Matthew E. Kutcher

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

The pericyte: Cellular regulator of microvascular blood flow

The vascular system - through its development, response to injury, and remodeling during disease - constitutes one of the key organ systems sustaining normal human physiology; conversely, its dysregulation also underlies multiple pathophysiologic processes. Regulation of vascular endothelial cell function requires the integration of complex signals via multiple cell types, including arterial smooth muscle, capillary and post-capillary pericytes, and other perivascular cells such as glial and immune cells. Here, we focus on the pericyte and its roles in microvascular remodeling, reviewing current concepts in microvascular pathophysiology and offering new insights into the specific roles that pericyte-dependent signaling pathways may play in modulating endothelial growth and microvascular tone during pathologic angiogenesis and essential hypertension.

Coagulopathy After Traumatic Brain Injury

Traumatic brain injury has long been associated with abnormal coagulation parameters, but the exact mechanisms underlying this phenomenon are poorly understood. Coagulopathy after traumatic brain injury includes hypercoagulable and hypocoagulable states that can lead to secondary injury by either the induction of microthrombosis or the progression of hemorrhagic brain lesions. Multiple hypotheses have been proposed to explain this phenomenon, including the release of tissue factor, disseminated intravascular coagulation, hyperfibrinolysis, hypoperfusion with protein C activation, and platelet dysfunction. The diagnosis and management of these complex patients are difficult given the lack of understanding of the underlying mechanisms. The goal of this review is to summarize the current knowledge regarding the mechanisms of coagulopathy after blunt traumatic brain injury. The current and emerging diagnostic tools, radiological findings, treatment options, and prognosis are discussed.

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 principal component analysis of coagulation after trauma

BACKGROUND: Clotting factor abnormalities underlying acute traumatic coagulopathy are poorly understood, with application of traditional regression techniques confounded by colinearity. We hypothesized that principal components analysis (PCA), a pattern‐finding and data reduction technique, would identify clinically predictive patterns in the complex clotting factor milieu after trauma. METHODS: Plasma was prospectively collected from 163 critically injured trauma patients. Prothrombin; factors V, VII, VIII, IX, X; D‐dimer; activated and native protein C; and antithrombin III levels were assayed and subjected to nonlinear PCA to identify principal components (PCs). RESULTS: Of 163 patients, 19.0% were coagulopathic on admission. PCA identified 3 significant PCs, accounting for 67.5% of overall variance. PC1 identified global clotting factor depletion; PC2 the activation of protein C and fibrinolysis; and PC3 factor VII elevation and VIII depletion. PC1 score correlated with penetrating injury and injury severity, predicting coagulopathy (odds ratio [OR], 4.67; p < 0.001) and mortality (OR, 1.47; p = 0.032). PC2 score correlated with injury severity, acidosis, and shock, and significantly predicted ventilator‐associated pneumonia (OR, 1.59; p = 0.008), acute lung injury (OR, 2.24; p < 0.001), multiorgan failure (OR, 1.83; p = 0.002), and mortality (OR, 1.62; p = 0.006) but was not associated with international normalized ratio (INR)–based or partial thromboplastin time (PTT)–based coagulopathy (p > 0.200). PC3 did not significantly predict outcomes. CONCLUSION: PCA identifies distinct patterns of coagulopathy: depletion coagulopathy predicts mortality and INR/PTT elevation, while fibrinolytic coagulopathy predicts infection, end‐organ failure, and mortality, without detectable differences in INR or PTT. While depletion coagulopathy is intuitive, fibrinolytic coagulopathy may be a distinct but often overlapping entity with differential effects on outcomes. LEVEL OF EVIDENCE: Prognostic study, level III.

Extracellular histone release in response to traumatic injury: implications for a compensatory role of activated Protein C

BACKGROUND Tissue injury leads to the release of DAMPs (damage-associated molecular patterns) that may drive a sterile inflammatory response; however, the role of extracellular histone levels after traumatic injury remains unexplored. We hypothesized that extracellular histone levels would be increased and associated with poor outcomes after traumatic injury. METHODS In this prognostic study, plasma was prospectively collected from 132 critically injured trauma patients on arrival and 6 hours after admission to an urban Level I trauma intensive care unit. Circulating extracellular histone levels and plasma clotting factors were assayed and linked to resuscitation and outcome data. RESULTS Of 132 patients, histone levels were elevated to a median of 14.0 absorbance units (AU) on arrival, declining to 6.4 AU by 6 hours. Patients with elevated admission histone levels had higher ISS (Injury Severity Score), lower admission GCS (Glasgow Coma Scale) score, more days of mechanical ventilation, and higher incidences of multiorgan failure, acute lung injury, and mortality (all p ⩽ 0.05). Histone levels correlated with prolonged international normalized ratio and partial thromboplastin time, fibrinolytic markers D-dimer and tissue-type plasminogen activator, and anticoagulants tissue factor pathway inhibitor and activated protein C (aPC; all p < 0.03). Increasing histone level from admission to 6 hours was a multivariate predictor of mortality (hazard ratio, 1.005; p = 0.013). When aPC level trends were included, the impact of histone level increase on mortality was abrogated (p = 0.206) by a protective effect of increasing aPC levels (hazard ratio, 0.900; p = 0.020). CONCLUSION Extracellular histone levels are elevated in response to traumatic injury and correlate with fibrinolysis and activation of anticoagulants. An increase in histone levels from admission to 6 hours is predictive of mortality, representing evidence of ongoing release of intracellular antigens similar to that seen in sepsis. Concomitant elevation of aPC abrogates this effect, suggesting a possible role for aPC in mitigating the sterile inflammatory response after trauma through the proteolysis of circulating histones. LEVEL OF EVIDENCE Prognostic study, level III.

Who should we feed? A Western Trauma Association multi-institutional study of enteral nutrition in the open abdomen after injury

BACKGROUND The open abdomen is a requisite component of a damage control operation and treatment of abdominal compartment syndrome. Enteral nutrition (EN) has proven beneficial for patients with critical injury, but its application in those with an open abdomen has not been defined. The purpose of this study was to analyze the use of EN for patients with an open abdomen after trauma and the effect of EN on fascial closure rates and nosocomial infections. METHODS We reviewed patients with an open abdomen after injury from January 2002 to January 2009 from 11 trauma centers. RESULTS During the 7-year study period, 597 patients required an open abdomen after trauma. Most were men (77%) sustaining blunt trauma (72%), with a mean (SD) age of 38 (0.7) years, an Injury Severity Score of 31 (0.6), an abdominal injury score of 3.8 (0.1), and an Abdominal Trauma Index score of 26.8 (0.6). Of the patients, 548 (92%) had an open abdomen after a damage control operation, whereas the remainder experienced an abdominal compartment syndrome. Of the 597 patients, 230 (39%) received EN initiated before the closure of the abdomen at mean (SD) day 3.6 (1.2) after injury. EN was started with an open abdomen in one quarter of the 290 patients with bowel injuries. For the 307 patients without a bowel injury, logistic regression indicated that EN is associated with higher fascial closure rates (odds ratio [OR], 5.3; p < 0.01), decreased complication rates (OR, 0.46; p = 0.02), and decreased mortality (OR, 0.30; p = 0.01). For the 290 patients who experienced a bowel injury, regression analysis showed no significant association between EN and fascial closure rate (OR, 0.6; p = 0.2), complication rate (OR, 1.7; p = 0.19), or mortality (OR, 0.79; p = 0.69). CONCLUSION EN in the open abdomen after injury is feasible. For patients without a bowel injury, EN in the open abdomen is associated with increased fascial closure rates, decreased complication rates, and decreased mortality. EN should be initiated in these patients once resuscitation is completed. Although EN for patients with bowel injuries did not seem to affect the outcome in this study, prospective randomized controlled trials would further clarify the role of EN in this subgroup. LEVEL OF EVIDENCE Therapeutic study, level III.

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.

Fibrinogen and platelet contributions to clot formation: implications for trauma resuscitation and thromboprophylaxis.

BACKGROUND 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. METHODS 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 (%MAFF) and platelets (%MAplatelets) were calculated as each MA divided by overall kaolin TEG MA. RESULTS Coagulopathic patients (international normalized ratio ≥ 1.3) had significantly lower admission %MAFF than noncoagulopathic patients (24.7% vs. 31.2%, p < 0.05). Patients requiring plasma transfusion had a significantly lower admission %MAFF (26.6% vs. 30.6%, p < 0.05). Higher admission %MAFF was predictive of reduced mortality (hazard ratio, 0.815, p < 0.001). %MAplatelets was higher than %MAFF at all time points, decreased over time, and stabilized at 72 hours (69.4% at 0 hour, 56.2% at 72 hours). In contrast, %MAFF increased over time and stabilized at 72 hours (30.6% at 0 hour, 43.8% at 72 hours). CONCLUSION FF TEG affords differentiation of fibrin- versus platelet-based clot dynamics. Coagulopathy and plasma transfusion were associated with a lower %MAFF. 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. LEVEL OF EVIDENCE Prognostic study, level III.