Mary F. Nelson

Critical role of activated protein C in early coagulopathy and later organ failure, infection and death in trauma patients.

Background: Recent studies have identified an acute traumatic coagulopathy that is present on admission to the hospital and is independent of iatrogenic causes. We have previously reported that this coagulopathy is due to the association of severe injury and shock and is characterized by a decrease in plasma protein C (PC) levels. Whether this early coagulopathy and later propensity to infection, multiple organ failure and mortality are associated with the activation of PC pathway has not been demonstrated and constitutes the aim of this study. Methods and Findings: This was a prospective cohort study of 203 major trauma patients. Serial blood samples were drawn on arrival in the emergency department, and at 6, 12, and 24 hours after admission to the hospital. PT, PTT, Va, VIIIa, PC aPC t-PA, and D-dimer levels were assayed. Comprehensive injury, resuscitation, and outcome data were prospectively collected. A total of 203 patients were enrolled. Patients with tissue hypoperfusion and severe traumatic injury showed a strong activation of the PC which was associated with a coagulopathy characterized by inactivation of the coagulation factors V and VIII and a derepression of the fibrinolysis with high plasma levels of plasminogen activator and high D-dimers. Elevated plasma levels of activated PC were significantly associated with increased mortality, organ injury, increased blood transfusion requirements, and reduced ICU ventilator-free days. Finally early depletion of PC after trauma is associated with a propensity to posttraumatic ventilator-associated pneumonia. Conclusions: Acute traumatic coagulopathy occurs in the presence of tissue hypoperfusion and severe traumatic injury and is mediated by activation of the PC pathway. Higher plasma levels of aPC upon admission are predictive of poor clinical outcomes after major trauma. After activation, patients who fail to recover physiologic plasma values of PC have an increased propensity to later nosocomial lung infection.

Characterization of platelet dysfunction after trauma

BACKGROUND The increased morbidity and mortality associated with coagulopathy and thrombocytopenia after trauma are well described. However, few studies have assessed platelet function after injury. METHODS 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. RESULTS 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). CONCLUSION 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. (J Trauma Acute Care Surg. 2012;73: 13–19. Copyright

Clinical and mechanistic drivers of acute traumatic coagulopathy.

BACKGROUND Acute traumatic coagulopathy (ATC) occurs after severe injury and shock and is associated with increased bleeding, morbidity, and mortality. The effects of ATC and hemostatic resuscitation on outcome are not well-explored. The PRospective Observational Multicenter Major Trauma Transfusion (PROMMTT) study provided a unique opportunity to characterize coagulation and the effects of resuscitation on ATC after severe trauma. METHODS Blood samples were collected upon arrival on a subset of PROMMTT patients. Plasma clotting factor levels were prospectively assayed for coagulation factors. These data were analyzed with comprehensive PROMMTT clinical data. RESULTS There were 1,198 patients with laboratory results, of whom 41.6% were coagulopathic. Using international normalized ratio of 1.3 or greater, 41.6% of patients (448) were coagulopathic, while 20.5% (214) were coagulopathic using partial thromboplastin time of 35 or greater. Coagulopathy was primarily associated with a combination of an Injury Severity Score (ISS) of greater than 15 and a base deficit (BD) of less than −6 (p < 0.05). Regression modeling for international normalized ratio–based coagulopathy shows that prehospital crystalloid (odds ratio [OR], 1.05), ISS (OR, 1.03), Glasgow Coma Scale (GCS) score (OR, 0.93), heart rate (OR, 1.08), systolic blood pressure (OR, 0.96), BD (OR, 0.92), and temperature (OR, 0.84) were significant predictors of coagulopathy (all p < 0.03). A subset of 165 patients had blood samples collected and coagulation factor analysis performed. Elevated ISS and BD were associated with elevation of aPC and depletion of factors (all p < 0.05). Reductions in factors I, II, V, VIII and an increase in aPC drive ATC (all p < 0.04). Similar results were found for partial thromboplastin time–defined coagulopathy. CONCLUSION ATC is associated with the depletion of factors I, II, V, VII, VIII, IX, and X and is driven by the activation of the protein C system. These data provide additional mechanistic understanding of the drivers of coagulation abnormalities after injury. Further understanding of the drivers of ATC and the effects of resuscitation can guide factor-guided resuscitation and correction of coagulopathy after injury. LEVEL OF EVIDENCE Epidemiologic/prognostic study, level IV.

A paradigm shift in trauma resuscitation: evaluation of evolving massive transfusion practices.

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 protocols 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.

Criteria for empiric treatment of hyperfibrinolysis after trauma

BACKGROUND 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. METHODS 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. RESULTS 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). CONCLUSION 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. LEVEL OF EVIDENCE Prognostic study, level III.

The whole is greater than the sum of its parts: Hemostatic profiles of whole blood variants

BACKGROUND 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. METHODS 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. RESULTS 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). CONCLUSION 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.

Cause and timing of death in massively transfused trauma patients.

BACKGROUND The purpose of this study was to characterize the cause of death in severely injured trauma patients to define potential responses to resuscitation. METHODS Prospective analysis of 190 critically injured patients who underwent massive transfusion protocol (MTP) activation or received massive transfusion (>10 U of packed red blood cells [RBC] per 24 hours). Cause of death was adjudicated into one of four categories as follows: (1) exsanguination, (2) early physiologic collapse, (3) late physiologic collapse, and (4) nonsurvivable injury. RESULTS A total 190 patients underwent massive transfusion or MTP with 76 deaths (40% mortality), of whom 72 deaths were adjudicated to one of four categories: 33.3% died of exsanguination, 16.6% died of early physiologic collapse, 11.1% died of late physiologic collapse, while 38.8% died of nonsurvivable injuries. Patients who died of exsanguination were younger and had the highest RBC/fresh frozen plasma ratio (2.97 [2.24]), although the early physiologic collapse group survived long enough to use the most blood products (p < 0.001). The late physiologic collapse group had significantly fewer penetrating injuries, was older, and had significantly more crystalloid use but received a lower RBC/fresh frozen plasma ratio (1.50 [0.42]). Those who were determined to have a nonsurvivable injury had a lower presenting Glasgow Coma Scale (GCS) score, fewer penetrating injuries, and higher initial blood pressure reflecting a preponderance of nonsurvivable traumatic brain injury. The average survival time for patients with potentially survivable injuries was 2.4 hours versus 18.4 hours for nonsurvivable injuries (p < 0.001). CONCLUSION Severely injured patients requiring MTP have a high mortality rate. However, no studies to date have addressed the cause of death after MTP. Characterization of cause of death will allow targeting of surgical and resuscitative conduct to allow extension of the physiologic reserve time, therefore rendering previously nonsurvivable injury potentially survivable. LEVEL OF EVIDENCE Prognostic study, level III.

Differences in degree, differences in kind: characterizing lung injury in trauma

BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSION 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. LEVEL OF EVIDENCE Prognostic and epidemiologic study, level III.

The acute respiratory distress syndrome following isolated severe traumatic brain injury.

BACKGROUND Acute respiratory distress syndrome (ARDS) is common after traumatic brain injury (TBI) and is associated with worse neurologic outcomes and longer hospitalization. However, the incidence and associated causes of ARDS in isolated TBI have not been well studied. METHODS We performed a subgroup analysis of 210 consecutive patients with isolated severe TBI enrolled in a prospective observational cohort at a Level 1 trauma center between 2005 and 2014. Subjects required endotracheal intubation and had isolated severe TBI defined by a head Abbreviated Injury Scale (AIS) score of 3 or greater and AIS score lower than 3 in all other categories. ARDS within the first 8 days of admission was rigorously adjudicated using Berlin criteria. Regression analyses were used to test the association between predictors of interest and ARDS. RESULTS The incidence of ARDS in the first 8 days after severe isolated TBI was 30%. Patients who developed ARDS were administered more crystalloids (4.3 L vs. 3.5 L, p = 0.005) and blood products in the first 12 hours of admission. Patients with ARDS had significantly worse clinical outcomes measured at 28 days, including longer median intensive care unit and hospital stays (4 days vs. 13 days, p < 0.001, and 7.5 days vs. 14.5 days, p < 0.001, respectively). In unadjusted logistic regression analyses, the odds of developing ARDS were significantly associated with head AIS score (odds ratio [OR], 1.8; p = 0.018), male sex (OR, 2.9; p = 0.012), and early transfusion of platelets (OR, 2.8; p = 0.003). These associations were similar in a multivariate logistic regression model. CONCLUSION In the era of balanced hemostatic resuscitation practices, severity of head injury, male sex, early crystalloids, and early transfusion of platelets are associated with a higher risk of ARDS after severe isolated TBI. Early transfusion of platelets after severe TBI may be a modifiable risk factor for ARDS, and these findings invite further investigation into causal mechanisms driving this observed association. LEVEL OF EVIDENCE Prognostic/epidemiologic study, level III.

Obesity and clotting: Body mass index independently contributes to hypercoagulability after injury.

BACKGROUND Although obese patients have high thrombosis rates following injury, the role of obesity in coagulation after trauma remains unknown. We hypothesized that body mass index (BMI) is independently associated with increased measures of hypercoagulability longitudinally after injury. METHODS Data were prospectively collected for 377 consecutive highest-level trauma activation patients with a BMI of 18.5 kg/m2 or greater. Standard coagulation measures, citrated kaolin and functional fibrinogen thromboelastography, as well as clotting factors were measured at 0 hour to 120 hours. BMI categories were defined as normal weight (18.5–24.99 kg/m2), overweight (25–29.99 kg/m2), and obese (≥30 kg/m2). RESULTS The 377 patients were mostly male (81%) and had blunt injury (61%), with a median BMI of 25.8 kg/m2. Of the patients, 42% were normal weight (median BMI, 22.5 kg/m2). There were no differences in age, sex, Injury Severity Score (ISS), or base deficit between groups. There were no differences in admission international normalized ratio/partial thromboplastin time or factors II, V, VII, VIII, and X; antithrombin III; or protein C. However, obese patients had higher admission platelet counts (303 × 109/L vs. 269 × 109/L, p = 0.004), lower D-dimer (1.88 &mgr;g/mL vs. 4.00 &mgr;g/mL, p = 0.004), and a trend toward higher factor IX (134% vs. 119% activity, p = 0.042) compared with normal weight patients. Measured by thromboelastography, clot strength (maximum amplitude) and functional fibrinogen level (FLEV) were also higher on admission for obese patients (maximum amplitude, 65.7 mm vs. 63.4 mm, p = 0.016; FLEV, 407 mg/dL vs. 351 mg/dL, p = 0.008). In multiple linear regression, the relationship of BMI to clot strength, FLEV, and factor IX persisted through 24 hours. Similarly, the relationship of BMI and platelet count persisted through 120 hours (all p < 0.05). In multiple logistic regression, for every 5-kg/m2 increase in BMI, there was an 85% increase in odds of thromboembolic complication (odds ratio, 1.85; 95% confidence interval, 1.13–3.08; p = 0.017). CONCLUSION Obese trauma patients are hypercoagulable compared with their similarly injured normal-weight counterparts, which persists longitudinally after injury. The significance of this hypercoagulability requires elucidation for guidance of anticoagulation in this at-risk group. LEVEL OF EVIDENCE Prognostic study, level III.