratification. In this study, a pig model comprising the lethal triad of trauma was used to determine prognostic patterns of early circulating trauma markers so as to predict the development of MODS and ACOT. We measured early expression of several biomarkers (neutrophil gelatinase-associated protein, high-mobility group box 1, C-reactive protein, tumor necrosis factor-α, heart-type fatty acid binding protein, and D-dimers) and clinical parameters for various organ injuries and abnormalities (creatinine, creatine kinase myocardial band, aspartate aminotransferase, and maximum clot firmness) at later time points. The strength of association between the early expression of several biomarkers to the development of MODS and ACOT in polytraumatized pigs was tested using the Spearman correlation coefficient. These biomarkers were found useful to predict the onset of renal, cardiac, hepatic, and hemostatic abnormalities. The findings show that these biomarkers could help to identify, guide, and streamline damage control surgery and earlier intervention to reverse the detrimental outcomes of MODS and ACOT.

Impact of β-adrenoceptor blockade on systemic inflammation and coagulation disturbances in rats with acute traumatic coagulopathy.

BackgroundSympathetic hyperactivity occurs early in acute traumatic coagulopathy (ATC) and is closely related to its development. β-adrenoceptor antagonists are known to alleviate adverse sympathetic effects and improve outcome in various diseases. We investigated whether β-blockers have protective effects against inflammation and endothelial and hemostatic disorders in ATC.Material/MethodsATC was induced in male Sprague-Dawley rats by trauma and hemorrhagic shock. Rats were randomly assigned to the sham, ATCC (ATC control), and ATCB (ATC with beta-adrenoceptor blockade) groups. Rats were injected intraperitoneally with propranolol or vehicle at baseline. Heart rate variability (HRV) and markers of inflammation, coagulation, and endothelial activation were measured, and Western blotting analysis of nuclear factor (NF)-κB was done after shock. Separate ATCC and ATCB groups were observed to compare overall mortality.ResultsHRV showed enhanced sympathetic tone in the ATCC group, which was reversed by propranolol. Propranolol attenuated the induction of pro-inflammatory cytokines TNF-α and IL-6, as well as fibrinolysis markers plasmin antiplasmin complex and tissue-type plasminogen activator. The increased serum syndecan-1 and soluble thrombomodulin were inhibited by propranolol, and the NF-κB expression was also decreased by propranolol pretreatment. But propranolol did not alter overall mortality in rats with ATC after shock.ConclusionsBeta-adrenoceptor blockade can alleviate sympathetic hyperactivity and exert anti-inflammatory, anti-fibrinolysis, and endothelial protective effects, confirming its pivotal role in the pathogenesis of ATC. Its mechanism in ATC should be explored further.

Management of uncontrolled hemorrhagic trauma: State of the art

Uncontrolled hemorrhagic trauma represents a challenge to the intensivist as it is a leading cause of potentially preventable death in trauma patients. Recently, damage control resuscitation and hemostatic resuscitation has become the standard of care for the management of these patients. The aim of this review is to highlight the pathophysiology of acute traumatic coagulopathy and the management of these challenging patients.

Beneficial effects of prehospital versus immediate in-hospital blood products during resuscitation in two models of severe military injury

Acute trauma coagulopathy (ATC) is seen in 30 to 40% of severely injured trauma casualties. Early use of blood products is thought to attenuate ATC. This study determined the potential impact of prehospital versus immediate in-hospital packed red blood cells and fresh frozen plasma (PRBC:FFP) in two models of severe battlefield injury.

A Prospective Evaluation of Acute Traumatic Coagulopathy and Effects of Damage Control Resuscitation in Military Trauma Patients in Afghanistan

▪Hemorrhage remains the leading cause of preventable morality, resulting in the death of over a third of all trauma patients. Additionally, twenty-five percent of trauma patients present on admission with acute traumatic coagulopathy (ATC) which portends a mortality approaching fifty percent. ATC has been defined by multiple parameters including international normalized ratio (INR) >1.2, rotational thromboelastometry (ROTEM) clot amplitude at 5 minutes (CA5) ≤ 35 mm and lysis at 60 minutes (LI60) ≤ 85%. Damage control resuscitation (DCR), the practice of the Joint Theater Trauma System in Iraq and Afghanistan, is based on rapid hemorrhage control, permissive hypotension and transfusion of blood products in a ratio that aims to deliver the functionality of whole blood (1:1:1, red cells:plasma:platelets), in addition to limiting crystalloid resuscitation. ROTEM defined ATC has not been observed over time among DCR eligible combat casualties. The goal of this study was to identify ATC and the effects of DCR in trauma patients treated at level III trauma hospitals in Afghanistan.In this prospective observational study, 88 trauma patients were treated at Craig Air Force Theatre Hospital – Bagram, or Kandahar NATO Hospital in the Afghanistan Theatre. We included only patients from coalition forces identified as having injury that would result in the loss of life or total disability resulting in activation of DCR. Blood was obtained for analysis upon admission and at 6 and 24 hours after admission by a designated research team. Blood was analyzed by ROTEM with multiple assays (EXTEM, FIBTEM, APTEM); however, data was not available to the treatment team. Complete blood counts and INR were also obtained and Injury Severity Scores (ISS) were determined. Transfusion requirements of red blood cells (RBCs), platelets (PLT), fresh frozen plasma (FFP) and cryoprecipitate were recorded for the first 24 hours following admission. ROTEM changes over time were analyzed using Wilcoxon signed-rank test.Forty patients in the cohort had ROTEM (EXTEM) data obtained for evaluation as equipment was unavailable during a portion of the study. The median ISS was 21.5 (IQR 14-27). Four of the patients in the cohort died. The median admission hemoglobin and hematocrit were 11.1 g/dL (IQR 10.1-12) and 32.3% (IQR 29-34.5) respectively. The median INR was 1.3 (IQR 1.2-1.4). The median patient RBC to FFP to PLT ratio was 1:1:0.8. The median clot time (CT) and maximum clot firmness (MCF) were 58.5 sec (IQR 51-65.5) and 56 mm (IQR 51-60.5) respectively. Median CA5 was 37.5 mm (IQR 31-45). ATC as identified by CA5 ≤ 35 mm was present in 15 of 40 patients (38%) upon admission. The median CA5 of patients who met criteria for ATC on admission was 26 mm (IQR 15-34) which improved to 38 mm (IQR 33-44) at 24 hours (p < 0.01). Median LI45 was 98% (IQR 96-99). Hyperfibrinolysis as defined by LI45 ≤ 85% was observed in 4 of 40 patients (10%) upon admission which did not change significantly at 24 hours.The incidence of acute traumatic coagulopathy as defined by ROTEM parameters in this high risk military cohort appears to be higher compared to that reported for civilian populations. These data suggest that current DCR practices including a 1:1:1 RBC:FFP:PLT ratio appropriately target high risk trauma patients with ATC and that this strategy appears to be associated with a reduction in the burden of coagulopathy by 24 hours. DisclosuresNo relevant conflicts of interest to declare.

Synergistic Anticoagulant Effect of Activated Protein C and Tissue Factor Pathway Inhibitor As a Mechanism for Acute Traumatic Coagulopathy

IntroductionSevere trauma with tissue damage and shock can rapidly (<30 min) result in abnormal coagulation function which is independent of consumption or dilution effects; this acute traumatic coagulopathy (ATC) has been linked to increased transfusion requirements, morbidity and mortality. It has been suggested that ATC is caused by an increase in activated protein C (aPC; from 40 pM in normal to 175 pM) which has been identified in trauma patients [Cohen MJ, Ann Surg 255:379 (2012)].aPC inactivates factor Va (FVa) as part of normal hemostasis, but our previous results indicate that aPC at trauma levels is not sufficient to prevent coagulation, particularly when platelets are present, as platelet fVa is resistant to aPC [Campbell JE, PLoS ONE 9:e99181 (2014); Camire RM, Blood 91:2818 (1998)].Tissue Factor Pathway Inhibitor (TFPI) is an endothelial-bound protein which inhibits coagulation through effects on factor Xa and the factor VIIa-tissue factor complex. It is released in the plasma (normal level 2.5nM, pathophysiologic states including trauma up to 10nM) and is typically cleared by the liver or kidneys. TFPIα accounts for 20% of circulating TFPI and binds FV and FVa [Ndonwi M, J Thromb Haemost 10:1944 (2012)]. Recently, a truncated FV (termed FV-short) produced by an autosomal dominant mutation was found to form complexes with TFPIα, resulting in retention of TFPIα in a 10-fold increase over normal levels in affected individuals [Vincent LM, J Clin Invest 123:3777 (2013)]. FV-short has significantly reduced thrombogenic potential and, by concomitantly raising TFPIα, causes a bleeding disorder.We hypothesize that the activation of PC in acute trauma may result in the production of FV-degradation products which could stabilize TFPIα similarly to the effect of FV-short. The combination of reduced FVa and increased TFPIα may contribute to ATC.MethodsWhole blood from healthy volunteers was drawn by phlebotomy into ACD-containing tubes. Platelet-rich plasma (PRP) and platelet-poor plasma (PPP) were collected by centrifugation (200g for 10 min and 1000g for 15 min, respectively). Calibrated automated thrombogram (CAT) assays and thromboelastography (TEG) were conducted using PRP and PPP with exogenously delivered aPC (0, 100pM, or 1nM) and TFPI (0, 2.5nM, or 10nM). An immunodepleted FV-deficient (<1% normal) plasma (FVdp) was used as a reference.ResultsCAT assays verified that aPC and TFPI each delay and suppress thrombin generation in PPP in a dose-dependent manner, but the combination of aPC and TFPI had a synergistic effect at the highest doses tested. The endogenous thrombin potential (ETP) was eliminated in PPP (control: 1663 nM-min; 1nM aPC + 10nM TFPI: 0 nM-min; P<0.001); lag time was similarly affected (control: 2.5 min; 1nM aPC + 10nM TFPI: >60 min; P<0.001). FVdp also featured a delayed lag time (11.17 min, P<0.001 versus control), but the delay induced by the addition of 10nM TFPI was not nearly as severe in FVdp (19.67 min) as in the PPP + 10nM aPC sample (>60 min, P<0.001). For PRP, there was no statistical difference between control and the highest doses of aPC and TFPI in ETP (1636 nM-min versus 1388 nM-min) or lag time (8.72 min versus 9.13 min).ConclusionsIn vitro studies suggest that PC activation is not the sole cause of ATC; the concentrations of aPC measured in trauma patient blood have little effect on the coagulation potential of plasma with or without platelets when aPC is delivered exogenously. The results here demonstrate that there is a synergistic effect between aPC and TFPI. When TFPI is added to FV deficient plasma, the thrombin generation is delayed and suppressed; however, in normal plasma digested with aPC (containing fragmented FVa), the addition of TFPI is sufficient to suppress the generation of thrombin beyond the window of measurement (>60 min). The addition of platelets to the milieu eliminated the effects of aPC, TFPI, and the combination on thrombin generation, highlighting the central role of platelets in maintaining hemostatic function. DisclosuresNo relevant conflicts of interest to declare.

Trauma and Hemorrhage: Functional Characterization of Acute Traumatic Coagulopathy

BACKGROUNDTrauma is the leading cause of death in individuals under the age of 44. Acute traumatic coagulopathy (ATC) occurs when severe injury is combined with shock and results in a hypocoagulable state resulting in increased bleeding, increased resuscitation requirements and worsened outcomes including a 4-fold increase in mortality. Our group has implicated protein C activation as a likely mechanism for ATC. We have evaluated whether activated protein C (APC) induces coagulopathy through cleavage of factor (f)V/Va by systematically evaluating 4 groups of increasing level of traumatic coagulopathy. METHODSFrom a large cohort of plasma samples collected from trauma patients at time of admission to a major level 1 trauma sample, 80 plasma samples distributed equally between the following trauma severity groupings were selected: Group 1: ISS ≤ 15 and BD > -6 (less injured, no shock); Group 2: ISS ≤ 15 and BD ≤ -6 (less injured, with shock); Group 3:ISS > 15 and BD > -6 (more injured, no shock); Group 4:ISS > 15 and BD ≤ -6 (more injured, with shock). Each plasma sample was evaluated for plasma composition (functional activity of fII, fV, fVII, fVIII, fIX, fX, antithrombin, tissue factor pathway inhibitor, protein C), plasmin-antiplasmin complex (PAP), α-thrombin-antithrombin complex (TAT), and mathematically modeled thrombin generation. Quantitative Western blot analyses were performed using an anti-fV antibody directed at the fV heavy chain (residues 307-506). Intact fV levels were quantified via densitometry to determine whether levels were the within range characterizing healthy individuals and the presence of APC derived and other degradation products assessed via mobility comparison to purified standards. Demographic, resuscitation, and outcomes data were collected in parallel. RESULTSAll data were quantitated and evaluated for having concentrations above and/or below the normal range for each analyte. For PAP, Groups 3 (18/20) and 4 (17/20) had a greater percentage of individuals over Groups 1 (5/20) and 2 (6/20) that were above the normal range. Groups 3 (12/20) and 4 (12/20) also had a higher percentage of detectable α-TAT over Groups 1 (5/20) and 2 (2/20). For fV antigen, Group 4 had 16/20 individuals that were below the lower limit of normal. Groups 1, 2 and 3 were all similar with 5/20 below the limit of normal but had 3-5/20 above the upper limit of normal. Products associated with activated protein C were found (fV 30kD fragment) but also other cleavage products not associated with APC were observed. There was more fV fragmentation in Group 4, with the 30kD fragment being detected in 10 individuals. No detectable fV 30kD fragments were detected in either Groups 1 or 2. In terms of the overall plasma composition there is a large variation in functional activity, especially fVIII. Group 4 showed a pattern of all factors reduced except for TFPI versus Groups 1,2, 3. These pro and anticoagulant differences between individuals results in heterogenous modeled thrombin generation profiles with the majority all being procoagulant versus a normal control. Group 4 had a higher percentage of individuals that had a prolonged clot time and a pattern towards diminished thrombin generation. CONCLUSIONSThese data suggest that the combination of injury and shock were associated with altered PAP, TAT and functional activity changes of the plasma composition resulting in hemorrhagic thrombin generation profiles. In addition the most severely injured and shocked patients had less fVa activity, less intact fV and increased degradation of fV/fVa suggesting the presence of increased APC activity in mediating ATC. DisclosuresNo relevant conflicts of interest to declare.

Global Activation of Coagulation Is the Initiating Event of Acute Coagulopathy of Trauma As Modeled By Hemorrhage and Lower Body Negative Pressure in Baboons

Up to 50% of preventable trauma deaths are due to truncal hemorrhage resulting in cardiovascular collapse. Lower body negative pressure (LBNP) causes central hypovolemia in humans, resulting in coagulation changes, platelet activation, and fibrinolysis. The model allows investigators to study impending hemorrhagic shock in a minimally invasive human model, but correlations to changes in clotting and lysis due to hemorrhage are not fully described. Published human data to date has not discriminated between altered coagulation due to the LBNP method versus changes attributable to incipient hemorrhagic shock. We measured multiple coagulation parameters in 16 baboons undergoing hemorrhage followed by LBNP and hypothesized that this model elicits early changes associated with acute coagulopathy due to hemorrhage.Baboons underwent incremental hemorrhage (HEM) under an ACURO-approved protocol, followed by LBNP 2-4 weeks later. Blood was sampled at baseline (T0) and after approximately 18.75% (T1), and 25% (T2) blood loss (or until presyncope), and at recovery (T3). LBNP levels were determined by matching the pulse and central venous pressures elicited by hemorrhage. Measurements included: complete blood count; blood chemistries; and coagulations tests. Parameters measured by thromboelastography (TEG) included: R-time, K-time, angle, maximum amplitude (MA), and lysis at 30 and 60 minutes (LY30, LY60). Coagulation factors were quantified over time during both experiments (STA-R Evolution, STAGO).Platelet count was measured and response to agonists (ADP, collagen, TRAP) assessed with impedance aggregometry (Multiplate, Roche Diagnostics). Markers of platelet activation were evaluated under flow cytometry (P-selectin, PAC-1, and leukocyte-platelet aggregates (CD45:CD41)).LBNP and hemorrhage caused activation of the coagulation system over time as measured by TEG R-time (HEM: T0=5.8±0.3 s; T2=4.7±0.3 s; LBNP: T0=6.5±0.3 s; T2=5.1±0.3 s; p<0.001), an increase in velocity of clot formation as measured by angle (HEM: T0=67±1°; T2=71±2°; LBNP: T0=67±1°; T3=70±1°; p=0.013), and clot strength as measured by MA (HEM: T0=60±2 mm; T2=66±2 mm; LBNP: T0=66±2 mm; T3=69±2 mm; p<0.003). R-time and angle differences between experiments were not significant (p≥0.05), whereas clot strength (MA) was higher in the LBNP experiment (p=0.015). Fibrinolysis at 30 and 60 minutes decreased over time with both study treatments (HEM LY30: T0=3.6±0.8%; T3=0.3±0.8%; LBNP LY30: T0=4.2±0.8%; T3=0.8±0.8%; HEM LY60: T0=7.2±1.3%; T3=1.8±1.4%; LBNP LY60: T0=7.3±1.3%; T3=2.9±1.3%; p<0.001), but effects between experiments were not significant (p≥0.05). D-Dimer measurements were not consistent with TEG lysis data, but rather increased over time during both experiments (HEM: T0=0.43±0.16 µg/ml; T3=0.96±0.16 µg/ml; LBNP: T0=0.58±0.16 µg/ml; T2=0.93±0.16 µg/ml; p<0.001). The coagulations factors V (FV), and VIII (VIII) changed over time; however effects were opposite, decreasing during hemorrhage and increasing during LBNP (HEM FV: T0=85±4%; T3=79±4%; LBNP FV: T0=88±4%; T3=102±4%; HEM FVIII: T0=122±7%; T3=117±7%; LBNP FVIII: T0=126±7%; T3=135±7%; p<0.001 for both factors). In contrast, Protein C (PC) levels decreased during both experiments, although baseline levels differed (HEM PC: T0=99±4%; T3=79±4%; LBNP PC: T0=113±4%; T3=99±4%; p<0.001). Fibrinogen decreased during recovery, but only during the HEM experiment (HEM: T0=211±20 mg/dl; T3=157±21 mg/dl, p<0.001; LBNP: T0=217±20 mg/dl; T3=216±20 mg/dl; p≥0.05). Platelet count did not change significantly over time during either experiment, but differences between HEM and LBNP were significant largely due to baseline effects (HEM: T0=199±12x109/mm3; LBNP: T0=234±12x109/mm3; p<0.001). Platelet aggregation (U) did not change over time or between groups (p≥0.05).LBNP-induced central hypovolemia and hemorrhage in the absence of tissue damage caused activation of the coagulation system in baboons, as well as increased clot formation velocity and strength. TEG and and Protein C results matched most closely between experiments and can be used with LBNP to study pre-hospital changes due blood loss. Lysis data, in contrast to human data, was contradictory. Central hypovolemia due to severe hemorrhage and LBNP caused global activation of coagulation function, indicating that this is the initiating event in acute coagulopathy of trauma. DisclosuresNo relevant conflicts of interest to declare.

Diet-induced obesity prevents the development of acute traumatic coagulopathy.

Obesity and hemorrhagic shock following trauma are predictors of mortality but have conflicting effects on coagulation. Following hemorrhage, tissue injury and hypoperfusion lead to acute traumatic coagulopathy (ATC), producing a hypocoagulable state. Inversely, obesity promotes clotting and impairs fibrinolysis to yield a hypercoagulable state. High rates of venous thromboembolism, organ failure, and early mortality may be caused by hypercoagulability in obese patients. We hypothesize that obesity prevents the development of ATC following injury-induced hemorrhagic shock. Male Sprague-Dawley rats (250-275 g) were fed a high-fat diet (32%kcal from fat) for 4 weeks to 6 weeks and diverged into obesity-resistant (OR, n = 9) and obesity-prone (OP, n = 9) groups. Age-matched control (CON) rats were fed normal diet (10% kcal from fat, n = 9). Anesthetized rats were subjected to an uncontrolled hemorrhage by a Grade V splenic injury to a mean arterial pressure (MAP) of 40 mm Hg. Hypotension (MAP, 30-40 mm Hg) was maintained for 30 minutes to induce shock. MAP, heart rate, lactate, base excess, cytokines, blood loss, and thrombelastography (TEG) parameters were measured before and after hemorrhagic shock. At baseline, OP rats exhibited a shorter time to 20-mm clot (K), and higher rate of clot formation (α angle), clot strength (maximal amplitude), and coagulation index, compared with the CON rats (p < 0.05), indicating enhanced coagulation. Physiologic parameters following shock were similar between groups. In the CON and OR rats, shock prolonged the time to clot initiation (R) and K and decreased α angle and coagulation index (all p < 0.05 vs. baseline). In contrast, shock had no effect on these TEG parameters in the OP rats. Maximal amplitude was the only TEG parameter affected by shock in the OP rats, which was decreased in all groups. Obesity prevents the development of ATC following hemorrhage shock. Complications associated with obesity following hemorrhagic shock may be attributed to the preserved hypercoagulable state.

The pathogenesis of traumatic coagulopathy.

Over the last 10years, the management of major haemorrhage in trauma patients has changed radically. This is mainly due to the recognition that many patients who are bleeding when they come in to the emergency department have an established coagulopathy before the haemodilution effects of fluid resuscitation. This has led to the use of new terminology: acute traumatic coagulopathy, acute coagulopathy of trauma shock or trauma-induced coagulopathy. The recognition of acute traumatic coagulopathy is important, because we now understand that its presence is a prognostic indicator, as it is associated with poor clinical outcome. This has driven a change in clinical management, so that the previous approach of maintaining an adequate circulating volume and oxygen carrying capacity before, as a secondary event, dealing with coagulopathy, has changed to haemostatic resuscitation as early as possible. While there is as yet no universally accepted assay or definition, many experts use prolongation of the prothrombin time to indicate that there is, indeed, a coagulopathy. Hypoxia, acidosis and hypothermia and hormonal, immunological and cytokine production, alongside consumption and blood loss, and the dilutional effects of resuscitation may occur to varying extents depending on the type of tissue damaged, the type and extent of injury, predisposing to, or amplifying, activation of coagulation, platelets, fibrinolysis. These are discussed in detail within the article.

Acute traumatic coagulopathy.

Mortality from trauma remains a global public health challenge, with most preventable deaths due to bleeding. The recognition of acute traumatic coagulopathy as a distinct clinical entity characterized by early coagulation dysfunction, arising prior to medical intervention, has revolutionized trauma management over the last decade. The aim of this article is to review our current understanding of acute traumatic coagulopathy. We focus on recent advances in the mechanistic understanding of acute traumatic coagulopathy, particularly the changes in coagulation factors, physiological anticoagulants, endothelial activation, fibrinolysis and platelet dysfunction. Evolving diagnostic and therapeutic approaches are discussed, including viscoelastic coagulation monitoring and the role of tranexamic acid and blood products. Emphasis is now placed on early prevention, diagnosis, and aggressive initial treatment of coagulopathy and fibrinolysis with haemostatic blood products and tranexamic acid in addition to red cell units in order to reduce bleeding and improve clinical outcomes.