Benjamin M. Howard

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.

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

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

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.

Prohemostatic interventions in trauma: resuscitation-associated coagulopathy, acute traumatic coagulopathy, hemostatic resuscitation, and other hemostatic interventions.

Trauma is the most common cause of death in the young and hemorrhage is the most important cause of death in patients with trauma. Recently redefined pathways of inflammation and coagulation, together with hypothermia and acidosis contribute to trauma-associated coagulopathy and aggravation of bleeding. Pharmacological prohemostatic agents may be useful to (partly) correct the coagulopathy in trauma patients and may serve as useful adjunctive treatment options in patients with severe blood loss after trauma. Recombinant factor VIIa, fibrinogen and prothrombin complex concentrates, and antifibrinolytic agents have been evaluated in clinical trials. These interventions show promising effects but their efficacy in reducing clinically important outcome parameters need to be confirmed in clinical studies.

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.

Limb salvage after complex repairs of extremity arterial injuries is independent of surgical specialty training

BACKGROUND Major peripheral vascular trauma is managed by several surgical specialties. The impact of surgical specialty training and certification on outcome has not been evaluated. We hypothesized that general surgeons without specialty training in vascular surgery would have outcomes equivalent to surgeons with vascular training in the management of extremity arterial injuries requiring interposition grafting. METHODS We performed a multicenter, retrospective study of patients undergoing interposition grafting for peripheral vascular injury between 1995 and 2010. Specialty was defined by training and certification. Outcomes were recorded at the time of discharge from the index hospitalization. Factors affecting limb salvage were determined using logistic regression. RESULTS From the 11 participating centers, 615 patients were identified. General surgeons performed 69.9%, cardiac/vascular surgeons performed 27.3%, and surgeons of other specialties performed 2.8% of the grafts. There were 32 amputations (5.2%). Outcomes did not differ by institution. Factors associated with amputation were blunt mechanism, older age, female sex, hospital length of stay, and Injury Severity Score (ISS). There was no significant difference in limb salvage among specialty groups (general surgeons, 94%; cardiac/vascular, 95%; other, 100%). CONCLUSION Limb salvage following major peripheral vascular injury is independent of surgeon specialty training. The majority of complex repairs are performed by general surgeons. LEVEL OF EVIDENCE Therapeutic/care management, level III.

The tissue factor pathway mediates both activation of coagulation and coagulopathy after injury.

BACKGROUND The initiation of coagulation in trauma is thought to originate from exposed tissue factor (TF); recent data have led to the alternative hypothesis that damage-associated molecular patterns may contribute to postinjury coagulation. In acute traumatic coagulopathy, aberrant coagulation is mediated via the activated protein C (aPC) pathway; the upstream regulators of this process and its relation to TF remain uncharacterized. To examine the role of the TF pathway in mediating acute traumatic coagulopathy, we used specific antibody blockades in an established murine model of traumatic hemorrhagic shock, hypothesizing that both coagulation activation after injury and aPC-mediated coagulopathy are driven by TF via thrombin. METHODS Mice underwent an established model of trauma and hemorrhage and were subjected to either sham (vascular cannulation) or trauma-hemorrhage (cannulation, laparotomy, shock to mean arterial pressure of 35 mm Hg); they were monitored for 60 minutes before sacrifice. Mice in each group were pretreated with either targeted anti-TF antibody to block the TF pathway or hirudin for specific blockade of thrombin. Plasma was assayed for thrombin-antithrombin (TAT) and aPC by enzyme-linked immunosorbent assay. RESULTS Compared with controls, trauma-hemorrhage mice treated with anti-TF antibody had significantly reduced levels of TAT (2.3 ng/mL vs. 5.7 ng/mL, p = 0.016) and corresponding decreases in aPC (16.3 ng/mL vs. 31.6 ng/mL, p = 0.034), with reductions to levels seen in sham mice. Direct inhibition of thrombin yielded similar results, with reduction in aPC to levels below those seen in sham mice. CONCLUSION In this study, blockade of the TF pathway led to the attenuation of both thrombin production and aPC activation observed in traumatic shock. Specific thrombin inhibition achieved similar results, indicating that aPC-related coagulopathy is mediated via thrombin activated by the TF pathway. The near-complete blockade of TAT and aPC observed in this model argues for a dominant role of the TF-thrombin pathway in both coagulation activation after injury and traumatic coagulopathy.

Discovering the truth about life after discharge: long-term trauma related mortality

BACKGROUND Outcome after traumatic injury has typically been limited to the determination at time of discharge or brief follow-up. This study investigates the natural history of long-term survival after trauma. METHODS All highest-level activation patients prospectively enrolled in an ongoing cohort study from 2005 to 2012 were selected. To allow for long-term follow-up, patients had to be enrolled at least 1 year before the latest available data from the National Death Index (NDI, 2013). Time and cause of mortality was determined based on death certificates. Survival status was determined by the latest date of either care in our institution or NDI query. Kaplan-Meier curves were created stratified for Injury Severity Score (ISS). Survival was compared with estimated actuarial survival based on age, sex, and race. RESULTS A total of 908 highest-level activation patients (median ISS, 18) were followed up for a median 1.7 years (interquartile range 1.0–2.9; maximum, 9.8 years). Survival data were available on 99.8%. Overall survival was 73% (663 of 908). For those with at least 2-year follow-up, survival was only 62% (317 of 509). Severity of injury predicted long-term survival (p < 0.0001) with those having ISS of 25 or greater with the poorest outcome (57% survival at 5 years). For all ISS groups, survival was worse than predicted actuarial survival (p < 0.001). When excluding early deaths (⩽30 days), observed survival was still significantly lower than estimated actuarial survival (p < 0.002). Eighteen percent (44 of 245 deaths) of all deaths occurred after 30 days. Among late deaths, 53% occurred between 31 days and 1 year after trauma. Trauma-related mortality was the leading cause of postdischarge death, accounting for 43% of the late deaths. CONCLUSION Postdischarge deaths represent a significant percentage of total trauma-related mortality. Despite having “survived” to leave the hospital, long-term survival was worse than predicted actuarial survival, suggesting that the mortality from injury does not end at “successful” hospital discharge. LEVEL OF EVIDENCE Prognostic study, level III.

Inducing Acute Traumatic Coagulopathy In Vitro: The Effects of Activated Protein C on Healthy Human Whole Blood

Introduction Acute traumatic coagulopathy has been associated with shock and tissue injury, and may be mediated via activation of the protein C pathway. Patients with acute traumatic coagulopathy have prolonged PT and PTT, and decreased activity of factors V and VIII; they are also hypocoagulable by thromboelastometry (ROTEM) and other viscoelastic assays. To test the etiology of this phenomenon, we hypothesized that such coagulopathy could be induced in vitro in healthy human blood with the addition of activated protein C (aPC). Methods Whole blood was collected from 20 healthy human subjects, and was “spiked” with increasing concentrations of purified human aPC (control, 75, 300, 2000 ng/mL). PT/PTT, factor activity assays, and ROTEM were performed on each sample. Mixed effect regression modeling was performed to assess the association of aPC concentration with PT/PTT, factor activity, and ROTEM parameters. Results In all subjects, increasing concentrations of aPC produced ROTEM tracings consistent with traumatic coagulopathy. ROTEM EXTEM parameters differed significantly by aPC concentration, with stepwise prolongation of clotting time (CT) and clot formation time (CFT), decreased alpha angle (α), impaired early clot formation (a10 and a20), and reduced maximum clot firmness (MCF). PT and PTT were significantly prolonged at higher aPC concentrations, with corresponding significant decreases in factor V and VIII activity. Conclusion A phenotype of acute traumatic coagulopathy can be induced in healthy blood by the in vitro addition of aPC alone, as evidenced by viscoelastic measures and confirmed by conventional coagulation assays and factor activity. This may lend further mechanistic insight to the etiology of coagulation abnormalities in trauma, supporting the central role of the protein C pathway. Our findings also represent a model for future investigations in the diagnosis and treatment of acute traumatic coagulopathy.