The increased morbidity and mortality associated with coagulopathy and thrombocytopenia after trauma are well described. However, few studies have assessed platelet function after injury.
Blood ...samples were prospectively collected from 101 patients with critical injury and trauma on arrival to the emergency department and serially after admission to a Level I urban trauma intensive care unit from November 2010 to October 2011 and functionally assayed for responsiveness to adenosine diphosphate, thrombin receptor-activating peptide, arachidonic acid (AA), and collagen using multiple electrode impedance aggregometry.
Of the 101 enrolled patients, 46 (45.5%) had below-normal platelet response to at least one agonist ("platelet hypofunction") at admission, and 92 patients (91.1%) had platelet hypofunction some time during their intensive care unit stay. Admission platelet hypofunction was associated with low Glasgow Coma Scale score and a nearly 10-fold higher early mortality. Logistic regression identified admission Glasgow Coma Scale (odds ratio, 0.819; p = 0.008) and base deficit (odds ratio, 0.872; p = 0.033) as independent predictors of platelet hypofunction. Admission AA and collagen responsiveness were significantly lower for patients who died (p < 0.01), whereas admission platelet counts were similar (p = 0.278); Cox regression confirmed thrombin receptor-activating peptide, AA, and collagen responsiveness as independent predictors of in-hospital mortality (p < 0.05). Receiver operating characteristic analysis identified admission AA and collagen responsiveness as negative predictors of both 24-hour (AA area under the curve AUC, 0.874; collagen AUC, 0.904) and in-hospital mortality (AA AUC, 0.769; collagen AUC, 0.717).
In this prognostic study, we identify clinically significant platelet dysfunction after trauma in the presence of an otherwise reassuring platelet count and standard clotting studies, with profound implications for mortality. Multiple electrode impedance aggregometry reliably identifies this dysfunction in injured patients, and admission AA and collagen responsiveness are sensitive and specific independent predictors of both early and late mortality.
Thromboelastography (TEG) is used to diagnose perturbations in clot formation and lysis that are characteristic of acute traumatic coagulopathy. With novel functional fibrinogen (FF) TEG, fibrin- and ...platelet-based contributions to clot formation can be elucidated to tailor resuscitation and thromboprophylaxis. We sought to describe the longitudinal contributions of fibrinogen and platelets to clot strength after injury, hypothesizing that low levels of FF and a low contribution of fibrinogen to clot strength on admission would be associated with coagulopathy, increased transfusion requirements, and worse outcomes.
A total of 603 longitudinal plasma samples were prospectively collected from 251 critically injured patients at a single Level 1 trauma center from 0 hour to 120 hours. TEG maximal amplitude (MA), FF MA, FF levels, von Clauss fibrinogen, and standard coagulation measures were performed in parallel. Percentage contributions of FF (%MA(FF)) and platelets (%MA(platelets)) were calculated as each MA divided by overall kaolin TEG MA.
Coagulopathic patients (international normalized ratio ≥ 1.3) had significantly lower admission %MA(FF) than noncoagulopathic patients (24.7% vs. 31.2%, p < 0.05). Patients requiring plasma transfusion had a significantly lower admission %MA(FF) (26.6% vs. 30.6%, p < 0.05). Higher admission %MA(FF) was predictive of reduced mortality (hazard ratio, 0.815, p < 0.001). %MA(platelets) was higher than %MA(FF) at all time points, decreased over time, and stabilized at 72 hours (69.4% at 0 hour, 56.2% at 72 hours). In contrast, %MA(FF) increased over time and stabilized at 72 hours (30.6% at 0 hour, 43.8% at 72 hours).
FF TEG affords differentiation of fibrin- versus platelet-based clot dynamics. Coagulopathy and plasma transfusion were associated with a lower %MA(FF). Despite this importance of fibrinogen, platelets had a greater contribution to clot strength at all time points after injury. This suggests that attention to these relative contributions should guide resuscitation and thromboprophylaxis and that antiplatelet therapy may be of underrecognized importance to thromboprophylaxis after trauma.
Prognostic study, level III.
Recent studies identify a survival benefit from the administration of antifibrinolytic agents in patients with severe injury and trauma. However, identification of hyperfibrinolysis requires ...thromboelastography, which is not widely available. We hypothesized that analysis of patients with thromboelastography-diagnosed hyperfibrinolysis would identify clinical criteria for empiric antifibrinolytic treatment in the absence of thromboelastography.
From November 2010 to March 2012, serial blood samples were collected from 115 patients with critical injury on arrival to the emergency department of an urban Level I trauma center. Rotational thromboelastography was performed to assess viscoelastic properties of clot formation in the presence and absence of aprotinin to identify treatable hyperfibrinolysis. For 20 patients identified with treatable hyperfibrinolysis, clinical predictors were investigated using receiver operating characteristic analysis.
Of the 115 patients evaluated, 20% had hyperfibrinolysis, defined as an admission maximal clot lysis of 10% or higher, reversible by aprotinin treatment. Patients with hyperfibrinolysis had significantly lower temperature, pH, and platelet counts and higher international normalized ratio, activated partial thromboplastin time, and D-dimer. Hyperfibrinolysis was associated with multiorgan failure (63.2% vs. 24.6%, p = 0.004) and mortality (52.2% vs. 12.9%, p < 0.001). We then evaluated all non-rotational thromboelastography clinical and laboratory parameters predictive of hyperfibrinolysis using receiver operating characteristic analysis to evaluate potential empiric treatment guidelines. The presence of hypothermia (temperature ≤36.0°C), acidosis (pH ≤7.2), relative coagulopathy (international normalized ratio ≥1.3 or activated partial thromboplastin time ≥30), or relative thrombocytopenia (platelet count ≤200) identified hyperfibrinolysis with 100% sensitivity and 55.4% specificity (area under the curve, 0.777).
Consideration of empiric antifibrinolytic therapy is warranted for patients with critical injury and trauma who present with acidosis, hypothermia, coagulopathy, or relative thrombocytopenia. These clinical predictors identified hyperfibrinolysis with 100% sensitivity while simultaneously eliminating 46.6% of inappropriate therapy compared with the empiric treatment of all injured patients. These criteria will facilitate empiric treatment of hyperfibrinolysis for clinicians without access to thromboelastography.
Prognostic study, level III.
IMPORTANCE The evolution of damage control strategies has led to significant changes in the use of resuscitation after traumatic injury. OBJECTIVE To evaluate changes in the administration of fluids ...and blood products, hypothesizing that a reduction in crystalloid volume and a reduced red blood cell (RBC) to fresh frozen plasma (FFP) ratio over the last 7 years would correlate with better resuscitation outcomes. DESIGN Observational prospective cohort study. SETTING Urban level I trauma center. PARTICIPANTS A total of 174 trauma patients receiving a massive transfusion (>10 units of RBCs in 24 hours) or requiring the activation of the institutional massive transfusion protocol from February 2005 to June 2011. EXPOSURE Patients had to either receive a massive transfusion or require the activation of the institutional massive transfusion protocol. MAIN OUTCOMES AND MEASURES In-hospital mortality. RESULTS The mean (SD) Injury Severity Score was 28.4 (16.2), the mean (SD) base deficit was −9.8 (6.3), and median international normalized ratio was 1.3 (interquartile range, 1.2-1.6); the mortality rate was 40.8%. Patients received a median of 6.1 L of crystalloid, 13 units of RBCs, 10 units of FFP, and 1 unit of platelets over 24 hours, with a mean RBC:FFP ratio of 1.58:1. The mean 24-hour crystalloid infusion volume and number of the total blood product units given in the first 24 hours decreased significantly over the study period (P < .05). The RBC:FFP ratio decreased from a peak of 1.84:1 in 2007 to 1.55:1 in 2011 (P = .20). Injury severity and mortality remained stable over the study period. When adjusted for age and injury characteristics using Cox regression, each decrease of 0.1 achieved in the massive transfusion protocol’s RBC:FFP ratio was associated with a 5.6% reduction in mortality (P = .005). CONCLUSIONS AND RELEVANCE There has been a shift toward a reduced crystalloid volume and the recreation of whole blood from component products in resuscitation. These changes are associated with markedly improved outcomes and a new paradigm in the resuscitation of severely injured patients.
Mounting evidence highlighting the benefits of hemostatic resuscitation has led to a renewed interest in whole blood (WB) and reconstituted WB (RWB). However, few data exist to characterize the ...clotting profiles of these variants. This study characterizes banked WB variants and RWB in standard 1:1:1 and 2:1:1 transfusion ratios of packed red blood cells, fresh frozen plasma, and platelets (PLTs). We hypothesized that the global hemostatic profile of 1:1:1 RWB is superior to 2:1:1 RWB and that PLT-modified WB (MWB) is superior to 1:1:1 RWB.
Twenty-three units of packed red blood cells, fresh frozen plasma, and PLTs were obtained from the regional blood collection center and mixed to create 23 1:1:1 and 23 2:1:1 RWB units. Freshly donated WB units were obtained and used to create 11 of each nonmodified WB (NMWB) (room temperature and cooled) and MWB (room temperature and cooled) variants. International normalized ratio (INR)/partial thromboplastin time (PTT), complete blood cell count, functional studies, and an extensive panel of procoagulant and anticoagulant factor assays were performed on all products.
The 1:1:1 RWB had significantly lower INR and PTT (1.31 vs. 1.55, p = 0.0029; 42 seconds vs. 50 seconds, p = 0.0008) and higher activity of factors II, V, VII, VIII, IX, and X; antithrombin III, as well as protein C and higher fibrinogen levels than did 2:1:1 RWB (factor IX, 86% vs. 70%, p = 0.0313; fibrinogen, 242 mg/dL vs. 202 mg/dL, p = 0.0385). There were no differences in INR/PTT or factor activity between MWB and NMWB. However, MWB had greater maximum clot firmness (MCF) by rotational thromboelastometry tissue factor-activated extrinsic clotting cascade measures than did NMWB (MCF, 61 mm vs. 50 mm, p = 0.0031). MWB also had greater MCF by rotational thromboelastometry tissue factor-activated extrinsic clotting cascade measures than did 1:1:1 RWB (MCF, 61 mm vs. 45 mm, p = 0.0005).
Although 1:1:1 RWB had a superior clotting profile relative to 2:1:1 RWB, MWB exhibited even better global hemostasis than did 1:1:1 RWB. Characterization of factor-level and functional clotting differences between WB variants is imperative for understanding the clinical benefits of hemostatic resuscitation.
Acute respiratory distress syndrome (ARDS) following trauma is historically associated with crystalloid and blood product exposure. Advances in resuscitation have occurred over the last decade, but ...their impact on ARDS is unknown. We sought to investigate predictors of postinjury ARDS in the era of hemostatic resuscitation.
Data were prospectively collected from arrival to 28 days for 914 highest-level trauma activations who required intubation and survived more than 6 hours from 2005 to 2016 at a Level I trauma center. Patients with ratio of partial pressure of oxygen to fraction of inspired oxygen of 300 mmHg or less during the first 8 days were identified. Two blinded expert clinicians adjudicated all chest radiographs for bilateral infiltrates in the first 8 days. Those with left-sided heart failure detected were excluded. Multivariate logistic regression was used to define predictors of ARDS.
Of the 914 intubated patients, 63% had a ratio of partial pressure of oxygen to fraction of inspired oxygen of 300 or less, and 22% developed ARDS; among the ARDS cases, 57% were diagnosed early (in the first 24 hours), and 43% later. Patients with ARDS diagnosed later were more severely injured (ISS 32 vs. 20, p = 0.001), with higher rates of blunt injury (84% vs. 72%, p = 0.008), chest injury (58% vs. 36%, p < 0.001), and traumatic brain injury (72% vs. 48%, p < 0.001) compared with the no ARDS group. In multivariate analysis, head/chest Abbreviated Injury Score scores, crystalloid from 0 to 6 hours, and platelet transfusion from 0 to 6 hours and 7 to 24 hours were independent predictors of ARDS developing after 24 hours.
Blood and plasma transfusion were not independently associated with ARDS. However, platelet transfusion was a significant independent risk factor. The role of platelets warrants further investigation but may be mechanistically explained by lung injury models of pulmonary platelet sequestration with peripheral thrombocytopenia.
Prognostic study, level IV.
OBJECTIVE:To investigate the natural history of coagulation factor perturbation after injury and identify longitudinal differences in clotting factor repletion by red blood cell:fresh frozen plasma ...(RBC:FFP) transfusion ratio.
BACKGROUND:Hemostatic transfusion ratios of RBC to FFP approaching 1:1 are associated with a survival advantage in traumatic hemorrhage, even in patients with normal coagulation studies.
METHODS:Plasma was prospectively collected from 336 trauma patients during their intensive care unit stay for up to 72 hours from February, 2005, to October, 2011. Standard coagulation studies as well as pro- and anticoagulant clotting factors were measured. RBC:FFP transfusion ratios were calculated at 6 hours after arrival and dichotomized into “low ratio” (RBC:FFP ≤ 1.5:1) and “high ratio” (RBC:FFP > 1.5:1) groups.
RESULTS:Factor-level measurements from 193 nontransfused patients provide an early natural history of clotting factor-level changes after injury. In comparison, 143 transfused patients had more severe injury, prolonged prothrombin time and partial thromboplastin time (PTT), and lower levels of both pro- and anticoagulants up to 24 hours. PTT was prolonged up to 12 hours and only returned to admission baseline at 48 hours in “high ratio” patients versus correction by 6 hours in “low ratio” patients. Better repletion of factors V, VIII, and IX was seen longitudinally, and both unadjusted and injury-adjusted survival was significantly improved in “low ratio” versus “high ratio” groups.
CONCLUSIONS:Resuscitation with a “low ratio” of RBC:FFP leads to earlier correction of coagulopathy, and earlier and prolonged repletion of some but not all procoagulant factors. This prospective evidence suggests hemostatic resuscitation as an interim standard of care for transfusion in critically injured patients pending the results of ongoing randomized study.
Alcohol has been associated with altered viscoelastic testing in trauma, indicative of impaired coagulation. Such alterations, however, show no correlation to coagulopathy-related outcomes. Other ...data suggest that alcohol may inhibit fibrinolysis. We sought to clarify these mechanisms after traumatic injury using thromboelastometry (ROTEM), hypothesizing that alcohol-related clot formation impairment may be counter-balanced by inhibited fibrinolysis.
Laboratory, demographic, clinical, and outcome data were prospectively collected from 406 critically injured trauma patients at a Level I trauma center. ROTEM and standard coagulation measures were conducted in parallel. Univariate comparisons were performed by alcohol level (EtOH), with subsequent regression analysis.
Among 274 (58%) patients with detectable EtOH, median EtOH was 229 mg/dL. These patients were primarily bluntly injured and had lower GCS (p < 0.05) than EtOH-negative patients, but had similar admission pH and injury severity (p = NS). EtOH-positive patients had prolonged ROTEM clotting time and rate of clot formation time (CFT/α); they also had decreased fibrinolysis (max lysis %; all p < 0.05). In linear regression, for every 100 mg/dL increase in EtOH, clotting time increased by 13 seconds and fibrinolysis decreased by 1.5% (both p < 0.05). However, EtOH was not an independent predictor of transfusion requirements or mortality. In high-EtOH patients with coagulopathic ROTEM tracings, transfusion rates were significantly lower than expected, relative to EtOH-negative patients with similar ROTEM findings.
As assayed by ROTEM, alcohol appears to have a bidirectional effect on coagulation in trauma, both impairing initial clot formation and inhibiting fibrinolysis. This balancing of mechanisms may explain lack of correlation between altered ROTEM and coagulopathy-related outcomes. Viscoelastic testing should be used with caution in intoxicated trauma patients.
Epidemiological study, level III.
Acute lung injury following trauma remains a significant source of morbidity and mortality. Although multiple trauma studies have used hypoxemia without radiographic adjudication as a surrogate for ...identifying adult respiratory distress syndrome (ARDS) cases, the differences between patients with hypoxemia alone and those with radiographically confirmed ARDS are not well described in the literature. We hypothesized that nonhypoxemic, hypoxemic, and ARDS patients represent distinct groups with unique characteristics and predictors.
Laboratory, demographic, clinical, and outcomes data were prospectively collected from 621 intubated, critically injured patients at an urban Level 1 trauma center from 2005 to 2013. Hypoxemia was defined as PaO2/FIO2 ratio of 300 or lower. ARDS was adjudicated using Berlin criteria, with blinded two-physician consensus review of chest radiographs. Group comparisons were performed by hypoxemia and ARDS status. Logistic regression analyses were performed to separately assess predictors of hypoxemia and ARDS.
Of the 621 intubated patients, 64% developed hypoxemia; 46% of these hypoxemic patients developed ARDS by chest radiograph. Across the three groups (no hypoxemia, hypoxemia, ARDS), there were no significant differences in age, sex, or comorbidities. However, there was an increase in severity of shock, injury, and chest injury by group, with corresponding trends in transfusion requirements and volume of early fluid administration. Outcomes followed a similar stepwise pattern, with pneumonia, multiorgan failure, length of intensive care unit stay, number of ventilator days, and overall mortality highest in ARDS patients. In multiple logistic regression, early plasma transfusion, delayed crystalloid administration, body mass index, and head and chest injury were independent predictors of hypoxemia, while head and chest injury, early crystalloid infusion, and delayed platelet transfusion were independent predictors of ARDS.
Hypoxemia and ARDS exist on a spectrum of respiratory dysfunction following trauma, with increasing injury severity profiles and resuscitation requirements. However, they also represent distinct clinical states with unique predictors, which require directed research approaches and targeted therapeutic strategies.
Prognostic and epidemiologic study, level III.
The effects of alcohol on coagulation after trauma remain unclear. In vitro studies show that alcohol may decrease clot strength and inhibit fibrinolysis. Observational data indicate that alcohol ...leads to altered thrombelastography (TEG) parameters indicative of impaired clot formation. Clinical studies have been inconclusive to date.
Longitudinal plasma samples were prospectively collected from 415 critically injured trauma patients at a single Level 1 trauma center and were matched with demographic and outcome data. Citrated kaolin TEG and standard coagulation measures were performed in parallel. Univariate and group comparisons were performed by alcohol status, with subsequent linear and logistic regression analysis.
A total of 264 patients (63.6%) had detectable blood alcohol levels (EtOH, >10 mg/dL). These patients were primarily male (87% vs. 79%), were bluntly injured (77% vs. 59%), and had lower median Glasgow Coma Scale (GCS) score (9.5 vs. 14, all p < 0.05) than the EtOH-negative patients. There were no notable differences in pH (7.29 vs. 7.31, p = nonsignificant) or injury severity (median Injury Severity Score ISS, 11 vs. 14; p = nonsignificant) between the groups. The alcohol-positive patients had a prolonged TEG citrated kaolin R-time (reaction time), or time to initial clot formation (5.91 minutes vs. 4.43 minutes, p = 0.013), prolonged K-time (kinetics time), or time to fixed level of clot strength (1.77 minutes vs. 1.43 minutes, p = 0.036), and decreased α angle (66.5 degrees vs. 70.2 degrees, p = 0.001). In multiple linear regression, for every 10-mg/dL increase in EtOH, R-time was prolonged by 3.84 seconds (p = 0.015), and α angle decreased by 0.11 degrees (p = 0.013). However, in multiple logistic regression analyses, EtOH was a negative predictor of coagulopathy by international normalized ratio (>1.3) and was not predictive of transfusion requirements or early or late mortality.
Patients with elevated EtOH present with impaired clot formation as assayed by TEG, but this does not correlate with standard measures of coagulopathy or with outcome. Reliance on TEG for determining coagulopathy in intoxicated trauma patients may lead to a misperceived hypocoagulable state and inappropriate transfusion. TEG appears to be affected by EtOH in a previously unreported way, warranting further investigation.
Prognostic and epidemiologic study, level III.
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