Impact of soluble thrombomodulin and activated protein C on dynamic hemostatic function in trauma: a focus on thrombin generation and clot lysis.

Trauma induced coagulopathy (TIC) describes a complex set of coagulation changes affecting severely injured patients. The thrombomodulin-protein C axis is believed to be central to the evolution of TIC. Soluble thrombomodulin (sTM) levels are elevated after injury. Our objectives were to explore whether sTM (at concentrations found in patients after injury) plays an important role in TIC, and specifically to evaluate the effect of sTM and activated protein C (APC) on thrombin generation (TG) and clot lysis time (CLT). Plasma from healthy volunteers was spiked with rising concentrations of sTM and APC and the effects on TG and CLT were analysed. Plasma samples from a cohort of trauma patients were evaluated using TG and CLT, and results correlated to clinical parameters and FVIII, FV, APC, sTM and fibrinolytic measures. Increasing sTM concentrations in volunteer plasma led to reductions in ETP and prolongation of 50% CLT times, in a dose dependent manner. No effect on TG or CLT was seen with rising APC concentrations. In 91 trauma patients, higher sTM values were associated with greater, rather than reduced, ETP (median 1483 vs. 1681 nM/min) and longer 50% CLT times (41.9 vs. 54.0 mins). In conclusion, sTM concentrations, across trauma ranges, impact both TG and 50% CLT times, unlike APC. Despite increased circulating sTM levels, the overriding dynamic coagulation effects seen after injury are: (a) accelerated thrombin generation and (b) increased rates of fibrinolysis. We find no evidence for sTM as the major determinant of the coagulation changes seen in early TIC.

Trauma induced coagulopathy is limited to only one out of four shock induced endotheliopathy (SHINE) phenotypes among moderate-severely injured trauma patients: an exploratory analysis.

BACKGROUND: Trauma induced coagulopathy remains to be an important cause of high transfusion requirements and mortality and shock induced endotheliopathy (SHINE) has been implicated. METHODS: European multicenter observational study of adult trauma patients with injury severity score ≥ 16 arriving within 2 h from injury to the trauma centers. Admission blood samples obtained were used for analysis of the SHINE biomarkers (syndecan-1, soluble thrombomodulin, adrenaline) and extensive analysis of coagulation, -and fibrinolytic factors together with collection of clinical data. Hierarchical clustering of the SHINE biomarkers was used to identify the SHINE phenotypes. RESULTS: The 313 patients clustered into four SHINE phenotypes. Phenotype 2, having the highest glycocalyx shedding, encompassing 22% of the whole cohort, had severe coagulopathy with lower levels of prothrombin, FV, IX, X, XI and severe hyperfibrinolysis with higher plasmin - alpha 2-antiplasmin (PAP) - and tPA levels and lower alpha2 - antiplasmin levels. This phenotype had significantly higher transfusion requirements and higher mortality (39% vs. 23%, 15% and 14%) but similar injury severity score (ISS) compared to the others phenotypes. CONCLUSIONS: Hierarchical clustering identified four SHINE phenotype in a cohort of trauma patients. Trauma induced coagulopathy was confined to only one of the SHINE phenotypes, encompassing 22% of the total cohort. This phenotype was characterized by severe hypocoagulability and hyperfibrinolysis, which translated to significantly higher transfusion requirements and higher mortality compared to the other SHINE phenotypes with similar injury severity, warranting further investigation.

Traumatic coagulopathy in the older patient: analysis of coagulation profiles from the Activation of Coagulation and Inflammation in Trauma-2 (ACIT-2) observational, multicenter study.

BACKGROUND: Most studies describing traumatic coagulopathy have used data from patient cohorts with an average age of between 35 and 45 years. The last 10 years has seen a steep increase in the number of patients admitted with significant injury and bleeding who are older than the age of 65 years. Many coagulation protein levels alter significantly with normal aging, and it is possible that traumatic coagulopathy has a different signature with age. OBJECTIVES: The aim of this study was to report the coagulation profiles, including standard and extended laboratory, as well as viscoelastic hemostatic assays, stratified according to age to explore age-related differences in hemostatic capability. METHODS: In total, 1576 patients were analyzed from 6 European level 1 trauma centers. RESULTS: As age increased, there was evidence of higher fibrinogen, greater thrombin generation, greater clotting factor consumption, and greater activation of fibrinolysis. Despite this, shock and severe injury led to the same pattern of changes within age groups: lower procoagulant factors (including fibrinogen), increased fibrinolysis, and higher levels of activated protein C. Thromboelastography and rotational thromboelastometry tests detected traumatic coagulopathy with prolongation of R/clotting time and reductions in clot amplitudes in each age cohort. Advancing age strongly correlated with higher fibrinogen levels and greater fibrinolysis. CONCLUSION: Age-related coagulation changes are evident in injured patients. Broadly, similar patterns of coagulation abnormalities are seen across age groups following severe injury/shock, but thresholds for single clotting factors differ. Age-related differences may need to be considered when clinical treatments (eg, transfusion therapy) are indicated.

A Delphi study to establish consensus on a definition of major bleeding in adult trauma.

BACKGROUND: The majority of potentially preventable deaths in trauma are due to uncontrolled hemorrhage and occur early after injury. How major bleeding is defined is integral to early identification and treatment of this group of high-risk patients. However, there is no consensus on a definition of major bleeding in trauma. The aim of this Delphi study was to develop a consensus definition for research, with transfusion used as a surrogate marker of bleeding. STUDY DESIGN AND METHODS: Trauma experts from three international groups were invited to take part in an online Delphi survey. Over the course of four rounds, the group developed a number of definitions of major bleeding and reached consensus on a new definition. RESULTS: Forty-four trauma experts agreed to become members of the Delphi panel, and 30 of 44 (68%) completed all four rounds. The panel agreed to exclude the historical massive transfusion definition (≥10 units of red blood cells within 24 hours). Consensus was reached on a new definition for use in clinical research: 4 or more units of any blood component within 2 hours of injury. CONCLUSION: This Delphi process has yielded a pragmatic transfusion-based definition of major bleeding. The consensus definition differs from historical definitions: a shorter time frame to reflect the acuity of bleeding, and multiple blood components in keeping with a balanced approach to resuscitation. The definition developed may be best suited to mature trauma systems (reflecting the demographics of the expert panel), and could be used to guide registry data recording and to characterize patients at risk of major bleeding.

Transfusion strategies for major haemorrhage in trauma.

Trauma is a leading cause of death worldwide in persons under 44 years of age, and uncontrolled haemorrhage is the most common preventable cause of death in this patient group. The transfusion management of trauma haemorrhage is unrecognisable from 20 years ago. Changes in clinical practice have been driven primarily by an increased understanding of the pathophysiology of trauma-induced coagulopathy (TIC), which is associated with poor clinical outcomes, including a 3- to 4-fold increased risk of death. Targeting this coagulopathy alongside changes to surgical and anaesthetic practices (an overarching strategy known as damage control surgery/damage control resuscitation) has led to a significant reduction in mortality rates over the last two decades. This narrative review will discuss the transfusion practices that are currently used for trauma haemorrhage and the evidence that supports these practices.

Transfusion strategies for traumatic coagulopathy.

Uncontrolled bleeding is the most common preventable cause of death for patients with severe injury. Coagulopathy inevitably accompanies severe bleeding, exacerbated by the ongoing blood loss and the treatments administered. There is debate about the underlying pathophysiological mechanisms of early traumatic coagulopathy and uncertainty about whether injury induces a unique coagulopathy when compared to other forms of major haemorrhage. This review describes current understanding of the coagulopathy of major blood loss and focuses on the early coagulation changes that occur following severe injury. It then reports on the contemporary management of coagulopathic bleeding using new transfusion strategies. Finally this review presents some practical points to the delivery of transfusion for major blood loss in the modern hospital setting.